Zbtb16 increases susceptibility of atrial fibrillation in type 2 diabetic mice via Txnip-Trx2 signaling.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia, and recent epidemiological studies suggested type 2 diabetes mellitus (T2DM) is an independent risk factor for the development of AF. Zinc finger and BTB (broad-complex, tram-track and bric-a-brac) domain containing 16 (Zbtb16) serve as transcriptional factors to regulate many biological processes. However, the potential effects of Zbtb16 in AF under T2DM condition remain unclear. Here, we reported that db/db mice displayed higher AF vulnerability and Zbtb16 was identified as the most significantly enriched gene by RNA sequencing (RNA-seq) analysis in atrium. In addition, thioredoxin interacting protein (Txnip) was distinguished as the key downstream gene of Zbtb16 by Cleavage Under Targets and Tagmentation (CUT&Tag) assay. Mechanistically, increased Txnip combined with thioredoxin 2 (Trx2) in mitochondrion induced excess reactive oxygen species (ROS) release, calcium/calmodulin-dependent protein kinase II (CaMKII) overactivation, and spontaneous Ca2+ waves (SCWs) occurrence, which could be inhibited through atrial-specific knockdown (KD) of Zbtb16 or Txnip by adeno-associated virus 9 (AAV9) or Mito-TEMPO treatment. High glucose (HG)-treated HL-1 cells were used to mimic the setting of diabetic in vitro. Zbtb16-Txnip-Trx2 signaling-induced excess ROS release and CaMKII activation were also verified in HL-1 cells under HG condition. Furthermore, atrial-specific Zbtb16 or Txnip-KD reduced incidence and duration of AF in db/db mice. Altogether, we demonstrated that interrupting Zbtb16-Txnip-Trx2 signaling in atrium could decrease AF susceptibility via reducing ROS release and CaMKII activation in the setting of T2DM.

A Nanounit Strategy Disrupts Energy Metabolism and Alleviates Immunosuppression for Cancer Therapy.

Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.

Heparin-Induced Thrombocytopenia Caused by Preventive Anticoagulation After Femoral Intertrochanteric Fracture Surgery: a Case Report.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe complication caused by heparin. It is characterized by occult onset and missed diagnosis. Misdiagnosis easily occurs. METHODS: This paper reported an 85-year-old woman with an intertrochanteric fracture of the femur which was treated with low molecular weight heparin (LMWH) and fondaparinux sodium to prevent venous thrombosis. Then, the patient developed HIT. This is the first case report of HIT induced by LMWH and fondaparinux in a patient with a hip fracture. This case highlights the severity of HIT in elderly patients with hip fractures using LMWH and fondaparinux and the need for platelet monitoring in these patients. RESULTS: LMWH was ceased in this HIT-confirmed patient, and non-heparin treatment was begun instead. Apixaban was given twice daily for therapeutic anticoagulation therapy. In the end, the platelet levels gradually returned to normal. CONCLUSIONS: We should pay more attention to HIT and platelets during the perioperative period of orthopedic surgery, especially in elderly patients. Once the disease is confirmed, it is necessary to stop heparin-related drugs immediately and administer oral anticoagulants instead.

The novel BRDT inhibitor NHWD870 shows potential as a male contraceptive in mice.

Small molecule inhibitors of the bromodomain and extraterminal domain (BET) family proteins have emerged as promising options not only for the treatment of multiple cancers but also for disturbing the process of sperm maturation with potential for use as viable contraceptive targets. In this study, we find that the BET family inhibitor NHWD870 and BRDT can bind well in vitro through bioinformatics software prediction and protein binding inhibition experiments. NHWD870 can produce a good contraceptive effect through animal experiments in vivo, and the fertility can be restored to normal after drug withdrawal. Transcriptomics and proteomics results suggest that NHWD870 affects pathways related to spermatogenesis and maturation, further contributing to the male infertility phenotype. Our results show that NHWD870 can induce a complete and reversible contraceptive effect in mice, which is stronger than that of JQ1 and its synthesized derivatives. This study is expected to eventually lead to clinical trials.

pH-Sensitive Polymeric Vesicles for GOx/BSO Delivery and Synergetic Starvation-Ferroptosis Therapy of Tumor.

