bluuebunny/crossref_metadata_2025 huggingface dataset:
Position Control of a Square-plate Ionic Polymer Actuator Using Output Feedback
Authors: Kothera Curt S. , Leo Donald J.
Published: December 2006

Ionic polymer materials exhibit coupling between the electrical, chemical, and mechanical domains that enables their use as both sensors and actuators. Because these materials are flexible and operate on battery-level voltages, they have received considerable attention in the recent years. While a universally accepted model for actuation is still in development, an empirical model is developed here between input current and center-point deflection of a square-plate polymer actuator that is clamped at its four corners. Characterization results show that a nonlinear model is needed due to the low frequency harmonic distortion that is present in the response. The square-plate actuator is used to demonstrate the potential that ionic polymers have in shape control applications for flexible structures, such as deformable mirrors. In this article, the authors demonstrate a tracking control concept, wherein the reference command signals are meant to correspond to focus adjustments in a lens.
The Effect of Discrete Layer Kinematics on the Global Response of Homogeneous and Composite Plates with Multiple Actuator Pairs
Authors: Robbins D. H. , Chopra Inderjit
Published: December 2006

For the simple case of a homogeneous, isotropic plate with a single, symmetric pair of actuators, previous work by the authors has demonstrated the importance of including discrete layer kinematics in predicting the global response of the actuated plate. The inclusion of discrete layer kinematics permits accurate modeling of the so-called local kinematic effect, whereby a portion of the total actuation is diverted to the production of localized transverse shear deformation near the edges of the actuator, thus reducing the amount of actuation energy available to produce the desired global deformation mode. The present study expands upon this previous effort, investigating the magnitude of the local kinematic effect for more complex actuated plates involving fiber-reinforced laminated composite substrates with multiple symmetric pairs of actuators. The results obtained from finite element simulations using a wide range of kinematic assumptions conclusively demonstrate that as the actuated span-to-thickness ratio decreases, the models with discrete layer kinematics predict a smaller global response than the models that use equivalent-single-layer kinematics. Thus, the local kinematic effect is observed to influence the global response of the actuated plates regardless of the material constitution of the structural substrate and regardless of the in-plane spacing between actuator pairs.
Damage Detection in Beams using Spatial Fourier Analysis and Neural Networks
Authors: Pawar Prashant M. , Venkatesulu Reddy Kanchi , Ganguli Ranjan
Published: December 2006

This study investigates the effect of damage on beams with fixed boundary conditions using Fourier analysis of mode shapes in the spatial domain. A finite element model is used to obtain the mode shapes of a damaged fixed—fixed beam, and the damaged mode shapes are expanded using a spatial Fourier series and the effect of damage on the harmonics is investigated. This approach contrasts with the typical time domain application of Fourier analysis for vibration problems. It is found that damage causes considerable change in the Fourier coefficients of the mode shapes, which are found to be sensitive to both damage size and location. Therefore, a damage index in the form of a vector of Fourier coefficients is formulated. A neural network is trained to detect the damage location and size using Fourier coefficients as input. Numerical studies show that damage detection using Fourier coefficients and neural networks has the capability to detect the location and damage size accurately. Finally, the performance of the method in the presence of noise is studied and it is found that the method performs satisfactorily in the presence of some noise in the data.
Influence of ERK activation on decreased chemotaxis of mature human cord blood monocyte–derived dendritic cells to CCL19 and CXCL12
Authors: Li Geling , Basu Sunanda , Han Myung-Kwan , Kim Young-June , Broxmeyer Hal E.
Published: December 2006

Dendritic cells (DCs) are important regulators in graft-versus-host disease (GVHD). To gain insight into cord blood (CB) DC immunology, we compared chemotactic responses of mature monocyte-derived DCs and maturation agent lipopolysaccharide (LPS)–induced signaling between CB and adult blood (AB). Mature CB DCs expressed reduced CCR7, but increased CXCR4. This was associated with reduced migratory efficiency toward both CCR7 ligand CCL19 and CXCR4 ligand CXCL12. LPS induced higher extracellular signal-regulated kinase (ERK) phosphorylation in CB than in AB DCs. Specific inhibition of ERK during CB DC maturation enhanced LPS-induced up-regulation of CCR7 and CXCR4 on CB DCs and their chemotaxis toward CCL19 and CXCL12, to a level similar to that of mature AB DCs. Overall, monocyte-derived CB DCs responded to LPS with stronger and sustained ERK activation, which negatively correlated with LPS-induced up-regulation of CCR7 and CXCR4 on CB DCs and their migratory responses. These findings may have potential relevance to better understanding DC function in CB transplantation.
Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias
Authors: Gojo Ivana , Jiemjit Anchalee , Trepel Jane B. , Sparreboom Alex , Figg William D. , Rollins Sandra , Tidwell Michael L. , Greer Jacqueline , Chung Eun Joo , Lee Min-Jung , Gore Steven D. , Sausville Edward A. , Zwiebel James , Karp Judith E.
Published: December 2006

MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly × 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly × 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease.
Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin
Authors: Hess Paul R. , Barnes Carie , Woolard Matthew D. , Johnson Michael D. L. , Cullen John M. , Collins Edward J. , Frelinger Jeffrey A.
Published: December 2006

CD8+ cytotoxic T lymphocytes (CTLs) are important effector cells responsible for tissue destruction in several autoimmune and allograft-related diseases. To discover if pathogenic T cells could be selectively deleted, we investigated the ability of a toxin coupled to major histocompatibility complex (MHC) class I tetramers to kill antigen-specific CD8+ T cells. H2-Db tetramers were assembled using streptavidin conjugated to the ribosome-inactivating protein (RIP) saporin (SAP). These tetramers inhibited ribosome activity in vitro, retained the T-cell receptor (TCR)–binding specificity of their nontoxic counterparts, and were internalized by 100% of target cells, leading to cell death in 72 hours. Cytotoxicity was dependent on the tetramer dose and avidity for the T cell. A single injection of the SAP-coupled tetramer eliminated more than 75% of cognate, but not control, T cells. This work demonstrates the therapeutic potential of cytotoxic tetramers to selectively eradicate pathogenic clonotypes while leaving overall T-cell immunity intact.
Notch activity synergizes with B-cell–receptor and CD40 signaling to enhance B-cell activation
Authors: Thomas Matthew , Calamito Marco , Srivastava Bhaskar , Maillard Ivan , Pear Warren S. , Allman David
Published: December 2006

How diverse environmental cues are integrated to regulate B-cell activation and development remains poorly understood. Here we show that Notch activity synergizes with B-cell receptor (BCR) and/or CD40 signaling to enhance several aspects of B-cell activation and function. We find that costimulation of follicular B cells with the Notch ligand Delta-like-1 leads to significant increases in BCR- and CD40-mediated proliferation and enhances production of IgG1+ cells in vitro and in vivo. We further find that coengagement of Notch and the BCR results in increased activation of the MAPK pathway, and MAPK and Notch inhibitors prevent B-cell activation events mediated by coengagement of Notch and the BCR. These data suggest that the BCR and CD40 signaling pathways collaborate with the Notch pathway to optimize B-cell activation.
Protease gene families in Populus and Arabidopsis
Authors: García-Lorenzo Maribel , Sjödin Andreas , Jansson Stefan , Funk Christiane
Published: December 2006

Background

Proteases play key roles in plants, maintaining strict protein quality control and degrading specific sets of proteins in response to diverse environmental and developmental stimuli. Similarities and differences between the proteases expressed in different species may give valuable insights into their physiological roles and evolution.

Results

We have performed a comparative analysis of protease genes in the two sequenced dicot genomes, Arabidopsis thaliana and Populus trichocarpa by using genes coding for proteases in the MEROPS database [1] for Arabidopsis to identify homologous sequences in Populus. A multigene-based phylogenetic analysis was performed. Most protease families were found to be larger in Populus than in Arabidopsis, reflecting recent genome duplication. Detailed studies on e.g. the DegP, Clp, FtsH, Lon, rhomboid and papain-Like protease families showed the pattern of gene family expansion and gene loss was complex. We finally show that different Populus tissues express unique suites of protease genes and that the mRNA levels of different classes of proteases change along a developmental gradient.

