New-Onset Atrial Fibrillation After Aortic Valve Replacement Comparison of Transfemoral, Transapical, Transaortic, and Surgical Approaches

ObjectivesThis study sought to determine the incidence of new-onset atrial fibrillation (AF) associated with different methods of isolated aortic valve replacement (AVR)—transfemoral (TF), transapical (TA), and transaortic (TAo) catheter-based valve replacement and conventional surgical approaches.BackgroundThe relative incidences of AF associated with the various access routes for AVR have not been well characterized.MethodsIn this single-center, retrospective cohort study, we evaluated a total of 231 consecutive patients who underwent AVR for degenerative aortic stenosis (AS) between March 2010 and September 2012. Patients with a history of paroxysmal, persistent, or chronic AF, with bicuspid aortic valves, and patients who died within 48 h after AVR were excluded. A total of 123 patients (53% of total group) qualified for inclusion. Data on documented episodes of new-onset AF, along with all clinical, echocardiographic, procedural, and 30-day follow-up data, were collated.ResultsAF occurred in 52 patients (42.3%). AF incidence varied according to the procedural method. AF occurred in 60% of patients who underwent surgical AVR (SAVR), in 53% after TA-TAVR, in 33% after TAo-TAVR cases, and 14% after TF-TAVR. The episodes occurred at a median time interval of 53 (25th to 75th percentile, 41 to 87) h after completion of the procedure. Procedures without pericardiotomy had an 82% risk reduction of AF compared with those with pericardiotomy (adjusted odds ratio: 0.18; 95% confidence interval: 0.05 to 0.59).ConclusionsAF was a common complication of AVR with a cumulative incidence of >40% in elderly patients with degenerative AS who underwent either SAVR or TAVR. AF was most common with SAVR and least common with TF-TAVR. Procedures without pericardiotomy were associated with a lower incidence of AF

Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis.

Yeast physiology is temporally regulated, this becomes apparent under nutrient-limited conditions and results in respiratory oscillations (YROs). YROs share features with circadian rhythms and interact with, but are independent of, the cell division cycle. Here, we show that YROs minimise energy expenditure by restricting protein synthesis until sufficient resources are stored, while maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells sequester and store metabolic resources via increased transport, autophagy and biomolecular condensation. Replete stores trigger increased H+ export which stimulates TORC1 and liberates proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates translational bursting, liquidation of storage carbohydrates, increased ATP turnover, and the export of osmolytes. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints selected for temporal organisation that promotes oscillatory behaviour

Tedisamil and dofetilide-induced torsades de pointes, rate and potassium dependence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73908/1/sj.bjp.0703967.pd

Low-dose carotid computed tomography angiography using pure iterative reconstruction

The aim of this study was to assess if a low-dose carotid computed tomography angiography (CTA) performed with pure iterative reconstruction (IR) is comparable to a conventional dose CTA protocol. Methods: Twenty patients were included. Radiation dose was divided into a low-dose acquisition reconstructed with pure IR and a conventional dose acquisition reconstructed with 40% hybrid IR. Dose, image noise, contrast resolution, spatial resolution, and carotid artery stenosis were measured. Results: Mean effective dose was significantly lower for low-dose than conventional dose studies (1.84 versus 3.71 mSv; P < 0.001). Subjective image noise, contrast resolution, and spatial resolution were significantly higher for the low-dose studies. There was excellent agreement for stenosis grading accuracy between low- and conventional dose studies (Cohen κ = 0.806). Conclusions: A low-dose carotid CTA protocol reconstructed with pure IR is comparable to a conventional dose CTA protocol in terms of image quality and diagnostic accuracy while enabling a dose reduction of 49.6%

Controlling the Response: Predictive Modeling of a Highly Central, Pathogen-Targeted Core Response Module in Macrophage Activation

We have investigated macrophage activation using computational analyses of a compendium of transcriptomic data covering responses to agonists of the TLR pathway, Salmonella infection, and manufactured amorphous silica nanoparticle exposure. We inferred regulatory relationship networks using this compendium and discovered that genes with high betweenness centrality, so-called bottlenecks, code for proteins targeted by pathogens. Furthermore, combining a novel set of bioinformatics tools, topological analysis with analysis of differentially expressed genes under the different stimuli, we identified a conserved core response module that is differentially expressed in response to all studied conditions. This module occupies a highly central position in the inferred network and is also enriched in genes preferentially targeted by pathogens. The module includes cytokines, interferon induced genes such as Ifit1 and 2, effectors of inflammation, Cox1 and Oas1 and Oasl2, and transcription factors including AP1, Egr1 and 2 and Mafb. Predictive modeling using a reverse-engineering approach reveals dynamic differences between the responses to each stimulus and predicts the regulatory influences directing this module. We speculate that this module may be an early checkpoint for progression to apoptosis and/or inflammation during macrophage activation

Structural Comparison of Human Mammalian Ste20-Like Kinases

BACKGROUND: The serine/threonine mammalian Ste-20 like kinases (MSTs) are key regulators of apoptosis, cellular proliferation as well as polarization. Deregulation of MSTs has been associated with disease progression in prostate and colorectal cancer. The four human MSTs are regulated differently by C-terminal regions flanking the catalytic domains. PRINCIPAL FINDINGS: We have determined the crystal structure of kinase domain of MST4 in complex with an ATP-mimetic inhibitor. This is the first structure of an inactive conformation of a member of the MST kinase family. Comparison with active structures of MST3 and MST1 revealed a dimeric association of MST4 suggesting an activation loop exchanged mechanism of MST4 auto-activation. Together with a homology model of MST2 we provide a comparative analysis of the kinase domains for all four members of the human MST family. SIGNIFICANCE: The comparative analysis identified new structural features in the MST ATP binding pocket and has also defined the mechanism for autophosphorylation. Both structural features may be further explored for inhibitors design. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins

Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4−/− and Myd88−/−, but not TRIF−/− mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system