Amyloid Structures from Alzheimer’s Disease Patients

Lu and colleagues report the structures of β-amyloid fibrils seeded from the brain extracts of two Alzheimer’s disease patients, a game-changing study that could open new avenues for a structure-based design of diagnostic imaging agents and aggregation inhibiting drugs

Therapeutic options for patients with advanced atrial fibrillation:from lifestyle and medication to catheter and surgical ablation

Atrial fibrillation (AF) is part of a vicious cycle that includes multiple cardiovascular risk factors and comorbidity which can promote atrial remodelling and AF progression. Most AF-related risk factors—hypertension, diabetes, sleep apnoea, obesity and sedentary lifestyle—are in essence modifiable which may prevent AF development. Treatment of associated cardiovascular conditions may prevent both symptoms and future cardiovascular events. For advanced forms of symptomatic AF refractory to lifestyle management and optimal medication, invasive ablation therapies have become a cornerstone. Although electrical trigger isolation from the pulmonary veins is reasonably effective and safe, more potent energy sources including high output-short duration radiofrequency, ultra-low cryo-energy, and electroporation, as well as more sophisticated arrays, balloons, and lattice-tipped catheter tools, are on their way to eliminate existing pitfalls and simplify the procedure. Electroanatomical navigation and mapping systems are becoming available to provide real-time information on ablation lesion quality and the critical pathways of AF in the individual patient to guide more extensive ablation strategies that may enhance long-term outcome for freedom of advanced AF. Surgical techniques, either stand-alone or concomitant to structural cardiac repair, hybrid, or convergent, with novel less invasive access options are developing and can be helpful in situations unsuitable for catheter ablation

Experimental evidence of an instability over an impedance wall in a duct with flow

An experimental investigation of the acoustical behaviour of a liner in a rectangu- lar channel with grazing flow has been conducted. The liner consists of a ceramic structure of parallel square channels: 1mm by 1 mm in cross section, 65 mm in length, and a surface density of 400 channels/inch square. The channels are rigidly terminated, thus constituting a locally reacting structure. In the absence of flow the liner reacts classically: There is a significant decrease in transmission coefficient around the frequency of minimal impedance. When the wall is exposed to a grazing flow this behaviour is changed: an increase in transmission coefficient appears at this resonance frequency. The transmission coefficient can be even rise above 1 (up to 3 for a Mach number of 0.3). This behaviour is caused by the appearance of a hydrodynamic instability above the liner. Furthermore, the stationary pressure drop induced by this liner is deeply affected by its acoustic behaviour. When a sound wave is added, at the resonance frequency of the liner, the pressure drop can increase by a factor 3 when the Mach number is 0.3. This effect is attributed to a modification of the turbulent boundary layer induced by the acoustic wave

Amphotericin forms an extramembranous and fungicidal sterol sponge.

For over 50 years, amphotericin has remained the powerful but highly toxic last line of defense in treating life-threatening fungal infections in humans with minimal development of microbial resistance. Understanding how this small molecule kills yeast is thus critical for guiding development of derivatives with an improved therapeutic index and other resistance-refractory antimicrobial agents. In the widely accepted ion channel model for its mechanism of cytocidal action, amphotericin forms aggregates inside lipid bilayers that permeabilize and kill cells. In contrast, we report that amphotericin exists primarily in the form of large, extramembranous aggregates that kill yeast by extracting ergosterol from lipid bilayers. These findings reveal that extraction of a polyfunctional lipid underlies the resistance-refractory antimicrobial action of amphotericin and suggests a roadmap for separating its cytocidal and membrane-permeabilizing activities. This new mechanistic understanding is also guiding development of what are to our knowledge the first derivatives of amphotericin that kill yeast but not human cells

Stroke risk in patients with device-detected atrial high-rate episodes

Cardiovascular implantable electronic devices (CIEDs) can detect atrial arrhythmias, i.e. atrial high-rate episodes (AHRE). The thrombo-embolic risk in patients showing AHRE appears to be lower than in patients with clinical atrial fibrillation (AF) and it is unclear whether the former will benefit from oral anticoagulants. Based on currently available evidence, it seems reasonable to consider antithrombotic therapy in patients without documented AF showing AHRE >24 hours and a CHA(2)DS(2)-VASc score (congestive heart failure, hypertension, age >= 75 years [doubled], diabetes mellitus, prior stroke [doubled], vascular disease, age 65-74 years and female sex) >= 1, awaiting definite answers from ongoing randomised clinical trials. In patients with AHR

Genome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours

Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P < 1×10−8), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25–1.66, P = 5.63 × 10−07), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD