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The present study evaluated risk factors related to persistent atrial fibrillation (AF) at discharge (AF-d) and recurrent atrial fibrillation (rAF) and all-cause death after the maze IV procedure. Two hundred nineteen patients (63 female, aged 52.5±8.8 years) with valve disease and persistent AF undergoing valve surgery and the maze IV procedure in our center between 2015 and 2016 were included. Baseline demographic and clinical data were obtained by review of medical records. The median follow-up period was 27 months (interquartile range 21–34 months) in our patient cohort. The primary end point was all-cause death. The secondary end point was AF-d or rAF. rAF is defined as AF recurrence at 3 months or later after the procedure. Twenty-eight patients (12.8%) died during follow-up. Multiple logistic regression analysis showed that thrombocytopenia, elevated serum total bilirubin level, a larger right atrium, AF-d, and rAF were independent determinants for all-cause death after the maze IV procedure after adjustment for age, sex, and clinical covariates, including New York Heart Association class III/IV disease, hypertension, and aortic regurgitation, while valvular disease duration and left atrial diameter greater than 80.5 mm were independent determinants for AF-d, and thrombocytopenia, elevated serum total bilirubin level, higher mean pulmonary artery pressure, and AF-d were independent predictors for rAF. In conclusion, thrombocytopenia, elevated serum total bilirubin level, an enlarged right atrium, AF-d, and rAF are independent predictors of all-cause death in patients undergoing the maze IV procedure.

Background Previous studies have shown that acetylation plays a critical role in regulating the progress of cardiovascular diseases by acetylated histone and non-histones protein. However, the global lysine acetylome during atrial fibrillation (AF) were not fully understood. Purpose The aim of the present study was to identify the underlying mechanisms of AF via profiling of the quantitative changes of global proteomics and lysine acetylome in the left atrial appendage (LAA) tissues from valvular heart disease patients with AF. Methods This study obtained LAA specimens from patients undergoing cardiac surgery for severe valvular heart disease. The LAA specimens were obtained from both 9 patients with AF and with sinus rhythm (SR). The changes of proteome and acetylome in the AF-LAA vs SR-LAA tissues were studied using dimethyl-labeling, HPLC fractionation, affinity enrichment, LC-MS/MS analysis, database Search and bioinformatic analysis. The acetylated levels of each lysine acetylated site were normalized on the basis of the corresponding protein abundance. Results The bioinformatic analysis indicates 294 up-regulated (AF/SR ratio >1.3) proteins and 169 down-regulated (AF/SR ratio Interaction network of Ac-proteins Conclusions This study details and expands our understanding of the changes of proteome and lysine acetylome in the LAA tissues from valvular heart disease patients with AF. The data suggest important expression differences of acetylated proteins related to energy metabolism and cardiac contraction which may be involved in the matrix of AF formation and maintainence. Acknowledgement/Funding This work was supported by the grants from the National Natural Science Foundation of China (no. 81600273, no. 81570310, no.81770337 and no.81870258)

Pulmonary artery-derived ventricular arrhythmia is gradually being recognized, which in a clinical context is recognized as an arterial ectopic beat. Our study aimed to provide new insights on the epidemiological characteristics, origin site, electrocardiogram (ECG) characteristics, intracardiac electrophysiological characteristics and radiofrequency catheter ablation (RFCA) strategies for pulmonary artery-derived ventricular arrhythmia. Patients with a distance between the origin site and the pulmonary valve of >10 mm have what is known as pulmonary trunk-derived ventricular arrhythmia, while patients with a distance between the origin site and the pulmonary valve of ≤10 mm have what is known as pulmonary sinus cusp-derived ventricular arrhythmia. It is very difficult to differentiate pulmonary artery-derived ventricular arrhythmia from right ventricular outflow tract-derived ventricular arrhythmia on ECGs as both share similar anatomical features, but pulmonary artery-derived ventricular arrhythmia shows obvious intracardiac electrophysiological characteristics. Currently, conclusions based on the epidemiological characteristics of pulmonary artery-derived ventricular arrhythmia, relationship between the origin site and the pulmonary valve, electrophysiological characteristics, and RFCA strategies are controversial and still need further study.

