Cardiothoracic CT: one-stop-shop procedure? Impact on the management of acute pulmonary embolism

In the treatment of pulmonary embolism (PE) two groups of patients are traditionally identified, namely the hemodynamically stable and instable groups. However, in the large group of normotensive patients with PE, there seems to be a subgroup of patients with an increased risk of an adverse outcome, which might benefit from more aggressive therapy than the current standard therapy with anticoagulants. Risk stratification is a commonly used method to define subgroups of patients with either a high or low risk of an adverse outcome. In this review the clinical parameters and biomarkers of myocardial injury and right ventricular dysfunction (RVD) that have been suggested to play an important role in the risk stratification of PE are described first. Secondly, the use of more direct imaging techniques like echocardiography and CT in the assessment of RVD are discussed, followed by a brief outline of new imaging techniques. Finally, two risk stratification models are proposed, combining the markers of RVD with cardiac biomarkers of ischemia to define whether patients should be admitted to the intensive care unit (ICU) and/or be given thrombolysis, admitted to the medical ward, or be safely treated at home with anticoagulant therapy

Identification of Rab11 as a target of edema factor and dominant-negative mutants of anthrax lethal factor

Anthrax is a fatal disease caused by the spore-formulating bacterium, Bacillus anthracis. The potential for anthrax as a bioterrorist weapon raises concern, and is still common in the developing world. Antibiotic treatment of anthrax is often not effective, because toxins released in the host bloodstream can cause death even after clearance of the bacterium. Thus, it is important to further develop our knowledge of how anthrax causes its deadly effects as well as develop treatments targeting the toxins themselves. The anthrax toxin edema factor (EF) is a calmodulin-dependent adenylate cyclase and lethal factor (LF) is a zinc metalloprotease, which cleaves and inactivates MAPKKs. Like many other bacterial toxins, their activity targets conserved cellular components, making it possible to study their activity using an invertebrate model such as Drosophila. Using UAS-EF and UAS-LF transgenic lines, an extensive interaction screen with candidate UAS lines was used to identify novel targets for toxin activity. EF and LF showed synergistic interaction with Rab11 GTPase, a recycling endosome regulator, and its exocyst binding partner Sec15. Also, loss of other exocyst components Sec5, Sec15, and Exo70 enhanced the severity of the LF phenotype. Two other candidates, CG5745 and CG17282, disrupt the exocyst through their action on Sec15 and possibly Rab11. Increased knowledge of toxin activity in the long run may prove to be useful in rational drug design. Furthermore, as a more direct approach to treatment development, I conducted a genetic screen, which generated two dominant negative mutants of lethal facto

Sin3a regulates epithelial progenitor cell fate during lung development

Mechanisms that regulate tissue-specific progenitors for maintenance and differentiation during development are poorly understood. Here, we demonstrate that the co-repressor protein Sin3a is crucial for lung endoderm development. Loss of Sin3a in mouse early foregut endoderm led to a specific and profound defect in lung development with lung buds failing to undergo branching morphogenesis and progressive atrophy of the proximal lung endoderm with complete epithelial loss at later stages of development. Consequently, neonatal pups died at birth due to respiratory insufficiency. Further analysis revealed that loss of Sin3a resulted in embryonic lung epithelial progenitor cells adopting a senescence-like state with permanent cell cycle arrest in G1 phase. This was mediated at least partially through upregulation of the cell cycle inhibitors Cdkn1a and Cdkn2c. At the same time, loss of endodermal Sin3a also disrupted cell differentiation of the mesoderm, suggesting aberrant epithelial-mesenchymal signaling. Together, these findings reveal that Sin3a is an essential regulator for early lung endoderm specification and differentiation

Cholera Toxin Disrupts Barrier Function by Inhibiting Exocyst-Mediated Trafficking of Host Proteins to Intestinal Cell Junctions

Cholera toxin (CT), a virulence factor elaborated by Vibrio cholerae, is sufficient to induce the severe diarrhea characteristic of cholera. The enzymatic moiety of CT (CtxA) increases cAMP synthesis in intestinal epithelial cells, leading to chloride ion (Cl(-)) efflux through the CFTR Cl(-) channel. To preserve electroneutrality and osmotic balance, sodium ions and water also flow into the intestinal lumen via a paracellular route. We find that CtxA-driven cAMP increase also inhibits Rab11/exocyst-mediated trafficking of host proteins including E-cadherin and Notch signaling components to cell-cell junctions in Drosophila, human intestinal epithelial cells, and ligated mouse ileal loops, thereby disrupting barrier function. Additionally, CtxA induces junctional damage, weight loss, and dye leakage in the Drosophila gut, contributing to lethality from live V. cholerae infection, all of which can be rescued by Rab11 overexpression. These barrier-disrupting effects of CtxA may act in parallel with Cl(-) secretion to drive the pathophysiology of cholera