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Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC., Activation of interleukin-17 (IL-17) receptor signaling within intestinal epithelial cells (IECs) promotes colorectal cancer development. Here, the authors show that miR-146a limits inflammation-induced colorectal carcinogenesis by inhibiting both IL-17 induction from myeloid cells and inhibiting IL-17R signaling within IECs.

Summary Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-β on their surface and LAPHi MCs that stimulate Foxp3+ Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-β inhibits the tolerogenic ability of LAPHi MCs. Furthermore, adoptive transfer of LAPHi MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAPHi MCs, slows cancer progression. Single-cell RNA-Seq analysis on tumor-derived immune cells revealed LAPHi dominated cell subsets with distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAPHi MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer., Graphical abstract, Highlights • Several myeloid cell subsets express surface LAP • Myeloid cells that express surface LAP possess immunosuppressive properties • LAP expressing myeloid cells induce Tregs and inhibit effector T cell function • LAP expressing myeloid cells promote tumor growth, Immunology; Cancer

Background: Ventricular fibrillation and atrial fibrillation are well-known arrhythmias in patients with Brugada syndrome. This study evaluated the characteristics of the atrial arrhythmogenic substrate using the signal-averaged electrogram (SAECG) in patients with Brugada syndrome. Methods: SAECGs were performed during normal sinus rhythm in 23 normal volunteers (control group), 21 patients with paroxysmal atrial fibrillation (PAF; PAF group), and 21 with Brugada syndrome (Brugada group). Results: The filtered P wave duration (fPd) in the control, Brugada, and PAF groups was 113.9 ± 12.9 ms, 125.3 ± 15.0 ms, and 137.1 ± 16.3 ms, respectively. The fPd in the PAF group was significantly longer compared to that in the control and Brugada groups (p

Key Clinical Message Ganglionated plexus (GP) plays an important role in the initiation and maintenance of atrial fibrillation (AF). The GP ablation has been found to be effective for AF treatment. In this case, we reported an AF case in which the pulmonary vein (PV) potentials of the anterior region of the left superior PV were eliminated by an inferior right GP ablation.

A 64 year-old man underwent percutaneous coronary intervention (PCI), and the conus branch was occluded. Ventricular fibrillation (VF) occurred five hours after the PCI procedure with a Brugada-like electrocardiogram. A continuous injection of amiodarone was effective for the suppression of VF.

The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.

Summary The roles of the microbiome and innate immunity in the pathogenesis of multiple sclerosis (MS) remain unclear. We have previously documented abnormally low levels of a microbiome-derived Toll-like receptor (TLR)2-stimulating bacterial lipid in the blood of MS patients and postulated that this is indicative of a deficiency in the innate immune regulating function of the microbiome in MS. We postulated further that the resulting enhanced TLR2 responsiveness plays a critical role in the pathogenesis of MS. As proof-of-concept, we reported that decreasing systemic TLR2 responsiveness by administering very low-dose TLR2 ligands attenuated significantly the mouse model of MS, experimental autoimmune encephalomyelitis. Studies of Toll-like receptor responses in patients with MS have been conflicting. Importantly, most of these investigations have focused on the response to TLR4 ligation and few have characterized TLR2 responses in MS. In the present study, our goal was to characterize TLR2 responses of MS patients using multiple approaches. Studying a total of 26 MS patients and 32 healthy controls, we now document for the first time that a large fraction of MS patients (50%) demonstrate enhanced responsiveness to TLR2 stimulation. Interestingly, the enhanced TLR2 responders include a significant fraction of those with progressive forms of MS, a subset of patients considered unresponsive to adaptive immune system-targeting therapies. Our results suggest the presence of a pathologically relevant TLR2 related innate immune abnormality in patients with both relapsing–remitting and progressive MS. These findings may have significant implications for understanding the role of innate immunity in the pathogenesis of MS.

Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3e 3m g/ kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3 e3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidolinduced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD. © 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Vesicular stomatitis virus (VSV) has been extensively studied as a vaccine vector and oncolytic agent. Nevertheless, safety concerns have limited its widespread use in humans. The type III lambda interferon (IFN-λ) family of cytokines shares common signaling pathways with the IFN-α/β family and thus evokes similar antiviral activities. However, IFN-λ signals through a distinct receptor complex that is expressed in a cell type-specific manner, which restricts its activity to epithelial barriers, particularly those corresponding to the respiratory and gastrointestinal tracts. In this study, we determined how IFN-λ expression from recombinant VSV would influence vector replication, spread, and immunogenicity. We demonstrate that IFN-λ expression severely attenuates VSV in cell culture. In vivo , IFN-λ limits VSV replication in the mouse lung after intranasal administration and reduces virus spread to other organs. Despite this attenuation, however, the vector retains its capacity to induce protective CD8 T cell and antibody responses after a single immunization. These findings demonstrate a novel method of viral vector attenuation that could be used in both vaccine and oncolytic virus applications. IMPORTANCE Viruses such as VSV that are used as vaccine vectors can induce protective T cell and antibody responses after a single dose. Additionally, IFN-λ is a potent antiviral agent that has certain advantages for clinical use compared to IFN-α/β, such as fewer patient side effects. Here, we demonstrate that IFN-λ attenuates VSV replication and spread following intranasal virus delivery but does not reduce the ability of VSV to induce potent protective immune responses. These findings demonstrate that the type III IFN family may have widespread applicability for improving the safety and efficacy of viral vaccine and oncolytic vectors.

Time-Domain T-Wave Alternans and Brugada Syndrome Aims T-wave alternans (TWA) is an indicator of vulnerability to ventricular arrhythmias and is useful for predicting sudden cardiac death (SCD) in patients with various structural heart diseases. We evaluated whether high levels of time-domain TWA on ambulatory ECG (AECG) are associated with a history of ventricular fibrillation (VF) in Brugada syndrome (BrS) patients. Methods and Results We examined the associations among VF history, family history of SCD, spontaneous type 1 electrocardiogram (ECG), late potentials, VF induction by programmed electrical stimulation, and TWA in 45 BrS patients (44 males; mean age, 45 ± 15 years). TWA analyzed from 24-h AECG recordings using the modified moving average method was positive in 13 of 43 patients (30%). Patients with a history of VF had a significantly higher incidence of a positive TWA test (82% vs. 13%; P < 0.001) and spontaneous type 1 ECG (92% vs. 38%; P = 0.007) than those without VF history. Multivariate analysis indicated that positive TWA (OR 7.217; 95% CI 2.503–35.504; P = 0.002) and spontaneous type 1 ECG (OR 5.530; 95% CI 1.651–34.337; P = 0.020) were closely associated with VF history. Spontaneous type 1 ECG had high sensitivity (92%) but low specificity (63%). Positive TWA was a reliable marker with high sensitivity and specificity (82% and 88%, respectively). Conclusion Elevated time-domain TWA on AECG confirms arrhythmia risk in symptomatic BrS patients without the need for provocative stimuli.

Incomplete Cure of TIC with Rate ControlBackground It is uncertain whether rate or rhythm control is more favorable for patients experiencing tachycardia-induced cardiomyopathy (TIC) secondary to rapid atrial fibrillation (AF). Methods and Results We compared the electrophysiological and hemodynamic properties and outcome after AF ablation in 20 patients with a history of decompensated TIC who maintained sinus rhythm or had paroxysmal AF (group 1), 32 with a history of decompensated TIC who had persistent or longstanding persistent AF (group 2), 377 without TIC who had paroxysmal AF (group 3), and 225 without TIC who had persistent or longstanding persistent AF (group 4). The corrected sinus node recovery time was more prolonged in group 2 than in groups 1, 3, or 4 (1,066 ± 946 vs. 416 ± 188, 450 ± 322 and 590 ± 329 milliseconds; P < 0.001, respectively). The mean left atrial pressure in group 2 was greater than that in groups 1, 3, or 4 (13.9 ± 6.5 vs. 7.5 ± 3.1, 8.2 ± 4.1 and 10.8 ± 4.2 mmHg; P < 0.001, respectively). The left ventricular ejection fraction assessed after the recovery from the decompensation was more decreased in group 2 than in group 1; however, it almost returned to normal if sinus rhythm was maintained after the AF ablation in group 2. The presence of a history of TIC did not predict an AF recurrence after the ablation. Conclusions Heart rate control during AF without sinus conversion may result in an incomplete cure of TIC, suggesting the advantages of rhythm control with ablation in patients with TIC.

