Portable Detection of Lysine Acetyltransferase Activity in Lung Cancer Cells Based on a Miniature Electrochemical Sensor.

The detection of lysine acetyltransferases is crucial for diagnosing and treating lung cancer, highlighting the necessity for highly efficient detection methods. We developed a portable, highly accurate, and sensitive technique using fast-scan cyclic voltammetry (FSCV) to determine the activity of the lysine acetyltransferase TIP60, employing a novel miniature electrochemical sensor. This approach involves a compact electrochemical cell, merely 3 mm in diameter, that holds solutions up to 50 µL, equipped with a conductive indium tin oxide working electrode. Uniquely, this system operates on a two-electrode model compatible with the FSCV, obviating the traditional requirement for a reference electrode. The system detects TIP60 activity through the continuous generation of CoA molecules that engage in reactions with Cu(II), thereby significantly improving the accuracy of the acetylation analysis. Remarkably, the detection limit achieved for TIP60 is notably low at 3.3 pg/mL (S/N = 3). The results show that the reversible dynamic acetylation can be effectively regulated by inhibitor incubation and glucose stimulation. This cutting-edge strategy enhances the analysis of a broad spectrum of biomarkers by modifying the responsive unit, and its miniaturization and portability significantly amplify its applicability in biomedical research, promising it to be a versatile tool for early diagnostic and therapeutic interventions in lung cancer.

A case of endocardial dissection caused by Micra implantation.

BACKGROUND: Leadless pacemakers are a recent technological advancement. It has many advantages, but there are still a few serious complications. CASE PRESENTATION: This article reports the case of a patient with an endocardial tear and dissection caused by contact with the tip of the Micra cup during surgery and summarises the relevant data. CONCLUSIONS: This case report details the occurrence and management of the incident and provides some guidance for future clinical management.

Clinical enrollment assay to detect preexisting neutralizing antibodies to AAV6 with demonstrated transgene expression in gene therapy trials.

Recombinant adeno-associated virus (AAV) vectors are the leading platform for gene delivery for a variety of clinical applications. Patients with preexisting antibodies to AAV are currently excluded from most AAV gene therapy trials to avoid vector neutralization and ensure response to therapy. Anti-AAV neutralizing antibodies (NAbs) are typically assessed by in vitro cell-based transduction inhibition (TI) assays. However, clinical relevance of the determined enrollment cutoff and the inherent variability of a cell-based assay present challenges for use as an enrollment screening test. Here, we describe an enrollment cutoff that was clinically validated and strategies to overcome assay challenges to enable long-term stable performance. A validated anti-AAV6 cell-based TI assay was used to support clinical enrollment across multiple investigational gene therapies and to evaluate AAV6 seroprevalence in healthy and disease populations. The clinical enrollment cutoff was determined statistically using samples collected from healthy donors, applying a 0.1% false error rate with the inclusion of a minimum significant ratio (MSR) metric and in consideration of results from in vivo mouse passive transfer studies. Our strategy for long-term monitoring and control of assay performance employed plate quality control samples flanking the predefined cutoff. An approach using donor samples was implemented to bridge different lots of critical reagents without the need to redefine the cutoff.

Increased ß1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models.

BACKGROUND: Autoimmune disorder is the emerging mechanism of atrial fibrillation (AF). The ß1-adrenergic receptor antibody (ß1-AAb) is associated with AF progress. Our study aims to investigate whether ß1-AAbs involves in atrial vulnerable substrate by mediating Ca2+ mishandling and atrial fibrosis in autoimmune associated AF. METHODS: Active immunization models were established via subcutaneous injection of the second extracellular loop (ECL2) peptide for ß1 adrenergic receptor (ß1AR). Invasive electrophysiologic study and ex vivo optical mapping were used to evaluate the changed electrophysiology parameters and calcium handling properties. Phospho-proteomics combined with molecular biology assay were performed to identify the potential mechanisms of remodeled atrial substrate elicited by ß1-AAbs. Exogenous ß1-AAbs were used to induce the cellular phenotypes of HL-1 cells and atrial fibroblasts to AF propensity. RESULTS: ß1-AAbs aggravated the atrial electrical instability and atrial fibrosis. Bisoprolol alleviated the alterations of action potential duration (APD), Ca2+ transient duration (CaD), and conduction heterogeneity challenged by ß1-AAbs. ß1-AAbs prolonged calcium transient refractoriness and promoted arrhythmogenic atrial alternans and spatially discordant alternans, which were partly counteracted through blocking ß1AR. Its underlying mechanisms are related to ß1AR-drived CaMKII/RyR2 activation of atrial cardiomyocytes and the myofibroblasts phenotype formation of fibroblasts. CONCLUSION: Suppressing ß1-AAbs effectively protects the atrial vulnerable substrate by ameliorating intracellular Ca2+ mishandling and atrial fibrosis, preventing the process of the autoimmune associated AF.

