miR-107 Attenuates Sepsis-Induced Myocardial Injury by Targeting PTEN and Activating the PI3K/AKT Signaling Pathway.

Sepsis is a public health problem worldwide. This study investigated the mechanism of miR-107 on sepsis-induced myocardial injury. Sepsis rat models were established by cecal ligation and puncture (CLP), and the cell model was established using lipopolysaccharide (LPS)-induced cardiomyocytes. Cardiac function indexes of rats were measured using echocardiography. Pathological changes in the rat myocardium were observed using histological staining. Expression of miR-107 in the serum of rats and in cardiomyocytes was detected after the treatment with miR-107 mimic and/or pcDNA3.1-PTEN, followed by assessment of cell cycle, proliferation, and apoptosis. Binding sites of miR-107 and PTEN were predicted. PTEN, PI3K, p-PI3K, AKT, and p-AKT levels in LPS-induced cardiomyocytes were measured. miR-107 was significantly downregulated in the serum of CLP rats and LPS-induced cardiomyocytes. miR-107 overexpression remarkably improved cardiac function and histological changes, decreased inflammatory factors, and alleviated the sepsis-induced myocardial injury in rats. In LPS-induced cardiomyocytes, miR-107 overexpression increased cardiomyocyte proliferation, inhibited apoptosis, and enhanced the proportion of cardiomyocytes arrested in S and G2/M phases. miR-107 targeted PTEN. PTEN overexpression partially reversed the inhibition of miR-107 mimic on cardiomyocyte apoptosis. miR-107 overexpression activated the PI3K/AKT pathway by inhibiting PTEN. To conclude, miR-107 activates the PI3K/AKT pathway by inhibiting PTEN, thus attenuating sepsis-induced myocardial injury and LPS-induced cardiomyocyte apoptosis.

MicroRNA-1246 regulates proliferation, invasion, and differentiation in human vascular smooth muscle cells by targeting cystic fibrosis transmembrane conductance regulator (CFTR).

MicroRNA (miRNA) plays a key role in the proliferation and invasion of vascular smooth muscle cells (VSMCs). However, the role and underlying mechanism of miRNAs in VSMCs are not fully understood. Therefore, this study was designed to investigate the role and mechanism of microRNA-1246 (miR-1246) in VSMCs. VSMCs were cultured, and the proliferation of VSMCs was stimulated by platelet-derived growth factor (PDGF-BB) or 15% fetal bovine serum (FBS). The quantitative reverse transcription PCR (qRT-PCR) was used to detect the expression levels of miR-1246 and cystic fibrosis transmembrane conductance regulator (CFTR) in VSMCs. The CCK-8 assay and transwell assay were used to detect the proliferation and invasion of VSMCs. Target gene prediction and screening and luciferase reporter assays were used to verify downstream target genes of miR-1246. Western blotting was used to detect the protein expression levels of PCNA, α-SMA, SM-MHC, Collagen-1, and Cyclin D1 in VSMCs. PDGF-BB and FBS treatment induced VSMCs proliferation and the upregulation of miR-1246 expression. Overexpression of miR-1246 promoted VSMCs proliferation, invasion, and differentiation towards synthetic phenotype, while knockdown of miR-1246 had opposite effects. In addition, CFTR was found to be a direct target for miR-1246, and miR-1246 inhibited the expression of CFTR. Moreover, overexpression of CFTR inhibited VSMC proliferation and synthetic differentiation, while overexpression of miR-1246 partly abolished the effects of CFTR overexpression on VSMCs proliferation and differentiation. Our data suggest that MiR-1246 promotes VSMC proliferation, invasion, and differentiation to synthetic phenotype by regulating CFTR. MiR-1246 may be a potential therapeutic target for atherosclerosis.

Staphylococcus epidermidis small basic protein (Sbp) forms amyloid fibrils, consistent with its function as a scaffolding protein in biofilms.

