In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic ...challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.
•We captured microscopic images of diesel, kerosene and RME at diesel engine conditions.•The fluid exits the nozzle with a mushroom-like structures that propels a ligament.•We propose that fuel can ...remain trapped in the injector holes after injection.•We showed this mechanism occurs under typical diesel engine conditions.
Detailed measurements of near-nozzle spray formation are essential to better understand and predict the physical processes involved in diesel fuel atomisation. We used long-range microscopy to investigate the primary atomisation of diesel, biodiesel and kerosene fuels in the near-nozzle region, both at atmospheric and realistic engine conditions. High spatial and temporal resolutions allowed a detailed observation of the very emergence of fuel from the nozzle orifice. The fluid that first exited the nozzle resembled mushroom-like structures, as occasionally reported by other researchers for atmospheric conditions, with evidence of interfacial shearing instabilities and stagnation points. We captured the dynamics of this phenomenon using an ultra-fast framing camera with frame rates up to 5 million images per second, and identified these structures as residual fluid trapped in the orifice between injections. The residual fluid has an internal vortex ring motion which results in a slipstream effect that can propel a microscopic ligament of liquid fuel ahead. We showed that this mechanism is not limited to laboratory setups, and that it occurs for diesel fuels injected at engine-like conditions with production injectors. Our findings confirm that fuel can remain trapped in the injector holes after the end of injection. Although we could not measure the hydrocarbon content of the trapped vapourised fluid, we observed that its density was lower than that of the liquid fuel, but higher than that of the in-cylinder gas. We conclude that high-fidelity numerical models should not assume in their initial conditions that the sac and orifices of fuel injectors are filled with in-cylinder gas. Instead, our observations suggest that the nozzle holes should be considered partially filled with a dense fluid.
In patients with or without left bundle branch block, left bundle branch pacing (LBBP) can produce near normalization of QRS duration (QRSd). This has recently emerged as an alternative technique to ...His bundle pacing.
The purpose of this study was to characterize a novel approach for LBBP in patients with bradycardia indications for pacing and to assess implant success rate and midterm safety.
Patients with bradycardia indications for pacing underwent LBBP by a trans-ventricular-septal method in the basal ventricular septum. Procedural success, pacing parameters, and complications were assessed at implantation and at 3 months follow-up.
This prospective study evaluated 87 patients (sinus node dysfunction 67.8%; atrioventricular conduction disease 32.2%) undergoing pacemaker implantation. LBBP implantation succeeded in 80.5% (70/87) of patients and the remaining 17 patients received right ventricular septal pacing. The procedure time of LBBP implantation was 18.0 ± 8.8 minutes with a fluoroscopic exposure time of 3.9 ± 2.7 minutes. LBBP produced narrower electrocardiographic QRSd than did right ventricular septal pacing (113.2 ± 9.9 ms vs 144.4 ± 12.8 ms; P < .001). There were no major implantation-related complications. The pacing threshold was low (0.76 ± 0.22 V at implantation and 0.71 ± 0.23 V at 3 months), with no loss of capture or lead dislodgment observed.
This study demonstrates that in patients with standard bradycardia pacing indications, LBBP results in QRSd < 120 ms in most patients and can be performed successfully and safely in the majority of patients.
Few studies have examined associations between long-term exposure to fine particulate matter (PM2.5) and lung function decline in adults.
To determine if exposure to traffic and PM2.5 is associated ...with longitudinal changes in lung function in a population-based cohort in the Northeastern United States, where pollution levels are relatively low.
FEV1 and FVC were measured up to two times between 1995 and 2011 among 6,339 participants of the Framingham Offspring or Third Generation studies. We tested associations between residential proximity to a major roadway and PM2.5 exposure in 2001 (estimated by a land-use model using satellite measurements of aerosol optical thickness) and lung function. We examined differences in average lung function using mixed-effects models and differences in lung function decline using linear regression models. Current smokers were excluded. Models were adjusted for age, sex, height, weight, pack-years, socioeconomic status indicators, cohort, time, season, and weather.
Living less than 100 m from a major roadway was associated with a 23.2 ml (95% confidence interval CI, -44.4 to -1.9) lower FEV1 and a 5.0 ml/yr (95% CI, -9.0 to -0.9) faster decline in FEV1 compared with more than 400 m. Each 2 μg/m(3) increase in average of PM2.5 was associated with a 13.5 ml (95% CI, -26.6 to -0.3) lower FEV1 and a 2.1 ml/yr (95% CI, -4.1 to -0.2) faster decline in FEV1. There were similar associations with FVC. Associations with FEV1/FVC ratio were weak or absent.
Long-term exposure to traffic and PM2.5, at relatively low levels, was associated with lower FEV1 and FVC and an accelerated rate of lung function decline.
The B cell antigen receptor (BCR) plays a central role in the self nonself selection of B lymphocytes and in their activation by cognate antigen during the clonal selection process. It was long ...thought that most cell surface receptors, including the BCR, were freely diffusing and randomly distributed. Since the advent of superresolution techniques, it has become clear that the plasma membrane is compartmentalized and highly organized at the nanometer scale. Hence, a complete understanding of the precise conformation and activation mechanism of the BCR must take into account the organization of the B cell plasma membrane. We review here the recent literature on the nanoscale organization of the lymphocyte membrane and discuss how this new information influences our view of the conformational changes that the BCR undergoes during activation.
The objective of this study is to ascertain the effects of the left (LV) and right (RV) ventricular lead tip position in response to cardiac resynchronization therapy (CRT).