Background:Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and may result in stroke or heart failure and poor prognosis. This study aimed to evaluate a novel index of total atrial conduction time derived from the P-wave onset (lead II) to the peak A’ wave on tissue Doppler imaging (PA-TDI duration). The PA-TDI duration was compared with previously reported predictors of POAF, and the optimal cutoff value of PA-DTI was calculated in patients undergoing aortic valve replacement (AVR) for AV stenosis (AS).Methods and Results:We enrolled 63 patients undergoing isolated AVR. They underwent transthoracic echocardiography with TDI preoperatively and were monitored postoperatively with continuous electrocardiographic telemetry for 7 days. The hospital stay was significantly longer in the 41 patients with POAF than in the 22 without POAF (33.8±19.7 vs. 24.1±8.1 days, P=0.03). Multivariate analysis revealed that PA-TDI duration (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.02–1.13; P=0.0072) and age (OR, 1.14; CI, 1.03–1.28; P=0.016) were significant independent predictors of POAF. Receiver-operating characteristic curve analysis showed the optimal cutoff values of PA-TDI duration and age were 147.3 ms and 74 years, respectively.Conclusions:The PA-TDI duration was an independent predictor of POAF after AVR for AS. Patients with PA-TDI duration >147 ms should be considered high risk and treated appropriately to improve outcomes. (Circ J 2014; 78: 2173–2181)

SUMMARY Smad7, a negative regulator of TGF-β signaling, has been implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC). Here, we found that Smad7 mediates intestinal inflammation by limiting the PDL2/1-PD1 axis in dendritic cells (DCs) and CD4+T cells. Smad7 deficiency in DCs promotes TGF-β responsiveness and the coinhibitory molecules PDL2/1 on DCs, and it further imprints T cell-PD1 signaling to promote Treg differentiation. DC-specific Smad7 deletion mitigates DSS-induced colitis by inducing CD103+PDL2/1+DCs and Tregs. In addition, Smad7 deficiency in CD4+T cells promotes PD1 and PD1-induced Tregs in vitro. The transfer of Smad7-deficient CD4+T cells enhances Tregs in vivo and protects against T cell-mediated colitis. Furthermore, Smad7 antisense ameliorates DSS-induced UC, increasing TGF-β and PDL2/1-PD1 signaling. Enhancing PD1 signaling directly via Fc-fused PDL2/1 is also beneficial. Our results identify how Smad7 mediates intestinal inflammation and leverages these pathways therapeutically, providing additional strategies for IBD intervention., In Brief Smad7, a negative regulator of TGF-β signaling, is implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs). Here, Garo et al. describe how Smad7 within both dendritic cells and CD4+ T cells limits PD1-mediated Treg induction to promote intestinal inflammation, providing additional therapeutic strategies for IBD intervention., Graphical Abstract

Variable Strategies for CTI Ablation Objectives This study aimed to investigate the anatomical characteristics complicating cavotricuspid isthmus (CTI) ablation and the effectiveness of various procedural strategies. Methods and Results This study included 446 consecutive patients (362 males; mean age 60.5 ± 10.4 years) in whom CTI ablation was performed. A total of 80 consecutive patients were evaluated in a preliminary study. The anatomy of the CTI was evaluated by multidetector row-computed tomography (MDCT) prior to the procedure. A multivariate logistic regression analysis revealed that the angle and mean wall thickness of the CTI, a concave CTI morphology, and a prominent Eustachian ridge, were associated with a difficult CTI ablation (P < 0.01). In the main study, 366 consecutive patients were divided into 2 groups: a modulation group (catheter inversion technique for a concave aspect, prominent Eustachian ridge, and steep angle of the CTI or increased output for a thicker CTI) and nonmodulation group (conventional strategy). The duration and total amount of radiofrequency energy delivered were significantly shorter and smaller in the modulation group than those in the nonmodulation group (162.2 ± 153.5 vs 222.7 ± 191.9 seconds, P < 0.01, and 16,962.4 ± 11,545.6 vs 24,908.5 ± 22,804.2 J, P < 0.01, respectively). The recurrence rate of type 1 atrial flutter after the CTI ablation in the nonmodulation group was significantly higher than that in the modulation group (6.3 vs 1.7%, P = 0.02). Conclusion Changing the procedural strategies by adaptating them to the anatomical characteristics improved the outcomes of the CTI ablation.

The total cellular lipids of Porphyromas gingivalis , a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The purpose of the present investigation was to fractionate all lipids of P. gingivalis and define which lipid classes account for the TLR2 engagement, based on both in vitro human cell assays and in vivo studies in mice. Specific serine-containing lipids of P. gingivalis , called lipid 654 and lipid 430, were identified in specific high-performance liquid chromatography fractions as the TLR2-activating lipids. The structures of these lipids were defined using tandem mass spectrometry and nuclear magnetic resonance methods. In vitro , both lipid 654 and lipid 430 activated TLR2-expressing HEK cells, and this activation was inhibited by anti-TLR2 antibody. In contrast, TLR4-expressing HEK cells failed to be activated by either lipid 654 or lipid 430. Wild-type (WT) or TLR2-deficient (TLR2 −/− ) mice were injected with either lipid 654 or lipid 430, and the effects on serum levels of the chemokine CCL2 were measured 4 h later. Administration of either lipid 654 or lipid 430 to WT mice resulted in a significant increase in serum CCL2 levels; in contrast, the administration of lipid 654 or lipid 430 to TLR2 −/− mice resulted in no increase in serum CCL2. These results thus identify a new class of TLR2 ligands that are produced by P. gingivalis that likely play a significant role in mediating inflammatory responses both at periodontal sites and, potentially, in other tissues where these lipids might accumulate.