Postcardiac injury syndrome caused by radiofrequency catheter ablation of persistent atrial fibrillation: severe pulmonary arterial hypertension with severe tricuspid regurgitation: a rare case report and literature review.

BACKGROUND: Postcardiac injury syndrome (PCIS) is an easy-to-miss diagnosis, but it is not an uncommon complication. The phenomenon of echocardiography (ECHO) showing both severe pulmonary arterial hypertension (PAH) and severe tricuspid regurgitation (TR) is indeed rare in PCIS after extensive radiofrequency ablation. CASE PRESENTATION: A 70-year-old male was diagnosed with persistent atrial fibrillation. The patient received radiofrequency catheter ablation due to his atrial fibrillation being refractory to antiarrhythmic drugs. After the anatomical three-dimensional models were created, ablations were performed on the left and right pulmonary veins, roof linear and bottom linear of the left atrium, and the cavo-tricuspid isthmus. The patient was discharged in sinus rhythm (SR). After 3 days, he was admitted to the hospital for gradually worsening dyspnea. Laboratory examination showed a normal leukocyte count with an increased percentage of neutrophils. The erythrocyte sedimentation rate, C-reactive protein concentration, interleukin-6, and N-terminal pro-B-type natriuretic peptide were elevated. ECG exhibited SR, V1-V4 of precordial lead P-wave amplitude which was increased but not prolonged, PR segment depression, and ST-segment elevation. Computed tomography angiography of the pulmonary artery revealed that the lung had scattered high-density flocculent flakes and a small amount of pleural and pericardial effusion. Local pericardial thickening was seen. ECHO showed severe PAH with severe TR. Diuretics and vasodilators did not relieve the symptoms. Tumors, tuberculosis, and immune system diseases were all excluded. Considering the patient's diagnosis of PCIS, the patient was treated with steroids. The patient recovered on the 19th day post ablation. The patient's condition was maintained until 2 years of follow-up. CONCLUSIONS: The phenomenon of ECHO showing severe PAH with severe TR is indeed rare in PCIS. Due to the lack of diagnostic criteria, such patients are easily misdiagnosed, leading to a poor prognosis.

Rulkov neural network coupled with discrete memristors.

The features of memristive-coupled neural networks have been studied extensively in the continuous field. However, the particularities of the discrete domain are rarely mentioned. This paper constructs a discrete memristor with sine-type conductance and applies the discrete memristor to coupling the Rulkov neuron maps for the first time. The properties of the proposed memristive-coupled bi-neuron Rulkov map and multi-neuron Rulkov neural network are probed. In order to better characterize the discrete system, many numerical simulation methods are used. Such as the normalized mean synchronization error, bifurcation diagrams, phase portraits, spatiotemporal patterns and so on. Numerical studies have shown that in discrete memristor-coupled neural networks, both parameters and coupling factors affect the dynamics of the system, resulting in complex and interesting behavioural changes.

Aging-induced atrial fibrosis in If current change and its effect on atrial fibrillation in dogs.

