Ultrastable Luminol-OH--(Ni-WOx-CNT) ECL System with High Strength and Its Applications in Sensing.

In traditional luminol electrochemiluminescence (ECL) systems, hydrogen peroxide (H2O2) and dissolved oxygen (DO) are the commonly used coreactants to generate reactive oxygen species (ROS) for ECL emission. However, the self-decomposition of hydrogen peroxide and the limited solubility and content of oxygen in solution undoubtedly restrict the luminescence efficiency and stability of the luminol ECL system. Inspired by the ROS-mediated ECL mechanism, we pioneered hydroxide ion as an advanced luminol ECL coreactant using nickel-doped and carbon nanotube-modified tungsten oxide (Ni-WOx-CNT) as the coreactant accelerator. Owing to the excellent catalytic activity of Ni-WOx-CNT, amounts of ROS were generated from OH- at a low excitation voltage, which subsequently reacted with luminol anion radicals and triggered intense ECL signals. Experiments confirmed an impressive ECL behavior in terms of high luminescent intensity (85,563 a.u.) and super stability over 1300 consecutive tests; both are superior to those recently reported luminol-H2O2 and luminol-DO systems with smaller ECL intensities and consecutive tests less than 25 times. To validate the feasibility and versatility of the developed system in sensor, traditional three-electrodes system and closed bipolar electrodes system with various sensing strategies of direct oxidation, "gate-effect" of molecularly imprinted polymer, immune reaction, and enzyme-catalyzed reaction were proposed to monitor uric acid (UA), C-reactive protein (CRP), immunoglobulin G (IgG), and glucose (Glu). The superior sensing performances confirmed the great application potential of the developed ROS-mediated ECL system.

Multifunctional Self-Signaling nanoMIP and Its Application for a Washing-Free Assay of Human Angiotensin-Converting Enzyme 2.

Molecular imprinting techniques have attracted a lot of attention as a potential biomimetic technology, but there are still challenges in protein imprinting. Herein, multifunctional nanosized molecularly imprinted polymers (nanoMIPs) for human angiotensin-converting enzyme 2 (ACE2) were prepared by epitope imprinting of magnetic nanoparticles-anchored peptide (magNP-P) templates, which were further applied to construct a competitive displacement fluorescence assay toward ACE2. A cysteine-flanked dodecapeptide sequence was elaborately selected as an epitope for ACE2, which was immobilized onto the surface of magnetic nanoparticles and served as a magNP-P template for imprinting. During polymerization, fluorescent monomers were introduced to endow fluorescence responsiveness to the prepared self-signaling nanoMIPs. A competitive displacement fluorescence assay based on the nanoMIPs was established and operated in a washing-free manner, yielding a wide range for ACE2 (0.1-6.0 pg/mL) and a low detection limit (0.081 pg/mL). This approach offers a promising avenue in the preparation of nanoMIPs for macromolecule recognition and expands potential application of an MIP in the detection of proteins as well as peptides.

The nonlinear correlation between alanine aminotransferase to high-density lipoprotein cholesterol ratio and the risk of diabetes: a historical Japanese cohort study.

BACKGROUND: Low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of alanine aminotransferase (ALT) are related to insulin resistance, metabolic syndrome, and diabetes mellitus (DM). However, evidence on the connection between the alanine aminotransferase to high-density lipoprotein cholesterol (ALT/HDL-C) ratio and diabetes mellitus (DM) risk was limited. The study aimed to investigate the relationship between baseline ALT/HDL-C ratio and DM among Japanese individuals. METHODS: This second analysis was based on a cohort study using open-source data. Data from 15,342 individuals who participated in the medical examination program were recorded at Murakami Memorial Hospital in Japan between 2004 and 2015. Smooth curve fitting, subgroup analysis, Cox proportional-hazards regression, and a series of sensitivity analyses were conducted to examine the relationship between ALT/HDL-C ratio and incident diabetes. The ability of the ALT/HDL-C ratio to predict diabetes was evaluated using a receiver operating characteristic curve analysis. RESULTS: After controlling for confounding covariates, the ALT/HDL-C ratio was found to be positively correlated to the DM risk in Japanese adults (HR: 1.01, 95%CI: 1.00-1.02, P = 0.049). This study also found a stable relationship between ALT/HDL-C ratio and diabetes after employing a series of sensitivity analyses. Additionally, there was a non-linear association between the ALT/HDL-C ratio and incident diabetes, and the ALT/HDL-C ratio inflection point was 30.12. When the ALT/HDL-C ratio was below 30.12, the present study discovered a significant positive association between the ALT/HDL-C ratio and incident diabetes (HR: 1.04, 95%CI: 1.02-1.06, P = 0.001). Furthermore, among liver enzymes, blood lipids, and anthropometric indicators, the ALT/HDL-C ratio best predicts DM (AUC = 0.75, 95%CI: 0.73-0.78). CONCLUSION: Increased ALT/HDL-C ratio levels at baseline correlated to incident DM. The relationship between ALT/HDL-C ratio and incident DM was also non-linear. When the ALT/HDL-C ratio is below 30.12, there is a statistically significant positive correlation between the ALT/HDL-C ratio and incident DM.

