Acetylsalicylic acid-induced release of HSP70 from mast cells results in cell activation through TLR pathway

OBJECTIVE: Mast cells are considered major players in IgE-mediated allergic responses, but have also recently been recognized as active participants in innate as well as specific immune responses. Heat stress can modulate innate immunity by inducing stress proteins such as heat shock proteins (HSPs). It has been reported that HSPs are capable of inducing the production of pro-inflammatory cytokines by the monocyte-macrophage system. In the current study, we explored whether the stress response induces HSPs and affects the signaling pathways of mast cells. METHODS: In mouse mast cells, derived from a culture of bone marrow cells of male BALB/cBy and null HSF-1(-/-) mice, responsiveness to exogenous and endogenous HSP70 was monitored by measuring cytokine release. RESULTS: Using BMMC, we show that treatment with heat shock or acetylsalicylic acid results in a selective induction of HSPs, and leads to release of HSP70 into the extracellular environment. The release of HSP70 from mast cells may be of functional importance. We found that after induction of HSP70, the production of TNF-alpha and IL-6 was increased. In a number of experiments, we demonstrated that exogenous/secreted HSP70 is most likely responsible for the activation of mast cells to produce cytokines. Extracellular HSP70 induced production of TNF-alpha and IL-6 through the activation of the TLR4 receptor pathway, which was evidenced by an abrogation of the response in mast cells cultured from TLR4(null) or HSF-1(-/-) mice. CONCLUSION: Our experiments suggest that stress conditions can induce pro-inflammatory cytokine production by mast cells through an autocrine or paracrine stimulation of TLR receptors after a heat shock response. The recognition that heat shock proteins induce mast cell activation suggests an involvement of these cells in the immunological processes induced by heat shock response.     

The effects of levofloxacin on ECG parameters and late potentials

In this study, our aim was to investigate the proarrhythmic effects of levofloxacin. Twenty-six patients who were diagnosed as having community-acquired pneumonia were enrolled in the study. Intravenous levofloxacin, 500 mg daily, was given, and 12-lead ECG measurements were obtained before the infusion, at 30 and 60 minutes during infusion, and 10 minutes after its cessation. Resting late potentials were recorded before and after infusion. Twelve female and 14 male patients were participated the study. Mean age was 51.3 +/- 22.3 years. Levofloxacin infusion increased the heart rate (HR) and prolonged the corrected QT (QTc) intervals significantly (baseline HR: 84.6 +/- 18.8 vs. HR at 60 minutes: 88.6 +/- 18, P = 0.02; baseline QTc: 413.5 +/- 36.9 milliseconds vs. QTc at 60 minutes: 426.1 +/- 34.7, P = 0,006). There was no significant difference between the late potential values obtained before and after infusion. None of our patients experienced severe arrhythmia that required stopping the treatment. A single dose of IV levofloxacin prolongs the QTc interval without significant change in late potentials. Monitoring ECG during levofloxacin infusion might be necessary in patients who have a condition that could affect the QTc interval.     

Consistent reconstruction of 4D fetal heart ultrasound images to cope with fetal motion

Purpose

4D ultrasound imaging of the fetal heart relies on reconstructions from B-mode images. In the presence of fetal motion, current approaches suffer from artifacts, which are unrecoverable for single sweeps.

Methods

We propose to use many sweeps and exploit the resulting redundancy to automatically recover from motion by reconstructing a 4D image which is consistent in phase, space, and time. An interactive visualization framework to view animated ultrasound slices from 4D reconstructions on arbitrary planes was developed using a magnetically tracked mock probe.

Results

We first quantified the performance of 10 4D reconstruction formulations on simulated data. Reconstructions of 14 in vivo sequences by a baseline, the current state-of-the-art, and the proposed approach were then visually ranked with respect to temporal quality on orthogonal views. Rankings from 5 observers showed that the proposed 4D reconstruction approach significantly improves temporal image quality in comparison with the baseline. The 4D reconstructions of the baseline and the proposed methods were then inspected interactively for accessibility to clinically important views and rated for their clinical usefulness by an ultrasound specialist in obstetrics and gynecology. The reconstructions by the proposed method were rated as ‘very useful’ in 71% and were statistically significantly more useful than the baseline reconstructions.

