Induction and modulation of monocyte/macrophage tissue factor/fibrin deposition and TNF secretion in the microenvironment of inflammation: The role of tyrosine phosphorylation

grantor: University of TorontoInflammatory mediators transduced at the cell boundary signal alterations in cell activation which may not be detrimental to the cell itself but may be injurious to the organism, suggesting preferential definition of the pathologic state in terms of signal transduction pathways. Understanding of these signaling processes and their attenuation could act to abrogate pathologic processes. This thesis follows the course of the monocyte/macrophage into the inflammatory microenvironment and involvement of the tyrosine kinase signaling cascade in cellular activation expressed as procoagulant activity and TNF secretion. Experiments demonstrate that monocyte trans-endothelial migration results in monocyte activation. The novel mechanism of this process was determined to be through integrin receptor molecules resulting in monocyte activation via induction of tyrosine phosphorylation. Following migration, these cells, now macrophages, are exposed to further inflammatory stimuli. Mast cells are known to inhabit areas surrounding the post-capillary venule, the site of monocyte diapedesis where the macrophage co-resides. Herein we report a novel role for these cells in macrophage activation. These processes are mediated via induction of tyrosine kinases. Murine Hepatitis Virus and endotoxin, were tested as potential viral and bacterial stimuli that might result in increased expression of cellular procoagulants via induction of tyrosine phosphorylation. Stimulation with these factors resulted in increased accumulation of tyrosine phosphoproteins identifying the signaling pathways in response to these stimuli. New therapeutic strategies to modify these processes were investigated. Tyrosine kinase inhibition, anti-oxidant treatments and anti-body mediated neutralization all proved effective in inhibiting induction of procoagulant activity and tissue factor in vitro and in vivo.Ph.D

Preoperative Thyroid Ultrasound Is Indicated in Patients Undergoing Parathyroidectomy for Primary Hyperparathyroidism

<p><b>Background:</b> Primary hyperaparathyroidism (pHPT) is often accompanied by underlying thyroid pathology that can confound preoperative parathyroid localization studies and complicate intra-operative decision making. The aim of this study was to examine the utility of preoperative thyroid ultrasonography (US) in patients prior to undergoing parathyroidectomy for pHPT.</p><p><b>Methods:</b> An Institutional Review Board approved prospective study was undertaken from January 2005 through July 2008. All patients with pHPT meeting inclusion criteria (n=94) underwent preoperative thyroid ultrasound in addition to standard ^99mTc-sestamibi scintigraphy for parathyroid localization. Demographics, operative management and final pathology were examined in all cases.</p><p><b>Results:</b> Fifty-four of the 94 patients (57%) were noted to have a thyroid nodule on preoperative US, of which 30 (56%) underwent further examination with fine needle aspiration biopsy. Alteration of the operative plan attributable to underlying thyroid pathology occurred in 16 patients (17%), with patients undergoing either total thyroidectomy (n=9) or thyroid lobectomy (n=7). Thyroid cancer was noted in 33% of patients undergoing thyroid resection, and 6% of all patients with HPT.</p><p><b>Conclusions:</b> The routine utilization of preoperative thyroid ultrasound in patients prior to undergoing parathyroid surgery for pHPT is indicated. The added information from this non-invasive modality facilitates timely management of co-incidental, and sometimes malignant, thyroid pathology.</p