Biofilms are communities of microbes embedded in a microbial extracellular matrix. Their formation is considered the main virulence mechanism enabling the opportunistic bacterial pathogen Staphylococcus epidermidis to cause devastating nosocomial, implant-associated infections. Biofilms often contain proteins, and an 18-kDa protein called small basic protein (Sbp) recently was discovered in the S. epidermidis biofilm matrix and may serve as a scaffolding protein in both polysaccharide intercellular adhesin (PIA)-dependent and accumulation-associated protein (Aap)-dependent biofilm formations. In Aap-mediated biofilm formation, Sbp colocalizes with Domain-B of Aap, implying that Sbp directly interacts with Aap's Domain-B. However, the structure of Sbp and its interaction with Aap, as well as the molecular mechanism underlying Sbp's roles in biofilm formation, are incompletely understood. In this work, we used small-angle X-ray scattering (SAXS), NMR, analytical size-exclusion chromatography, and isothermal titration calorimetry analyses to determine the Sbp structure and characterize its interaction with Aap's Domain-B. We found that Sbp is monomeric and partially folded in solution, and, unexpectedly, we observed no direct interactions between Sbp and Aap Domain-B. Instead, we noted that Sbp forms amyloid fibrils both in vitro and in vivo Atomic force, transmission electron, and confocal fluorescence microscopy methods confirmed the formation of Sbp amyloid fibrils and revealed their morphology. Taken together, the Sbp amyloid fibril structures identified here may account for Sbp's role as a scaffolding protein in the S. epidermidis biofilm matrix.

Comparison of Empiric Isolation and Conventional Isolation of Superior Vena Cava in Addition to Pulmonary Vein Isolation on the Outcome of Paroxysmal Atrial Fibrillation Ablation.

Radiofrequency catheter ablation (RFCA) in the treatment of AF is currently based on pulmonary vein isolation (PVI). Some studies have investigated the efficacy of empiric SVC isolation (SVCI) in addition to conventional PVI in order to improve success rates and reduce recurrence rates. However, the results of the studies have given conflicting data.We performed a meta-analysis to evaluate the efficacy and safety of the empiric SVCI compared with conventional SVCI for paroxysmal atrial fibrillation (PAF) ablation.We searched MEDLINE, EMBASE, the Web of Science, and the Cochrane Database from the period January 1986 to August 2016 and identified qualified studies. The primary clinical outcome was the recurrence rate of atrial tachyarrhythmias, and the secondary clinical outcomes were procedure time, fluoroscopy time, and complications.We identified 3 randomized controlled trials (RCTs) and one nonrandomized, observational study (nROS) involving 245 patients with empiric SVCI and 269 patients with conventional SVCI. The empiric SVCI group had a lower recurrence rate of atrial tachyarrhythmia after a single procedure compared with the conventional SVCI group (16.7% versus 29.4%, OR: 0.48, 95%CI: 0.31 to 0.74, P = 0.0009). There was no significant difference in fluoroscopic time (P = 0.22), procedure time (P = 0.32), or clinical complications (P = 0.33) between the two groups.Empiric SVCI is more effective than conventional SVCI in terms of the long-term outcomes of PAF patients after a single PVI procedure, with the same fluoroscopic time, procedure time, and clinical complications.

[Ischemia/reperfusion injury study in isolated mouse hearts using a pressure-volume curve].