The triglyceride glucose-body mass index: a non-invasive index that identifies non-alcoholic fatty liver disease in the general Japanese population.

BACKGROUND: By identifying individuals at high risk for non-alcoholic fatty liver disease (NAFLD), interventional programs could be targeted more effectively. Some studies have demonstrated that triglyceride glucose-body mass index (TyG-BMI) showed an independent positive association with NAFLD. However, research on its diagnostic value in patients with suspected NAFLD is limited. In this study, we aimed to evaluate whether TyG-BMI was accurate in detecting NAFLD in the general Japanese population. METHODS: A cross-sectional study of 14,280 individuals who underwent a comprehensive health examination was conducted. Standard protocols were followed to collect anthropometric measurements, lab data, and ultrasonography features. All participants were randomly stratified into the development group (n = 7118) and validation group (n = 7162). The TyG-BMI was calculated. Following this, the diagnostic value of the TyG-BMI was evaluated based on the area under the receiver-operating characteristic curve (AUROC). Two cutoff points were selected and used to rule out or rule in the NALFD, and the specificity, sensitivity, negative predictive value, and positive predictive value were explored, respectively. In order to verify the stability of the results, external verification was performed. RESULTS: There were 1272 and 1243 NAFLD participants in the development and validation groups, respectively. The area under the ROC curve (AUC) of TyG-BMI was 0.888 (95% CI 0.876-0.896) and 0.884 (95% CI 0.875-0.894) for the training and validation group, respectively. Using the low TyG-BMI (182.2) cutoff, NAFLD could be excluded with high accuracy (negative predictive value: 96.9% in estimation and 96.9% in validation). The presence of NAFLD could effectively be determined by applying the high cutoff of TyG-BMI (224.0), as the positive predictive value of the estimation and validation groups is 70.7% and 70.1%, respectively. As a result of applying this model, 9996 (70%) of the 14,280 participants would not have undergone ultrasonography, with an accurate prediction of 9308 (93.1%). AUC was 0.874 for external validation using 183,730 Chinese non-obese participants. TyG-BMI was demonstrated to be an excellent diagnostic tool by both internal and external validation. CONCLUSIONS: In conclusion, the present study developed and validated a simple, non-invasive, and cost-effective tool to accurately separate participants with and without NAFLD in the Japanese population, rendering ultrasonography for identifying NAFLD unnecessary in a substantial proportion of people.

The non-linear link between remnant cholesterol and diabetic retinopathy: a cross-sectional study in patients with type 2 diabetic mellitus.