Context: Axillary vein puncture is an alternative method for pacemaker leads implantation. However, the safety and effectiveness of axillary vein puncture become an issue for debate now. Aims: The aim of this study was to investigate the safety, feasibility, and efficacy of a modified axillary vein technique for pacemaker implantation. Settings and Design: This modified axillary vein technique refers to a novel axillary vein puncture method combined with caudal 35° fluoroscopy and surface anatomic landmarks including deltopectoral groove, coracoid process, and the first rib. Subjects and Methods: This technique was applied to 139 consecutive patients referred for pacemaker implantation between March 1, 2016, and December 31, 2016, at our department. Statistical Analysis Used: None. Results: Success rate of pacemaker implantation was 96.4% (134/139). Five patients (3.60%) were switched to an alternate approach for leads implantation. There were no procedure-related complications such as pneumothorax, hemopneumothorax, major bleeding, and significant pocket hematoma. Conclusion: This modified axillary vein puncture strategy combining caudal 35° fluoroscopy and surface anatomic landmarks is safe and feasible for pacemaker implantation.

The objective of this study is to characterize the relationship between forkhead box C2 protein (Foxc2) and leptin under adipose inflammatory response.Lipopolysaccharide (LPS)-induced inflammatory model was conducted. Data from wild-type and ob/ob mice were used to compare the alternative role of leptin on Foxc2-mediated inflammation and browning. Transcriptional regulation and protein-protein interaction were analyzed by bioinformatics and proved by chromatin immunoprecipitation and co-immunoprecipitation experiment.Foxc2 and leptin correlated with inflammation and browning of white adipose tissue (WAT) in LPS-treated mice. Moreover, Foxc2-mediated inhibition of inflammation involved downstream activation of leptin signal and promoted WAT browning. We then determined CREB, the potential transcriptional factor of leptin, was required for Foxc2-mediated inflammation in the regulation of WAT browning. Foxc2 alleviated adipocyte inflammation by reducing leptin-mediated Janus-activated kinase 2/signal transducer and activator of transcription 3 (STAT3) pathway. Importantly, STAT3 physically interacted with PRDM16 and formed a complex to promote WAT browning. Exogenous Foxc2 overexpression also ameliorated inflammation and promoted adipose browning in high fat diet (HFD)-induced obese mice.Our results indicated that Foxc2 inhibited inflammation and promoted browning of WAT through positive regulation of leptin signal and the STAT3-PRDM16 complex. These findings identify a new potential means to prevent and treat obese caused metabolic syndrome of mammals.

Background Real-time radiofrequency (RF) ablation lesion assessment is a major unmet need in cardiac electrophysiology. Objective The purpose of this study was to assess whether improved temperature measurement using a novel thermocoupling (TC) technology combined with information derived from impedance change, contact force (CF) sensing, and catheter orientation allows accurate real-time prediction of ablation lesion formation. Methods RF ablation lesions were delivered in the ventricles of 15 swine using a novel externally irrigated-tip catheter containing 6 miniature TC sensors in addition to force sensing technology. Ablation duration, power, irrigation rate, impedance drop, CF, and temperature from each sensor were recorded. The catheter "orientation factor" was calculated using measurements from the different TC sensors. Information derived from all the sources was included in a mathematical model developed to predict lesion depth and validated against histologic measurements. Results A total of 143 ablation lesions were delivered to the left ventricle (n = 74) and right ventricle (n = 69). Mean CF applied during the ablations was 14.34 ± 3.55g, and mean impedance drop achieved during the ablations was 17.5 ± 6.41 Ω. Mean difference between predicted and measured ablation lesion depth was 0.72 ± 0.56 mm. In the majority of lesions (91.6%), the difference between estimated and measured depth was ≤1.5 mm. Conclusion Accurate real-time prediction of RF lesion depth is feasible using a novel ablation catheter-based system in conjunction with a mathematical prediction model, combining elaborate temperature measurements with information derived from catheter orientation, CF sensing, impedance change, and additional ablation parameters.

