CXCR2 deficient mice display macrophage-dependent exaggerated acute inflammatory responses

CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response

Perioperative risk stratification in non cardiac surgery: role of pharmacological stress echocardiography

Perioperative ischemia is a frequent event in patients undergoing major non-cardiac vascular or general surgery. This is in agreement with clinical, pathophysiological, and epidemiological evidence and constitutes an additional diagnostic therapeutic factor in the assessment of these patients. Form a clinical standpoint, it is well known that multidistrict disease, especially at the coronary level, is a severe aggravation of the operative risk. From a pathophysiological point of view, however, surgery creates conditions able to unmask coronary artery disease. Prolonged hypotension, hemorrhages, and haemodynamic stresses caused by aortic clamping and unclamping during major vascular surgery are the most relevant factors endangering the coronary circulation with critical stenoses. From the epidemiological standpoint, coronary disease is known to be the leading cause of perioperative mortality and morbidity following vascular and general surgery: The diagnostic therapeutic corollary of these considerations is that coronary artery disease – and therefore the perioperative risk – in these patients has to be identified in an effective way preoperatively

Non-invasive cardiac assessment in high risk patients (The GROUND study): rationale, objectives and design of a multi-center randomized controlled clinical trial

Background: Peripheral arterial disease (PAD) is a common disease associated with a considerably increased risk of future cardiovascular events and most of these patients will die from coronary artery disease (CAD). Screening for silent CAD has become an option with recent non-invasive developments in CT (computed tomography)-angiography and MR (magnetic resonance) stress testing. Screening in combination with more aggressive treatment may improve prognosis. Therefore we propose to study whether a cardiac imaging algorithm, using non-invasive imaging techniques followed by treatment will reduce the risk of cardiovascular disease in PAD patients free from cardiac symptoms. Design: The GROUND study is designed as a prospective, multi-center, randomized clinical trial. Patients with peripheral arterial disease, but without symptomatic cardiac disease will be asked to participate. All patients receive a proper risk factor management before randomization. Half of the recruited patients will enter the 'control group' and only undergo CT calcium scoring. The other half of the recruited patients (index group) will undergo the non invasive cardiac imaging algorithm followed by evidence-based treatment. First, patients are submitted to CT calcium scoring and CT angiography. Patients with a left main (or equivalent) coronary artery stenosis of > 50% on CT will be referred to a cardiologist without further imaging. All other patients in this group will undergo dobutamine stress magnetic resonance (DSMR) testing. Patients with a DSMR positive for ischemia will also be referred to a cardiologist. These patients are candidates for conventional coronary angiography and cardiac interventions (coronary artery bypass grafting (CABG) or percutaneous cardiac interventions (PCI)), if indicated. All participants of the trial will enter a 5 year follow up period for the occurrence of cardiovascular events. Sequential interim analysis will take place. Based on sample size calculations about 1200 patients are needed to detect a 24% reduction in primary outcome. Implications: The GROUND study will provide insight into the question whether non-invasive cardiac imaging reduces the risk of cardiovascular events in patients with peripheral arterial disease, but without symptoms of coronary artery disease. Trial registration: Clinicaltrials.gov NCT0018911

TgICMAP1 Is a Novel Microtubule Binding Protein in Toxoplasma gondii

The microtubule cytoskeleton provides essential structural support for all eukaryotic cells and can be assembled into various higher order structures that perform drastically different functions. Understanding how microtubule-containing assemblies are built in a spatially and temporally controlled manner is therefore fundamental to understanding cell physiology. Toxoplasma gondii, a protozoan parasite, contains at least five distinct tubulin-containing structures, the spindle pole, centrioles, cortical microtubules, the conoid, and the intra-conoid microtubules. How these five structurally and functionally distinct sets of tubulin containing structures are constructed and maintained in the same cell is an intriguing problem. Previously, we performed a proteomic analysis of the T. gondii apical complex, a cytoskeletal complex located at the apical end of the parasite that is composed of the conoid, three ring-like structures, and the two short intra-conoid microtubules. Here we report the characterization of one of the proteins identified in that analysis, TgICMAP1. We show that TgICMAP1 is a novel microtubule binding protein that can directly bind to microtubules in vitro and stabilizes microtubules when ectopically expressed in mammalian cells. Interestingly, in T. gondii, TgICMAP1 preferentially binds to the intra-conoid microtubules, providing us the first molecular tool to investigate the intra-conoid microtubule assembly process during daughter construction

ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary

These guidelines address the diagnosis and management of atherosclerotic, aneurysmal, and thromboembolic peripheral arterial diseases (PADs). The clinical manifestations of PAD are a major cause of acute and chronic illness, are associated with decrements in functional capacity and quality of life, cause limb amputation, and increase the risk of death. Whereas the term “peripheral arterial disease” encompasses a large series of disorders that affect arterial beds exclusive of the coronary arteries, this writing committee chose to limit the scope of the work of this document to include the disorders of the abdominal aorta, renal and mesenteric arteries, and lower extremity arteries. The purposes of the full guidelines are to (a) aid in the recognition, diagnosis, and treatment of PAD of the aorta and lower extremities, addressing its prevalence, impact on quality of life, cardiovascular ischemic risk, and risk of critical limb ischemia (CLI); (b) aid in the recognition, diagnosis, and treatment of renal and visceral arterial diseases; and (c) improve the detection and treatment of abdominal and branch artery aneurysms. Clinical management guidelines for other arterial beds (e.g., the thoracic aorta, carotid and vertebral arteries, and upper-extremity arteries) have been excluded from the current guidelines to focus on the infradiaphragmatic arterial system and in recognition of the robust evidence base that exists for the aortic, visceral, and lower extremity arteries