BACKGROUND: Atrial fibrillation (AF) is a very common type of cardiac arrhythmia that threatens public health. Aging is an independent AF risk factor. However, the mechanism of age-related AF remains unclear. METHODS: A total of 36 Beagle dogs were selected and divided into three groups (12 in each group): two groups were 9-year-old aged dogs, and one group was 4-year-old adult dogs. Electrophysiological testing was employed to determine if modeling is successful. Patch-clamp technique was employed to measure the If current. The expression of protein and mRNA related to If current were also tested. Collagen deposition was observed with the use of Masson staining. RESULTS: Aging resulted in a higher collagen deposition percentage in the left atrium. The hyperpolarization-activated cyclic nucleotide-gated (HCN)2 and HCN4 expressions were increased in the atria and pulmonary veins but decreased in the sinus node of the aged group. Moreover, in the aged group, the left atrium mRNA expressions of Kcnd2 (Potassium voltage-gated channel subfamily D member 2), Kcnh2, Kcnq1, Kcnj2, Kcnj11, and CACNA1H were significantly downregulated. The aged AF group also demonstrated sustained AF and significant changes in electrophysiological characteristics. The If current demonstrated an increased amplitude and was easier to activate in the aged AF group than in younger group. Finally, AF occurrence exacerbated aging-induced cardiac fibrosis, thereby aggravating the above-listed symptoms. CONCLUSION: With age, the increase in atrial fibrosis affected the expression of the ion channels, thereby modulating the If current. Moreover, AF also further exacerbated the degree of atrial fibrosis.

Incidence, Risk Factors, and Prognosis of Tricuspid Regurgitation After Cardiac Implantable Electronic Device Implantation: A Systematic Review and Meta-analysis.

This study aimed to determine the pooled incidence, risk factors, and clinical prognosis of tricuspid regurgitation (TR) deterioration after implantation of a cardiac implantable electronic device (CIED). The study was designed as a meta-analysis of randomized controlled trials and observational studies. Patients with indications for CIEDs were selected as participants and CIED implantation was the intervention. PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Data, and China Science and Technology Journal Database were searched systematically to identify studies. Thirty-seven studies with 8,144 patients were included. The pooled incidence of TR deterioration of at least one grade was 25.1% (95% confidence interval [CI], 20.9-29.3; Z = 11.60; p < 0.01; I2 = 94.8%, p < 0.01). Compared with TR incidence after permanent pacemaker implantation, that after implantable cardioverter-defibrillator implantation did not significantly increase (22.68% v 29.18%; odds ratio [OR], 0.615; 95% CI, 0.271-1.339; Z =1.16; p = 0.246). The pooled incidence of TR deterioration of at least two grades was 9.4% (95% CI, 6.6-12.1; Z = 6.72; p < 0.01; I2 = 86.0%, p < 0.01). Lead interference (OR, 8.704; 95% CI,4.450-17.028; Z= 6.32; p < 0.001) and pacemaker implantation time (OR, 1.153; 95% CI, 1.082-1.229; Z = 4.37; p < 0.001) were risk factors for worsening TR. Baseline atrial fibrillation, age, baseline mild TR, and left ventricular ejection fraction were not associated with TR. All-cause mortality (>one year after pacemaker implantation) was higher in patients with TR deterioration (hazard ratio, 1.598; 95% CI, 1.275-2.002; Z = 4.07; p < 0.01; I2 = 0%). TR is a common complication after CIED implantation. Lead interference and pacemaker implantation time were risk factors for TR worsening. Compared with patients without TR deterioration after pacemaker implantation, patients with TR deterioration had a poorer prognosis.

Evaluation of safety and feasibility of leadless pacemaker implantation following the removal of an infected pacemaker.

BACKGROUND: Leadless pacemakers provide safe and effective pacing options for patients with device-related infections. This study was aimed at observing and evaluating the safety and feasibility of extracting an infected pacemaker device followed by the implantation of a leadless pacemaker in the same location for patients without systemic infection. METHODS: Between December 2019 and September 2020, following a well-planned re-implantation strategy, pacemaker electrodes were removed from patients with device infection and leadless pacemakers were immediately implanted at our center. The patients were then followed up for up to 10 months to assess the safety and practicality of the procedure. RESULTS: Pacemaker electrode removal and immediate leadless pacemaker implantation were successfully achieved in eight patients with pocket infection. After a minimum follow-up period of 1 month and a maximum follow-up of 10 months, the pacing parameters for the patients remained stable and there was no infection at the original capsular bag or in the leadless pacemaker. CONCLUSION: Direct implantation of a leadless pacemaker is safe and feasible for patients with local infection of the pacing system after removal of the electrode as an alternative to a bridge period with a temporary pacemaker. This strategy may be a better option for pacing-dependent patients.

A prospective comparison of four methods for preventing pacemaker pocket infections.