Alpha-melanocyte stimulating hormone (αMSH) has an important role in the regulation of body weight and energy expenditure. Nevertheless, the molecular mechanisms of circulating αMSH on preadipocyte proliferation remain elusive. We found αMSH was reduced by high fat diet (HFD) while leptin was elevated in adipose tissue. Leptin resistance and endoplasmic reticulum (ER) stress of adipose tissue were increased in obese mice. αMSH increased leptin sensitivity and alleviated ER stress along with increased p-STAT3 level and reduced SOCS3, GRP78, CHOP, ATF4, p27 and p53 levels. αMSH and leptin co-treatment alleviated ER stress through decreasing the levels of GRP78 and CHOP. Tunicamycin (TM) or thapsigargin (Tg) induced ER stress blunted leptin sensitivity and inhibited preadipocyte proliferation. αMSH and leptin co-treatment increased the cell number, augmented G1-S transition, elevated leptin sensitivity, and reduced ER stress; it also activated Notch1 signal and stimulated preadipocyte proliferation, whereas ER stress marker genes were decreased during this process. However, the effects of αMSH and leptin were blocked by the specific inhibitor of Notch1 signal. In summary, our data revealed αMSH enhanced leptin sensitivity and preadipocyte proliferation, meanwhile inhibited ER stress of preadipocytes by activating Notch1 signal.

Leptin is an adipocyte-derived hormone and maintains adipose function under challenged conditions. Autophagy is also essential to maintain cellular homeostasis and regulate characteristics of adipose tissue. However, the effects of leptin on autophagy of adipocyte remain elusive. Here, we demonstrated endoplasmic reticulum (ER) stress and leptin were correlated with autophagy and inflammation by transcriptome sequencing of adipose tissue. Leptin-mediated inhibition of autophagy was involved in upstream reduction of ER stress proteins such as Chop, GRP78, and Atf4, since blockage of autophagy using pharmacological approach had no effect on tunicamycin-induced ER stress. Moreover, we determined KLF4, the potential transcriptional factor of Atf4, was required for the leptin-mediated autophagy in the regulation of adipocyte inflammation. Importantly, ATF4 physically interacted with ATG5 and subsequently formed a complex to promote adipocyte autophagy. Further analysis revealed that Atg5, a core component of autophagosome, was the target for leptin-mediate autophagy. In addition, leptin alleviated ER stress-induced inflammation by reducing autophagy-mediated degradation of IκB in adipocytes. Exogenous leptin treatment also ameliorated autophagy and inflammation of white adipose tissue in ob/ob mice. Taken together, our results indicated that leptin inhibited ER stress-mediated autophagy and inflammation through the negatively regulation of Atf4/Atg5 complex in adipocytes. These findings identify a new potential means for intervention of autophagy to prevent or treat obese caused metabolic syndrome of mammals.