Typical glucose oxidase (GOx)-based starvation therapy is a promising strategy for tumor treatment; however, it is still difficult to achieve an effective therapeutic effect via a single starvation therapy. Herein, we designed a pH-sensitive polymeric vesicle (PV) self-assembled by histamine-modified chondroitin sulfate (CS-his) for codelivery of GOx and l-buthionine sulfoximine (BSO). GOx can consume glucose to induce the starvation therapy after the PVs reach cancer cell. Moreover, the product H2O2 will be reduced by a high concentration of glutathione (GSH) in the tumor cell, resulting in a reduction of the GSH content. The released BSO finally further reduced the GSH level. As a result, the signaling pathway of the ferroptosis will be activated. The in vivo results demonstrated that GOx/BSO@CS PVs exhibit a good inhibitory effect on the growth of 4T1 tumors in mice. Thus, this work provides a facile strategy to prepare pH-sensitive nanomedicine for synergistic starvation-ferroptosis therapy of tumor.

Culture-negative versus culture-positive in pyogenic spondylitis and analysis of risk factors for relapse.

OBJECTIVES: This study aims to compare and analyze the clinical features, diagnosis, treatment and prognosis of culture-negative and culture-positive primary pyogenic spondylitis. METHODS: In a retrospective analysis, 202 cases of adult primary pyogenic spondylitis with complete clinical data in our hospital from January 2013 to January 2020 were divided into two groups according to bacterial culture results: culture negative (n = 126) and culture positive (n = 76). We compare the clinical characteristics, diagnosis, treatment and prognosis of patients with different culture results. RESULTS: The culture positive rate was 37.62% (76/202). There were no significant differences in age, gender, affected segment, spinal abscess, diabetes mellitus, course of disease, surgery, recurrence, and follow-up time between the two groups (p>.05). There were statistically significant differences in hospital admission erythrocyte sedimentation rate (ESR), admission C-reactive protein (CRP), admission white blood cell (WBC) count, discharge ESR, discharge CRP, ESR decline rate, CRP (p<.05). There were statistically significant differences in the rate of decline, hospitalization days, and body temperature ≥38 °C (p<.05). Higher CRP levels on admission, antibiotic treatment time <6 weeks, and body temperature ≥ 38 °C are independent risk factors for infection recurrence. CONCLUSIONS: The culture-negative group's admission WBC, admission ESR, admission CRP, discharge ESR, discharge CRP, ESR decline rate, CRP decline rate, and hospital stay were lower than the culture positive group, the difference was statistically significant (p<.05). The independent risk factors for infection recurrence are higher CRP levels in hospital admission, antibiotic treatment time <6 weeks, and body temperature ≥ 38 °C.

Discharge-Induced Enhancement of the Oxygen Evolution Reaction.

The fundamental understanding of the surface reconstruction induced by the applied potential is of great significance for enhancing the oxygen evolution reaction (OER). Here, we show that a previously overlooked discharge current in the low applied potential region also leads to in situ electrochemical activation of a nitrogen-doped nickel oxyhydroxide surface. We exploit the fact that doping of heteroatoms weakens the surface structure, and hence, a weak discharge current originating from the capacitive nature of nickel oxyhydroxide has a strong structure-reforming ability to promote the formation of nitrogen and oxygen vacancies. The current density at 1.4 V (vs. Hg/HgO) can dramatically increase by as much as 31.3 % after discharge in the low applied potential region. This work provides insight into in situ enhancement of the OER and suggests that the low applied potential region must be a primary consideration in evaluating the origin of the activity of electrocatalysts.

A Time-Programmed Release of Dual Drugs from an Implantable Trilayer Structured Fiber Device for Synergistic Treatment of Breast Cancer.

