Clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis in China.

INTRODUCTION/AIMS: Descriptions of the clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis (triple-negative myasthenia gravis, TNMG) are lacking in the current literature. Therefore, we investigated the clinical characteristics of TNMG in Chinese patients. METHODS: We retrospectively analyzed 925 patients with MG registered in the Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences from January 2015 to March 2021. RESULTS: One hundred six patients diagnosed with TNMG were included in the study. The average age of onset was 32.4 y, with a male-to-female ratio of 1:1. The age of onset showed a bimodal distribution: 0-9 y and 40-49 y. Adult patients were more likely to have weakness of limb and bulbar muscles (p < .05). Thymic hyperplasia was found in 20.2% of the patients. Younger patients were more likely to relapse. The rate of adult early-onset myasthenia gravis reaching complete stable remission and pharmacological remission was 47.6%, and the prognosis was better than that in juvenile-onset myasthenia gravis (p = .019). Older age of onset was the only risk factor for the development of generalized TNMG from ocular TNMG (R = 1.046, p = .002, 95% confidence interval 1.017-1.077). DISCUSSION: This study showed that the clinical characteristics of patients with TNMG varied among the different age groups. Significant findings included a bimodal distribution of onset age, coexisting thymic hyperplasia, and a generally favorable prognosis.

Association of latent class analysis-derived subphenotypes of acute kidney injury with mortality in critically ill patients with cardiovascular disease: a retrospective cohort study.

BACKGROUND: To explore the potential heterogeneity of acute kidney injury (AKI) and evaluate the prognostic differences among AKI subphenotypes in critically ill patients with cardiovascular diseases. METHODS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-III database. Latent class analysis (LCA) was used to explore the potential subphenotypes of AKI in critically ill patients with cardiovascular diseases. The number of classes was identified by the Bayesian information criterion and entropy. The differences in prognostic ability among the AKI subphenotypes were evaluated by logistic regression analysis. RESULT: A total of 7738 AKI patients were enrolled in this study. Using LCA, AKI patients were divided into 4 heterogeneous subphenotypes, which were obviously different from the Kidney Disease: Improving Global Outcomes (KDIGO) stages. Interestingly, class 3 classified by LCA was dominated by stage 2, while the mortality rate in class 3 was significantly different from that in class 1 (15.2% vs. 1.6%, p < 0.05). After further adjustment, the mortality rate in class 3 remained higher than that in class 1, with an odds ratio of 12.31 (95% confidence interval, 8.96-16.89). CONCLUSIONS: LCA was feasible for AKI classification in critically ill patients with cardiovascular disease, and 4 distinct subphenotypes of AKI patients with different prognoses were identified. Our results highlighted the potential heterogeneity of AKI patients, which is worthy of further investigation.

Clinical Efficacy and Safety of Combination Therapy with Amlodipine and Olmesartan or an Olmesartan/Hydrochlorothiazide Compound for Hypertension: A Prospective, Open-Label, and Multicenter Clinical Trial in China.

BACKGROUND: Amlodipine (AML) is the initial therapy most commonly prescribed for patients with hypertension in China. However, AML monotherapy is often less effective in achieving blood pressure (BP) control than other agents. OBJECTIVE: We performed a clinical study to evaluate efficacy and safety of a combination therapy with AML, olmesartan (OLM), or an OLM/hydrochlorothiazide (HCTZ) compound for Chinese patients with mild-to-moderate hypertension. METHODS: In the clinical trial, patients were initially treated with OLM 20 mg/d combined with AML 5 mg/d. Then OLM was uptitrated to 40 mg/d or changed to an OLM/HCTZ (20/12.5 mg/d) compound if the patients did not reach the target of seated diastolic BP <90 mm Hg (<80 mm Hg in patients with diabetes) after 8 weeks. RESULTS: The overall response rate of the combination therapy was 59.2% (95% CI, 54.23%-63.97%) at Week 2 and gradually increased to 97.1% (95% CI, 94.93%-98.47%) at the end of the study (Week 16). CONCLUSIONS: The combination therapy with OLM or OLM/HCTZ was well tolerated. The total incidence of adverse events was 42.9% (n = 176). Most of the adverse events were mild in severity (39.5%; n = 162) and not associated with the drugs (33.2%). In conclusion, combination therapy with AML, OLM, or OLM/HCTZ can significantly lower BP safely and achieve a high BP control rate in patients with mild-to-moderate hypertension in China. ClinicalTrial.org identifier: ChiCTR-ONC-12001963.