OBJECTIVE: Research on residual cholesterol (RC) and diabetic retinopathy (DR) remains limited. As a result, the current study was designed to investigate the relationship between RC and DR in patients with type 2 diabetic mellitus (T2DM). METHODS: This cross-sectional study consecutively and non-selectively collected a total of 1964 type 2 diabetic mellitus patients in two hospitals in Taiwan from April 2002 to November 2004. A binary logistic regression model was then used to assess the independent relationship between RC level and DR and proliferative diabetic retinopathy (PDR). A generalized additive model (GAM) and smooth curve fitting were used to investigate the actual shape of the curve between them. It was stated that the data had been uploaded to the website: https://journals.plos.org/plosone . RESULTS: The average age of the participants was 64.10+/- 11.32 years old, with 42.92% being male. The prevalence of DR and PDR was 35.13 and 18.13%, respectively. The mean RC level was 30.57 ± 14.60 mg/dL. We found no significant association between RC and DR (OR = 1.001; 95% CI 0.991, 1.011) or PDR (OR = 1.008; 95% CI 0.995, 1.021) based on a fully adjusted logistic regression model. Results remained robust across a series of sensitivity analyses. However, a non-linear relationship was detected between RC and DR. Using a two-piece logistic regression model and a recursive algorithm, we found an inflection point of RC was 13.0 mg/dL. A 1-unit increase in the RC level was associated with 19.4% greater adjusted odds of DR (OR = 1.194; 95% CI 1.070, 1.333) when RC < 13.0 mg/dL. There was also a non-linear relationship between RC and PDR, and the inflection point of the RC was 39.0 mg/dL. When RC < 39.0 mg/dL, a 1-unit increase in the RC level was associated with 2.1% greater adjusted odds of PDR (OR = 1.021; 95% CI 1.004, 1.038). CONCLUSION: This study demonstrates a non-linear relationship between RC and DR or PDR in type 2 diabetic mellitus patients. Our findings provide new insights into advancing research on the link between RC and DR or PDR.

Non-linear relationship between high-density lipoprotein cholesterol and incident diabetes mellitus: a secondary retrospective analysis based on a Japanese cohort study.

BACKGROUND AND OBJECTIVE: High-density lipoprotein cholesterol (HDL-C) may be directly involved in glucose metabolism by enhancing insulin sensitivity and insulin secretion. This current study aimed to explore the association between HDL-C and the risk of diabetes mellitus (DM) in Japanese population. METHODS: This retrospective cohort study was based on a publicly available DRYAD dataset. We enrolled 15,388 Japanese participants who received medical examinations from 2004 to 2015 at Murakami Memorial Hospital. Our study selected HDL-C at baseline and incident DM during follow-up as the target independent variable and the dependent variable, respectively. Cox proportional-hazards regression was used to investigate the association between HDL-C and DM, generalized additive models to identify non-linear relationships. RESULTS: After adjusting for the demographic and clinical covariates, the result showed low HDL-C levels were associated with increased risk for diabetes (HR = 0.54, 95%CI (0.35, 0.82)). The results remained robust in a series of sensitive analysis. A non-linear relationship was detected between HDL-C and incident DM with an inflection point of HDL-C at 1.72 mmol/L (Log-likelihood ratio test P = 0.005). Subgroup analysis showed that a stronger association could be found in ex-smokers and current-smokers. The same trend was also seen in the community with hypertension (P for interaction = 0.010, HR = 1.324). CONCLUSION: This study demonstrates a negative and non-linear relationship between HDL-C and diabetes in the Japanese population. There is a threshold effect between HDL-C and diabetes. When HDL-C is lower than 1.72 mmol/L, the decreased HDL-C levels were associated with an increased risk for diabetes.

Association between hemoglobin and chronic kidney disease progression: a secondary analysis of a prospective cohort study in Japanese patients.

