It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial ...cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.
Idiopathic ventricular tachycardias (VTs) and premature ventricular contractions (PVCs) arising from the tricuspid annulus have been reported.
The purpose of this study was to clarify the prevalence ...and characteristics of VT/PVCs originating from the tricuspid annulus.
The ECG characteristics and results of radiofrequency (RF) catheter ablation were analyzed in 454 patients with idiopathic VT/PVCs.
Thirty-eight (8%) patients had VT/PVCs arising from the tricuspid annulus: 28 VT/PVCs (74%) originated from the septal portion of the tricuspid annulus and the remaining 10 (26%) from the free wall of the tricuspid annulus. QRS duration and Q-wave amplitude in each of leads V1-V3 were greater in VT/PVCs arising from the free wall of the tricuspid annulus than those from the septum of the tricuspid annulus (all P < .01). "Notching" of the QRS complex was observed more often in VT/PVCs arising from the free wall of the tricuspid annulus than those from the septum of the tricuspid annulus (P < .01). A Q wave in lead V1 was observed more often in VT/PVCs arising from the septum of the tricuspid annulus than those from the free wall of the tricuspid annulus (P < .005). R-wave transition occurred beyond lead V3 more often in VT/PVCs arising from the free wall of the tricuspid annulus than those from the septum of the tricuspid annulus (P < .005). RF catheter ablation eliminated 90% of the VT/PVCs arising from the free wall of the tricuspid annulus but only 57% of the VT/PVCs arising from septum of the tricuspid annulus.
Idiopathic VT/PVCs arising from tricuspid annulus are not rare, and the detailed origin can be determined by ECG analysis. The preferential site of origin was the septum but also could be the free wall of the tricuspid annulus.
Although previous studies have suggested that appendix seems to be involved in the colitis, the role of this in the pathogenesis remains unclear. In this study, we assessed the importance of ...appendiceal lymphoid follicles, specifically the cecal patches (CP) in mice, using an experimental colitis model. Treatment with oxazolone resulted in ulcerations particularly at CP with follicular expansion as well as colitis. The colitis was attenuated by either appendectomy or the absence of mature B cells. We therefore established an intravital imaging system accompanied by the fluorescence resonance energy transfer technology to analyze the dynamic immune response of CP B cells. Our observation revealed frequent Ca2+ signaling in CP B cells during the early phase of colitis development. These findings suggested that the CP B cells may be involved in the pathogenesis of colitis including inflammatory bowel diseases in humans.
•Cecal patch (CP) ulcerations are seen in the oxazolone colitis model.•Th1, Th2 and Th17 responses in the colon are induced by oxazolone treatment.•Appendectomy attenuates colitis along with decrease in these Th responses.•Colitis and CP ulcerations are also attenuated by the absence of mature B cells.•Intravital imaging shows B cell activation in CP in the setting of colitis.
Abstract Background In a given individual, a consistent relationship exists between oxygen uptake ( V ˙ O 2 ) and heart rate (HR) during exercise. The quotient of V ˙ O 2 and HR ( V ˙ O 2 / HR ) is ...called the oxygen pulse (O2 pulse), and its value is dependent on stroke volume (SV). However, it is difficult to believe that the O2 pulse would indicate the SV when HR has been modified as with the use of beta-adrenergic receptor blockers (BB). Until now, the effect of BB on peak O2 pulse has not been precisely studied. We tried to clarify the effect of BB on the relationship between O2 pulse and SV. Methods Of 699 consecutive heart disease subjects who performed cardiopulmonary exercise tests (CPX) from 2012 to 2014, we enrolled 430 subjects who had sinus rhythm and could perform CPX until exhaustion. One hundred and fifty-seven subjects were taking BB. SV was evaluated during CPX using impedance cardiography, and we compared the peak O2 pulse with peak SV between patients without BB (Group A) and with BB (Group B). Results The HRs at rest and peak exercise in Group A were greater than those in Group B (74.4 ± 13.0/min vs. 71.8 ± 11.3/min, p < 0.01, 134.9 ± 21.7/min vs. 124.9 ± 23.6/min, p < 0.01, respectively). The regression line of the peak O2 pulse against the peak SV was steeper in Group B than in Group A. When we divided the patients into two groups according to the average values of the peak SV and peak V ˙ O 2 , O2 pulse/SV ratio in Group B above the average was greater than that in Group A, whereas it was similar in the two groups that were below average. Conclusion We found that the increase in the O2 pulse was disproportionately greater than the SV that was measured by impedance cardiography when a BB was used in patients with preserved SV and exercise tolerance.