Carotid Artery Stenting Versus Carotid Endarterectomy for Treatment of Asymptomatic Carotid Artery Stenosis.

Asymptomatic carotid stenosis is common and is associated with increased risk of stroke. The relative efficacy and safety of carotid endarterectomy (CEA) and carotid stenting (CAS) in patients with asymptomatic carotid stenosis remain unclear. Five studies that recruited patients with asymptomatic but significant carotid stenosis, who underwent CEA or CAS, were included in this systematic review and meta-analysis. The analyzed outcomes included risks of stroke, myocardial infarction (MI), and death. Risk ratio (RR) and 95% confidence interval (95% CI) were calculated and pooled for meta-analysis. Pooled analysis demonstrated that compared with CEA, CAS was associated with a decreased risk of MI (RR = 0.49, 95%CI = 0.26-0.91, P = 0.023) and slightly increased risk of stroke, although not significant (RR = 1.69, 95% CI = 0.97-2.92, P = 0.063). There was no difference in the death rates between the groups (RR = 0.60, 95% CI = 0.17-2.18, P = 0.436). In the subgroup analysis, CAS was associated with a decreased risk of MI in mixed patients (RR = 0.45, 95% CI = 0.26-0.78, P = 0.005), but not in asymptomatic patients (RR = 0.549, 95% CI = 0.26-1.17, P = 0.119). Compared with CAS, CEA was associated with decreased risk of perioperative stroke and increased risk of MI; it did not affect the risk of death in patients with asymptomatic carotid stenosis. In the subgroup analysis, the decreased risk of MI after CAS was significant only in the mixed patients group. CAS was associated with higher risk of stroke but lower risk of MI than those with CEA. Both procedures appeared equivalent in terms of the risk of death.

CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells.

High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [(3)H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.

Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues.

CD40 is a member of the tumor necrosis factor receptor family. We reveal here a correlation between CD40 expression and colon cancer differentiation. Upon CD40 ligand (CD40L) binding, CD40/CD40L signaling inhibited colon cancer proliferation, induced apoptosis, stalled cells at G0/G1, and influenced cell adhesion and metastasis. Clustering analysis identified the elevation of aryl hydrocarbon receptor repressor (AHRR) expression along with activation of CD40/CD40L signaling. Examination of clinical specimens revealed that both AHR and AHRR levels correlated with colon cancer histological grade. In addition, high expression of AHRR was associated with high expression of CD40 in tumor cells, with CD40L expression being particularly high in the tumor interstitium. Real-time PCR and western blotting analysis showed that AHRR expression in colon cancer cells was up-regulated by CD40L binding. The likely mediating signaling pathways for the effects of CD40 are described herein.

Synthesis of dual models multivalent activatable aptamers based on HCR and RCA for ultrasensitive detection of Salmonella typhimurium.

Aptamers have superior structural properties and have been widely used in bacterial detection methods. However, the problem of low affinity still exists in complex sample detection. In contrast, hybridization chain reaction (HCR)-based model I and rolling circle amplification (RCA)-based model II multivalent activatable aptamers (multi-Apts) can fulfill the need for low-cost, rapid, highly sensitive and high affinity detection of S. typhimurium. In our research, two models of multi-Apts were designed. First, a monovalent activatable aptamer (mono-Apt) was constructed by fluorescence resonance energy transfer (FRET) with an S. typhimurium aptamer and its complementary chain of BHQ1. Next, the DNA scaffold was obtained by HCR and RCA, and the multi-Apts were obtained by self-assembly of the mono-Apt with a DNA scaffold. In model I, when target was presented, the complementary chain BHQ1 was released due to the binding of multi-Apts to the target and was subsequently adsorbed by UIO66. Finally, a FRET-based fluorescence detection signal was obtained. In mode II, the multi-Apts bound to the target, and the complementary chain BHQ1 was released to become the trigger chain for the next round of amplification of HCR with a fluorescence detection signal. HCR and RCA based multi-Apts were able to detect S. typhimurium as low as 2 CFU mL-1 and 1 CFU mL-1 respectively. Multi-Apts amplification strategy provides a new method for early diagnosis of pathogenic microorganisms in foods.