This study aims to evaluate four pacemaker pocket cleaning methods for preventing implantation-related infections. This single-center trial prospectively randomized 910 patients undergoing first-time pacemaker implantation or replacement into four pocket cleaning methods: hemocoagulase (group A, n = 228), gentamicin (group B, n = 228), hemocoagulase plus gentamicin (group C, n = 227), and normal saline (group D, n = 227). Before implanting the pacemaker battery, the pockets were cleaned with gauze presoaked in the respective cleaning solutions. Then, these patients were followed up to monitor the occurrence of infections for 1 month after implantation. Twelve implantation-related infections occurred in 910 patients (1.32%): four patients from group A (1.75%), three patients from group B (1.32%), two patients from group C (0.88%), and three patients from group D (1.32%) (P > .05). Furthermore, two patients developed bloodstream infections (0.22%), and both of these patients were associated with pocket infection (one patient was from group A, while the other patient was from group C, respectively). No cases of infective endocarditis occurred. The differences in the number of infections in these study groups were not statistically significant. The application of hemocoagulase, gentamicin, hemocoagulase plus gentamicin, or normal saline on the presoaked gauze before implantation was equally effective in preventing pocket-associated infections.

Cholinergic Elicitation Prevents Ventricular Remodeling via Alleviations of Myocardial Mitochondrial Injury Linked to Inflammation in Ischemia-Induced Chronic Heart Failure Rats.

BACKGROUND: Cholinergic anti-inflammatory pathway (CAP) is implicated in cardioprotection in chronic heart failure (CHF) by downregulating inflammation response. Mitochondrial injuries play an important role in ventricular remodeling of the CHF process. Herein, we aim to investigate whether CAP elicitation prevents ventricular remodeling in CHF by protecting myocardial mitochondrial injuries and its underlying mechanisms. METHODS AND RESULTS: CHF models were established by ligation of anterior descending artery for 5 weeks. Postoperative survival rats were assigned into 5 groups: the sham group (sham, n = 10), CHF group (CHF, n = 11), Vag group (CHF+vagotomy, n = 10), PNU group (CHF+PNU-282987 for 4 weeks, n = 11), and Vag+PNU group (CHF+vagotomy+PNU-282987 for 4 weeks, n = 10). The antiventricular remodeling effect of cholinergic elicitation was evaluated in vivo, and H9C2 cells were selected for the TNF-α gradient stimulation experiment in vitro. In vivo, CAP agitated by PNU-282987 alleviated the left ventricular dysfunction and inhibited the energy metabolism remodeling. Further, cholinergic elicitation increased myocardium ATP levels and reduced systemic inflammation. CAP induction alleviates macrophage infiltration and cardiac fibrosis, of which the effect is counteracted by vagotomy. Myocardial mitochondrial injuries were ameliorated by CAP activation, including the reserved ultrastructural integrity, declining ROS overload, reduced myocardial apoptosis, and enhanced mitochondrial fusion. In vitro, TNF-α intervention significantly exacerbated the mitochondrial damage in H9C2 cells. CONCLUSION: CAP elicitation effectively improves ischemic ventricular remodeling by suppressing systemic and cardiac inflammatory response, attenuating cardiac fibrosis and potentially alleviating the mitochondrial dysfunction linked to hyperinflammation reaction.

Association of Obesity Measures with Atrial Fibrillation Recurrence After Cryoablation in Patients with Paroxysmal Atrial Fibrillation.

BACKGROUND Obesity increases the risk of atrial fibrillation (AF) recurrence after ablation. This study explored the relationship between various obesity indexes and risk of recurrence after cryoablation of paroxysmal AF (PAF). MATERIAL AND METHODS Our prospective study included 100 patients with PAF who underwent first cryoablation. Physical examination and fasting blood lipids levels were measured at baseline. Seven obesity indexes were determined: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-hip ratio (WHR), cardiometabolic index (CMI), lipid accumulation product (LAP), and body adiposity index (BAI). AF recurrence was confirmed by electrocardiograms and Holter monitor at follow-up visits after the initial 3-month blanking period. Receiver operating characteristic (ROC) curves were drawn to assess the abilities of obesity indicators in predicting AF recurrence. Multivariable Cox regression analysis was used to examine independent predictors of AF recurrence. RESULTS During a mean follow-up of 13.4 months, 31 patients (31.0%) had recurrent AF. Patients with recurrence had higher BMI, WC, WHtR, LAP, and BAI compared with those without recurrence. ROC analysis indicated the potential predictive value of BAI with an AUC of 0.657 (95% confidence interval [CI]: 0.534-0.779), followed by WC, WHtR, LAP, and BMI (all P<0.05). Diagnosis-to-ablation time (HR 1.034, 95% CI: 1.002-1.068), left atrial diameter (HR 1.147, 95% CI: 1.026-1.281), and WC (HR 1.026, 95% CI: 1.000-1.053) were independent predictive factors for AF recurrence after multivariable adjustment. CONCLUSIONS In this study population, WC appears to be a potential indicator for the prediction of recurrence in patients with PAF after cryoablation.