Variable Strategies for CTI Ablation Objectives This study aimed to investigate the anatomical characteristics complicating cavotricuspid isthmus (CTI) ablation and the effectiveness of various procedural strategies. Methods and Results This study included 446 consecutive patients (362 males; mean age 60.5 ± 10.4 years) in whom CTI ablation was performed. A total of 80 consecutive patients were evaluated in a preliminary study. The anatomy of the CTI was evaluated by multidetector row-computed tomography (MDCT) prior to the procedure. A multivariate logistic regression analysis revealed that the angle and mean wall thickness of the CTI, a concave CTI morphology, and a prominent Eustachian ridge, were associated with a difficult CTI ablation (P < 0.01). In the main study, 366 consecutive patients were divided into 2 groups: a modulation group (catheter inversion technique for a concave aspect, prominent Eustachian ridge, and steep angle of the CTI or increased output for a thicker CTI) and nonmodulation group (conventional strategy). The duration and total amount of radiofrequency energy delivered were significantly shorter and smaller in the modulation group than those in the nonmodulation group (162.2 ± 153.5 vs 222.7 ± 191.9 seconds, P < 0.01, and 16,962.4 ± 11,545.6 vs 24,908.5 ± 22,804.2 J, P < 0.01, respectively). The recurrence rate of type 1 atrial flutter after the CTI ablation in the nonmodulation group was significantly higher than that in the modulation group (6.3 vs 1.7%, P = 0.02). Conclusion Changing the procedural strategies by adaptating them to the anatomical characteristics improved the outcomes of the CTI ablation.

Background The indications for catheter ablation have been expanded to include persistent atrial fibrillation (AF) to enable a high degree of sinus rhythm maintenance. We occasionally encounter patients undergoing pacemaker implantation in whom sick sinus syndrome became clinically evident after ablation. This study investigated whether underlying sinus node dysfunction (SND) during persistent AF can be predicted before deciding the indications for ablation. Methods and results In total, 87 consecutive patients with persistent AF who underwent catheter ablation between January 2010 and July 2011 were enrolled in the study. Nocturnal polysomnography as well as transthoracic and transesophageal echocardiography were performed in all patients before ablation. We used the double Lasso catheter and electroanatomical mapping-guided extensive encircling pulmonary vein isolation (EEPVI) method. We performed electrophysiological studies after EEPVI, and SND was defined as a corrected SN recovery time of ≥550 ms. SND was detected in 42 (48%) patients (SND group); the other patients showed normal sinus node function (NSN group). The apnea/hypopnea index (AHI) was significantly greater in the SND group than in the NSN group (25.7 ± 13 vs. 17.5 ± 11, p = 0.002). Multivariate analysis revealed that moderate to severe sleep-disordered breathing (defined as AHI ≥ 15) was an independent predictor of SND after catheter ablation for persistent AF. Conclusion The results suggest that underlying SND in patients with persistent AF can be predicted by evaluating sleep-disordered breathing before catheter ablation.

Aims We aimed to determine how many electrical cardioversions (ECs) should be applied to treat repetitive persistent recurrences of atrial fibrillation (AF) following ablation of persistent AF within the early post-procedural period. Methods and results A total of 40 patients with >1 episode of recurrent AF in the form of persistent atrial arrhythmias within 3 months following the ablation were recruited from 108 patients who underwent ablation for persistent or long-standing persistent AF. Electrical cardioversions were applied up to six times, if necessary, to restore sinus rhythm at clinical visits at 2-week intervals until 3 months after the ablation. Fourteen (35%) ablation failures defined as recurrences of AF identified from the 3rd month after the ablation procedure were finally diagnosed during the follow-up period (14 ± 4 month). The patients with an ablation failure more frequently required ECs than those without (3.7 ± 0.3 vs. 1.2 ± 0.2 times; P < 0.0001). A receiver-operating characteristic curve identified a number of ECs of ≥3 as the optimal cut-off value for predicting an ablation failure (area under the curve 0.91; sensitivity, 86%, and specificity, 96%; P = 0.0007). In the multivariate logistic regression analysis, a number of ECs of ≥3 was the only independent predictor of an ablation failure (odds ratio, 11.32; 95% confidence interval, 3.83–58.22; P = 0.0019). Conclusion It was difficult to maintain sinus rhythm in patients with persistent AF who required several ECs for recurrences of AF within the early post-ablation period.