UIO66 low background signal and fluorescence synergism strategy for highly sensitive detection of Salmonella typhimurium.

Successful construction of a detection method for Salmonella typhimurium (S. typhimurium) based on the synergy of hybridization chain reaction (HCR) and fluorescence was realized in this paper. First, the aptamer modified with the quenching group Black Hole Quencher-1 acid (BHQ1) was immobilized on the magnetic beads in combination with the complementary chain of the aptamer modified with 6-carboxyfluorescein (6-FAM). Second, S. typhimurium and cDNA-6-FAM immobilized on magnetic beads competitively bound to the aptamer. Finally, the cDNA-6-FAM was released after magnetic separation acted as a promoter to trigger HCR amplification when the target presented. The fluorescence signal could be significantly improved by the combination of green SYBR Green I (SGI) and HCR long double-stranded DNA and the fluorescent synergy of 6-FAM and SGI. Because of the separation of target and its aptamer, the trigger strand was abstracted by magnetic separation. There was no HCR to generate long double-stranded DNA, and the fluorescence of excess hairpin/SGI could be adsorbed through UIO66 so that only a very low background signal was detected. This fluorescent sensor was capable of monitoring S. typhimurium in the range of 10-3.2 × 107 CFU mL-1 with a limit of detection as low as 1.5 CFU mL-1. Because of the excellent properties of the aptasensor and the validity of SGI fluorescence synergy, this HCR enzyme-free amplification strategy could be generalized to other areas.

Advances in signal amplification strategies applied in pathogenic bacteria apta-sensing analysis-A review.

Pathogenic bacteria are primarily kinds of food hazards that provoke serious harm to human health via contaminated or spoiled food. Given that pathogenic bacteria continue to reproduce and expand once they contaminate food, pathogenic bacteria of high concentration triggers more serious losses and detriments. Hence, it is essential to detect low-dose pollution at an early stage with high sensitivity. Aptamers, also known as "chemical antibodies", are oligonucleotide sequences that have attracted much attention owing to their merits of non-toxicity, small size, variable structure as well as easy modification of functional group. Aptamer-based bioanalysis has occupied a critical position in the field of rapid detection of pathogenic bacteria. This is attributed to the unique advantage of using aptamers as recognition elements in signal amplification strategies. The signal amplification strategy is an effective means to improve the detection sensitivity. Some diverse signal amplification strategies emphasize the synthesis and assembly of nanomaterials with signal amplification capabilities, while others introduce various nucleic acid amplification techniques into the detection system. This review focuses on a variety of signal amplification strategies employed in aptamer-based detection approaches to pathogenic bacteria. Meanwhile, we provided a detailed introduction to the design principles and characteristics of signal amplification strategies, as well as the improvement of sensor sensitivity. Ultimately, the existing issues and development trends of applying signal amplification strategies in apta-sensing analysis of pathogenic bacteria are critically proposed and prospected. Overall, this review discusses from a new perspective and is expected to contribute to the further development of this field.

Study on the relationship between atrial high-rate episode and left atrial strain in patients with cardiac implantable electronic device.