// Qingda Meng 1 , Davide Valentini 2 , Martin Rao 1 , Zhenjiang Liu 1 , Shanshan Xie 1 , Ann Morgell 3 , Ernest Dodoo 1 , Matthias Lohr 3 , Elena Rangelova 3 , Marco del Chiaro 3 , Ingemar Ernberg 4 and Markus Maeurer 1, 2 1 Division of Therapeutic Immunology (TIM), Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden 2 Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden 3 Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden 4 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Correspondence to: Markus Maeurer, email: markus.maeurer@gmail.com Keywords: pancreatic cancer; mesothelin; interferon gamma; survival; antigen-specific response Received: February 27, 2017 Accepted: June 19, 2017 Published: April 27, 2018 ABSTRACT Most patients with pancreatic cancer present with extensive metastasis at diagnosis, with a 5-year survival rate of approximately 5%, despite chemotherapy and surgery. New treatment modalities are needed to improve survival. Mesothelin is a tumor-associated antigen (TAA) in patients with pancreatic cancer that could be used to gauge cellular immune responses directed against transformed cells since up to 100 percent of pancreatic ductal adenocarcinoma cells have been shown to strongly express mesothelin. A prospective, observational study was carried out in twenty-six, chemotherapy-naive patients with resectable pancreatic ductal adenocarcinoma. Participants were between 48 and 81 years (median age: 64.5 years), 15 males and 11 females. All participants were clinically followed-up between 439 and 853 days post-surgery (n=14) or until death (n=12). Peripheral blood drawn on the day of surgery was stimulated with a mesothelin peptide pool (42 peptides, non-overlapping), individual mesothelin peptides, positive (anti-CD3 antibody, OKT3) and negative controls (medium) with or without adding IL-21. Kaplan-Meier estimators were used to gauge patients’ survival pattern in relation to mesothelin-specific IFN-γ responses. A survival benefit was linked with IFN-γ responses to peptides corresponding to mature mesothelin (p=0.018) and targeted recognition of the mesothelin 601-615 epitope (MQEALSGTPCLLGPG) (p=0.006) in the presence of IL-21. Conversely, production of high levels of IFN-γ to OKT3 stimulation with IL-21 conditioning was associated with reduced survival of patients (p=0.016). Gauging anti-Mesothelin- directed immune responses will aid to identify patients i) in need of a more intensive clinical follow-up and ii) who may benefit from immunotherapeutic approaches targeting mesothelin.

Background The origin of pulmonary sinus cusp (PSC)-derived ventricular arrhythmia (VA) is a highly specialized anatomical structure; therefore, insertion of the radiofrequency ablation catheter tip to the target site to ensure safe ablation is a major challenge for clinicians. Purpose To summarize ablation methods, and provide valuable experience for the treatment of pulmonary sinus cusp-derived VA with ablation. Methods A retrospective analysis and summary of the clinical data of 15 patients undergoing catheter ablation for pulmonary sinus cusp-derived VA in Cardiac Intervention Therapy Center, The Second Xiangya Hospital of Central South University between January 2013 and July 2015 was conducted. Results For the 15 patients, the pulmonary sinus cusp-derived VA originated from the lower regions of the pulmonary sinuses, leading from the right, left and anterior sinuses of the pulmonary sinus cusp in 4, 6 and 5 patients, respectively. Nine patients with pulmonary sinus cusp-derived VAs originating from the right and anterior sinuses underwent successful reversed U-curve catheter ablation, while the other 6 cases with arrhythmias originating from the left sinus underwent successful ablation with the conventional method (non-reversed U-curve catheter ablation). All the patients were followed-up for 6–31 months, and no cases of recurrence or complications occurred. Conclusions Reversed U-curve catheter ablation is suitable for VAs originating from the right and anterior pulmonary sinus cusps, while conventional ablation can also be used for those originating from the left PSCs. This article is protected by copyright. All rights reserved

Background The modification of cardiac energy metabolism during atrial fibrillation (AF) has been demonstrated in previous studies, indicating a close association between these 2 processes. The aim of the present study was to identify the underlying mechanisms via profiling of the expression of energy metabolism-related proteins in the left atrial appendage (LAA) of patients with AF. Methods and results Isobaric tag for relative and absolute quantification-coupled 2-D liquid chromatography-tandem mass spectrometry (iTRAQ-coupled 2-D LC-MS/MS) was used to profile the expression of energy metabolism-related proteins in the LAA from valvular disease patients with sinus rhythm (SR; n=6) and AF (n=8). Using ProteinPilot 4.0, 122 energy metabolism-related proteins, consisting of 39 carbohydrate metabolism-related proteins, 22 proteins involved in lipid metabolism, 49 biological oxidation-related proteins and 12 other kinds of proteins, were identified. Most of them were key enzymes involved in energy metabolism. Moreover, most of the proteins that were expressed differently in the LAA between the AF and SR patients, and which were related to energy metabolism, were downregulated. These results were further validated on western blot. Conclusions Atrial myocardium energy production in valvular disease patients is impaired during permanent AF, and this impairment in energy production may be involved in the matrix of AF formation.