Combination chemotherapy with time-programmed administration of multiple drugs is a promising method for cancer treatment. However, realizing time-programmed release of combined drugs from a single carrier is still a great challenge in enhanced cancer therapy. Here, an implantable trilayer structured fiber device is developed to achieve time-programmed release of combined drugs for synergistic treatment of breast cancer. The fiber device is prepared by a modified microfluidic-electrospinning technique. The glycerol solution containing chemotherapy agent doxorubicin (Dox) forms the internal periodic cavities of the fiber, and poly(l-lactic acid) and poly(ε-caprolactone) containing the angiogenesis inhibitor apatinib (Apa) form the double walls of the fiber. Rapid release of Dox can be obtained by adjusting the wall thickness of the cavities, meanwhile sustained release of Apa is achieved through the slow degradation of the fiber matrix. After the fiber device is implanted subcutaneously near to the implanted solid tumor of mice, an excellent synergistic therapeutic effect is achieved through time-programmed release of the combined dual drugs. The fiber device provides a platform to sequentially co-deliver dual or multiple drugs for enhanced combined therapeutic efficacy.

Aspergillus spondylitis: case series and literature review.

BACKGROUND: Spinal fungal infections, especially spinal Aspergillus infections, are rare in the clinic. Here, we introduce the clinical features, diagnosis, treatment, and prognoses of 6 cases of Aspergillus spondylitis. METHODS: We retrospectively analysed the complete clinical data of patients with Aspergillus spondylitis treated in our hospital from January 2013 to January 2020. RESULTS: Aspergillus fumigatus was isolated in 4 cases, and Aspergillus spp. and Aspergillus niger were isolated in 1 case each. All six patients reported varying degrees of focal spinal pain; one patient reported radiating pain, one patient experienced bowel dysfunction and numbness in both lower limbs, and three patients had fever symptoms. One case involved the thoracic spine, one case involved the thoracolumbar junction, and 4 cases involved the lumbar spine. Three patients were already in an immunosuppressed state, and three patients entered an immunosuppressed state after spinal surgery. All six patients were successfully cured, and five required surgery. Of the 5 patients who underwent surgical treatment, 2 had spinal cord compression symptoms, and 3 had spinal instability. At the end of follow-up, 1 patient reported left back pain and 1 patient reported left limb numbness. CONCLUSION: The clinical manifestations of Aspergillus spondylitis are non-specific, and the diagnosis depends on typical imaging findings and microbiological and histopathological examination results. When there is no spinal instability, spinal nerve compression symptoms, or progressive deterioration, antifungal therapy alone may be considered. If spinal instability, spinal nerve compression, or epidural abscess formation is present, surgery combined with antifungal therapy is recommended.

Efficacy and Safety of Adjunctive Substrate Modification During Pulmonary Vein Isolation for Atrial Fibrillation: A Meta-Analysis.

BACKGROUND: The efficacy and safety of adjuvant substrate modification (SM; either linear ablation [LA] or complex fractionated atrial electrogram [CFAE] ablation) in addition to pulmonary vein isolation (PVI) for the treatment of symptomatic, drug-refractory atrial fibrillation (AF), have still not been clarified and need further assessment. METHOD: We systematically searched the PubMed, MEDLINE, and Cochrane databases for studies comparing PVI with adjunctive SM versus PVI alone for treatment of drug-refractory AF. RESULTS: Twenty-six (26) studies including 3,409 patients (1,975 PVI + SM; 1,434 PVI alone) were included for further analysis. Atrial fibrillation/atrial tachycardia-free survival of patients with PVI + SM was comparable with that of PVI alone (relative risk [RR], 1.06; 95% confidence interval [CI], 0.98-1.14; p = 0.143). In line with this, the primary clinical outcomes were robust, irrespective of additional LA (RR, 1.07; 95% CI, 0.97-1.18; p = 0.194) or CFAE ablation (RR, 1.04; 95% CI, 0.93-1.16; p = 0.534). Adjuvant SM is associated with longer procedural time (weighted mean difference, 20.72; 95% CI, 10.25-31.20; p = 0.0) and fluoroscopy time (weighted mean difference, 6.66; 95% CI, 1.74-11.58; p = 0.000); surprisingly, it presented similar procedure-related complications as PVI alone during AF catheter ablation (RR, 1.01; 95% CI, 0.68-1.50; p = 0.946). CONCLUSIONS: Adjuvant LA or CFAE ablation do not provide incremental benefit over PVI alone. Although substrate-based ablation markedly prolonged procedural and fluoroscopic duration, there was no evidence of increased risk of procedure-related complications.