Background: Although atrial high-rate episode (AHRE) and atrial fibrillation (AF) cannot entirely be identical, recent studies suggest AHRE is linked to AF development and shares some characteristics with AF regarding thromboembolism. At present, there is still lack of predictive indicators for AHRE and diagnostic methods and clinical indicators for AHRE in patients without cardiac implantable electronic device (CIED). The aim of this study was thus to explore the relationship between AHRE and left atrial (LA) strain parameters with the goal of identifying high-risk populations of AHRE by LA strain characteristics. Methods: From February 2022 to May 2023, a total of 105 CIED patients were enrolled and divided into two groups based on whether AHRE had occurred: AHRE (-) group (n=65) and AHRE (+) group (n=40). Real-time three-dimensional echocardiography (RT-3DE) technique was used to obtain the LA time-volume curve. The collected dynamic images were analyzed on the Echopac 204 workstation to obtain the parameters of LA. The four-dimensional automatic LA quantitative analysis (4D Auto LAQ) technology was used to analyze the LA strain parameters: LA reservoir longitudinal strain (LASr), LA conduit longitudinal strain (LAScd), LA contraction longitudinal strain (LASct), LA reservoir circumferential strain (LASr-c), LA conduit circumferential strain (LAScd-c), LA contraction circumferential strain (LASct-c). Correlation analysis was carried out using Binary logistic regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic performance of LASct in AHRE. Results: Body surface area (BSA) [odds ratio (OR) =8.34, 95% confidence interval (CI): 1.32-72.30, P=0.037], LASct (OR =1.20, 95% CI: 1.05-1.39, P=0.013) and LA end-systolic volume (LAESV) (OR =1.02, 95% CI: 1.00-1.04, P=0.023) were the influencing factors of AHRE. Only LASct (OR =1.18, 95% CI: 1.01-1.38, P=0.041) was found to be an independent influencing factor of AHRE. This result remained significant after adjusting for age, sex, hypertension, diabetes, and stroke history. The ROC curve showed that the cut-off for predicting AHRE was LASct =-4.125% with sensitivity of 37.5% and specificity of 87.7%. Conclusions: This cross-sectional study found that decreased LASct (absolute value) is an independent risk factor for the AHRE and has diagnostic efficacy in certain degree for the occurrence of AHRE.

Novel cross-linkable fluorescent probe with oriented antibody to enhance lateral immunoassay strip for the detection of acetamiprid.

Time-resolved fluorescent lateral immunoassay strip (TRFLIS) is a reliable and rapid method for detecting acetamiprid. However, its sensitivity is often affected by the structural patterns and stability of the fluorescent probe. Researchers have shown significant interests in using goat anti-mouse IgG (GaMIgG) which is indirectly bound to time-resolved fluorescent microsphere (TRFM) and antibody. This allowed for oriented modification of the antibody. However, the stability of fluorescent probe in this binding mode remained unexplored. Herein, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride was innovatively used as a cross-linking agent to enhance the binding of antibody to GaMIgG, which improved the stability of the fluorescent probe. Under optimal working conditions, this strategy exhibited a wide linear response range of 5-700 ng/mL. Its limit of detection (LOD) was 0.62 ng/mL, the visual LOD was 5 ng/mL, and the limit of quantification (LOQ) of 2.06 ng/mL. Additionally, under tomato matrix, leek matrix and Chinese cabbage matrix, the linear response ranges were 5-400, 5-300, and 5-700 ng/mL, with LODs of 0.16, 0.60, and 0.41 ng/mL, with LOQs of 0.53, 2.01 and 1.37 ng/mL, respectively. In conclusion, this strategy effectively reduced the dosage of acetamiprid antibody compared with TRFM directly linking acetamiprid antibody, and greatly increased the sensitivity of TRFLIS. Meanwhile, it demonstrated outstanding specificity and accuracy in acetamiprid detection and had been successfully applied to vegetable samples. This method enables rapid and accurate detection of large-volume samples by combining qualitative and quantitative methods. As such, it has great potential in the development of low-cost and high-performance immunochromatographic platforms.

Erratum: ß-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling.

[This corrects the article on p. 370 in vol. 11, PMID: 33575077.].

Radiofrequency catheter ablation for improving myocardial work in patients with ventricular pre-excitation.

Background: Previous studies have not consistently found significant improvements in left ventricular ejection fraction or global longitudinal strain (GLS) after radiofrequency catheter ablation (RFCA) in patients with ventricular pre-excitation. The aim of this study was thus to explore the effects of RFCA on left ventricular function in patients with ventricular pre-excitation using a new noninvasive echocardiographic method of myocardial work. Methods: A total of 34 patients with ventricular pre-excitation who underwent RFCA and 18 healthy controls were prospectively included in this study. Before and after participants underwent RFCA, electrocardiographic and echocardiographic data of the patients were collected at resting and pacing heart rates (HRs) of 100 beats per minute (bpm) and 120 bpm (controlled by high right atrial pacing during the procedure). Clinical data of the healthy controls at resting HR were also collected. A self-controlled paired sample t test was used to compare the differences before and after participants underwent RFCA. Results: After participants underwent RFCA, the global wasted work (GWW) of the included patients decreased (resting HR: 165.3±68.8 vs. 92.6±42.5 mmHg%, P<0.001; HR of 100 bpm: 276.3±121.2 vs. 187.9±96.0 mmHg%, P<0.001; HR of 120 bpm: 323.9±126.7 vs. 181.0%±74.3 mmHg%. P<0.001), while the global work efficiency (GWE) increased (resting HR: 91.5%±3.8% vs. 94.9%±1.6%; P<0.001; HR of 100 bpm: 87.0%±5.2% vs. 91.0%±3.3%, P<0.001; HR of 120 bpm: 85.0%±5.1% vs. 90.3%±3.7%, P<0.001). Conclusions: In patients with ventricular pre-excitation, impaired GWW and GWE can be improved with RFCA. In clinical practice, noninvasive myocardial work assessment can be used in patients with ventricular pre-excitation.