Objective: To establish and assess the feasibility and sensitivity of left ventricular elasticity, compliance and stiffness for study of ischemia/reperfusion injury in an isolated mouse heart model utilizing the pressure-volume curve framework. Methods: An isolated, balloon-in-ventricle, isovolumically contracting, crystalloid-perfused Langendorff heart preparation was set up from 15 male C57/6BL mice aged 12-14 weeks. End-systolic pressure-volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) were obtained by measuring left ventricular (LV) systolic pressure (LVSP) and diastolic pressure under different balloon volumes. End-systolic elasticity (E(es)), end-diastolic stiffness (S(ed)) and compliance (C(ed)) were calculated from the slope of ESPVR and EDPVR. Measurements of LVSP, developed pressure (LVDP), end of diastolic pressure (EDP), the rate of pressure development dp/dt(max) and dp/dt(min) were monitored during 30 min stabilization, 20 min global ischemia and 40 min reperfusion. The reliability and coefficient of variation (CV) of these parameters were compared with E(es) and C(ed). Results: During stabilization, the heart rate was (395±40) bpm, LVDP was (126±25) mmHg, + dp/dt(max) was (5 590±625) mmHg/s, -dp/dt(min) was (-4 128±625) mmHg/s, E(es) was 5.7±0.3, C(ed) was 0.7±0.2, S(ed) was 1.4±0.1. Ischemia/reperfusion injury resulted in significant decrease in contractile function parameters. The recovery level of LVSP, LVDP, dp/dt(max) and dp/dt(min) were (57±19)%, (23±6)%, (23±7)% and (21±5)% (all P<0.001), respectively. The EDP increased to (5.4±2.0) times than the baseline after ischemia/reperfusion injury. The E(es) and C(ed) was deceased to (42±2)% and (33±2)%, compared with baseline. The stiffness was increased up to (3.1±0.2) times higher than the baseline. The CV of E(es,)S(ed) and C(ed) were lower than LVSP, LVDP, EDP, dp/dt(max,)dp/dt(min,)while the reliability of E(es), S(ed) and C(ed) were higher than the classic contractile function parameters. Conclusion: Pressure-volume curves are feasible during ischemia/reperfusion injury in the isolated mouse heart model with acceptable reliability and sensitivity.

Leonurine Exerts Anti-Inflammatory Effects in Lipopolysaccharide (LPS)-Induced Endometritis by Modulating Mouse JAK-STAT/PI3K-Akt/PPAR Signaling Pathways.

Endometritis is a common disease in postpartum cows, characterized by delayed uterine recovery due to endometrial inflammation. Although antibiotics and hormones are commonly used, they have certain limitations. One potential alternative is using motherwort extract, specifically leonurine, which exhibits anti-inflammatory properties. However, leonurine's exact molecular mechanism of action remains unclear. In this study, 40 mice were randomly divided into four groups: a control group, endometritis model group, LPS + leonurine group (30 mg/kg), and LPS + dexamethasone group (5 mg/kg). Transcriptomic analysis revealed that leonurine modulates multiple signaling pathways, including JAK-STAT/PI3K-Akt, and influences the expression of key genes, such as Prlr, Socs2, Col1a1, and Akt1. Furthermore, leonurine effectively reduces levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1ß (p < 0.01), which play a crucial role in regulating acute endometritis. Additionally, leonurine helps maintain cholesterol homeostasis and attenuates inflammation through the peroxisome proliferator-activated receptor (PPAR) signaling pathway by modulating genes such as Cyp27a1, Hmgcs1, and Scd2. These findings suggest that leonurine has a protective effect against LPS-induced endometritis and that its anti-inflammatory properties involve multiple pathways and targets, which are potentially mediated by regulating signaling pathways such as JAK-STAT/PI3K-Akt and PPAR.

Noninvasive pressure-strain loop quantitative assessment of left ventricular function in anemic preterm infants with different modes of respiratory support.

To investigate noninvasive pressure-strain loop (PSL) combined with two-dimensional speck tracking imaging and left ventricular pressure measurement in the evaluation of cardiac function changes in anemia of prematurity (AOP) with different modes of respiratory support, and to explore its value in detecting subclinical myocardial injury in preterm infants. This retrospective study included 79 preterm infants with anemia, according to different modes of respiratory support, who were divided into invasive respiratory support group (39 cases) and noninvasive respiratory support group (40 cases). A control group of 40 nonanemic preterm infants with matched age, sex, and gestational age were also included. Complete echocardiography was performed for each included infant. There are PSL parameters that used to evaluate cardiac function, including global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) among the three groups were compared. Compared with the control group, the value of GWI, GCW, and GWE were significantly lower and GWW was higher in the AOP groups (P < 0.05), and GWI, GCW and GWE were much significantly lower in the invasive respiratory support group than in the noninvasive respiratory support group (P < 0.05). There was no significant difference in GLS among the three groups (P > 0.05). Noninvasive PSL analysis can quantitatively assess myocardial work in AOP with different respiratory support, which is more sensitive than other conventional echocardiographic indices. This technique may provide a new method for monitoring subclinical myocardial injury with AOP.