The REVERSE randomized ...trial examined the effects of CRT in patients with asymptomatic or mildly symptomatic heart failure (HF).
We analysed data collected from the active group (CRT-ON) of REVERSE in whom the precise locations of the LV and RV ventricular lead tips were determined from postoperative chest roentgenograms as part of a prespecified sub-study. LV position was classified as lateral or non-lateral, and apical or non-apical. RV position was classified as apical or non-apical. Echocardiographic LV end-systolic volume index (LVESVi), QRS duration, and clinical outcomes at 12-24 months of follow-up were evaluated with respect to the lead tip position. The primary trial endpoint was the proportion of patients with a worsened HF clinical composite response, scored as improved, unchanged, or worsened.
Totally 346 patients included in this analysis were followed for a median of 12.6 months (interquartile range: 11.9-23.9 months). The proportion of worsened HF clinical composite response did not correlate with lead position, whereas a significantly greater decrease in the powered secondary endpoint of LVESVi was observed with the non-apical vs. the apical LV lead positions. CRT-paced QRS duration was significantly shorter than at baseline in patients with lateral vs. non-lateral LV position, as well non-apical vs. apical LV position. The incidence of composite endpoint of death and first hospitalization for HF was lower in the LV lateral than in the non-lateral (HR 0.44; 95% CI 0.19-0.99; P= 0.04), and in the LV non-apical than in the apical group (HR 0.27; 95% CI 0.11-0.63; P= 0.001). No significant differences were observed between RV apical and non-apical positions of the lead tip.
A more favourable outcome of CRT with regard to LV reverse remodelling and the composite of time to death or first HF hospitalization was observed when the LV lead tip was implanted in the lateral wall, away from the apex, while the position of the RV lead tip was indifferent. The long-term change in QRS duration was significantly associated with the position of the LV lead tip. ClinicalTrials.gov Identifier: NCT00271154.
ASSERT demonstrated that subclinical atrial fibrillation (SCAF) is common in pacemaker patients without prior AF and is associated with increased risk of ischemic stroke or systemic embolism. SCAF ...episodes vary in duration and little is known about the incidence of different durations of SCAF, or their prognosis.
ASSERT followed 2580 patients receiving a pacemaker or ICD, aged >65 years with hypertension, without prior AF. The effect of SCAF duration on subsequent risk of ischemic stroke or embolism was evaluated with time-dependent covariate Cox models. Patients in whom the longest SCAF was ≤6 min were excluded from the analysis (n=125). Among 2455 patients during mean follow-up of 2.5 years, the longest single episode of SCAF lasted >6 min to 6 h in 462 patients (18.8%), >6-24 h in 169 (6.9%), and >24 h in 262 (10.7%). SCAF duration >24 h was associated with a significant increased risk of subsequent stroke or systemic embolism (adjusted hazard ratio HR 3.24, 95% confidence interval CI 1.51-6.95, P=0.003). The risk of ischemic stroke or systemic embolism in patients with SCAF between 6 min and 24 h was not significantly different from patients without SCAF.
SCAF >24 h is associated with an increased risk of ischemic stroke or systemic embolism.
We quantified the impacts of wildfire-related PM
on 2 million hospital admissions records due to cardiorespiratory diseases in Brazil between 2008 and 2018. The national analysis shows that wildfire ...waves are associated with an increase of 23% (95%CI: 12%-33%) in respiratory hospital admissions and an increase of 21% (95%CI: 8%-35%) in circulatory hospital admissions. In the North (where most of the Amazon region is located), we estimate an increase of 38% (95%CI: 30%-47%) in respiratory hospital admissions and 27% (95%CI: 15%-39%) in circulatory hospital admissions. Here we report epidemiological evidence that air pollution emitted by wildfires is significantly associated with a higher risk of cardiorespiratory hospital admissions.
The most frequent complications associated with implantable cardioverter-defibrillators (ICDs) involve the transvenous leads. A subcutaneous implantable cardioverter-defibrillator (S-ICD) has been ...developed as an alternative system. This study evaluated the safety and effectiveness of the S-ICD System (Cameron Health/Boston Scientific) for the treatment of life-threatening ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation).
This prospective, nonrandomized, multicenter trial included adult patients with a standard indication for an ICD, who neither required pacing nor had documented pace-terminable ventricular tachycardia. The primary safety end point was the 180-day S-ICD System complication-free rate compared with a prespecified performance goal of 79%. The primary effectiveness end point was the induced ventricular fibrillation conversion rate compared with a prespecified performance goal of 88%, with success defined as 2 consecutive ventricular fibrillation conversions of 4 attempts. Detection and conversion of spontaneous episodes were also evaluated. Device implantation was attempted in 321 of 330 enrolled patients, and 314 patients underwent successful implantation. The cohort was followed for a mean duration of 11 months. The study population was 74% male with a mean age of 52±16 years and mean left ventricular ejection fraction of 36±16%. A previous transvenous ICD had been implanted in 13%. Both primary end points were met: The 180-day system complication-free rate was 99%, and sensitivity analysis of the acute ventricular fibrillation conversion rate was >90% in the entire cohort. There were 38 discrete spontaneous episodes of ventricular tachycardia/ventricular fibrillation recorded in 21 patients (6.7%), all of which successfully converted. Forty-one patients (13.1%) received an inappropriate shock.
The findings support the efficacy and safety of the S-ICD System for the treatment of life-threatening ventricular arrhythmias.
Cardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to ...identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data.
An individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58-73) years, QRS duration was 160 (146-176) ms, LVEF was 24 (20-28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value.
QRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response.
NCT00170300, NCT00271154, NCT00251251.
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