Tragus Nerve Stimulation Suppresses Post-Infarction Ventricular Arrhythmia by Modulating Autonomic Activity and Heterogeneities of Cardiac Receptor Distribution.

BACKGROUND Imbalanced cardiac autonomic control and cardiac receptors redistribution contribute to the arrhythmogenic substrate under the myocardial infarction (MI) condition. Stimulating the auricular branch of vagus nerve (AB-VNS) has been proven to reduce post-infarction ventricular arrhythmia (VAs), but its potential mechanisms were largely unknown. This study aimed to investigate whether long-term intermittent low-intensity AB-VNS could produce a protective effect on modulating autonomic activities and abnormal redistribution of autonomic nerve efferent receptors in a MI canine model. MATERIAL AND METHODS Twelve healthy beagle dogs underwent ligation of the left anterior descending coronary artery to establish a MI model and were randomized into 2 groups: an AB-VNS group, (AB-VNS for 4 weeks) and a control group (sham stimulation for 4 weeks). Dynamic electrocardiogram recording, neural recording, catecholamine concentration, and histological studies were conducted subsequently. RESULTS Compared to the control group, the AB-VNS group had significantly suppressed post-infarction VAs, reduced low frequency (LF) power and increased high frequency (HF) power. In the AB-VNS group, with the progression of reduced cardiac sympathetic activities and augmented cardiac parasympathetic activities, the catecholamine concentration in heart tissue declined in the peripheral infarction area and right ventricle (RV); tyrosine hydroxylase (TH)-positive neurons decreased in the inferior cardiac sympathetic nerve, and choline acetyltransferase (ChAT)-positive neurons increased in the cervical vagus nerve. Expression of TrkA and P75NGFR were reduced in the peripheral MI (peri-MI) and non-MI area with AB-VNS. The mRNA expression of adrenergic and nicotinic receptors (ß1-AR, ß3-AR, and CHRNA7) significantly declined in the peri-MI and non-MI area of the AB-VNS group. CONCLUSIONS Chronic intermittent low-intensity AB-VNS effectively suppressed post-infarction VAs by potentially rebalancing extracardiac intrathoracic autonomic activities, reducing excessive cardiac sympathetic denervation, and attenuating the heterogeneities of cardiac efferent nerve receptors distribution.

LDL-C/HDL-C is associated with ischaemic stroke in patients with non-valvular atrial fibrillation: a case-control study.

BACKGROUND: This study explored the relationships between the low-/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) and other clinical indicators and ischaemic stroke (IS) in patients with non-valvular atrial fibrillation (NVAF) in Xinjiang. The findings could provide a theoretical and therapeutic basis for NVAF patients. METHODS: NVAF patients who were admitted to 10 medical centres across Xinjiang were divided into stroke (798 patients) and control (2671 patients) groups according to the occurrence of first acute IS. Univariate and multivariate logistic regression analysis were used to examine the independent risk factors for IS in NVAF patients. Factor analysis and principal component regression analysis were used to analyse the main factors influencing IS. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminatory ability of LDL-C/HDL-C for predicting the occurrence of IS. RESULTS: The stroke group had an average age of 71.64 ± 9.96 years and included 305 females (38.22%). The control group had a mean age of 67.30 ± 12.01 years and included 825 females (30.89%). Multivariate logistic regression showed that the risk of IS in the highest LDL-C/HDL-C quartile (≥2.73) was 16.23-fold that of the lowest quartile (< 1.22); IS risk was 2.27-fold higher in obese patients than in normal-weight subjects; IS risk was 3.15-fold higher in smoking patients than in non-smoking patients. The area under the ROC curve of LDL-C/HDL-C was 0.76, the optimal critical value was 2.33, the sensitivity was 63.53%, and the specificity was 76.34%. Principal component regression analysis showed that LDL-C/HDL-C, age, smoking, drinking, LDL-C and hypertension were risk factors for IS in NVAF patients. CONCLUSIONS: LDL-C/HDL-C > 1.22, smoking, BMI ≥24 kg/m2 and CHA2DS2-VASc score were independent risk factors for IS in NVAF patients; LDL-C/HDL-C was the main risk factor.