From prospecting to mining: A review of enabling technologies, LCAs, and LCCAs for improved construction and demolition waste management.

Knowledge gained from anthropogenic resource prospecting can shed light on the theoretical potential of secondary resources stored in anthropogenic systems. Among others, secondary resources accumulated in the built environment account for a big fraction of anthropogenic resources, indicating great potential for urban mining. However, realizing these opportunities and developing urban mining strategies will require a comprehensive understanding of the technical viability of urban mining technologies, and how their implementation will affect the technical, economic, and environmental performance of a construction and demolition waste (C&DW) management system. To address these important issues, this review summarizes (1) current and emerging technologies that can enable the transition from anthropogenic resource prospecting to anthropogenic resource mining, (2) Life Cycle Assessment (LCA) and Life Cycle Cost Analysis (LCCA) results to date on various C&DW management systems, (3) key parameters that govern the technical, economic, and environmental performance of a C&DW management system, and (4) opportunities for improving the methodology of LCAs and LCCAs for future C&DW management. We find that enhancing the utility of extant LCAs and LCCAs in guiding technology deployment and policy decisions can be achieved by considering key parameters governing the techno-economic and environmental performance of C&DW management. In addition, it is critical to adopt and upscale emerging technologies to increase the added value of materials or products recovered from C&DW.

Efficacy and Safety of Catheter Ablation Combined with Left Atrial Appendage Closure in the Treatment of Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND: Catheter ablation combined with left atrial appendage closure is effective in treating atrial fibrillation. However, the effectiveness of this combined treatment compared with catheter ablation alone is still controversial. METHODS: We searched studies in databases, including The Cochrane Library, PubMed, EMBASE, and Web of Science, that compared catheter ablation combined with left atrial appendage closure and catheter ablation alone in the treatment of atrial fibrillation. These studies reported at least one of the following outcomes: the freedom from atrial arrhythmia rate, the procedure time, the fluoroscopy time, perioperative complications, thromboembolic events, and bleeding events during follow-up. The risk ratio and standard mean difference with 95% CI were analyzed by the random-effects model. RESULTS: Five studies involving 699 people were included in our meta-analysis. We found no significant difference in the freedom from atrial arrhythmia rate (risk ratio=0.93, 95% CI=0.83-1.04, I 2=0%, P=.21) between the 2 groups. Catheter ablation combined with left atrial appendage closure showed significantly longer procedure and fluoroscopy times than catheter ablation alone (standard mean difference=1.26, 95% CI=0.85-1.67, P <.00001 and standard mean difference=1.19, 95% CI=0.53-1.85, P=.0004, respectively). With regard to safety outcomes, no significant differences were observed in perioperative complications (RR=1.62, 95% CI=0.99-2.63, I 2=0%, P=.05), thromboembolic events (RR=0.67, 95% CI=0.15-3.11, I 2=0%, P=.61), or bleeding events (RR=0.67, 95% CI=0.11-3.88, P=.65) between the 2 groups during follow-up. CONCLUSION: The freedom from atrial arrhythmia rate and safety outcomes of catheter ablation combined with left atrial appendage closure are similar to those of catheter ablation alone. Catheter ablation combined with left atrial appendage closure appears to have longer procedure and fluoroscopy times than catheter ablation alone.

Community Structure and Ecological Network's Changes of Vaginal Microbiome in Women Right After Delivery.

Objectives: Vaginal microbiota is not only an important source of bacterial colonization for neonates, but also plays a crucial role in maternal and neonatal health. This study aimed to investigate the vaginal microbial community structure right after delivery and its impact on the neonatal oral microbiome. Methods: In this study, 27 women were recruited from Bao'an Maternal and Child Health Hospital. Bacterial compositions of vaginal samples before and right after delivery and neonatal oral samples right after birth were investigated using 16S rRNA sequencing of V3-V4 hyperregions. Results: Vaginal microbiome before delivery was dominated by the genus Lactobacillus. After delivery, the vaginal microbial community was altered, with significantly decreased proportion of Lactobacillus, increased alpha-diversity, and a more diverse ecological network. A large number subjects dominated by Lactobacillus species before delivery shifted to CST (community state type) IV after delivery. In addition, similar changes were observed in the neonatal oral microbiome, and its community profile was closer to vaginal samples after delivery than before delivery with principal coordinates analysis and microbial source tracking analysis. Conclusion: The vaginal microbiome was altered right after delivery and impacted the colonization of the neonatal oral microbiome in China. Further, it is vital to understand the longitudinal influence on maternal and neonatal health of vaginal microbiome community changes after delivery.

Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model.

Objectives: Probenecid is an anion transport inhibitor, which, according to the connectivity map (CMap; a biological application database), interferes with hypoxia-induced gene expression changes in retinal vascular endothelial cells (ECs). Here, we investigated the influence of probenecid on retinal EC cytotoxicity and retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model. Methods: The retinal EC growth rate in the presence of hypoxia-mimicking concentrations of cobalt chloride (CoCl2) was determined using the thiazolyl blue tetrazolium bromide (MTT) assay and proliferating cell nuclear antigen (PCNA) expression. In OIR rats, probenecid was administered by intraperitoneal injection (i.p.) from postnatal day (P) 1 to P7. The concentrations of vitreous humor vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, and placental growth factor (PlGF) were determined by using the ELISA kit at P21. The amount of newly formed vascular lumen was evaluated by histopathological examination. Retinopathy and neovascularization were assessed by scoring isolectin B4 fluorescein-stained retinal flat mounts. Western blots for liver tissue HIF-1α and hepcidin (HAMP) were performed. Results: In vitro, probenecid led to the recession of the hypoxia-induced EC growth rate. In vivo, compared to the OIR retina, the upregulation of VEGF, HIF-1α, and PlGF in phase II retinopathy of prematurity (ROP) was inhibited by probenecid administration. Moreover, probenecid ameliorated neovascularization and resulted in significantly reduced relative leakage fluorescence signal intensity in fluorescein-stained retinal flat mounts (p < 0.05). Probenecid alleviated the liver overactivation of HAMP and downregulation of HIF-1α in OIR rats. Conclusions: This is the first demonstration that implies that probenecid might be a protective compound against retinal angiogenesis in OIR. These changes are accompanied with decreased hyperoxia-mediated hepcidin overproduction. Although the relevance of the results to ROP needs further research, these findings may help establish potential pharmacological targets based on the CMap database.

The Effect of STAT3 Signal Pathway Activation on Retinopathy of Prematurity.

Objective: To investigate the mechanism of activation of the signal transducer and activator of transcription 3 (STAT3) signal pathway in the process of retinopathy of prematurity (ROP). Methods: Sixty newborn Sprague-Dawley (SD) rats were randomly separated into the hyperoxia and air control groups (n = 30/in each group). The serum hepcidin level on 21 d was measured using the enzyme-linked immunosorbent assay (ELISA). The expression of HAMP and STAT3 protein in the liver was determined using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. Retinal neovasculature was evaluated by hematoxylin and eosin (HE) stain and fluorescein lectin. The retinal endothelial cells were treated with 250 µmol/L cobalt chloride for 72 h and added S3I-201. The STAT3 level was determined by western blotting. Results: The expression of STAT3 protein increased significantly after hyperoxia stimulation. The expression of HAMP mRNA in the hyperoxia group was significantly higher than that of the control group. The proliferation of retinal cells was inhibited, and the expression of STAT3 was increased. No significant difference was noted in vascular endothelial growth factor (VEGF) mRNA. The expression of STAT3 and VEGF mRNA was significantly reduced. Conclusion: The activation of the STAT3 signal pathway increased hepcidin expression, contributing to the pathogenesis of ROP. S3I-201 inhibited the expression of STAT3 and VEGF mRNA levels. This information provides potential novel therapeutic approach to the prevention and treatment of ROP.

Impact of catheter-tissue contact force on lesion size during right ventricular outflow tract ablation in a swine model.