Conclusions

Multi-sweep fetal heart ultrasound acquisitions in combination with consistent 4D image reconstruction improves quality as well as clinical usefulness of the resulting 4D images in the presence of fetal motion.

     

Ca2+-dependent modulation of single human cardiac L-type calcium channels by the calcineurin inhibitor cyclosporine

OBJECTIVE: Activity of single L-type calcium channels (LTCC) is enhanced in human failing myocardium (Circulation 98 (1998) 969.), most likely due to impaired dephosphorylation. Protein phosphatase 2B (calcineurin) has recently been shown to be involved in heart failure pathophysiology. We now focus on the regulation of single LTCC by calcineurin that were prevented by Ca(2+)-free experimental conditions in our previous study. METHODS: Single LTCC currents were recorded in myocytes from human atrium and ventricle. Charge carriers were 70 mM Ba(2+), or a mixture of 30 mM Ca(2+) and 60 mM Ba(2+) to facilitate Ca(2+) permeation through recorded channels. The calcineurin inhibitor cyclosporine (10 microM) was used to reveal a putative role for calcineurin in regulation of LTCC. RESULTS: A mixture of Ca(2+) and Ba(2+) as charge carriers allowed for Ca(2+) permeation through recombinant human embryonic kidney cells and native (atrial and ventricular) human cardiac LTCC. With only Ba(2+) as the charge carrier, activities of both ventricular and atrial LTCC were strongly decreased by cyclosporine. In contrast, channel activity remained constant when Ca(2+) permeation was provided. In the presence of thapsigargin and (S)-BayK 8644, cyclosporine here even increased channel activity. CONCLUSIONS: We propose a dual cyclosporine effect on human cardiac LTCC. A non-specific inhibitory effect prevails with Ba(2+) permeation but can be compensated or overcome by a specific Ca(2+)-dependent stimulation with Ca(2+) permeation. More complete restoration of physiological Ca(2+) movements (e.g., Ca(2+) release from sarcoplasmic reticulum) will help to define even more precisely the involvement of calcineurin in regulation of human cardiac LTCC.     

Effect of aortic pulse and fractional pulse pressures on early patency of sapheneous vein grafts

BACKGROUND: Coronary artery bypass grafting has a mortality benefit compared to medical therapy in some patient groups, such as those with left main or left anterior descending coronary artery disease, and those with left ventricular dysfunction. Therefore, patency of grafts, especially sapheneous grafts, is an important issue. Aortic pulse and fractional pulse pressures are strong and independent indicators of the risk of atherosclerosis. We studied whether there was any negative effect of increased aortic pulse and fractional pulse pressures on saphenous vein graft (SVG) patency in the short term. METHODS: We evaluated aortic pulse and fractional pulse pressures of patients with occluded and patent SVGs, and investigated the relation between the two groups. One hundred and twenty-six patients with occluded SVGs with a mean age of 65.9+/-8.9 years and 114 patients with patent SVGs with a mean age of 66.9+/-8.6 years were studied consecutively. Aortic systolic and diastolic pressures were measured, and mean, pulse, and fractional pulse pressures (aortic pulse pressure/mean pressure) were calculated. RESULTS: Aortic pulse and fractional pulse pressures were significantly higher in the occluded SVG group than in the patent SVG group (58+/-19 and 48+/-13 mmHg, P=0.001; 0.59+/-0.16 and 0.50+/-0.10, P<0.001, respectively). In addition, a cut-off value of 50 mmHg and 0.52 for aortic pulse and fractional pulse pressures were determined, respectively. Increased aortic pulse (>50 mmHg) and fractional pulse (>0.52) pressures were present in 54.0 and 58.7% of patients in group 1 and 28.1 and 33.3% of patients in group 2, respectively (P=0.004 and P=0.005, respectively). Having increased aortic pulse and fractional pulse pressures increased the risk of SVG occlusion by 3.00 and 2.85-folds, respectively. The multiple-adjusted odds ratio of the risk of SVG occlusion was 6.86 (95% confidence interval 2.14-21.96) and 4.76 (95% confidence interval 1.58-14.30) for the higher aortic pulse and fractional pulse pressure levels compared with lower levels, respectively. CONCLUSION: Increased ascending aorta pulse and fractional pulse pressures have a significant and independent negative effect on the fate of SVGs.     