The characteristics of idiopathic ventricular tachycardias (VTs) or idiopathic premature ventricular contractions (PVCs) arising from the pulmonary artery (PA) have not been sufficiently clarified.
...The purpose of this study was to clarify the prevalence, characteristics, and preferential sites of idiopathic VT/PVCs arising from the PA (PA-VT/PVCs).
Data obtained from 276 patients with idiopathic VT/PVCs who underwent radiofrequency (RF) catheter ablation were analyzed.
Twelve VT/PVCs (4%) were PA-VT/PVCs, and their onset (34 +/- 14 years) was the youngest among all subgroups. Because those QRS morphologies were similar to VT/PVCs arising from the right ventricular outflow tract (RVOT-VT/PVC) and the earliest ventricular activation was from the RVOT, an initial ablation was performed in the RVOT in all patients. However, RF catheter ablation at the RVOT resulted in a QRS morphology change in all patients, so thereafter PA mapping and ablation was performed. A characteristic potential during sinus rhythm and/or the arrhythmia was recorded at the successful PA ablation site in all patients. A perfect or good pace map was obtained in 7 (70%) of 10 patients. The successful ablation site was the septal side of the PA close to the posterolateral attachment in 9 patients (75%) and the septal side close to the anterior attachment in the remaining 3 (25%). No PA-VT/PVCs recurred during follow-up of 27 +/- 13 months.
PA-VT/PVCs should always be considered when the ECG suggests RVOT-VT/PVCs and RF catheter ablation in the RVOT results in both a failed ablation and a change in QRS morphology. PA-VT/PVCs often originate from the septal side of the PA.
Abstract Background This study aimed to evaluate an approach for an endpoint of non-inducibility using a combined high-dominant frequency (DF) and continuous complex fractionated atrial electrogram ...(CFAE) ablation following circumferential pulmonary vein isolation (PVI) in a sequential fashion, including linear ablation as compared to PVI alone. Methods and results A total of 84 non-paroxysmal patients with atrial fibrillation (AF) were investigated retrospectively. The AF patients were divided into two groups: patients with PVI following a combined high-DF and continuous CFAE ablation with linear ablation (substrate modification group, n = 59) and those with PVI alone ( n = 25). DF sites of ≥8 Hz and then continuous CFAE sites defined by fractionation intervals of ≤50 ms were modified after PVI. The ablation endpoint was non-inducibility. Atrial tachyarrhythmias (ATs) could not be induced in 54 of 59 (92%) patients after a sequential ablation, and in 18 of 25 (64%) with PVI alone. The ATs freedom without antiarrhythmic drugs in the substrate modification group was significantly greater than that in those with PVI alone after 1 procedure during 12 months of follow-up (78.6% vs. 53.8%, log-rank test p = 0.039). Conclusion This sequential approach using a substrate based ablation was associated with a better clinical long-term outcome as compared to PVI alone.
Background:According to troponin-based criteria of myocardial infarction (MI), patients without elevation of creatine kinase (CK), formerly classified as unstable angina (UA), are now diagnosed as ...non-ST-elevation MI (NSTEMI), but little is known about their outcomes.Methods and Results:Between July 2012 and March 2014, 3,283 consecutive patients with MI were enrolled. Clinical follow-up data were obtained up to 3 years. The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure and urgent revascularization for UA. There were 2,262 patients with ST-elevation MI (STEMI), 563 NSTEMI with CK elevation (NSTEMI+CK) and 458 NSTEMI without CK elevation (NSTEMI-CK). From day 0, Kaplan-Meier curves for the primary endpoint began to diverge in favor of NSTEMI-CK for up to 30 days. The 30-day event rate was significantly lower in patients with NSTEMI-CK (3.3%) than in STEMI (8.6%, P<0.001) and NSTEMI+CK (9.9%, P<0.001). Later, the event curves diverged in favor of STEMI. The event rate from 31 days to 3 years was significantly lower in patients with STEMI (19.8%) than in NSTEMI+CK (33.6%, P<0.001) and NSTEMI-CK (34.2%, P<0.001). Kaplan-Meier curves from 31 days to 3 years were almost identical between NSTEMI+CK and NSTEMI-CK (P=0.91).Conclusions:Despite smaller infarct size and better short-term outcomes, long-term outcomes of NSTEMI-CK after convalescence were as poor as those for NSTEMI+CK and worse than for STEMI.
