Genetic and Pharmacological Modifications of Thrombin Formation in Apolipoprotein E-deficient Mice Determine Atherosclerosis Severity and Atherothrombosis Onset in a Neutrophil-Dependent Manner

Background: Variations in the blood coagulation activity, determined genetically or by medication, may alter atherosclerotic plaque progression, by influencing pleiotropic effects of coagulation proteases. Published experimental studies have yielded contradictory findings on the role of hypercoagulability in atherogenesis. We therefore sought to address this matter by extensively investigating the in vivo significance of genetic alterations and pharmacologic inhibition of thrombin formation for the onset and progression of atherosclerosis, and plaque phenotype determination. Methodology/principal findings: We generated transgenic atherosclerosis-prone mice with diminished coagulant or hypercoagulable phenotype and employed two distinct models of atherosclerosis. Gene-targeted 50% reduction in prothrombin $(FII^{−/WT}:ApoE^{−/−})$ was remarkably effective in limiting disease compared to control $ApoE^{−/−}$ mice, associated with significant qualitative benefits, including diminished leukocyte infiltration, altered collagen and vascular smooth muscle cell content. Genetically-imposed hypercoagulability in $TM^{Pro/Pro}:ApoE^{−/−}$ mice resulted in severe atherosclerosis, plaque vulnerability and spontaneous atherothrombosis. Hypercoagulability was associated with a pronounced neutrophilia, neutrophil hyper-reactivity, markedly increased oxidative stress, neutrophil intraplaque infiltration and apoptosis. Administration of either the synthetic specific thrombin inhibitor Dabigatran etexilate, or recombinant activated protein C (APC), counteracted the pro-inflammatory and pro-atherogenic phenotype of pro-thrombotic $TM^{Pro/Pro}:ApoE^{−/−}$ mice. Conclusions/significance: We provide new evidence highlighting the importance of neutrophils in the coagulation-inflammation interplay during atherogenesis. Our findings reveal that thrombin-mediated proteolysis is an unexpectedly powerful determinant of atherosclerosis in multiple distinct settings. These studies suggest that selective anticoagulants employed to prevent thrombotic events may also be remarkably effective in clinically impeding the onset and progression of cardiovascular disease

3D Airway changes using CBCT in patients following mandibular setback surgery ± maxillary advancement

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149310/1/ocr12291_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149310/2/ocr12291.pd

Protein C anticoagulant system—anti-inflammatory effects

Activated protein C (APC) plays active roles in preventing progression of a number of disease processes. These include thrombosis due to its direct anticoagulant activity which is likely augmented by its cytoprotective activity, thereby limiting exposure of procoagulant cellular membrane surfaces on cells. Beyond that, the pathway signals the cells to prevent apoptosis, to dampen inflammation, to increase endothelial barrier function, and to selectively downregulate some genes implicated in disease progression. Most of these functions are manifested to APC binding to endothelial protein C receptor (EPCR) allowing PAR1 activation, but activation of other PARS is also implicated in some cases. In addition to EPCR orchestrating these changes, CD11b is also capable of supporting APC signaling. Selective control of these pathways offers potential in new therapeutic approaches to disease

Assessment of bone segmentation quality of cone-beam CT versus multislice spiral CT: a pilot study.

Item does not contain fulltextOBJECTIVES: The objective of this study was to quantitatively assess the quality of jawbone models generated from cone beam computed tomography (CBCT) by comparison with similar models obtained from multislice spiral computed tomography (MSCT). MATERIAL AND METHODS: Three case studies were performed involving images of anthropomorphic head phantoms and real patients acquired with 3 CBCT (NewTom 9000 DVT, Accuitomo 3D, and i-CAT) and 2 MSCT scanners (Somatom VolumeZoom and Lightspeed). Bone was segmented from the CBCT and MSCT images using global thresholding. CBCT vs MSCT segmentation differences were assessed by comparing bone thickness measurements at anatomically corresponding sites, identified automatically by CBCT to MSCT image registration. RESULTS: There was a statistically significant difference between the MSCT and CBCT segmented bone thicknesses, varying from 0.05 +/- 0.47 mm (i-CAT) up to 1.2 +/- 1.00 mm (3D Accuitomo, posterior maxilla). CONCLUSIONS: An automated, reproducible, and observer-independent method has been developed to assess the quality of CBCT bone models using MSCT as a clinically established method of reference. Our validation method is generally applicable in cases where no geometric ground-truth is available

Anticoagulant therapy in critical organ ischaemia/reperfusion injury

Ischaemia/reperfusion (I/R) injury is central to a number of pathologies including myocardial infarction and stroke. Several cellular processes are involved in the progress of I/R injury, involving complex interactions between coagulation and inflammatory or apoptotic processes. Besides for their anti-coagulant function, anticoagulant proteins such as activated protein C (APC), active site inhibited factor Vila (ASIS), tissue factor pathway inhibitor (TFPI), and antithrombin (AT) are also known for their anti-inflammatory or cell protective effects. This review gives an overview of the application of these anti-coagulants in several animal models of I/R injury in critical organs and describes the effects of these proteins on cellular processes including inflammation and apoptosis. The future testing of mutant forms of some of these inhibitors including APC in a clinical setting should be actively explored