OBJECTIVE: Anemia has been reported as a risk factor for chronic kidney disease (CKD) progression. However, there are still few studies examining the relationship between specific hemoglobin (Hb) levels and renal prognosis and renal function decline simultaneously. Meanwhile, the possible non-linear relationship between Hb and CKD progression also deserves further exploration. On that account, our primary goal is to explore the link of Hb on renal prognosis and renal function decline in patients with CKD. METHODS: This study was a secondary analysis of a prospective cohort study, which consecutively and non-selectively collected 962 participants from the research of CKD-ROUTE in Japan from November 2010 to December 2011. We used the Cox proportional-hazards and linear regression models to evaluate the independent association between baseline Hb and renal prognosis (renal composite endpoint, initiation of dialysis during follow-up or 50% decline in eGFR from baseline) and renal function decline(annual eGFR decline), respectively. A multivariate Cox proportional hazards regression analysis with cubic spline functions model and smooth curve fitting (penalized spline method) were conducted to address Hb and CKD prognosis's non-linearity. At the same time, a generalized additive model (GAM) and smooth curve fitting (penalized spline method) was conducted to explore the exact shape of the curve between Hb and renal function decline. Additionally, we did a series of sensitivity analyses to ensure the robustness of the results. Moreover, we conducted subgroup analyses. RESULTS: The mean age of the included patients was 67.35 ± 13.56 years old, and 69.65% were male. The mean baseline Hb and estimated glomerular filtration rate (eGFR) was 12.06 ± 2.21 g/dL and 33.04 ± 18.01 ml/min per 1.73 m2. The annual decline in eGFR was 2.09 mL/min/1.73 m2/year. During a median follow-up time of 33.5 months, 252(26.2%) people experienced renal composite endpoint. After adjusting covariates, the results showed that Hb was negatively associated with renal composite endpoint (HR = 0.836, 95%CI: 0.770, 0.907) and renal function decline (ß = -0.436, 95%CI: -0.778, -0.093). There was also a non-linear relationship between Hb and renal composite endpoint, and the inflection point of Hb was 8.6 g/dL. The effect sizes(HR) on the left and right sides of the inflection point were 1.257 (0.841, 1.878) and 0.789 (0.715, 0.870), respectively. And the sensitive analysis demonstrated the robustness of the results. Subgroup analysis showed that Hb was more strongly associated with the renal composite endpoint in non-hypertensive, SBP < 140 mmHg, urine protein-to-creatinine ratio (UPCR) < 0.5 g/gCr, and diuretic use patients. In contrast, the weaker association was probed in hypertensive and non-diuretic use patients and the patients with SBP ≥ 140 mmHg, and UPCR ≥ 0.5 g/gCr. CONCLUSION: This study demonstrates a negative and non-linear relationship between Hb and renal prognosis and renal function decline in Japanese CKD patients. Hb is strongly related to renal prognosis when Hb is above 8.6 g/dL.

Association between nonalcoholic fatty liver disease and incident diabetes mellitus among Japanese: a retrospective cohort study using propensity score matching.

BACKGROUND: Previous studies have demonstrated that nonalcoholic fatty liver disease (NAFLD) is a significant risk factor for diabetes mellitus (DM). However, these studies did not completely determine the relationship between NAFLD and DM due to unbalanced confounding factors. The propensity score (PS) is the conditional probability of having a particular exposure, given a set of baseline measured covariates. Propensity score matching (PSM) analysis could minimise the effects of potential confounders. Thus, this study aimed to use PSM analysis to explore the association between NAFLD and DM in a large Japanese cohort. METHODS: This retrospective PSM cohort study was performed on 14,280 Japanese participants without DM at baseline in Murakami Memorial Hospital between 2004 and 2015. The independent variable was NAFLD at baseline, and the outcome was the incidence of DM during follow-up. One-to-one PSM revealed 1671 participants with and without NAFLD. A doubly robust estimation method was applied to verify the correlation between NAFLD and DM. RESULTS: The risk of developing DM in participants with NAFLD increased by 98% according to the PSM analysis (HR = 1.98, 95% confidence interval [CI]: 1.41-2.80, P < 0.0001). The risk of developing DM in the NAFLD participants was 2.33 times that of the non-NAFLD participants in the PSM cohort after adjusting for the demographic and laboratory biochemical variables (HR = 2.33, 95% CI: 1.63-3.32, P < 0.0001). The participants with NAFLD had a 95% increased risk of DM after adjusting for PS (HR = 1.95, 95% CI: 1.39-2.75, P = 0.0001). All potential confounding variables were not significantly associated with NAFLD and DM after PSM in the subgroup analysis. In the sensitivity analysis, the participants with NAFLD had a 2.17-fold higher risk of developing DM in the original cohort (HR = 2.17, 95% CI: 1.63-2.88, P < 0.0001) and were 2.27-fold more likely to develop DM in the weighted cohort (HR = 2.27, 95% CI: 1.91-2.69, P < 0.00001). CONCLUSIONS: NAFLD was an independent risk factor for the development of DM. The risk of developing DM in the NAFLD participants was 2.33 times that of the non-NAFLD participants in the PSM cohort after adjusting for the demographic and laboratory biochemical variables. The participants with NAFLD had a 95% increased risk of DM after adjusting for PS.

Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes.