A novel mutation KCNQ1p.Thr312del is responsible for long QT syndrome type 1.

Patients with high-risk long QT syndrome (LQTS) mutations may experience life-threatening cardiac events. The present study sought to characterize a novel pathogenic mutation, KCNQ1p.Thr312del, in a Chinese LQT1 family. Clinical and genetic analyses were performed to identify this novel causative gene mutation in this LQTS family. Autosomal dominant inheritance of KCNQ1p.T312del was demonstrated in the three-generation pedigree. All mutation carriers presented with prolonged QT intervals and experienced recurrent syncope during exercise or emotional stress. The functional consequences of the mutant channel were investigated by computer homology modeling as well as whole-cell patch-clamp, western-blot and co-immunoprecipitation techniques using transfected mammalian cells. T312 is in the selectivity filter (SF) of the pore region of the KCNQ1-encoded channel. Homology modeling suggested that secondary structure was altered in the mutant SF compared with the wild-type (WT) SF. There were no significant differences in Kv7.1 expression, membrane trafficking or physical interactions with KCNE1-encoded subunits between the WT and mutant transfected channels. However, the KCNQ1p.T312del channels expressed in transfected cells were non-functional in the absence or presence of auxiliary KCNE1-subunits. Dominant-negative suppression of current density and decelerated activation kinetics were observed in cells expressing KCNQ1WT and KCNQ1p.T312del combined with KCNE1 (KCNQ1WT/p.T312del + KCNE1 channels). Those electrophysiological characteristics underlie the pathogenesis of this novel mutation and also suggest a high risk of cardiac events in patients carrying KCNQ1p.T312del. Although protein kinase A-dependent current increase was preserved, a significant suppression of rate-dependent current facilitation was noted in the KCNQ1WT/p.T312del + KCNE1 channels compared to the WT channels during 1- and 2-Hz stimulation, which was consistent with the patients' phenotype being triggered by exercise. Overall, KCNQ1p.Thr312del induces a loss of function in channel electrophysiology, and it is a high-risk mutation responsible for LQT1.

Catalyzed and Electrocatalyzed Oxidation of l-Tyrosine and l-Phenylalanine to Dopachrome by Nanozymes.

Catalyzed oxygen insertion into C-H bonds represents a continuous challenge in chemistry. Particularly, driving this process at ambient temperature and aqueous media represents a "holy grail" in catalysis. We report on the catalyzed cascade transformations of l-tyrosine or l-phenylalanine to dopachrome in the presence of l-ascorbic acid/H2O2 as oxidizing mixture and CuFe-Prussian Blue-like nanoparticles, Fe3O4 nanoparticles or Au nanoparticles as catalysts. The process involves the primary transformation of l-tyrosine to l-DOPA that is further oxidized to dopachrome. The transformation of l-phenylalanine to dopachrome in the presence of CuFe-Prussian Blue-like nanoparticles and l-ascorbic acid/H2O2 involves in the first step the formation of l-tyrosine and, subsequently, the operation of the catalytic oxidation cascade of l-tyrosine to l-DOPA and dopachrome. Electron spin resonance experiments demonstrate that ascorbate radicals and hydroxyl radicals play cooperative functions in driving the different oxygen-insertion processes. In addition, the aerobic elecrocatalyzed oxidation of l-tyrosine to dopachrome in the presence of naphthoquinone-modified Fe3O4 nanoparticles and l-ascorbic acid is demonstrated. In this system, magnetic-field attraction of the naphthoquinone-modified Fe3O4 nanoparticles onto the electrode allows the quinone-mediated electrocatalyzed reduction of O2 to H2O2 (bias potential -0.5 V vs SCE). The electrogenerated H2O2 is then utilized to promote the transformation of l-tyrosine to dopachrome in the presence of l-ascorbic acid and Fe3O4 catalyst.