We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI

Alpha melanocyte stimulating hormone (α-MSH) and Forkhead box C2 protein (Foxc2) enhance lipolysis in multiple tissues. However, their relationship in adipose fatty acid oxidation (FAO) remains unclear. Here, we demonstrated that α-MSH and Foxc2 increased palmitate oxidation to CO2 in white (WAT) and brown adipose tissue (BAT). C/EBPβ expression was reduced by α-MSH and Foxc2. FFA level was elevated by α-MSH and pc-Foxc2 treatment along with increased FAO in white and brown adipocytes. The expression of FAO key enzymes, medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were increased in α-MSH and pc-Foxc2 group. Combination of α-MSH and Foxc2 treatment synergistically promoted FAO through increasing the activity of CPT-1 and phosphorylation of ACC. We found C/EBPβ bind to MC5R and Foxc2 promoter regions and inhibited FAO. cAMP level was increased by α-MSH and Foxc2 individually treated or combined treatment. Furthermore, cAMP/PKA pathway-specific inhibitor (H89) blocked the FAO, despite in α-MSH and Foxc2 both added group. While forskolin, the cAMP agonist, promoted FAO and enhanced the effect of α-MSH and Foxc2. Collectively, α-MSH and Foxc2 mutual promote FAO in WAT and BAT via cAMP/PKA signal pathway. And C/EBPβ as a transcription suppressor inhibits α-MSH and Foxc2 expression and FAO.

Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin.

Rationale: This study aimed to describe the case of a 3-year-old girl with old bilateral facet dislocation on cervical vertebrae 6 and 7, who had spinal cord transection, received surgical treatment, and achieved a relative satisfactory therapeutic effect. Patient concerns: A 3-year-old girl was urgently transferred to the hospital after a car accident. Diagnoses: she was diagnosed with splenic rupture, intracranial hemorrhage, cervical dislocation, spinal transection, and Monteggia fracture of the left upper limb. Interventions: The girl underwent emergency splenectomy and was transferred to the intensive care unit of the hospital 15 days later. One-stage anterior–posterior approach surgery (anterior discectomy, posterior laminectomy, and pedicle screw fixation) was performed when the patient stabilized after 45-day symptomatic treatment. The operation was uneventful. Outcomes: The reduction of lower cervical dislocation was satisfactory, with sufficient spinal cord decompression. The internal fixation position was good, and the spinal sequence was well restored. The girl was discharged 2 weeks later after the operation and followed up for 2 years. The major nerve function of both upper limbs was recovered, with no obvious retardation of the growth of immature spine. Lessons: A satisfactory therapeutic effect was achieved for a pediatric old subaxial cervical dislocation with bilateral locked facets using anterior discectomy, posterior laminectomy, and pedicle screw fixation. The posterior pedicle screw fixation provided a good three-dimensional stability of the spine, with reduced risk and complications caused by anterior internal fixation. The growth of immature spine was not obviously affected during the 2-year follow-up.