BACKGROUND: Aberrant microRNA (miRNA) expression affects biologic processes and downstream genes that are crucial to CKD initiation or progression. The miRNA miR-204-5p is highly expressed in the kidney but whether miR-204-5p plays any role in the development of chronic renal injury is unknown. METHODS: We used real-time PCR to determine levels of miR-204 in human kidney biopsies and animal models. We generated Mir204 knockout mice and used locked nucleic acid-modified anti-miR to knock down miR-204-5p in mice and rats. We used a number of physiologic, histologic, and molecular techniques to analyze the potential role of miR-204-5p in three models of renal injury. RESULTS: Kidneys of patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy exhibited a significant decrease in miR-204-5p compared with controls. Dahl salt-sensitive rats displayed lower levels of renal miR-204-5p compared with partially protected congenic SS.13BN26 rats. Administering anti-miR-204-5p to SS.13BN26 rats exacerbated interlobular artery thickening and renal interstitial fibrosis. In a mouse model of hypertensive renal injury induced by uninephrectomy, angiotensin II, and a high-salt diet, Mir204 gene knockout significantly exacerbated albuminuria, renal interstitial fibrosis, and interlobular artery thickening, despite attenuation of hypertension. In diabetic db/db mice, administering anti-miR-204-5p exacerbated albuminuria and cortical fibrosis without influencing blood glucose levels. In all three models, inhibiting miR-204-5p or deleting Mir204 led to upregulation of protein tyrosine phosphatase SHP2, a target gene of miR-204-5p, and increased phosphorylation of signal transducer and activator of transcription 3, or STAT3, which is an injury-promoting effector of SHP2. CONCLUSIONS: These findings indicate that the highly expressed miR-204-5p plays a prominent role in safeguarding the kidneys against common causes of chronic renal injury.

Application of Multiplex Microfluidic Electrochemical Sensors in Monitoring Hematological Tumor Biomarkers.

Rapid yet accurate detection of disease-related biomarkers is key for point of care testing, where there is an increasing demand for multi-index analysis. Here, we present a versatile device for multianalyte quantification based on the microfluidic technique and electrochemical sensor array. The analytes were shunted through inner-built channels to screen-printed electrodes installed at different positions of the chip. These electrodes were modified with different nanomaterials and sensing agents to afford specific responses to the corresponding indicators. To prove the applicability of the platform for multifunction, we chose leukemia as the model disease and determined four relevant markers: methotrexate (MTX), lactate dehydrogenase (LDH), uric acid (UA), and urea. They are indicative as/for the therapeutic drug (MTX), prognosis (LDH), and side effect (UA and urea). The sensing chip exhibited low detection limits of 35 nM, 25 U/L, 450 nM, and 20 µM toward the four analytes, which are much lower than their minimum contents in human serum. Furthermore, practical application of the chip was demonstrated by simultaneous detection of the four analytes in the blood plasma of rabbit. By simply replacing the modification agents, the sensing platform is expected to serve the detection of a wide range of chem/biosubstances in various fields.

(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis.

RATIONALE: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin-angiotensin system. OBJECTIVES: To investigate the physiological role of (P)RR in lipid metabolism in vivo. METHODS AND RESULTS: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis. CONCLUSIONS: Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

A New Criterion for Pediatric AKI Based on the Reference Change Value of Serum Creatinine.

BACKGROUND: Current definitions of AKI do not take into account serum creatinine's high variability in children. METHODS: We analyzed data from 156,075 hospitalized children with at least two creatinine tests within 30 days. We estimated reference change value (RCV) of creatinine on the basis of age and initial creatinine level in children without kidney disease or known AKI risk, and we used these data to develop a model for detecting pediatric AKI on the basis of RCV of creatinine. We defined pediatric AKI according to pediatric reference change value optimized for AKI in children (pROCK) as creatinine increase beyond RCV of creatinine, which was estimated as the greater of 20 µmol/L or 30% of the initial creatinine level. RESULTS: Of 102,817 children with at least two serum creatinine tests within 7 days, 5432 (5.3%) had AKI as defined by pROCK compared with 15,647 (15.2%) and 10,446 (10.2%) as defined by pediatric RIFLE (pRIFLE) and Kidney Disease Improving Global Outcomes (KDIGO), respectively. Children with pROCK-defined AKI had significantly increased risk of death (hazard ratio, 3.56; 95% confidence interval, 3.15 to 4.04) compared with those without AKI. About 66% of patients with pRIFLE-defined AKI and 51% of patients with KDIGO-defined AKI, mostly children with initial creatinine level of <30 µmol/L, were reclassified as non-AKI by pROCK, and mortality risk in these children was comparable with risk in those without AKI by all definitions. CONCLUSIONS: pROCK criterion improves detection of "true" AKI in children compared with earlier definitions that may lead to pediatric AKI overdiagnosis.