Background: In previous studies, the minimal luminal diameter (MLD) of lesions treated with a bare metal stent (BMS) was shown to improve from 6 months to 3 years. However, the long-term response to a sirolimus-eluting stent (SES) implantation remains unclear. Methods and Results: To evaluate 6-month, 12-month and 3-year outcomes, clinical and angiographic follow-up data were analyzed for 367 consecutive patients (506 de novo lesions) who underwent successful SES implantation compared to follow-up data for 617 consecutive patients (802 de novo lesions) who underwent BMS implantation. Clinical follow-up information was obtained for 363 SES-treated patients (98.9%) and 581 BMS-treated patients (94.2%) at 1 year, and 334 SES-treated patients (91.0%) and 566 BMS-treated patients (91.7%) at 3 years. At 3 years, there were no significant differences in the cumulative cardiac death and myocardial infarction. Target lesion revascularization (TLR) rates were significantly higher in BMS-treated patients than in SES-treated patients. In BMS-treated patients, most TLR was performed within 450 days, however, after 450 days, the TLR rate was significantly lower than that for the SES-treated patients. In quantitative coronary angiographic data, among lesions that required no revascularization at the initial 12-month follow up, MLD increased significantly from the 12-month to the 3-year follow-up angiography in BMS-treated lesions. However, MLD decreased significantly in SES-treated lesions. Conclusions: From a 12-month follow-up to a 3-year follow-up, stenosis in BMS-treated lesions regressed, but stenosis in SES-treated lesions progressed. And late TLR was more frequently required in the SES-treated patients. (Circ J 2010; 74: 1104 - 1110)

Left ventricular thrombus (LVT) after acute myocardial infarction (AMI) is a risk factor for embolic complications. Although warfarin has traditionally been used to treat LVT, it has relevant disadvantages that limit its use. We herein describe the case of a 78-year-old man with AMI who had a history of paroxysmal atrial fibrillation. Following 10 days of urgent coronary reperfusion therapy, transthoracic echocardiography revealed a moderately sized LVT in the apex, which subsequently disappeared after 18 days of treatment with dabigatran. This case demonstrates that dabigatran may represent an alternative to warfarin as a therapeutic option in patients with LVT after AMI.

The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-β therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients. We now show that Cbl-b(-/-) T cells demonstrate significant lymph node trafficking abnormalities. We thus asked whether the MS-approved drug, FTY720, postulated to trap T cells in lymphoid tissues, is less effective in the context of Cbl-b dysfunction. We now report that FTY720 significantly inhibits EAE in Cbl-b(-/-) mice. Our results newly document a role for Cbl-b in T cell trafficking but suggest nevertheless that MS patients with Cbl-b abnormalities may still be excellent candidates for FTY720 treatment.

We have reported that the third component of complement (C3) is observed in the pattern of microscale non-denaturing two-dimensional electrophoresis (2-DE) after removal of IgG and IgA using protein A agarose and antibodies.1) For the investigation of constitutive polypeptides of the C3, the constituent polypeptides of human plasma proteins were analyzed using non-denaturing isoelectric focusing (IEF) in the first dimension and treated with mercaptoethanol/SDS, and then subjected to the second dimensional SDS electrophoresis (non-denaturing IEF/reduced-SDS PAGE). The α chain of C3 spot was detected in the pattern of non-denaturing IEF/reduced-SDS PAGE, but, the β chain of C3 spot was hidden by albumin spot. After albumin was removed using polyethylene glycol, both C3α and C3β spots were observed in the pattern of the non-denaturing IEF/reduced-SDS PAGE. The combining analysis of C3 in the non-denaturing 2-DE and the constituent polypeptides in the non-denaturing IEF/reduced-SDS PAGE can be useful for the analysis of C3 and its fragments during the activation of complements.