BACKGROUND: The catheter-tissue contact force (CF) is one of the significant determinants of lesion size and thus has a considerable impact on the effectiveness of ablation procedures. This study aimed to evaluate the impact of CF on the lesion size during right ventricular outflow tract (RVOT) ablation in a swine model. METHODS: Twelve Guangxi Bama miniature male pigs weighing 40 to 50 kg were studied. After general anesthesia, a ThermoCool SmartTouch contact-sensing ablation catheter was introduced to the RVOT via the femoral vein under the guidance of the CARTO 3 system. The local ventricular voltage amplitude and impedance were measured using different CF levels. We randomly divided the animals into the following four groups according to the different CF levels: group A (3-9 g); group B (10-19 g); group C (20-29 g); and group D (30-39 g). Radiofrequency ablations were performed at three points in the free wall and septum of the RVOT in power control mode at 30 W for 30 s while maintaining the saline irrigation rate at 17 mL/min. At the end of the procedures, the maximum depth, surface diameter, and lesion volume were measured and recorded. A linear regression analysis was performed to determine the relationship between continuous variables. RESULTS: A total of 72 ablation lesions were created in the RVOT of the 12 Bama pigs. The maximum depth, surface diameter, and volume of the lesions measured were well correlated with the CF (free wall: ß = 0.105, ß = 0.162, ß = 3.355, respectively, P < 0.001; septum: ß = 0.093, ß = 0.150, ß = 3.712, respectively, P < 0.001). The regional ventricular bipolar voltage amplitude, unipolar voltage amplitude, and impedance were weakly positively associated with the CF (ß = 0.065, ß = 0.125, and ß = 1.054, respectively, P < 0.001). There was a significant difference in the incidence of steam pops among groups A, B, C, and D (free wall: F = 7.3, P = 0.032; septum: F = 10.5, P = 0.009); and steam pops occurred only when the CF exceeded 20 g. Trans-mural lesions were observed when the CF exceeded 10 g in the free wall, while the lesions in the septum were non-trans-mural even though the CF reached 30 g. CONCLUSIONS: CF seems to be a leading predictive factor for the size of formed lesions in RVOT ablation. Maintaining the CF value between 3 and 10 g may be reasonable and effective for creating the necessary lesion size and reducing the risk of complications, such as steam pops and perforations.

Transient hypertrophic cardiomyopathy and hypertension associated with hydrocortisone in preterm infant: A case report.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a heterogeneous, usually familial disorder of heart muscle. The hypertrophic form of cardiomyopathy is frequently genetic, or as part of several neuromuscular disorders. In neonates, especially prematurity, HCM could also be secondary to corticosteroid treatment. PATIENT CONCERNS: We reported here a 34 weeks gestational age preterm infant presented with profound cardiomegaly after multiple doses of hydrocortisone used to treat blood pressure instability associated with septic shock and persistent pulmonary hypertension (PPHN). DIAGNOSIS: Patient presented auscultation of a grade III/IV harsh systolic ejection murmur from day 14, which was absent before. Profound cardiomegaly was indicated at chest film at day 30. Echocardiography showed severe thickening of the IVS (13.8 mm, z score = 8.29) and mild thickening of the posterior left ventricular wall (LVPW, 6 mm). INTERVENTIONS: Propranolol and captopril were started along with supportive care. The patient was also admitted to NICU for further treatment with 24-hour Holter electrocardiographic monitoring. OUTCOMES: A reversible course was observed without left ventricular outflow tract obstruction nor arrhythmias within 4 weeks. LESSONS: The risk/benefit ratio must be carefully considered when corticosteroids are used in prematurity. Monitors such as echocardiography and electrocardiograph should be conducted in order to guide cardiovascular management. Systematic surveys of the incidence of cardiac complications in a larger population of preterm infant treated with corticosteroid are needed in the future.

Isolated sigmoid colon metastasis from lung micropapillary adenocarcinoma: a case report.