Facile Fabrication of Hierarchically Thermoresponsive Binary Polymer Pattern for Controlled Cell Adhesion.

A versatile platform allowing capture and detection of normal and dysfunctional cells on the same patterned surface is important for accessing the cellular mechanism, developing diagnostic assays, and implementing therapy. Here, an original and effective method for fabricating binary polymer brushes pattern is developed for controlled cell adhesion. The binary polymer brushes pattern, composed of poly(N-isopropylacrylamide) (PNIPAAm) and poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) chains, is simply obtained via a combination of surface-initiated photopolymerization and surface-activated free radical polymerization. This method is unique in that it does not utilize any protecting groups or procedures of backfilling with immobilized initiator. It is demonstrated that the precise and well-defined binary polymer patterns with high resolution are fabricated using this facile method. PNIPAAm chains capture and release cells by thermoresponsiveness, while POEGMA chains possess high capability to capture dysfunctional cells specifically, inducing a switch of normal red blood cells (RBCs) arrays to hemolytic RBCs arrays on the pattern with temperature. This novel platform composed of binary polymer brush pattern is smart and versatile, which opens up pathways to potential applications as microsensors, biochips, and bioassays.

[Current progress in single sperm cryopreservation].

Sperm cryopreservation has been widely used in assisted reproduction, but conventional techniques are not suitable for the cryopreservation of small numbers of sperm. The application of the single sperm cryopreservation technique has significantly improved the clinical treatment of cryptozoospermia and non-obstructive azoospermia. Ever since Cohen et al first developed the method of single sperm cryopreservation in 1997, constant efforts have been made to develop the carriers for this technique. In this review, we mainly discuss the existing methods and clinical outcomes of single sperm cryopreservation.

Haplodeficiency of activin receptor-like kinase 4 alleviates myocardial infarction-induced cardiac fibrosis and preserves cardiac function.

Cardiac fibrosis (CF), a repairing process following myocardial infarction (MI), is characterized by abnormal proliferation of cardiac fibroblasts and excessive deposition of extracellular matrix (ECM) resulting in inevitable resultant heart failure. TGF-ß (transforming growth factor-ß)/ALK5 (Activin receptor-like kinase 5)/Smad2/3/4 pathways have been reported to be involved in the process. Recent studies have implicated both activin and its specific downstream component ALK4 in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 is upregulated in the pressure-overloaded heart and its partial inhibition attenuated the pressure overload-induced CF and cardiac dysfunction. However, the role of ALK4 in the pathogenesis of MI-induced CF, which is usually more severe than that induced by pressure-overload, remains unknown. Here we report: 1) In a wild-type mouse model of MI, ALK4 upregulation was restricted in the fibroblasts of the infarct border zone; 2) In contrast, ALK4+/- mice with a haplodeficiency of ALK4 gene, showed a significantly attenuated CF in the border zone, with a smaller scar size, a preserved cardiac function and an improved survival rate post-MI; 3) Similarly to pressure-overloaded heart, these beneficial effects might be through a partial inactivation of the Smad3/4 pathway but not MAPK cascades; 4) The apoptotic rate of the cardiomyocytes were indistinguishable in the border zone of the wild-type control and ALK4+/- mice; 5) Cardiac fibroblasts isolated from ALK4+/- mice showed reduced migration, proliferation and ECM synthesis in response to hypoxia. These results indicate that partial inhibition of ALK4 may reduce MI-induced CF, suggesting ALK4 as a novel target for inhibition of unfavorable CF and for preservation of LV systolic function induced by not only pressure-overload but also MI.

Role of contact force-guided radiofrequency catheter ablation for treatment of atrial fibrillation: A systematic review and meta-analysis.