Multitarget Therapy for Maintenance Treatment of Lupus Nephritis.

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P=0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; P<0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P=0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.

Elevation of fumarase attenuates hypertension and can result from a nonsynonymous sequence variation or increased expression depending on rat strain.

The activity of fumarase, an enzyme in the tricarboxylic acid cycle, is lower in Dahl salt-sensitive SS rats compared with SS.13BN rats. SS.13BN rats have a Brown Norway (BN) allele of fumarase and exhibit attenuated hypertension. The SS allele of fumarase differs from the BN allele by a K481E sequence variation. It remains unknown whether higher fumarase activities can attenuate hypertension and whether the mechanism is relevant without the K481E variation. We developed SS-TgFh1 transgenic rats overexpressing fumarase on the background of the SS rat. Hypertension was attenuated in SS-TgFh1 rats. Mean arterial pressure in SS-TgFh1 rats was 20 mmHg lower than transgene-negative SS littermates after 12 days on a 4% NaCl diet. Fumarase overexpression decreased H2O2, while fumarase knockdown increased H2O2 Ectopically expressed BN form of fumarase had higher specific activity than the SS form. However, sequencing of more than a dozen rat strains indicated most rat strains including salt-insensitive Sprague-Dawley (SD) rats had the SS allele of fumarase. Despite that, total fumarase enzyme activity in the renal medulla was still higher in SD rats than in SS rats, which was associated with higher expression of fumarase in SD. H2O2 can suppress the expression of fumarase. Renal medullary interstitial administration of fumarase siRNA in SD rats resulted in higher blood pressure on the high-salt diet. These findings indicate elevation of total fumarase activity attenuates the development of hypertension and can result from a nonsynonymous sequence variation in some rat strains and higher expression in other rat strains.

Multitarget therapy for induction treatment of lupus nephritis: a randomized trial.

BACKGROUND: Treatment of lupus nephritis (LN) remains challenging. OBJECTIVE: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN. DESIGN: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616). SETTING: 26 renal centers in China. PATIENTS: Adults (aged 18 to 65 years) with biopsy-proven LN. INTERVENTION: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy. MEASUREMENTS: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events. RESULTS: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]). LIMITATION: The study was limited to 24 weeks of follow-up. CONCLUSION: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN. PRIMARY FUNDING SOURCE: National Basic Research Program of China, National Key Technology R&D Program.

Non-linear relationship between pulse pressure and the risk of pre-diabetes: a secondary retrospective Chinese cohort study.

OBJECTIVE: Previous research has shown that pulse pressure (PP) has a significant role in the start and development of type 2 diabetes mellitus. However, there is little proof that PP and pre-diabetes mellitus (Pre-DM) are related. Our study aimed to investigate the relationship between PP and incident pre-DM in a substantial cohort of Chinese participants. DESIGN: The 'DATADRYAD' database (www.Datadryad.org) was used to retrieve the data for this secondary retrospective cohort analysis. PARTICIPANTS: Data from 182 672 Chinese individuals who participated in the medical examination programme were recorded in this retrospective cohort study between 2010 and 2016 across 32 sites and 11 cities in China. SETTING: PP assessed at baseline and incident pre-DM during follow-up were the target-independent and dependent variables. The association between PP and pre-DM was investigated using Cox proportional hazards regression. PRIMARY OUTCOME MEASURES: The outcome was incident pre-DM. Impaired fasting glucose levels (fasting blood glucose between 5.6 and 6.9 mmol/L) were used to define pre-DM. RESULTS: After controlling for confounding variables, PP was positively correlated with incident pre-DM among Chinese adults (HR 1.009, 95% CI 1.007 to 1.010). Additionally, at a PP inflection point of 29 mm Hg, a non-linear connection between the PP and incident pre-DM was discovered. Increased PP was an independent risk factor for developing pre-DM when PP was greater than 29 mm Hg. However, their association was not significant when PP was less than 29 mm Hg. According to subgroup analyses, females, never-smokers and non-obesity correlated more significantly with PP and pre-DM. CONCLUSION: We discovered that higher PP independently correlated with pre-DM risk in this study of Chinese participants. The connection between PP and incident pre-DM was also non-linear. High PP levels were related to a higher risk of pre-DM when PP was above 29 mm Hg. ARTICLE FOCUS: Our study investigated the relationship between PP and incident pre-DM in a secondary retrospective cohort of Chinese participants.