Obesity is associated with macrophage infiltration and metabolic inflammation, both of which promote metabolic disease progression. Melatonin is reported to possess anti-inflammatory properties by inhibiting inflammatory response of adipocytes and macrophages activation. However, the effects of melatonin on the communication between adipocytes and macrophages during adipose inflammation remain elusive. Here, we demonstrated melatonin alleviated inflammation and elevated α-ketoglutarate (αKG) level in adipose tissue of obese mice. Mitochondrial isocitrate dehydrogenase 2 (Idh2) mRNA level was also elevated by melatonin in adipocytes leading to increase αKG level. Further analysis revealed αKG was the target for melatonin inhibition of adipose inflammation. Moreover, sirtuin 1 (Sirt1) physically interacted with IDH2 and formed a complex to increase the circadian amplitude of Idh2 and αKG content in melatonin-inhibited adipose inflammation. Notably, melatonin promoted exosomes secretion from adipocyte and increased adipose-derived exosomal αKG level. Our results also confirmed that melatonin alleviated adipocyte inflammation and increased ratio of M2 to M1 macrophages by transporting of exosomal αKG to macrophages and promoting TET-mediated DNA demethylation. Furthermore, exosomal αKG attenuated signal transducers and activators of transduction-3 (STAT3)/NF-κB signal by its receptor oxoglutarate receptor 1 (OXGR1) in adipocytes. Melatonin also attenuated adipose inflammation and deceased macrophage number in chronic jet-lag mice. In summary, our results demonstrate melatonin alleviates metabolic inflammation by increasing cellular and exosomal αKG level in adipose tissue. Our data reveal a novel function of melatonin on adipocytes and macrophages communication, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory disease.

To explore the impact of different left ventricular (LV) lead pacing sites on clinical outcome of cardiac resynchronization therapy (CRT) or the device with defibrillator (CRT-D). The location of the LV lead was assessed by means of coronary venograms in right and left anterior oblique views which

Fatty acid binding protein 4 (FABP4), plays key role in fatty acid transportation and oxidation and increases with leptin synergistically during adipose inflammation process. However, the regulation mechanism between FABP4 and leptin on mitochondrial fatty acid oxidation remains unclear. In this study, we found that FABP4 reduced the expression of leptin, CPT-1 and AOX1 in mice adipocytes. Conversely, FABP4 was down-regulated in a time-dependent manner by leptin treatment. Additionally, forced expression of FABP4 attenuated the expression of PGC1-α, UCP2, CPT-1, AOX1 and COX2 compared with leptin incubation. Moreover, mitochondrial membrane potential, fatty acid oxidation enzyme medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD) and Cyt C levels were reduced in response to the overexpression of FABP4. These reductions correspond well with the reduced release of free fatty acid and the inactivation of mitochondrial complexes I and III by FABP4 overexpression. Furthermore, addition of the Akt/mTOR pathway-specific inhibitor (MK2206) blocked the mitochondrial fatty acid oxidation and respiration factors, whereas interference of FABP4 overcame these effects. Taken together, FABP4 could reverse the activation of the leptin-induced mitochondrial fatty acid oxidation and the inhibition of Akt/mTOR signal pathway played a key role in this process.

Pyroptosis is a proinflammatory form of cell death that is associated with pathogenesis of many chronic inflammatory diseases. Melatonin is substantially reported to possess anti-inflammatory properties by inhibiting inflammasome activation. However, the effects of melatonin on inflammasome-induced pyroptosis in adipocytes remain elusive. Here, we demonstrated that melatonin alleviated lipopolysaccharides (LPS)-induced inflammation and NLRP3 inflammasome formation in mice adipose tissue. The NLRP3 inflammasome-mediated pyroptosis was also inhibited by melatonin in adipocytes. Further analysis revealed that gasdermin D (GSDMD), the key executioner of pyroptosis, was the target for melatonin inhibition of adipocyte pyroptosis. Importantly, we determined that nuclear factor κB (NF-κB) signal was required for the GSDMD-mediated pyroptosis in adipocytes. We also confirmed that melatonin alleviated adipocyte pyroptosis by transcriptional suppression of GSDMD. Moreover, GSDMD physically interacted with interferon regulatory factor 7 (IRF7) and subsequently formed a complex to promote adipocyte pyroptosis. Melatonin also attenuated NLRP3 inflammasome activation and pyroptosis, which was induced by LPS or obesity. In summary, our results demonstrate that melatonin alleviates inflammasome-induced pyroptosis by blocking NF-κB/GSDMD signal in mice adipose tissue. Our data reveal a novel function of melatonin on adipocyte pyroptosis, suggesting a new potential therapy for melatonin to prevent and treat obesity caused systemic inflammatory response.

