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

Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice

Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure

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