Relationships between triglyceride-glucose index and incident gestational diabetes mellitus: a prospective cohort study of a Korean population using publicly available data.

Background: The connection between the triglyceride-glucose index (TyG index) and gestational diabetes mellitus (GDM) is currently debated. Our study aimed to investigate the connection between the TyG index and GDM within the Korean population. Methods: Using publically accessible data in Korea, we performed a secondary study on a sample of 589 pregnant women who were carrying a single fetus. The analysis employed a binary logistic regression model, some sensitivity analyses, and subgroup analysis to investigate the association between the TyG index and the occurrence of GDM. To assess the TyG index's potential to predict GDM, a receiver operating characteristic (ROC) study was also carried out. Results: The mean age of the pregnant women was 32.065 ± 3.798 years old, while the mean TyG index was 8.352 ± 0.400. The prevalence rate of GDM was found to be 6.112%. Upon adjusting for potential confounding variables, a positive association was detected between the TyG index and incident GDM (OR = 12.923, 95%CI: 3.581-46.632, p = 0.00009). The validity of this connection was further confirmed by subgroup analysis and sensitivity analyses. With an area under the ROC curve of 0.807 (95%CI: 0.734-0.879), the TyG index showed strong predictive power for GDM. The TyG index's ideal cutoff value for detecting GDM was found to be 8.632, with a sensitivity of 78.7% and a specificity of 72.2%. Conclusion: The findings of our study provide evidence that an increased TyG index is significantly associated with the occurrence of GDM. Utilizing the TyG index during the 10-14 week gestational period may be a valuable tool in identifying pregnant individuals at a heightened risk for developing GDM. Early detection enables timely and efficacious interventions, thereby enhancing the prognosis of affected individuals.

Association between alanine aminotransferase to high-density lipoprotein cholesterol ratio and nonalcoholic fatty liver disease: a retrospective cohort study in lean Chinese individuals.

There is limited research on the association between the alanine aminotransferase to high-density lipoprotein cholesterol ratio (ALT/HDL-C) ratio and nonalcoholic fatty liver disease (NAFLD). The purpose of the current research was to look into the connection between the ALT/HDL-C ratio and the risk of NAFLD in lean Chinese individuals. Between January 2010 and December 2014, 11,975 non-obese people participated in this prospective cohort research. The relationship between the ALT/HDL-C ratio and the risk of developing NAFLD was assessed using the Cox proportional-hazards regression model, Cox proportional hazards regression with cubic spline functions and smooth curve fitting, sensitivity analysis, and subgroup analyses. The ALT/HDL-C ratio's potential value as a NAFLD prognostic marker was to be evaluated using the receiver operating characteristic curve analysis. A total of 5419 (45.253%) women comprised the research's participant population, and the research participants' average age was 43.278 ± 14.941 years. The ALT/HDL-C ratio was 11.607 (7.973-17.422) at the median (interquartile ranges). 2087 (17.428%) patients had NAFLD diagnoses throughout a median follow-up of 24.967 months. The study's findings demonstrated a positive connection between the ALT/AHDL-C ratio and the incident NAFLD (HR = 1.037, 95% CI: 1.031-1.042) when adjusting for relevant factors. The ALT/HDL-C ratio and NAFLD risk had a nonlinear connection, with 12.963 as the ratio's inflection point. Effect sizes (HR) were 1.023 (95% CI: 1.017-1.029) and 1.204 (95% CI: 1.171-1.237), respectively, on the right and left sides of the inflection point. The sensitivity analysis also showed how reliable our findings were. According to subgroup analysis, those with BMI < 24 kg/m2 and DBP < 90 mmHg had a stronger correlation between the ALT/HDL-C ratio and NAFLD risk. The current study shows a positive and non-linear connection between the ALT/HDL-C ratio and NAFLD risk in lean Chinese individuals. When the ALT/HDL-C ratio is less than 12.963, it is significantly linked to NAFLD. Therefore, from a therapy standpoint, it is advised to keep the ALT/HDL-C ratio less than the inflection point.