Introduction: Idiopathic ventricular outflow tract tachycardia or premature ventricular contractions (OT‐VTs) can originate from several different sites in the outflow tract, including the left ...ventricular (LV) endocardium and epicardium. The aims of this study were (1) to develop an ECG algorithm to predict the origin of OT‐VT and (2) to test prospectively the accuracy of the algorithm.
Methods and Results: An algorithm was developed by correlating the 12‐lead ECG findings with the catheter ablation site in 80 patients with OT‐VT. The ECG characteristics of the QRS complex during the arrhythmia were analyzed. The catheter sites were verified by multiplane fluoroscopy. The outflow tract was classified into six subdivisions: right ventricular (RV) septum, RV free wall, RV near the His‐bundle region, LV endocardium, left sinus of Valsalva (LSV), and LV epicardium remote from the LSV. An OT‐VT originating from the LV epicardium remote from the LSV was defined as an OT‐VT in which the earliest ventricular activation was recorded at the LSV and radiofrequency ablation from the LSV failed. This algorithm subsequently was tested prospectively in 88 patients. Overall sensitivity was 88% and specificity was 95%. The positive and negative predictive values were 88% and 96%, respectively.
Conclusion: We describe a new ECG algorithm having a high sensitivity and specificity to identify the optimal ablation site for idiopathic ventricular outflow tachycardia or premature ventricular contractions. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1280‐1286, December 2003)
Background Central sleep apnea, often found in patients with chronic heart failure (CHF), has a high risk of poor prognosis. Methods and Results This study involved 20 patients with CHF (left ...ventricular ejection fraction (LVEF) <45%, M/F =19/1, age 65±10 years) and an apnea-hypopnea index (AHI) >5 times/h who were divided into 2 groups: 10 patients treated with nocturnal home oxygen therapy (HOT) and 10 patients without HOT (non-HOT). All patients had dilated cardiomyopathy and underwent overnight polysomnography, cardiopulmonary exercise testing, and nuclear cardiac examinations to evaluate AHI, exercise capacity according to the specific activity scale and oxygen uptake at anaerobic threshold and peak exercise (peak VO2). Cardiac function according to 99mTc-MIBI QGS, and the total defect score (TDS), H/M ratio and the washout rate (WR) on 123I-metaiodobenzylguanidine (MIBG) imaging were calculated for all patients. As compared with the non-HOT group, the HOT group demonstrated a greater reduction in AHI (26.1±9.1 to 5.1±3.4), 123I-MIBG TDS (31±8 to 25±9), and 123I-MIBG WR (48±8% to 41±5%) and a greater increase in the specific activity scale (4.0±0.9 to 5.8±1.2 Mets), peak VO2 (16.0±3.8 to 18.3±4.7 ml · min-1 · kg-1), and LVEF (27±9% to 37±10%). Conclusions HOT improves exercise capacity, cardiac function, and cardiac sympathetic nerve activity in patients with CHF and central sleep apnea. (Circ J 2009; 73: 299 - 304)
Psoriasis is a chronic, inflammatory skin disease caused by a combination of environmental and genetic factors. The Tnip1 gene encodes A20 binding and inhibitor of NF-κB-1 (ABIN-1) protein and is ...strongly associated with susceptibility to psoriasis in humans. ABIN-1, a widely expressed ubiquitin-binding protein, restricts TNF- and TLR-induced signals. In this study, we report that mice lacking ABIN-1 specifically in dendritic cells (DCs), ABIN-1(fl) CD11c-Cre mice, exhibit perturbed immune homeostasis. ABIN-1-deficient DCs display exaggerated NF-κB and MAPK signaling and produce more IL-23 than do normal cells in response to TLR ligands. Challenge of ABIN-1(fl) CD11c-Cre mice with topical TLR7 ligand leads to greater numbers of Th17 and TCRγδ T cells and exacerbated development of psoriaform lesions. These phenotypes are reversed by DC-specific deletion of the TLR adaptor MyD88. These studies link ABIN-1 with IL-23 and IL-17, and they provide cellular and molecular mechanisms by which ABIN-1 regulates susceptibility to psoriasis.
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