Background Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery and results in increased health-care utilization. This study identified new transthoracic echocardiographic predictors of POAF using an index of the total atrial conduction time derived on tissue Doppler imaging (PA-TDI duration) in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Methods and results A total of 88 patients undergoing isolated OPCAB were enrolled. They were examined preoperatively on transthoracic echocardiography with tissue Doppler evaluations and monitored postoperatively with continuous electrocardiographic telemetry for 7 days. POAF occurred in 35 patients (39.8%). Patients with POAF had a significantly longer duration of hospital stay than those without (44.9±6.2 vs. 37.3±3.3 days, P=0.04). Multivariate analysis showed that PA-TDI duration (odds ratio [OR], 1.11; 95% confidence interval [CI]: 1.06-1.16; P=0.0001) and left atrial volume index (LAVI; OR, 1.11; 95% CI: 1.02-1.20; P=0.01) were independent predictors of POAF. Moreover, PA-TDI duration was more reliable, given an area under the receiver operating characteristic curve of 0.85 (sensitivity, 74.3%; specificity, 86.8%). Conclusions PA-TDI duration was an independent predictor of POAF following OPCAB. Awareness of risk of POAF may lead to the prevention of POAF, a rapid response to POAF, shortened hospital stay, and improved prognosis.

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67–5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A I334V, VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A I334V (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A I334V. Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A I334V genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A I334V in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA., Author Summary Unexplained cardiac arrest with documented ventricular fibrillation (UCA) is defined as spontaneous ventricular fibrillation (VF) that is not associated with known structural or electrical heart diseases and is one of the major causes of sudden cardiac death. Identification of the genes responsible for UCA may further increase our understanding of mechanisms of UCA and facilitate more accurate diagnosis and preventive treatment, especially in asymptomatic disease-carrying relatives of the patient. However, molecular mechanisms of UCA have not been fully clarified due to the high mortality rate and difficulty of diagnosis. In this study, UCA patients are shown to have a high incidence of a polymorphism in the Semaphorin 3A gene (rs138694505, SEMA3A I334V). The result confirms previous reports that the abnormal sympathetic innervation is a trigger of UCA because SEMA3A is crucial for the establishment of normal innervation patterns in the heart. Furthermore, experimental data presented here indicate that SEMA3A I334V disrupts the SEMA3A function and impairs appropriate innervation patterning. Finally, the study suggests that SEMA3A I334V is a risk factor for human UCA and contributes to the etiology of UCA.

Sinus node dysfunction (SND) occasionally coexists with atrial flutter (AFL). However, the identification of SND during AFL is difficult. We investigated whether we could predict underlying SND in patients with persistent AFL using the flutter cycle length (FCL).We retrospectively studied 211 successfully ablated patients with persistent cavotricuspid isthmus (CTI)-dependent AFL and measured the FCL before the ablation and corrected sinus node recovery time (CSNRT) after the ablation. Twenty-four patients (11%) required a permanent pacemaker implantation (PMI) for significant SND after AFL termination and had a longer FCL (295 ± 37 vs. 236 ± 34 ms; P0.0001) and greater CSNRT (1727 ± 1014 vs. 603 ± 733 ms; P0.0001) than those not requiring a PMI. A receiver-operating characteristic curve identified an FCL of273 ms as the optimal cut-off value for predicting SND requiring a PMI (area under the curve 0.91; sensitivity, 83% and specificity, 89%; P0.0001). Multiple linear and logistic regression analyses revealed that the left ventricular ejection fraction (LVEF) (β = -0.2; P= 0.0016) and FCL (β = 0.46; P0.0001) were independently associated with the CSNRT, and that females [odds ratio (OR), 2.43; 95% confidence interval (CI), 1.32-4.62; P= 0.0046], an LVEF50% (OR, 2.10; 95% CI, 1.20-3.87; P= 0.012), and an FCL of273 ms (OR, 5.34; 95% CI, 3.08-10.08; P0.0001) were independent predictors of SND requiring a PMI.Although this study was based on a review of a database, the results suggest that assessing the FCL in patients with persistent CTI-dependent AFL could be helpful in the risk stratification of underlying SND.

In previous studies, the minimal luminal diameter (MLD) of lesions treated with a bare metal stent (BMS) was shown to improve from 6 months to 3 years. However, the long-term response to a sirolimus-eluting stent (SES) implantation remains unclear.To evaluate 6-month, 12-month and 3-year outcomes, clinical and angiographic follow-up data were analyzed for 367 consecutive patients (506 de novo lesions) who underwent successful SES implantation compared to follow-up data for 617 consecutive patients (802 de novo lesions) who underwent BMS implantation. Clinical follow-up information was obtained for 363 SES-treated patients (98.9%) and 581 BMS-treated patients (94.2%) at 1 year, and 334 SES-treated patients (91.0%) and 566 BMS-treated patients (91.7%) at 3 years. At 3 years, there were no significant differences in the cumulative cardiac death and myocardial infarction. Target lesion revascularization (TLR) rates were significantly higher in BMS-treated patients than in SES-treated patients. In BMS-treated patients, most TLR was performed within 450 days, however, after 450 days, the TLR rate was significantly lower than that for the SES-treated patients. In quantitative coronary angiographic data, among lesions that required no revascularization at the initial 12-month follow up, MLD increased significantly from the 12-month to the 3-year follow-up angiography in BMS-treated lesions. However, MLD decreased significantly in SES-treated lesions.From a 12-month follow-up to a 3-year follow-up, stenosis in BMS-treated lesions regressed, but stenosis in SES-treated lesions progressed. And late TLR was more frequently required in the SES-treated patients.