We read with great interest the paper by Di Biase et al. [(1)][1]. These investigators suggested that the recurrence of atrial fibrillation (AF) was significantly reduced by combined pulmonary vein and left atrial appendage (LAA) isolation (LAAI) for the treatment of persistent and long-standing

Melatonin is synthesized in the pineal gland and controls circadian rhythm of peripheral adipose tissue, resulting in changes in body weight. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms of circadian rhythm-mediated proliferation in adipose tissue is still limited. Here, we showed that melatonin (20 mg/kg/d) promoted circadian and proliferation processes in white adipose tissue. The circadian amplitudes of brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1, P

Renal-artery stenosis, a common disease among persons older than 65 years,may result in hypertension, ischemic nephropathy, and multiple long-term complications [1]. Early studies [2] suggested that renal-artery angioplasty or stentingmay result in significant reductions in systolic blood pressure. However, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial [3] recently presented a definitive test of the usefulness of renal-artery stents for moderately severe renalartery stenosis and made a conclusion that renal-artery stenting is no better than medical therapy alone in preventing clinical events. It seems that stenting for renal-artery stenosis after years of its clinical use hits a blind alley. However, pathophysiological changes after stenting include not only improvement in the diameter of the stenotic renal artery but also the tissues of and around the artery, particularly the sympathetic nerve fibers which lie in the adventitia of the renal artery (Fig.1). A recent research [4] demonstrated that balloon angioplasty can reduce the number of sympathetic nerve fibers of the renal artery. So this may be more than just a theoretical consideration. Renal-artery stenosis is characterized not onlybyactivationof the renin–angiotensin system, but also byheightened sympathetic drive [5] which contributes to the pathophysiology of numerous chronic cardiovascular diseases such as essential hypertension, heart failure, chronic kidney disease, diabetes and so on. Nowadays percutaneous catheter-based renal denervation (RDN) is emerging as a new, effective and safe approach to achieve sustained blood pressure reduction in patients with resistant hypertension which can decrease sympathetic activity by interrupting the afferent and efferent renal sympathetic nervous fibers located in the adventitia of the renal arteries by delivery of radiofrequency energy. Herein, we hypothesize that RDN on patients with prior renal stents may enhance the damages of renal sympathetic nervous fibers and reduce the sympathetic activities to a much lower level. However, renal-artery stenosis and prior renal stents are considered a contraindication in routine clinical practice of RDN due to technological unavailability and a worry of deterioration of stenosis. Nevertheless, one case report [6] explored and demonstrated the feasibility and potential effectiveness of the combination of RDN and renal stenting. What's more, a recent small animal study [7] proved that vascular brachytherapy which has been approved for the treatment of in-stent restenosis can also cause renal sympathetic nerve fibrosis while avoiding significant damage to the renal artery. All theseexplorationsmaybreak new ground of therapy with renal-artery stenosis.