Neurotoxicity and related mechanisms of flame retardant TCEP exposure in mice.

Objective: To explore the neurotoxicity and mechanism of tris(2-chloroethyl) phosphate (TCEP) exposure in mice.Methods: Total 30 adult Kunming mice were randomly divided into normal control group (0 mg/kg·d), low-dose TCEP group (10 mg/kg·d), and high-dose TCEP group (100 mg/kg·d), and administered continuously by gavage for 30 days.Results: Compared with the control group, the water intake of high-dose TCEP group was declined significantly (p < 0.05), and the organ index of liver and spleen were increased significantly (p < 0.05). In addition, the escape latency of TCEP exposed mice were longer than that in the control group in water maze test (p < 0.05), while the total swimming course of high-dose TCEP group was elevated and the swimming time in target quadrant was obviously shortened compared with the control group (p < 0.05). The serum levels of total-triiodothyronine (TT3) and free triiodothyronine (FT3) were significantly higher in the high-dose TCEP group than in the control group (p＜0.05). Compared with the control group, the activities of glutathione transferase (GST) and super oxide dismutase (SOD) in the high-dose TCEP group were increased, and GST in the low-dose TCEP group were decreased, while the content of malonaldehyde (MDA) in both groups was increased (p＜0.05). In the CCK8 assay, the viability of PC12 cells decreased with an increase of TCEP concentration, indicating a concentration dependent neurotoxicity.Conclusion: TCEP exposure can cause neurotoxicity by increasing thyroid hormones and inducing oxidative damage in mice.

Renal Sympathetic Denervation Improves Outcomes in a Canine Myocardial Infarction Model.

BACKGROUND Myocardial infarction (MI) is the main cause of heart failure (HF), and sympathetic nerve activity is associated with prognosis chronic heart failure. Renal sympathetic denervation (RDN) is noted for its powerful effect on the inhibition of sympathetic nerve activity. This study investigated the effect of RDN on heart failure in dogs after myocardial infarction. MATERIAL AND METHODS The experimental animals were randomized into 2 groups: the MI group (n=12) and the sham operation group (n=6). In the MI group we established an MI model by permanently ligating the left anterior descending branch. After 4 weeks, the MI dogs were randomly divided into 2 groups: the MI+RDN group (MI+renal sympathetic denervation, n=6) and the simple MI group (n=6). Animals in the MI+RDN group underwent both surgical and chemical renal denervation. RESULTS Compared with sham operation group, left ventricular fraction shortening (LVFS) and left ventricular ejection fraction (LVEF) were significantly reduced in the simple MI group, while the reduction was partly reversed in the MI+RDN group. RDN reduced sympathetic nerve activity and release of B-type natriuretic peptide (BNP) and Angiotensin II (AngII) in the MI+ RDN group but not in the simple MI group. CONCLUSIONS Canine renal sympathetic denervation prevents myocardial malignant remodeling by lowering the activity of the systemic sympathetic nerve and inhibiting renin-angiotensin-aldosterone system (RASS) activation, providing a new target and method for the treatment of heart failure.

Screening of differentially expressed microRNAs of essential hypertension in Uyghur population.

