Mechanisms of oxidative stress in human aortic aneurysms — association with clinical risk factors for atherosclerosis and disease severity

Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2radical dot−) production in human AAA. Methods and results: AAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n = 16) than in risk factor matched controls (n = 16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2radical dot− in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size. Conclusions: Increased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients

TGFβ (transforming growth factor-β) blockade induces a human-like disease in a nondissecting mouse model of abdominal aortic aneurysm

Objective-Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGF beta (transforming growth factor-beta) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Approach and Results-Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGF beta using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGF beta blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1 beta or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1 beta after disease initiation has no effect on AAA progression to rupture. Conclusions-Endogenous TGF beta activity is required for the healing of AAA. TGF beta blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets

Emerging pharmacological treatments to prevent abdominal aortic aneurysm growth and rupture

Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1 beta inhibition, anti-angiogenic agents and urocortins

Clinical implications of the anisotropic analytical algorithm for IMRT treatment planning and verification

PURPOSE: To determine the implications of the use of the Anisotropic Analytical Algorithm(AAA) for the production and dosimetric verification of IMRT plans for treatments of the prostate, parotid, nasopharynx and lung. METHODS: 72 IMRT treatment plans produced using the Pencil Beam Convolution (PBC)algorithm were recalculated using the AAA and the dose distributions compared. 24 of the plans were delivered to inhomogeneous phantoms and verification measurements made using a pinpoint ionisation chamber. The agreement between the AAA and measurement was determined. RESULTS: Small differences were seen in the prostate plans, with the AAA predicting slightly lower minimum PTV doses. In the parotid plans, there were small increases in the lens and contralateral parotid doses while the nasopharyngeal plans revealed a reduction in the volume of the PTV covered by the 95% isodose (the V95%) when the AAA was used. Large changes were seen in the lung plans, the AAA predicting reductions in the minimum PTV dose and large reductions in the V95%. The AAA also predicted small increases in the mean dose to the normal lung and the V20. In the verification measurements, all AAA calculations were within 3% or 3.5mm distance to agreement of the measured doses. Conclusions: The AAA should be used in preference to the PBC algorithm for treatments involving low density tissue but this may necessitate re-evaluation of plan acceptability criteria. Improvements to the Multi-Resolution Dose Calculation algorithm used in the inverse planning are required to reduce the convergence error in the presence of lung tissue. There was excellent agreement between the AAA and verification measurements for all sites

Clinical implications of the anisotropic analytical algorithm for IMRT treatment planning and verification

PURPOSE: To determine the implications of the use of the Anisotropic Analytical Algorithm(AAA) for the production and dosimetric verification of IMRT plans for treatments of the prostate, parotid, nasopharynx and lung. METHODS: 72 IMRT treatment plans produced using the Pencil Beam Convolution (PBC)algorithm were recalculated using the AAA and the dose distributions compared. 24 of the plans were delivered to inhomogeneous phantoms and verification measurements made using a pinpoint ionisation chamber. The agreement between the AAA and measurement was determined. RESULTS: Small differences were seen in the prostate plans, with the AAA predicting slightly lower minimum PTV doses. In the parotid plans, there were small increases in the lens and contralateral parotid doses while the nasopharyngeal plans revealed a reduction in the volume of the PTV covered by the 95% isodose (the V95%) when the AAA was used. Large changes were seen in the lung plans, the AAA predicting reductions in the minimum PTV dose and large reductions in the V95%. The AAA also predicted small increases in the mean dose to the normal lung and the V20. In the verification measurements, all AAA calculations were within 3% or 3.5mm distance to agreement of the measured doses. Conclusions: The AAA should be used in preference to the PBC algorithm for treatments involving low density tissue but this may necessitate re-evaluation of plan acceptability criteria. Improvements to the Multi-Resolution Dose Calculation algorithm used in the inverse planning are required to reduce the convergence error in the presence of lung tissue. There was excellent agreement between the AAA and verification measurements for all sites

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease

IPv6 Network Mobility

Network Authentication, Authorization, and Accounting has been used since before the days of the Internet as we know it today. Authentication asks the question, “Who or what are you?” Authorization asks, “What are you allowed to do?” And fi nally, accounting wants to know, “What did you do?” These fundamental security building blocks are being used in expanded ways today. The fi rst part of this two-part series focused on the overall concepts of AAA, the elements involved in AAA communications, and highlevel approaches to achieving specifi c AAA goals. It was published in IPJ Volume 10, No. 1[0]. This second part of the series discusses the protocols involved, specifi c applications of AAA, and considerations for the future of AAA

AAA architectures applied in multi-domain IMS (IP multimedia subsystem)

There is a group of communication services that use\ud resources from multiple domains in order to deliver their service.\ud Authorization of the end-user is important for such services,\ud because several domains are involved. There are no current\ud solutions for delivering authentication, authorization and\ud accounting (AAA) to multi-domain services. In our study we\ud present two architectures for the delivery of AAA to such\ud services. The architectures are analyzed on their qualitative\ud aspects. A result of this analysis is that direct interconnection of\ud AAA servers is an effective architectural solution. In current\ud multi-domain IP Multimedia Subsystem (IMS) architectures,\ud direct interconnection of AAA servers, such as the Home\ud Subscriber Servers (HSS), is not yet possible. In this paper we\ud argue and recommend to extend the IMS specification by adding\ud a new interface to HSS in order to support the direct\ud interconnection of HSS/AAA servers located in different IMS\ud administrative domains

Theoretical studies of the historical development of the accounting discipline: a review and evidence

Many existing studies of the development of accounting thought have either been atheoretical or have adopted Kuhn's model of scientific growth. The limitations of this 35-year-old model are discussed. Four different general neo-Kuhnian models of scholarly knowledge development are reviewed and compared with reference to an analytical matrix. The models are found to be mutually consistent, with each focusing on a different aspect of development. A composite model is proposed. Based on a hand-crafted database, author co-citation analysis is used to map empirically the entire literature structure of the accounting discipline during two consecutive time periods, 1972–81 and 1982–90. The changing structure of the accounting literature is interpreted using the proposed composite model of scholarly knowledge development

Quality of life, symptoms and treatment satisfaction in patients with aortic aneurysm using new abdominal aortic aneurysm-specific patient-reported outcome measures.

BACKGROUND: The aim of this study was to present preliminary data on quality of life (QoL), symptoms and treatment satisfaction gathered using three new abdominal aortic aneurysm (AAA)-specific patient-reported outcome measures (PROMs). METHODS: Patients with AAA were recruited from five National Health Service Trusts to complete the three new PROMs: the AneurysmDQoL, AneurysmSRQ and AneurysmTSQ. Patients were either under surveillance or had undergone AAA repair (open or endovascular) during the preceding 24 months. Data were initially collected as part of a study assessing the psychometric properties of the new measures, before being used in the observational analysis of outcomes presented here. RESULTS: Results, although largely non-significant, showed interesting trends. The impact of AAA repair on QoL appeared to worsen progressively after open repair (OR) and improve progressively after endovascular aneurysm repair (EVAR). Conversely, symptoms seemed to become progressively worse after EVAR and progressively better after OR. Information and understanding were key sources of dissatisfaction before the intervention, whereas postoperative dissatisfaction was related to bother from symptoms, follow-up and feedback about scan results. CONCLUSION: Although a larger, prospective data set is necessary to explore outcomes more fully with the new AAA-specific PROMs, the observational data presented here suggest there may be clinically important differences in the symptoms, impact on QoL and treatment satisfaction associated with OR and EVAR