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology. Infectious agents have been suggested to have a role as environmental factors in MS, but this concept remains controversial. Recently, gastrointestinal commensal bacteria have been implicated in the pathogenesis of autoimmune diseases, but mechanisms underlying the relationship of human systemic autoimmunity with the commensal microbiome have yet to be identified. Consistent with the lack of understanding of pathogenic mechanisms and relevant environmental factors in MS, no blood biomarkers have been identified that distinguish MS patients from healthy individuals. We recently identified a unique gastrointestinal and oral bacteria-derived lipodipeptide, Lipid 654, which is produced by commensal bacteria and functions as a human and mouse Toll-like receptor 2 ligand. Using multiple-reaction-monitoring mass spectrometry, a critical approach in targeted lipidomics, we now report that Lipid 654 can be recovered in the serum of healthy individuals. Most interestingly, we find that Lipid 654 is expressed at significantly lower levels in the serum of patients with MS compared with both healthy individuals and patients with Alzheimer's disease. These results thus identify for the first time a potential mechanism relating the gastrointestinal and oral commensal microbiome to a human systemic autoimmune disease. In addition, these results also identify a potential etiologic environmental factor and novel clinically relevant serum biomarker for MS.

Introduction Vaccines based on replicating viral vectors that express foreign antigens can generate superior durable antibody and memory CD8 T cell responses compared to inactivated virus or recombinant protein, with the added benefit of potential needle-free intranasal administration. Despite these significant advantages, safety concerns related to viral vectors as vaccine platforms can be an issue with this approach. Replicating viral vectors are perceived as less safe alternatives compared to other immunization modalities, especially in the context of intranasal administration, where the potential exists for systemic virus spread from the lung. The type III interferons (IL-29, IL-28A, IL-28B; also known as IFN-lambda1, 2, and 3) play a critical role in protecting epithelial cells in the lung and gut from virus infection, and can also stimulate adaptive immunity. We therefore examined the ability of this cytokine family to improve the safety and efficacy of a viral vector by limiting its systemic spread and vector-associated pathological effects after intranasal delivery. Methods Vesicular stomatitis virus (VSV) based vectors are promising candidates for use as vaccines and oncolytic agents. We generated recombinant VSV vectors expressing mouse IL-28A either from the fifth position or the more highly expressing first position of the viral genome, and measured virus replication in cell culture and mice. Results We found that IL-28A is properly expressed, secreted, and active when produced by VSV-infected cells. In cell culture, expression of IL-28A from VSV attenuated virus replication in type III IFN-sensitive cells, but not in type III IFN-resistant cells. Following intranasal inoculation in mice, spread of the VSV.IL28A vector from the lung to the lymph nodes, spleen, blood, liver, and brain was significantly reduced compared to recombinant wild-type VSV. Despite this attenuation, the VSV.mIL28A vector generated virus-specific CD8 T cell and antibody responses in mice that were comparable to wild-type VSV. Conclusion These studies demonstrate the ability of the type III interferon cytokine family to improve the safety and efficacy of a clinically promising viral vaccine vector. These results may potentially also inform the enhancement of VSV oncolytic activity by increasing selectivity of the virus for type III IFN-resistant tumor cells.

Purpose: Myocardial thickness is particularly thick at the ridge between the left pulmonary vein (PV) and the left atrial appendage (LAA) by dissection. We investigated whether the atrial fibrillation (AF) ablation outcome was influenced by altering ablation strategies according to the thickness of the PV-LAA ridge using preprocedural multidetector computed tomography (MDCT). Methods: Patients with AF scheduled for extensive encircling circumferential pulmonary vein isolation (EEPVI) (110 pts) were divided into two groups. In the nonmodulation group (32 pts), EEPVI lines were created using a 3.5-mm tip irrigated catheter at a maximum power of 30 W for 15–20 s at each site. In the modulation group (78 pts), ablation was extended (30–40 s) at the PV-LAA ridge if its thickness was >4.0 mm on MDCT. Results: In the modulation group, extended ablation at the PV-LAA ridge was observed in 37 pts. During 25±9 months of follow-up, the recurrence was significantly less in the modulation group (10% vs. 28%, p=0.018). Logistic regression analysis demonstrated that modifications in the ablation time and LA volume index were independent predictors of arrhythmia-free recovery after ablation. Conclusion: Recurrence following EEPVI could be reduced by modifications in the ablation time at the PV-LAA ridge.