Left atrial enlargement and high uric acid level are risk factors for left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate embolic risk assessed by CHA2DS2-VASC score.

Aims: To investigate the correlation and predictive value of left atrial diameter and blood uric acid levels with the occurrence of left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate CHA2DS2-VASc scores. Methods and results: A total of 849 inpatients diagnosed with atrial fibrillation who had low to moderate CHA2DS2-VASc scores and complete transesophageal echocardiography were included in this study. Among them, 66 patients had left atrial thrombus or dense spontaneous echo contrast. When different models were used to correct other known risk factors, acid levels and abnormal left atrial diameter were identified as additional risk factors for left atrial thrombus or dense spontaneous echo contrast. The incidence of left atrial thrombus or dense spontaneous echo contrast was higher in patients with abnormal serum uric acid levels than in the control group (12.4% vs. 5.6%, p < 0.05), and this difference persisted after correcting the baseline data with propensity score matching (10.6% vs. 4.1%, p < 0.05). Abnormal left atrial diameter was another risk factor suggested by regression analysis, with an increased incidence of left atrial thrombus or dense spontaneous echo contrast in the abnormal left atrial diameter group compared to the control group, both before (18.0% vs. 3.5%, p < 0.05) and after (15.5% vs. 5.2%, p < 0.05) propensity score matching. The best predictive value was obtained by adding both abnormal serum uric acid levels and abnormal left atrial diameter. Conclusion: Left atrial enlargement and high uric acid levels increase the risk of left atrial thrombus or dense spontaneous echo contrast in atrial fibrillation patients with low to moderate CHA2DS2-VASc scores.

Empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of vascular smooth muscle cells.

SGLT-2 inhibitors, such as empagliflozin, have been shown to reduce the occurrence of cardiovascular events and delay the progression of atherosclerosis. However, its role in atherosclerotic calcification remains unclear. In this research, ApoE-/- mice were fed with western diet and empagliflozin was added to the drinking water for 24 weeks. Empagliflozin treatment significantly alleviated arterial calcification assessed by alizarin red and von kossa staining in aortic roots and reduced the lipid levels, while had little effect on body weight and blood glucose levels in ApoE-/- mice. In vitro studies, empagliflozin significantly inhibits calcification of primary vascular smooth muscle cells (VSMCs) and aortic rings induced by osteogenic media (OM) or inorganic phosphorus (Pi). RNA sequencing of VSMCs cultured in OM with or without empagliflozin showed that empagliflozin negatively regulated the osteogenic differentiation of VSMCs. And further studies confirmed that empagliflozin significantly inhibited osteogenic differentiation of VSMCs via qRT-PCR. Our study demonstrates that empagliflozin alleviates atherosclerotic calcification by inhibiting osteogenic differentiation of VSMCs, which addressed a critical need for the discovery of a drug-based therapeutic approach in the treatment of atherosclerotic calcification.

How the trabeculae protrude within the left atrial appendage is the key factor affecting thrombosis in patients with atrial fibrillation.