Association between estimated glomerular filtration rate and reversion to normoglycemia in people with impaired fasting glucose: a 5-year retrospective cohort study.

OBJECTIVES: The present body of evidence regarding the correlation between the estimated glomerular filtration rate (eGFR) and the reversal of impaired fasting glucose (IFG) to normoglycemia remains constrained. Consequently, the objective of our study is to examine the relationship between eGFR and the restoration of normoglycemia in individuals with IFG. METHODS: This retrospective cohort study consecutively collected data from 24,541 non-selective participants with IFG at Rich Healthcare Group in China from January 2010 to 2016. We aimed to investigate the association between baseline eGFR and reversion to normoglycemia using the Cox proportional-hazards regression model. Through the utilization of a Cox proportional hazards regression model featuring cubical spline smoothing, we were able to ascertain the non-linear correlation between eGFR and the return to normoglycemia. Furthermore, various sensitivity and subgroup analyses were carried out, and a competing risk multivariate Cox regression was employed to examine the progression to diabetes as a competing risk for the reversal of normoglycemic events. RESULTS: In our study, comprising 24,541 participants, the average age was 49.25 ± 13.77 years, with 66.28% being male. The baseline eGFR mean was 104.16 ± 15.78 ml/min per 1.73 m2. During a median follow-up period of 2.89 years, we observed a reversion rate to normoglycemia of 45.50%. Upon controlling for covariates, our findings indicated a positive correlation between eGFR and the probability of returning to normoglycemia (HR = 1.008, 95% CI 1.006-1.009). In addition, a non-linear association was observed between eGFR and the likelihood of transitioning from IFG to normoglycemia. The inflection point of eGFR was found to be 111.962 ml/min per 1.73 m2, with HRs of 1.003 (95% CI 1.001, 1.005) on the left side of the point and 1.019 (95% CI 1.015, 1.022) on the right side. Our robust results were supported by competing risks multivariate Cox's regression and sensitivity analysis. CONCLUSIONS: The findings of our investigation indicate a favorable and non-linear correlation between eGFR and the restoration of normoglycemia in Chinese individuals with IFG. Specifically, a reduction in renal function at an early stage in these patients may considerably diminish the likelihood of attaining normoglycemia.

Improved automatic segmentation of brain metastasis gross tumor volume in computed tomography images for radiotherapy: a position attention module for U-Net architecture.

Background: Brain metastases present significant challenges in radiotherapy due to the need for precise tumor delineation. Traditional methods often lack the efficiency and accuracy required for optimal treatment planning. This paper proposes an improved U-Net model that uses a position attention module (PAM) for automated segmentation of gross tumor volumes (GTVs) in computed tomography (CT) simulation images of patients with brain metastases to improve the efficiency and accuracy of radiotherapy planning and segmentation. Methods: We retrospectively collected CT simulation imaging datasets of patients with brain metastases from two centers, which were designated as the training and external validation datasets. The U-Net architecture was enhanced by incorporating a PAM into the transition layer, which improved the automated segmentation capability of the U-Net model. With cross-entropy loss employed as the loss function, the samples from the training dataset underwent training. The model's segmentation performance on the external validation dataset was assessed using metrics including the Dice similarity coefficient (DSC), intersection over union (IoU), accuracy, sensitivity, specificity, Matthews correlation coefficient (MCC), and Hausdorff distance (HD). Results: The proposed automated segmentation model demonstrated promising performance on the external validation dataset, achieving a DSC of 0.753±0.172. In terms of evaluation metrics (including the DSC, IoU, accuracy, sensitivity, MCC, and HD), the model outperformed the standard U-Net, which had a DSC of 0.691±0.142. The proposed model produced segmentation results that were closer to the ground truth and could reveal more detailed features of brain metastases. Conclusions: The PAM-improved U-Net model offers considerable advantages in the automated segmentation of the GTV in CT simulation images for patients with brain metastases. Its superior performance in comparison with the standard U-Net model supports its potential for streamlining and improving the accuracy of radiotherapy. With its ability to produce segmentation results consistent with the ground truth, the proposed model holds promise for clinical adoption and provides a reference for radiation oncologists to make more informed GTV segmentation decisions.