Plasma levels of tumor necrosis factor-α and its receptors in patients with mitral stenosis and sinus rhythm undergoing percutaneous balloon valvuloplasty

This study aimed to determine whether plasma levels of tumor necrosis factor-α (TNF-α) and soluble TNF receptor (sTNF-R) increases in rheumatic mitral stenosis (MS) patients with sinus rhythm and to examine the effect of percutaneous mitral balloon valvuloplasty (PMBV) on these parameters. Twenty-six patients with MS and sinus rhythm (study group, 20 female, mean age 33 ± 8 years), who were scheduled for PMBV, and a well-matched control group consisting of 21 healthy volunteers (15 female, mean age 35 ± 6 years) were enrolled in the study. Tumor necrosis factor-α and sTNF-R levels were compared between study patients and controls, and between peripheral and left atrium (LA) blood. Changes in TNF α and sTNF-R levels 24 h and 4 weeks after PMBV were analyzed. Significantly higher baseline TNF-α and sTNF-R levels were noted in the study group. In the study group, TNF-α and its receptors were also found to be higher in LA blood than in baseline peripheral blood. After PMBV, mitral valve area (MVA) increased and transmitral pressure gradient decreased significantly. At the 24th hour after PMBV, the TNF-α level decreased from 29.61 ± 12.22 pg/ml to 22.42 ± 8.81 pg/ml (P < 0.0001) and at the 4th week, from 22.42 ± 8.81 pg/ml to 18.92 ± 7.37 pg/ml (P < 0.0001). Similar reductions were observed in the sTNF-R level. Regression analysis between the difference in sTNF-R level measured 24 h after and before PMBV and the difference in MVA measured 24 h after and before PMBV showed a significant direct relationship between these variables. This study suggests that isolated rheumatic MS without atrial fibrillation is accompanied by increased TNF-α and sTNF-R level. The successful PMBV establishes a significant reduction in TNF-α and its receptors, probably due to improved postprocedural hemodynamic parameters.     

Gemcitabine treatment in patients with inoperable locally advanced/metastatic pancreatic cancer and prognostic factors

Objective. Most patients with pancreatic cancer show an inoperable locally advanced/ metastatic tumour at the time of diagnosis. The present study was aimed at determining the prognostic factors in patients with advanced pancreatic carcinoma treated with gemcitabine. Material and methods. Sixty-seven unresectable or metastatic pancreatic cancer patients treated with gemcitabine were included in the study and a total of 258 cycles of treatment were applied. Results. The overall response rate was 5%. Thirty-one percent of the patients had stable disease, whereas progressive disease was seen in 49%. Clinical benefit response rate was 15%. The median duration of response was 7.3 months. Median progression-free survival was 3 months, while median overall survival was 9 months. Univariate analysis revealed that worse results were found in patients with performance status (PS)?=?2, and in patients with primary tumour location in the body or tail of the pancreas (p<0.05). Multivariate analysis of data revealed that the most important factor was PS of the patient, as the patients with PS?=?2 had worse results than the patients with PS?=?0–1 (p<0.05). Conclusions. Low PS is a negative predictive factor for the survival of patients with advanced pancreatic carcinoma treated with gemcitabine.     

Influence of Heavy Cigarette Smoking on Heart Rate Variability and Heart Rate Turbulence Parameters