INTRODUCTION: CF-sensing catheter emerged as a novel ablation technology and was increasingly used in clinical practice. Nonetheless, available evidence of efficacy and safety comparison between CF-guided RF catheter ablation and non-CF-guided ablation for treatment of AF was still lacking. METHODS AND RESULTS: Twenty-two eligible studies were included after systematic review through the MEDLINE, Google Scholar, the Cochrane Library and PubMed databases. AF/atrial tachycardia-free survival was markedly improved in CF-guided catheter ablation compared with non-CF-guided ablation at a median 12-month follow-up (RR: 1.12, 95% CI: 1.06-1.19, P = 0.000, fixed). Notably, CF-guided catheter ablation presented a robust survival benefit for treatment of paroxysmal AF (RR: 1.10, 95% CI: 1.03-1.18, P = 0.005, fixed), but not persistent AF (RR: 1.07, 95% CI: 0.89-1.28, P = 0.466, fixed). Moreover, procedure time (WMD: -23.87, 95% CI: -33.83 to -13.91, P = 0.000, random), fluoroscopy time (WMD: -7.78, 95% CI: -13.93 to -1.63, P = 0.013, random) and RF time (WMD: -3.98, 95% CI: -7.78 to -0.17, P = 0.040, random) were significantly reduced in CF-guided catheter ablation. The incidence of procedure-related complications did not differ between these two technologies (RR: 0.83, 95% CI: 0.59 to 1.16, P = 0.271, fixed). CONCLUSION: CF-guided RF catheter ablation was associated with a significant AF/atrial tachycardia-free survival benefit compared with non-CF-guided ablation in patients with paroxysmal AF rather than persistent AF. In addition, CF-guided ablation strategy also reduced the procedure time, fluoroscopy time, as well as RF time despite no distinct effect on the alleviation of procedure-related complications.

Role of adenosine-guided pulmonary vein isolation in patients undergoing catheter ablation for atrial fibrillation: a meta-analysis.

AIMS: Adenosine had been reported to unmask dormant conduction and thus identify pulmonary vein at risk of reconnection. However, the role of adjunctive adenosine infusion after pulmonary vein isolation (PVI) on long-term arrhythmia-free survival was still contentious. The purpose of the present meta-analysis was to assess the association of adenosine testing with long-term ablation success in patients with atrial fibrillation (AF) (i.e. freedom from AF recurrence). METHODS AND RESULTS: We systematically searched the electronic databases and finally included 10 studies, with 1771 patients undergoing adenosine-guided PVI and 1787 patients undergoing conventional PVI. In comparison to conventional PVI alone, adenosine-guided PVI improved the arrhythmia-free survival by 17% during a median follow-up of 12 months [relative risk (RR): 1.17; 95% confidence interval (CI): 1.07 to 1.27; P = 0.014]. Patients undergoing adenosine-guided PVI had similar fluoroscopy time to those who undergoing conventional PVI [weighted mean difference (WMD): 1.76; 95% CI: -5.66 to 9.17; P = 0.64], despite longer procedure time (WMD: 20.6; 95% CI: 0.70 to 40.50; P = 0.042). CONCLUSION: From the available data of clinical studies, adenosine-guided PVI was associated with an increased arrhythmia-free survival when compared with conventional PVI in patients undergoing catheter ablation for AF.

Cryoablation vs. radiofrequency ablation for treatment of paroxysmal atrial fibrillation: a systematic review and meta-analysis.