Adiponectin is a cytokine produced predominantly by adipose tissue and correlates with glucose and lipid homeostasis. However, the effects of adiponectin on endoplasmic reticulum (ER) stress and apoptosis of adipose tissue remain elusive. In this study, we found that tunicamycin-induced ER stress increased serum free fatty acid (FFA) and impaired glucose tolerance, elevated the mRNA levels of GRP78, Chop, ATF2 and caspase 3, but reduced adiponectin mRNA level in white adipose tissue. Moreover, ER stress-triggered adipocyte apoptosis by increasing cellular FFA level and Ca2+ level. Further analysis revealed that adiponectin alleviated ER stress-induced adipocyte apoptosis by elevating peroxisome proliferator-activated receptor alpha (PPARα) mRNA level. Our data also confirmed that adiponectin reduced early apoptotic cells and blocked the mitochondrial apoptosis pathway by activating the AdipoR1/AMP-activated protein kinase (AMPK) signal pathway. In addition, PPARα bound to ATF2 promoter region and inhibited transcription of ATF2. The inhibition of adipocyte apoptosis by adiponectin was correlated with transcriptional suppression of ATF2. Furthermore, adiponectin inhibited ER stress-induced apoptosis by activating the AMPK/PKC pathway. In summary, our data demonstrate adiponectin inhibited ER stress and apoptosis of adipocyte in vivo and in vitro by activating the AMPK/PPARα/ATF2 pathway. Our study establishes that adiponectin is an important adipocytokine for preventing and treating obesity.

Defibrillation threshold (DFT) testing has traditionally been a routine part of implantable cardioverter-defibrillator (ICD) implantation. DFT testing was developed in the early days of the ICD when failure of defibrillation was common, recipients had a high-risk of ventricular tachycardia (VT) or ventricular fibrillation (VF), and the only therapy for rapid VT or VF was a shock. However, modern ICD systems have such a high rate of successful defibrillation that many electrophysiologists now question whether DFT testing is still worthwhile. Studies found that long-term mortality was not higher among patients not undergoing DFT testing. Moreover, there was no survival difference between patients with a lower DFT and a higher DFT. Other studies have demonstrated that DFT testing poses some risk to the patient such as myocardial damage, embolic stroke in patient with atrial fibrillation and DFT testing-related death. If DFT testing is abandoned, more patients may have the opportunity to be treated with ICD, especially in regions with few or no electrophysiologists. It may be argued that other physicians, such as those currently implanting pacemakers, would more readily implant ICDs if not for the requirement of DFT testing.

Radiofrequency (RF) catheter ablation of left-sided accessory pathways is really a great challenge in patients with prosthetic heart valves so that it is in general delayed or even avoided in such patients due to concerns of the higher perceived risks of mechanical complications and difficulty of

Neural tube defects (NTDs) are common birth defects, whose specific biomarkers are needed. The purpose of this pilot study is to determine whether protein profiling in NTD-mothers differ from normal controls using SELDI-TOF-MS. ProteinChip Biomarker System was used to evaluate 82 maternal serum samples, 78 urine samples and 76 amniotic fluid samples. The validity of classification tree was then challenged with a blind test set including another 20 NTD-mothers and 18 controls in serum samples, and another 19 NTD-mothers and 17 controls in urine samples, and another 20 NTD-mothers and 17 controls in amniotic fluid samples. Eight proteins detected in serum samples were up-regulated and four proteins were down-regulated in the NTD group. Four proteins detected in urine samples were up-regulated and one protein was down-regulated in the NTD group. Six proteins detected in amniotic fluid samples were up-regulated and one protein was down-regulated in the NTD group. The classification tree for serum samples separated NTDs from healthy individuals, achieving a sensitivity of 91% and a specificity of 97% in the training set, and achieving a sensitivity of 90% and a specificity of 97% and a positive predictive value of 95% in the test set. The classification tree for urine samples separated NTDs from controls, achieving a sensitivity of 95% and a specificity of 94% in the training set, and achieving a sensitivity of 89% and a specificity of 82% and a positive predictive value of 85% in the test set. The classification tree for amniotic fluid samples separated NTDs from controls, achieving a sensitivity of 93% and a specificity of 89% in the training set, and achieving a sensitivity of 90% and a specificity of 88% and a positive predictive value of 90% in the test set. These suggest that SELDI-TOF-MS is an additional method for NTDs pregnancies detection.