The left atrial appendage (LAA) is a major site of thrombosis in patients with non-valvular atrial fibrillation. The myocardial trabeculae within the LAA have a peculiar tendency to protrude but its relationship to thrombosis remains unknown. This study aimed to investigate the relationship between the condition of trabeculae protrusion and LAA thrombosis. This retrospective study consecutively selected patients diagnosed with non-valvular atrial fibrillation and prepared for radiofrequency ablation from January 2011 to May 2020. Patients were divided into the thrombus group (n = 43), the sludge group (n = 35), and the normal group (n = 407) according to whether the thrombus or sludge was present. The trabeculae protruding angle (TPA), which was measured by the CT scans, was used to quantify the trabeculae protrusion condition. Patients' clinical data, TPA, LAA emptying velocity, and other factors were collected and compared among the three groups. A total of 485 patients were enrolled. The range of TPA was between 0 and 158 degrees, with an average of 89.3 ± 35.6 degrees. The TPA was significantly greater in the thrombus (109.3 ± 14.8 degrees) and sludge groups (110.8 ± 12.8 degrees) than in the normal group (85.3 ± 37.1). The incidence of LAA thrombus and sludge increased with increasing TPA. Multivariate regression analysis showed that the TPA was an independent risk factor for LAA thrombus (OR = 1.046, 95%CI: 1.020-1.073, p < 0.001) and sludge (OR = 1.035, 95%CI: 1.017-1.053, p < 0.001). Further analysis revealed that the TPA was negatively correlated with LAA emptying velocity but its effect on promoting thrombosis was not only mediated by slowing down the flow velocity. The TPA can well reflect the condition of trabeculae protrusion. This study revealed that the TPA was an independent risk factor for LAA thrombus or sludge, providing a potential indicator for future thrombosis risk assessment.

Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle.

Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.

Local activation of cardiac stem cells for post-myocardial infarction cardiac repair.

The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue-specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time-consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC-based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post-MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC-based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.

Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model.

The effects of amiodarone on ventricular electrophysiological parameters, especially the dispersion of ventricular repolarization, were investigated in a canine model of congestive heart failure (CHF). Dogs were randomized to either a control, amiodarone, CHF, or CHF+amiodarone group. Dogs in the CHF and CHF+amiodarone groups underwent 4-5 weeks of rapid ventricular pacing; dogs in the control and amiodarone groups underwent sham operation only. Amiodarone (20 mg/kg per day) was administered orally, beginning on postoperative Day 1, in the treatment groups; ventricular electrophysiological variables were evaluated 4-5 weeks after rapid pacing or sham operation. In CHF dogs, the transmural dispersion ventricular repolarization time (TDVRT) increased significantly. Amiodarone significantly decreased the TDVRT in CHF dogs. The ventricular fibrillation threshold (VFT) decreased in the CHF group. Amiodarone increased the VFT in CHF dogs. The TDVRT increased in CHF dogs, but amiodarone decreased TDVRT and increased VFT in these dogs. These results suggest a beneficial effect of amiodarone on malignant arrhythmias and may provide the basis for its use in CHF patients.

Predicting Risk Factors of Acute Kidney Injury in the First 7 Days after Admission: Analysis of a Group of Critically Ill Patients.

Background: Acute kidney injury (AKI) is a common complication in critically ill patients. Some predictive models have been reported, but the conclusions are controversial. The aim of this study was the formation of nomograms to predict risk factors for AKI in critically ill patients within the first 7 days after admission to the intensive care unit (ICU). Methods: Data were extracted from the Medical Information Mart for Intensive Care- (MIMIC-) III database. The random forest method was used to fill in the missing values, and least absolute shrinkage and selection operator (Lasso) regression analysis was performed to screen for possible risk factors. Results: A total of 561 patients were enrolled. Complication with AKI is significantly associated with a longer length of stay (LOS). For all patients, the predictors contained in the prediction nomogram included hypertension, coronary artery disease (CAD), cardiopulmonary bypass (CPB), coronary artery bypass grafting (CABG), Simplified Acute Physiology Score II (SAPS II), central venous pressure (CVP) measured for the first time after admission, and maximum and minimum mean artery pressure (MAP). The model showed good discrimination (C - index = 0.818, 95% CI: 0.779-0.857). In the subgroup of patients with well-controlled blood glucose levels, the significant predictors included hypertension, CABG, CPB, SAPS II, and maximum and minimum MAP. Good discrimination was also present before (C - index = 0.785, 95% CI: 0.736-0.834) and after adjustment (adjusted C - index = 0.770). Conclusion: Hypertension, CAD, CPB, CABG, SAPS II, CVP measured for the first time after admission, and maximum and minimum MAP were independent risk factors for AKI in critically ill patients.