AIMS: Cryoablation is a promising alternative technique to RF ablation for treating paroxysmal AF with encouraging results. However, data about the efficacy and safety comparison between cryoablation and RF ablation is still lacking. METHODS AND RESULTS: We systematically search the PubMed, the Cochrane Library, MEDLINE and Google Scholar databases, and finally identify 16 eligible studies including 7195 patients (2863 for cryoablation; 4332 for RF ablation). Freedom from AF/atrial tachycardial replase is slightly higher in cryoablation than RF ablation during a median 12 months of follow-up, with no statistical significant (RR: 1.05, 95% CI: 0.98-1.13, P = 0.159). In cryoablation, the procedure time is substantially shortened (WMD: -27.66, 95% CI: -45.24 to - 10.08, P = 0.002), whereas the fluoroscopy time is identical to RF ablation (WMD: -0.37, 95% CI: -2.78 to 2.04, P = 0.763). Procedure-related adverse events in cryoablation are parallel with that in RF ablation (RR: 1.08, 95% CI: 0.86-1.35, P = 0.159). CONCLUSIONS: Compared with RF ablation, cryoablation present a comparable long-term AF/atrial tachycardial-free survival and procedure-related adverse events. Meanwhile, cryoablation markedly shorten the procedure time, nonetheless, with negligible impact on the fluoroscopy time.

Oxidative Stress-Induced Afterdepolarizations and Protein Kinase C Signaling.

BACKGROUND: Hydrogen peroxide (H2O2)-induced oxidative stress has been demonstrated to induce afterdepolarizations and triggered activities in isolated myocytes, but the underlying mechanisms remain not fully understood. We aimed to explore whether protein kinase C (PKC) activation plays an important role in oxidative stress-induced afterdepolarizations. METHODS: Action potentials and ion currents of isolated rabbit cardiomyocytes were recorded using the patch clamp technique. H2O2 (1 mM) was perfused to induce oxidative stress and the specific classical PKC inhibitor, Gö 6983 (1 µM), was applied to test the involvement of PKC. RESULTS: H2O2 perfusion prolonged the action potential duration and induced afterdepolarizations. Pretreatment with Gö 6983 prevented the emergence of H2O2-induced afterdepolarizations. Additional application of Gö 6983 with H2O2 effectively suppressed H2O2-induced afterdepolarizations. H2O2 increased the late sodium current (INa,L) (n = 7, p < 0.01) and the L-type calcium current (ICa,L) (n = 5, p < 0.01), which were significantly reversed by Gö 6983 (p < 0.01). H2O2 also increased the transient outward potassium current (Ito) (n = 6, p < 0.05). However, Gö 6983 showed little effect on H2O2-induced enhancement of Ito. CONCLUSIONS: H2O2 induced afterdepolarizations via the activation of PKC and the enhancement of ICa,L and INa,L. These results provide evidence of a link between oxidative stress, PKC activation and afterdepolarizations.

Dual-specificity phosphatase 14 protects the heart from aortic banding-induced cardiac hypertrophy and dysfunction through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway.

Dual-specificity phosphatase 14 (Dusp14), an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways, has been implicated in inflammatory immune response, cancers, cell differentiation and proliferation. The role of Dusp14 in chronic pressure overload-induced cardiac hypertrophy has not been explored. Here we have shown that Dusp14-/- knockout mice and cardiac-specific Dusp14 transgenic mice were generated and subjected to aortic banding (AB) for 4 weeks. Our results demonstrated that genetic loss of Dusp14 significantly aggravated cardiac hypertrophy, fibrosis, ventricular dilation and dysfunction, whereas transgenic cardiac-specific Dusp14 overexpression significantly attenuated AB-induced cardiac dysfunction and remodeling. In vitro, adenoviral overexpression of constitutive Dusp14 blocked angiotensin II-induced hypertrophic growth of cardiomyocytes, while Dusp14 knockdown led to opposite effects. Mechanistically, excessive phosphorylation of TAK1, P38MAPK and JNK1/2 was evidenced in Dusp14-/- knockout mice post-AB and inactivation of TAK1-P38MAPK and -JNK1/2 signaling using TAK1 inhibitor 5Z-7-ox shares similar antihypertrophic effect as Dusp14 overexpression. Moreover, we show that Dusp14 directly interacted with TAK1. Results from present experiments indicate that Dusp14 protects the heart from AB-induced cardiac hypertrophy and dysfunction possibly through inactivation of TAK1-P38MAPK/-JNK1/2 signaling pathway. Future studies are warranted to test the feasibility of overexpressing Dusp14 as a therapeutic strategy to attenuate cardiac hypertrophy and failure.