Inflammation initiated by stressed organelles

Key cellular functions including those related to energy metabolism, organization of the genetic information or production of membrane-bound and secreted proteins are compartmentalized within organelles. Various stresses such as differentiation programs, viral and bacterial infections, perturbations in protein production, mechanical constraints, changes in the environment and nutriment accessibility can impact cellular homeostasis and organelle integrity. Perturbations of these cellular compartments trigger repair and adaptation programs aimed at restoring homeostasis. These events are often associated with low-grade inflammation also termed parainflammation. While the nature and mechanisms of danger signals released by irremediably damaged cells are well understood, how transiently stressed cells trigger inflammation is still poorly understood. Emerging studies highlighted new mechanisms by which stress pathways promote inflammation. Cytosolic innate immune pathways are engaged by signals stemming from perturbed organelles such as the mitochondria, the endoplasmic reticulum (ER) or the nuclear envelope (NE). These observations indicate that these pathways function as guardians of cellular homeostasis and may contribute to disease in pathologies characterized by perturbations of cellular homoeostasis. Mitochondria-stress, ER-stress or NE-stress are emerging as proinflammatory signals that contribute to human conditions and diseases.     

Far-field R wave oversensing in dual chamber pacemakers designed for atrial arrhythmia management: effect of pacing site and lead tip to ring distance

INAMA, G., et al.: Far-Field R Wave Oversensing in Dual Chamber Pacemakers Designed for Atrial Arrhythmia Management: Effect of Pacing Site and Lead Tip to Ring Distance. The aim of the study was to determine the incidence and practical implications of far-field R wave oversensing (FFRWO) and its association with pacing site and lead tip to ring spacing (TTRS) in implantable devices designed to diagnose and treat atrial tachyarrhythmias and programmed with a fixed and short postventricular blanking period. The study included 395 patients who were implanted with a DDDRP pacemaker and prospectively followed. At implant and follow-up visits FFRWO was assessed by analyzing lead electrical measures and atrial tachyarrhythmic episodes collected in the device diagnostics. During a median follow-up of 12 months 11 (2.8%) of 395 patients showed a clinically significant FFRWO that induced inappropriate detection or pacemaker malfunctioning. The atrial pacing site of these 11 patients was right atrium appendage (RAA) for 3 patients, representing 1.1% of 254 RAA patients, coronary sinus ostium (CSO) for 7 patients, representing 7.4% of 94 CSO patients (P < 0.005 vs RAA), and lateral wall (LW) for 1 (2.9%) of 34 LW patients. The minimal value of the FFRWO to P wave ratio, measured at implant, associated with a clinically significant FFRWO was 0.6; therefore, a value of 0.5 was used as a cutoff to identify patients at risk of undesirable device behavior induced by FFRWO: there were 11 (9.6%) of 114 of RAA patients with short (< or = 10 mm) TTRS, 22 (18.8%) of 117 of RAA patients with long (> or = 17 mm) TTRS (P < 0.05 vs short TTRS), 21 (30.6%) of 64 of CSO patients short TTRS (P < 0.001 vs RAA patients with short TTRS) and 3 (30%) of 10 of CSO patients with long TTRS. The analysis showed that, despite the short postventricular blanking time, FFRWO inducing undesired functioning in AT500 pacemakers is infrequent (2.8% of patients). Compared to RAA, the CSO lead position was more frequently associated with FFRWO.TTRS < 10 mm was associated with lower risk of clinically significant FFRWO in RAA. (PACE 2004; 27:1221-1230).     

Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis

OBJECTIVES: To compare the effects of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, stroke, cardiovascular mortality and total mortality. METHODS: We conducted a meta-analysis of randomized comparative trials between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. Inclusion criteria were publication in peer-reviewed journals indexed in Medline, randomized comparison of angiotensin II receptor blockers vs. angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers + angiotensin-converting enzyme inhibitors vs. angiotensin-converting enzyme inhibitors, report of major complications including myocardial infarction, stroke, cardiovascular mortality or all-cause mortality; average follow-up of at least 1 year in at least 200 patients. RESULTS: Six trials fulfilled the inclusion criteria, for a total of 49 924 patients. In the pooled estimate, there were no significant differences between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction (odds ratio 1.01; 95% confidence interval 0.95-1.07; P = 0.75), cardiovascular mortality (odds ratio 1.03; 95% confidence interval 0.98-1.08; P = 0.23) and total mortality (odds ratio 1.03; 95% confidence interval 0.97-1.10; P = 0.20). This was the case also when the analysis involved only the comparison between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Overall, the risk of stroke was slightly lower with angiotensin II receptor blockers than angiotensin-converting enzyme inhibitors (odds ratio 0.92; 95% confidence interval 0.85-0.99; P = 0.037), the direct angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers comparison showing a nonsignificant trend in a similar direction. Statistical heterogeneity among trials was not significant, with a low to null inconsistency statistic, for stroke (P = 0.67), myocardial infarction (P = 0.86), cardiovascular mortality (P = 0.14) and total mortality (P = 0.12). CONCLUSION: This overview suggests that angiotensin II receptor blockers are as effective as angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, cardiovascular mortality and total mortality. Angiotensin II receptor blockers may be slightly more protective than angiotensin-converting enzyme inhibitors on the risk of stroke.     