BACKGROUND: Essential hypertension can cause many kinds of cardiovascular diseases. The pathogenesis of essential hypertension is very complex, and the mechanism is still unclear. The microRNAs have been identified as novel biomarkers for pre-diagnosis and prognosis of hypertension. However, the kinds of microRNAs that can be used as specific biomarkers for hypertension are unknown. METHODS AND RESULTS: Plasma samples were isolated from Uyghur subjects with essential hypertension and the healthy individuals. Microarray was used to identify differentially expressed microRNAs. The microarray data were clustered and annotated with online software. The target genes of differentially expressed microRNAs were also analyzed. The microarray results were further verified by quantitative real-time PCR. We identified 257 microRNAs that were differentially expressed between patients with essential hypertension and the healthy individuals. These microRNAs had a total of 6580 target genes. The 47 microRNAs that had target genes, including 24 up-regulated and 23 down-regulated microRNAs, were further screened out to construct a reference set of potential microRNA biomarkers. Most of the 47 microRNAs were located at chromosome 19 (40 microRNAs) and chromosome 1 (45 microRNAs). Their target genes were mainly enriched in metal ion binding, transcription regulation, cell adhesion and junction, indicating that these candidate microRNAs may regulate mineral ion binding and cell communication process of essential hypertension. The quantitative real-time PCR results of miR-198 and miR-1183 (which were the two most significantly up-regulated microRNAs by microarray), and, miR-30e-5p and miR-144-3p (which were the two most significantly down-regulated microRNAs by microarray) were consistent with the microarray results. CONCLUSIONS: A reference set of potential microRNA biomarkers that may be involved in essential hypertension is constructed. Our study may provide experimental evidence for further studying the mechanism of essential hypertension.

Epidemiological investigation of sudden cardiac death in multiethnic Xinjiang Uyghur autonomous region in Northwest China.

BACKGROUND: The epidemiological characteristics of sudden cardiac death (SCD) in the autonomous region of Xinjiang Uygur have been largely unknown. This study aimed to evaluate the incidence and demographic risk factors of SCD in Xinjiang, China. METHODS: This retrospective study reviewed medical records from 11 regions in Xinjiang with different geography (north and south of the Tian Shan mountain range), gross domestic product, and ethnicity (Han, Uyghur, Kazakh, and Hui). SCD was defined as unexpected death due to cardiac reasons within 1 hour after the onset of acute symptoms, including sudden death, unexpected death, and nonviolent death. Monitoring was conducted throughout 2015. Demographic and mortality data were recorded and age-adjusted standardized risk ratio (SRR) was analyzed. RESULTS: Among 3,224,103 residents, there were 13,308 all-cause deaths and 1244 events of SCD (784 men and 460 women; overall incidence 38.6 per 100,000 residents). SCD was associated with age (χ2 = 2105.3), but not geography. Men had an increased risk of SCD compared with women (SRR: 1.75, 95% CI: 1.10-2.79). The risk of SCD was highest in residents of the Uyghur (SRR: 1.59, 95% CI: 1.05-2.42) and Kazakh (SRR: 1.92, 95% CI: 1.29-2.87) compared with those of the Han. Poor economic development was associated with elevated risk of SCD (SRR: 1.55, 95% CI: 1.02-2.38). CONCLUSION: SCD is an important public health issue in China. Our understanding of the demographic differences on SCD in Xinjiang, China may improve the risk stratification and management to reduce the incidence and lethality of SCD.

A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-ß precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease ß-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the ß-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.

Clinical Effects of "Selective Drug" Regulating Vagus Nerve Signal Pathway in Vagally-Mediated Atrial Fibrillation.

BACKGROUND The cardiac autonomic nervous system plays a crucial role in genesis and development of atrial fibrillation (AF) through the G protein signal transduction pathway. Therefore, intervening in the G protein signal transduction pathway may be a new "selective drug" method to regulate autonomic nerve activity to prevent vagally-mediated AF. MATERIAL AND METHODS Seventeen adult beagles were randomized into 3 groups: shame-operation control group (group A, n=5), empty vector gene control group (group B, n=6), and Gαi2ctp gene experimental group (group C, n=6). Group A was injected with normal saline into the anterior atrial wall, and group B and group C animals were injected with recombinant adenovirus with empty vector or Gαi2ctp vector in the same region. AF was induced by the method of rapid atrial pacing in groups B and C. To determine the clinical effect of vagal modulation, the effective refractory periods (ERP) and field action potential duration (FAPD) were evaluated by electrophysiological study. The expression levels of tyrosine hydroxylase (TH) and choline acetyl transferase (CHAT) in different parts were determined with immunohistochemistry. RESULTS After successful Gai2ctp gene transfer, in group B, the ERP and FAPD significantly decreased (P<0.05), and TH and CHAT expression observably increased (P<0.05), while those differences were absent between groups A and C (P>0.05). CONCLUSIONS Recombinant adenovirus-mediated overexpression of Gαi2ctp in canine myocardial cells can interfere with the activity of the vagus nerve, reverse the development and progression of electrical remodeling, and reduce the incidence of AF.