Conclusion

Recent gene family expansion and contractions have made the Arabidopsis and Populus complements of proteases different and this, together with expression patterns, gives indications about the roles of the individual gene products or groups of proteases.
Human antimicrobial peptide LL-37 is present in atherosclerotic plaques and induces death of vascular smooth muscle cells: a laboratory study
Authors: Ciornei Cristina D , Tapper Hans , Bjartell Anders , Sternby Nils H , Bodelsson Mikael
Published: December 2006

Background

Death of smooth muscle cells in the atherosclerotic plaques makes the plaques more prone to rupture, which can initiate an acute ischemic event. The development of atherosclerosis includes the migration of immune cells e.g. monocytes/macrophages and T lymphocytes into the lesions. Immune cells can release antimicrobial peptides. One of these, human cathelicidin antimicrobial peptide hCAP-18, is cleaved by proteinase 3 generating a 4.5 kDa C-terminal fragment named LL-37, which has been shown to be cytotoxic. The aim of the study was to explore a potential role of LL-37 in the pathophysiology of atherosclerosis.

Methods

We investigated the presence of LL-37 in human atherosclerotic lesions obtained at autopsy using immunohistochemistry. The direct effects of LL-37 on cultured vascular smooth muscle cells and isolated neutrophil granulocytes were investigated with morphological, biochemical and flow cytometry analysis.

Results

The neointima of atherosclerotic plaques was found to contain LL-37-like immunoreactivity, mainly in macrophages. In cultured smooth muscle cells, LL-37 at 30 μg/ml caused cell shrinkage, membrane blebbing, nuclear condensation, DNA fragmentation and an increase in caspase-3 activity as studied by microscopy, ELISA and enzyme activity assay, respectively. Flow cytometry demonstrated that LL-37 in a subset of the cells caused a small but rapidly developing increase in membrane permeability to propidium iodide, followed by a gradual development of FITC-annexin V binding. Another cell population stained heavily with both propidium iodide and FITC-annexin V. Neutrophil granulocytes were resistant to these effects of LL-37.

Conclusion

This study shows that LL-37 is present in atherosclerotic lesions and that it induces death of vascular smooth muscle cells. In a subset of cells, the changes indicate the development of apoptosis triggered by an initial mild perturbation of plasma membrane integrity. The findings suggest a role for LL-37 as a mediator of immune cell-induced death of vascular smooth muscle cells in atherosclerosis.
Radiosensitization by 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide under oxia and hypoxia in human colon cancer cells
Authors: Itani Wafica , Geara Fady , Haykal Joelle , Haddadin Makhluf , Gali-Muhtasib Hala
Published: January 2007

Background

The sensitizing effects of 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ) and ionizing radiation (IR) were determined in four colon cancer cells and in FHs74Int normal intestinal cells.

Methods

Cell cycle modulation, TUNEL assay, clonogenic survival and DNA damage were examined under oxia or hypoxia. Effects on apoptotic molecules and on p-Akt and Cox-2 protein expression were investigated.

Results

The four cell lines responded differently to DCQ+IR; HT-29 cells were most resistant. Combination treatment caused significant increases in preG1(apoptosis) in HCT-116, while G2/M arrest occurred in DLD-1. DCQ potentiated IR effects more so under hypoxia than oxia. Pre-exposure of DLD-1 to hypoxia induced 30% apoptosis, and G2/M arrest in oxia. The survival rate was 50% lower in DCQ+IR than DCQ alone and this rate further decreased under hypoxia. FHs74Int normal intestinal cells were more resistant to DCQ+IR than cancer cells.Greater ssDNA damage occurred in DLD-1 exposed to DCQ+IR under hypoxia than oxia. In oxia, p-Akt protein expression increased upon IR exposure and drug pre-treatment inhibited this increase. In contrast, in hypoxia, exposure to IR reduced p-Akt protein and DCQ restored its expression to the untreated control. Apoptosis induced in hypoxic DLD-1 cells was independent of p53-p21 modulation but was associated with an increase in Bax/Bcl-2 ratio and the inhibition of the Cox-2 protein.

Conclusion

DCQ is a hypoxic cell radiosensitizer in DLD-1 human colon cancer cells.
Vibrometry
Authors: AGARWAL GAUTAM , MOZES GEZA , KINNICK RANDALL R. , GLOVICZKI PETER , BRUHNKE RUSSELL E. , CARMO MICHELE , HOSKIN TANYA L. , BENNETT KEVIN E. , GREENLEAF JAMES L.
Published: December 2006