Role of galectin-3 immunodetection in the cytological diagnosis of thyroid cystic papillary carcinoma

OBJECTIVE: Cystic thyroid lesions can harbour an occult papillary carcinoma, which fine needle aspiration (FNA) biopsy may fail to detect. Recently, new markers such as galectin-3 lectin have been proposed to distinguish benign from malignant thyroid lesions of follicular origin. The aim of this study was to assess the role of galectin-3 immunodetection in a series of FNA cytological samples of benign and malignant thyroid cystic nodules. METHODS: We retrospectively analysed galectin-3 expression by immunoperoxidase staining on 32 cytological paraffin-embedded samples of cystic papillary carcinoma and on 12 samples of benign cysts, both obtained by FNA biopsy. Specificity, sensitivity, positive/negative predictive values, and accuracy of standard cytological examination and galectin-3 immunodetection were assessed. RESULTS: Among cystic papillary carcinomas, 29 of 32 samples were galectin-3 positive, whereas standard FNA cytology made a correct diagnosis in only 25 of 32 samples. All the benign cysts were negative for galectin-3. In comparing the sensitivity and specificity of the two methods, it appeared that both had a 100% specificity, whereas the sensitivity of cytological examination alone was 75% versus 89.3% obtained by galectin-3 immunohistochemistry. CONCLUSIONS: Galectin-3 immunostaining represents a valid pre-operative adjunct to pick up malignant cells in those cases where a very poor number of epithelial cells may lead to a cytological misdiagnosis. Therefore, we suggest that in poorly cellular FNA biopsies of simple or complex thyroid cysts, galectin-3 expression by epithelial cells is consistent with a cystic carcinoma and supports surgical treatment indication.     

Dynamic Left Ventricular Outflow Tract Obstruction During Myocardial Ischemia in Mitral Valve Prolapse Syndrome

Systolic anterior motion of the mitral valve (MV) with dynamic left ventricular (LV) outflow tract obstruction is a well known phenomenon in hypertrophic cardiomyopathy, or other forms of hyper-dynamic LV function associated with hypovolemic states, or LV hypertrophy. We report three patients with MV prolapse in the absence of the above predisposing factors, who developed an LV outflow dynamic gradient during acute transient myocardial ischemia. An interaction between structural abnormalities of the mitral apparatus and ischemia-dependent LV shape deformity most likely accounted for the outflow gradient.     

Modeling strategies to improve parameter estimates in prognostic factors analyses with patient-reported outcomes in oncology

Purpose

The inclusion of patient-reported outcome (PRO) questionnaires in prognostic factor analyses in oncology has substantially increased in recent years. We performed a simulation study to compare the performances of four different modeling strategies in estimating the prognostic impact of multiple collinear scales from PRO questionnaires.

Methods

We generated multiple scenarios describing survival data with different sample sizes, event rates and degrees of multicollinearity among five PRO scales. We used the Cox proportional hazards (PH) model to estimate the hazard ratios (HR) using automatic selection procedures, which were based on either the likelihood ratio-test (Cox-PV) or the Akaike Information Criterion (Cox-AIC). We also used Cox PH models which included all variables and were either penalized using the Ridge regression (Cox-R) or were estimated as usual (Cox-Full). For each scenario, we simulated 1000 independent datasets and compared the average outcomes of all methods.

Results

The Cox-R showed similar or better performances with respect to the other methods, particularly in scenarios with medium–high multicollinearity (ρ?=?0.4 to ρ?=?0.8) and small sample sizes (n?=?100). Overall, the Cox-PV and Cox-AIC performed worse, for example they did not select one or more prognostic collinear PRO scales in some scenarios. Compared with the Cox-Full, the Cox-R provided HR estimates with similar bias patterns but smaller root-mean-squared errors, particularly in higher multicollinearity scenarios.

Conclusions

Our findings suggest that the Cox-R is the best approach when performing prognostic factor analyses with multiple and collinear PRO scales, particularly in situations of high multicollinearity, small sample sizes and low event rates.