Lung cancer is a common malignant neoplasm that is prone to distant metastasis. Gastrointestinal metastasis from lung cancer is rather rare no matter what stage. Herein, we presented a case of pulmonary adenocarcinoma six months after thoracoscopic Lobectomy isolated metastasis to sigmoid colon. Then the patient underwent radical resection of metastatic tumors of sigmoid colon. The pathologic morphology and immunohistochemistry of lung adenocarcinoma is highly consistent with the sigmoid colon tumor and their gene profiles are likely similar expect for an AXIN1 mutation in primary tumor and not in the metastatic lesion.

Interaction of α Carboxyl Terminus 1 Peptide With the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia-Reperfusion Injury.

Background α Carboxyl terminus 1 (αCT1) is a 25-amino acid therapeutic peptide incorporating the zonula occludens-1 (ZO-1)-binding domain of connexin 43 (Cx43) that is currently in phase 3 clinical testing on chronic wounds. In mice, we reported that αCT1 reduced arrhythmias after cardiac injury, accompanied by increases in protein kinase Cε phosphorylation of Cx43 at serine 368. Herein, we characterize detailed molecular mode of action of αCT1 in mitigating cardiac ischemia-reperfusion injury. Methods and Results To study αCT1-mediated increases in phosphorylation of Cx43 at serine 368, we undertook mass spectrometry of protein kinase Cε phosphorylation assay reactants. This indicated potential interaction between negatively charged residues in the αCT1 Asp-Asp-Leu-Glu-Iso sequence and lysines (Lys345, Lys346) in an α-helical sequence (helix 2) within the Cx43-CT. In silico modeling provided further support for this interaction, indicating that αCT1 may interact with both Cx43 and ZO-1. Using surface plasmon resonance, thermal shift, and phosphorylation assays, we characterized a series of αCT1 variants, identifying peptides that interacted with either ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 or Cx43-CT, but with limited or no ability to bind both molecules. Only peptides competent to interact with Cx43-CT, but not ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 alone, prompted increased pS368 phosphorylation. Moreover, in an ex vivo mouse model of ischemia-reperfusion injury, preischemic infusion only with those peptides competent to bind Cx43 preserved ventricular function after ischemia-reperfusion. Interestingly, a short 9-amino acid variant of αCT1 (αCT11) demonstrated potent cardioprotective effects when infused either before or after ischemic injury. Conclusions Interaction of αCT1 with the Cx43, but not ZO-1, is correlated with cardioprotection. Pharmacophores targeting Cx43-CT could provide a translational approach to preserving heart function after ischemic injury.

Efficacy and safety of the second-generation cryoballoons versus radiofrequency ablation for the treatment of paroxysmal atrial fibrillation: a systematic review and meta-analysis.

PURPOSE: Currently, radiofrequency (RF) and cryoballoon are the most commonly used ablation technologies for atrial fibrillation (AF). We performed a meta-analysis to assess the efficacy and safety of the second-generation cryoballoons (CB-2) compared with RF for paroxysmal atrial fibrillation (PAF) ablation. METHODS: The PubMed, Cochrane Library, and Embase databases were searched and qualified studies were identified. The primary clinical outcome was the recurrence rate of atrial tachyarrhythmia (AT), and the secondary clinical outcomes were procedure time, fluoroscopy time, and the complications that followed. RESULTS: Nine observational studies (2336 patients) with a mean follow-up period ranging from 8.8 to 16.8 months were included. The CB-2 group was associated with a significantly lower recurrence rate of ATs (20.8 versus 29.8 %, p = 0.01). In subgroup analysis, compared with non-contact force sensing (NCF) catheter, using CB-2 showed significantly reduced incidence of ATs (22.0 versus 38.5 %, p < 0.00001). However, the difference became negligible in contrast with contact force sensing (CF) catheter. Moreover, the CB-2 group had a tendency to decrease procedure time (weighted mean difference -39.72 min, p = 0.0003), whereas fluoroscopy time was similar between the two groups. The total complication rate showed no statistical difference (8.8 versus 4.4 %, p = 0.08). Almost all the cases of phrenic nerve palsy occurred in the CB-2 group, whereas pericardial tamponade was seldom manifested in the CB-2 group. CONCLUSIONS: CB-2 tended to be more effective in comparison to NCF catheter and at least non-inferior to CF catheter, with shorter procedure time and similar safety endpoint.