Background: Cigarette smoking increases the risk of cardiovascular events related with several mechanisms. The most suggested mechanism is increased activity of sympathetic nervous system. Heart rate variability (HRV) and heart rate turbulence (HRT) has been shown to be independent and powerful predictors of mortality in a specific group of cardiac patients. The goal of this study was to assess the effect of heavy cigarette smoking on cardiac autonomic function using HRV and HRT analyses. Methods: Heavy cigarette smoking was defined as more than 20 cigarettes smoked per day. Heavy cigarette smokers, 69 subjects and nonsmokers 74 subjects (control group) were enrolled in this study. HRV and HRT analyses [turbulence onset (TO) and turbulence slope (TS)] were assessed from 24‐hour Holter recordings. Results: The values of TO were significantly higher in heavy cigarette smokers than control group (?1.150 ± 4.007 vs ?2.454 ± 2.796, P = 0.025, respectively), but values of TS were not statistically different between two groups (10.352 ± 7.670 vs 9.613 ± 7.245, P = 0.555, respectively). Also, the number of patients who had abnormal TO was significantly higher in heavy cigarette smokers than control group (23 vs 10, P = 0.006). TO was correlated with the number of cigarettes smoked per day (r = 0.235, P = 0.004). While LF and LF/HF ratio were significantly higher, standard deviation of all NN intervals (SDNN), standard deviation of the 5‐minute mean RR intervals (SDANN), root mean square of successive differences (RMSSD), and high‐frequency (HF) values were significantly lower in heavy smokers. While, there was significant correlation between TO and SDNN, SDANN, RMSSD, LF, and high frequency (HF), only HF was correlated with TS. Conclusion: Heavy cigarette smoking has negative effect on autonomic function. HRT is an appropriate noninvasive method to evaluate the effect of cigarette on autonomic function. Simultaneous abnormal HRT and HRV values may explain increased cardiovascular event risk in heavy cigarette smokers.     

Resolution of late sirolimus-eluting stent thrombosis after tirofiban treatment

A 40-year-old male patient was admitted to the hospital with acute chest pain. A sirolimus-eluting stent (SES) had been deployed to the circumflex artery (Cx) 3 years before. Now, inferior ST-segment elevations were observed and coronary angiography revealed stent thrombosis with distal TIMI 3 grade flow in the Cx. Tirofiban infusion was administered and the control angiography 2 days later revealed complete resolution of the thrombus. Stent thrombosis is a rare but usually poor prognostic event, frequently associated with large myocardial infarction (MI) or death. Very late drug-eluting stent (DES) thrombosis remains a major problem of interventional cardiology due to its high morbidity and mortality. We conclude that tirofiban may be an interesting candidate drug for treatment of very late stent thrombosis.     

Catheter ablation of ventricular tachycardias using remote magnetic navigation: a consecutive case-control study

Remote Magnetic Navigation for VT Ablation. Background: This study aimed to compare acute and late outcomes of VT ablation using the magnetic navigation system (MNS) to manual techniques (MAN) in patients with (SHD) and without (NSHD) structural heart disease. Methods: Ablation data of 113 consecutive patients (43 SHD, 70 NSHD) with ventricular tachycardia treated with catheter ablation at our center were analyzed. Success rate, complications, procedure, fluoroscopy, and ablation times, and recurrence rates were systematically recorded for all patients. Results: A total of 72 patients were included in the MNS group and 41 patients were included in the MAN group. Patient age, gender, and right ventricular and left ventricular VT were equally distributed. Acute success was achieved in 59 patients in the MNS group (82%) versus 27 (66%) patients in the MAN group (P = 0.046). Overall procedural time (177 ± 79 vs 232 ± 99 minutes, P < 0.01) and mean patient fluoroscopy time (27 ± 19 vs 56 ± 32 minutes, P < 0.001) were all significantly lower using MNS. In NSHD pts, higher acute success was achieved with MNS (83,7% vs 61.9%, P = 0.049), with shorter procedure times (151 ± 57 vs 210 ± 96, P = 0.011), whereas in SHD‐VT these were not significantly different. No major complications occurred in the MNS group (0%) versus 1 cardiac tamponade and 1 significantly damaged ICD lead in the MAN group (4.9%, NS). After follow‐up (20 ± 11 vs 20 ± 10 months, NS), VT recurred in 14 pts (23.7%) in the MNS group versus 12 pts (44.4%) in the MAN group (P = 0.047). Conclusions: The use of MNS offers advantages for ablation of NSHD‐VT, while it offers similar efficacy for SHD‐VT. ((J Cardiovasc Electrophysiol, Vol. 23, pp. 948‐954, September 2012)