Enhanced expression and activation of proinflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm,”

A B S T R A C T Inflammation plays a key role in the pathogenesis of an AAA (abdominal aortic aneurysm); however, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is controversial. In the present study, we set out to determine the aortic levels of inflammatory cytokines in relation to downstream inflammatory transcription factors and cellular responses. A comparison of AAA wall samples with atherosclerotic wall samples taken from the same aortic region allowed AAA-specific inflammatory parameters to be identified that distinguish AAAs from ASD (aortic atherosclerotic disease). RT-PCR (real-time PCR), ELISA, Western blotting and immunohistochemistry were combined to assess cytokines and transcription factors at the mRNA and protein level, and their activation status. Compared with ASD, inflammatory parameters associated with Th1-type [T-bet, IL (interleukin)-2, IFN-γ (interferon-γ ), TNF-α (tumour necrosis factor-α), IL-1α and cytotoxic T-cells] and Th2-type [GATA3, IL-4, IL-10, IL-13 and B-cells] responses were all increased in AAA samples. Evaluation of major downstream inflammatory transcription factors revealed higher baseline levels of C/EBP (CCAAT/enhancer-binding protein) α, β and δ in the AAA samples. Baseline p65 NF-κB (nuclear factor κB) and c-Jun [AP-1 (activator protein-1)] levels were comparable, but their activated forms were strongly increased in the AAA samples. Downstream target genes of p65 NF-κB, c-Jun, IL-6 and IL-8 were hyperexpressed. Molecular and cellular processes associated with IL-6 and IL-8 hyperactivation were enhanced in the AAA samples, i.e. the expression of phospho-STAT-3 (signal transducer and activator of transcription-3) and perforin were elevated, and the content of plasma cells, neutrophils and vasa vasorum was increased. In conclusion, our findings demonstrate that an AAA is a general inflammatory condition which is characterized by enhanced expression and activation of pro-inflammatory transcription factors, accompanied by IL-6 and IL-8 hyperexpression and exaggerated downstream cellular responses, which together clearly distinguish an AAA from ASD

Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study

Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (−0.51 μg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease

How do surgeons' probability estimates of operative mortality compare with a decision analytic model?

The aim of this study is to compare surgeons' estimates of operative mortality of patients with an abdominal aneurysm ( = dilation of the aorta) with the operative mortality derived from a decision analytic model and to determine how surgeons use clinical information. Four experienced surgeons are asked to estimate, among other things, the operative mortality of 137 patients. Results concerning the accuracy of surgeons' estimates show that surgeons' average operative mortality estimates are quite accurate as compared to the calculated mortalities. The standard deviations of surgeons' estimates are lower than the standard deviation of the model, however, indicating that the surgeons are not as good in distinguishing the high and low risk patients. Furthermore, surgeons show substantial inconsistencies in the weighing of the clinical information, and also differ from the model in how clinical information is weighed. Finally, when comparing the operative mortalities of the patients who died and those who did not, the model shows a modest, but higher discrimination than the surgeons. Physicians' performance seems to be influenced by the difficulty of the task (i.e. the unpredictability of the event and the multidimensionality of the task). In order to improve physicians' probability estimates, the calculations of the decision model can be used as learning tool

Education in vascular surgery: Critical issues around the globe—training and qualification in vascular surgery in Europe

In 1958, the Union Européene des Médecins Spécialistes (UEMS), or European Union (EU) of Medical Specialists the European Union, was founded by the professional organizations of medical specialists in Europe. Among the objectives of the UEMS are to promote the highest level of patient care in the EU and to promote the harmonization of high-quality training programs within the various specialities throughout the EU. Within the 38 Specialist Sections of the UEMS are the European Boards, which are the working groups of the Specialist Sections. In 2005 Vascular Surgery was recognized as a separate and independent Section, a monospecialty, within the UEMS. The efforts of the UEMS are directed at facilitating the free exchange of training and work of trainees and medical specialists between EU countries. This situation, in combination with large differences in requirements and length of training in vascular surgery within the EU, stresses the importance of harmonization in training and certification in vascular surgery within the EU. For that reason, the European Board of Vascular Surgery has organized voluntary examinations yearly since 1996. The candidates who pass qualify as “Fellow of the European Board of Vascular Surgery” (FEBVS) since 2005. The first part of the examination evaluates the eligibility of the candidate (Certificate of Completion of Specialist Training, training center, logbook). The second part is a viva voce assessment that includes (1) case analyses, (2) a review of a scientific article, (3) an overall assessment, (4) a technical skills, and (5) an endovascular skills assessment. To pass the examination, the candidates must achieve a 67% success rate in each part of the examination. During the last 10 years, approximately 75% of the candidates have successfully taken the examination. In the near future the Section and Board, in close collaboration with the vascular societies in the EU, will develop a European vascular surgical syllabus and curriculum that will further harmonize and professionalize the training and certification of vascular surgery in Europe