Background: Indication of ablation has been expanded to include chronic atrial fibrillation (CAF) for enabling high degree of sinus rhythm maintenance. We have encountered patients undergoing pacemaker implantation, in whom sick sinus syndrome became clinically evident after ablation. The study aims to investigate whether underling sinus node dysfunction (SND) during CAF can be predicted before deciding the indication for ablation. Methods and Results: Sixty consecutive patients with CAF who underwent ablation between January to December 2010 were enrolled in the study. Nocturnal polysomnography as well as echocardiography was performed for all patients before ablation. We used the double Lasso catheter and electro anatomical mapping guided extensive encircling pulmonary vein isolation (EEPVI). We performed electrophysiological studies after EEPVI, and SND was defined as corrected SN recovery time of ≥550 ms. SND was detected in 26 (43%) patients (SND group); the other patients showed normal sinus node function (NSN group). The apnea/hypopnea index (AHI) was significantly greater in the SND group than in the NSN group (25.7±13 vs 15.8±10, P=0.0022). On multivariate analysis, sleep apnea syndrome (SAS) was an independent predictor of SND after ablation for CAF. Conclusion: This study suggested that underlying SND in CAF patients can be predicted by evaluating SAS before ablation.

Music and other sounds have been played to provide a pleasant sound environment for workers in a factory. In terms of "Sound Perspicuity" this case study was conducted to assess audibility of spatial sounds, which were adjusted in level without increasing total sound pressure level (SPL) at the workstation. Furthermore, the added sounds were not audible at other workstations. Three speaker systems, including line‐array speaker (60 cm in length), were used for the case study. The ratio of added sound (Signal) to factory noise (Noise) was analyzed at every measuring point on a grid of 50 cm by 50 cm. Audibility listening tests were performed for the added sounds, such as natural‐environment sounds and musical instrument tones, with Signal to Noise ratios analyzed from three types of speaker. As a result, a sound is recognized as "Kiwadachi" by a Japanese adjective word even when the factory noise has higher levels than the added sounds. Audibility test results for each added sound are discussed with differe...

Recently, speech privacy to avoid oral information leakage in healthcare facilities has become an important issue. This study investigated effectiveness of sound masking system in regard to masking efficiency, annoyance and its influence on speech conversation for medical examination rooms in an experimental approach. Considering actual application, two adjacent medical examination rooms partitioned by a low sound insulation wall in a typical healthcare facility were selected as an experimental field and sound masking system was temporally installed. In the rooms, acoustic environment was measured and reproduced in an anechoic room with a 3‐D sound field simulation system using a 6‐ch sound recording/reproduction technique. In the simulated acoustic condition, subjective tests were designed to quantify the masking efficiency and annoyance caused by the masking sound. The annoyance test was conducted in listening condition (with high attention to the sound) and in talking condition (with low attention). As a result, mixed maskers composed by water stream, synthesized speech signals, and steady state noise showed high performance in both aspect of masking efficiency and annoyance.

Background Myocardial thickness is particularly thick at the ridge between the left pulmonary vein (PV) and the left atrial appendage (LAA) by dissection. We investigated whether atrial fibrillation (AF) ablation outcome was influenced by altering ablation strategies according to the thickness of the PV–LAA ridge using preprocedural multidetector computed tomography (MDCT). Methods and results Patients with AF scheduled for extensive encircling circumferential pulmonary vein isolation (EEPVI) (110 patients) were divided into 2 groups. In the nonmodulation group (32 patients), EEPVI lines were created using a 3.5-mm tip irrigated catheter at a maximum power of 30 W for 20–30 s at each site. In the modulation group (78 patients), ablation was extended (40–60 s) at the PV–LAA ridge if its thickness was >4.0 mm on MDCT examination. Extended ablation at the PV–LAA ridge was noted in 37 patients in the modulation group. During 25 ± 9 months of follow-up, recurrence was significantly less in the modulation group than in the nonmodulation group (10% vs. 28%; p = 0.018). Logistic regression analysis showed that modifications in the ablation time and left atrium volume index were independent predictors of arrhythmia-free recovery after ablation. Conclusions Recurrence following EEPVI could be reduced by modifications in the ablation time at the PV–LAA ridge.