Ventricular Tachycardia Originating from Moderator Band: New Perspective on Catheter Ablation.

A 59-year-old woman was referred to the institution with burdens of idiopathic ventricular tachycardia (IVT). Electroanatomic mapping revealed a complex fractionated, high frequency potential with long duration preceding the QRS onset of the IVT. The real end point of ablation was the disappearance of the conduction block of Purkinje potential during the sinus rhythm besides the disappearance of the inducible tachycardia. Location of distal catheter was at the moderator band (MB) by transthoracic echocardiography (TTE). Only irrigated radiofrequency current was delivered at both insertions of the MB which can completely eliminate the IVT.

Anaesthesia modalities during laser photocoagulation for retinopathy of prematurity: a retrospective, longitudinal study.

OBJECTIVES: Laser photocoagulation surgery is a routine treatment for threshold retinopathy of prematurity (ROP). However, little is known about which anaesthesia protocols provide efficient pain control while minimising exposure risk to vulnerable infants. In this study, therefore, we assessed the efficacy and tolerability of multiple anaesthesia techniques used on premature infants during laser therapy. DESIGN AND MAIN OUTCOME MEASURES: Anaesthesia modalities consisted of topical eye drops anaesthesia, general anaesthesia and intravenous fentanyl sedation with mechanical ventilation. Laser treatment efficacy and detailed operative information were retrospectively and consecutively analysed. Cardiorespiratory stability was assessed and compared. The Neonatal Pain Agitation and Sedation Scale (N-PASS) was used to evaluate tolerability in infants that underwent intravenous fentanyl sedation. RESULTS: 97 cases of prematurity were included in this study. In 94/97 (96.9%) cases, vascular proliferation regressed. In the topical anaesthesia groups, the ophthalmologist needed 12-16 min more to complete the treatment. During the 3 postoperative days, topical anaesthesia demonstrated the greatest instability; 4/31 (12.90%) infants in this group suffered from life threatening events requiring resuscitation. The only instability observed in general anaesthesia and fentanyl sedation was attributed to difficulty in extubating within 24 hours after surgery. During laser therapy, the N-PASS score increased to 1.8 in the fentanyl sedation group. CONCLUSIONS: Topical anaesthesia was associated with more cardiorespiratory instability during ROP laser treatment. While general anaesthesia and fentanyl sedation had similar postoperative cardiorespiratory results, the latter demonstrated acceptable pain stress control. However, the difficulty of weaning off mechanical ventilation in some cases after surgery needs to be addressed in future studies.

Signaling through hepatocyte vasopressin receptor 1 protects mouse liver from ischemia-reperfusion injury.

Terlipressin has been used extensively in the management of certain complications associated with end-stage liver diseases (ESLDs). In our pilot study, terlipressin treatment showed beneficial effects on liver function in patients with decompensated cirrhosis, however whether it plays a role in liver ischemia-reperfusion injury (IRI) remains unknown. Using a mouse nonlethal hepatic IR model, we found terlipressin administration significantly ameliorated IR-induced liver apoptosis, necrosis and inflammation. Furthermore, despite its known effect on visceral vasoconstriction, hemodynamic evaluation of murine hepatic tissue after IR revealed no change of overall hepatic blood flow after terlipressin treatment. Further studies identified the upregulation of vasopressin receptor 1 (V1R) expression on hepatocytes upon IR. In isolated hepatocyte hypoxia/reoxygenation model, the active component of terlipressin, lysine vasopressin, conferred hepatocytes resistant to oxidative stress-induced apoptosis. Mechanistic studies revealed the V1R engagement activated the Wnt/ß-catenin/FoxO3a/AKT pathway, which subsequently circumvented the proapoptotic events, thus ameliorated hepatocyte apoptosis. Furthermore, genetic knockdown of V1R expression in hepatocyte cell lines or blockade of this signaling pathway abrogated such protective effect. CONCLUSION: These data highlight the functional importance of the hepatocyte V1R/Wnt/ß-catenin/FoxO3a/AKT pathway in protecting liver from oxidative stress-induced injury.