Abstract:  Our objective was to test vibrometry as a means to measure changes in aneurysm sac pressure in an in vitro aneurysm model. Explanted porcine abdominal aortas and nitrile rubber tubes were used to model an aneurysm sac. An ultrasound beam was used to vibrate the surface of the aneurysm model. The motion generated on the surface was detected either by reflected laser light or by a second ultrasound probe. This was recorded at different aneurysm pressures. The phase of the propagating wave was measured to assess changes in velocity and to see if there was a correlation with aneurysm pressure. The cumulative phase shift detected by laser or Doppler correlated well with increasing hydrostatic pressure in both the rubber and the porcine aorta model. The square of the mean pressure correlated well with the cumulative phase shift when dynamic pressure was generated by a pump. However, the pulse pressure was poorly correlated with the cumulative phase shift. Noninvasive measurement of changes in aortic aneurysm sac tension is feasible in an in vitro setting using the concept of vibrometry. This could potentially be used to noninvasively detect wall stress in native aneurysms and endotension after endovascular aneurysm repair (EVAR) and to predict the risk of rupture.
Pharmacological Approaches to Prevent Abdominal Aortic Aneurysm Enlargement and Rupture
Authors: RENTSCHLER MARK , BAXTER B. TIMOTHY
Published: December 2006

Abstract:  Current efforts to limit the mortality from abdominal aortic aneurysm (AAA) are dependent on detection and elective repair. Even by conservative estimates, there are more than 300,000 undetected AAAs in the United States, most of which are small and would not require immediate intervention. Current practice following detection of a small AAA includes education, risk factor management, and serial observation. This approach, based on the statistical probability of death from rupture compared to the morbidity and mortality of repair, can be unsettling to patients and lead to a decline in perceived quality of life. While the pathophysiology of AAA is not completely understood, observations from human tissues and animal studies have identified a number of potential targets for inhibiting aneurysm expansion. It is clear that the prominent inflammatory response identified in aneurysm tissue has a role in promoting aortic expansion. This inflammatory response is thought to account for increased expression of proteolytic enzymes. Recent work has suggested a unifying hypothesis centered on the MAP kinase family affecting both the regulation of matrix synthesis and the expression of proteolytic enzymes. The tetracycline antibiotics and antihypertensive medications that affect the angiotensin‐converting enzyme system can inhibit proteolysis. There are adequate preliminary data to support a large prospective randomized trial of doxycycline to prevent aneurysm expansion.
Endothelial Progenitor Cells and Abdominal Aortic Aneurysms
Authors: DAWSON JOE , TOOZE JENNY , COCKERILL GILLIAN , CHOKE EDWARD , LOFTUS IAN , THOMPSON MATT M.
Published: December 2006

Abstract:  Endothelial progenitor cells (EPCs) are a population of circulating stem cells that hone in to sites of vascular injury where they undergo differentiation to become incorporated into damaged tissue. The aim of this study was to enumerate EPCs in patients with abdominal aortic aneurysms (AAA). CD133+ peripheral blood mononuclear cells were immunomagnetically selected and CD34/CD133 was used as a marker of EPCs. EPCs were detected using flow cytometry. AAA patients had significantly higher levels of circulating EPCs than age‐matched controls (2.43% vs. 1.25% of all events, P= 0.008). The role and function of EPCs in AAA remain to be determined, but their implication with angiogenesis may represent one plausible mechanism.
Features and Genomic Origins of Matrix Cell Adhesion Molecules‐1 and ‐2 Expressed by Fibroblasts of Human Aortic Adventitial Origin
Authors: TILSON M.D.
Published: December 2006

Abstract:  Precursor mRNAs for proteins that we have called matrix cell adhesion molecules‐1 and ‐2 (Mat‐CAM‐1 and Mat‐CAM‐2) were cloned from fibroblasts cultured from a specimen of human abdominal aorta. Both protein sequences have the unusual feature that there is an immunoglobulin kappa (Igκ)‐like domain at the N terminus and they are glycine/proline rich in the C‐terminal domain. Antibodies were raised in rabbit against peptides synthesized for a specific unique sequence of Mat‐CAM‐1 and Mat‐CAM‐2, respectively (not detected in any other proteins referenced in GenBank). Both antibodies were immunoreactive with adventitial microfibrils of the aorta and some additional arteries. Mat‐CAM‐1 was detected in the common/internal iliac arteries, but it was not detected in the external iliac artery. Conversely, Mat‐CAM‐2 was conspicuous in the external iliac artery, but not the common/internal iliac arteries. Thus, these proteins show features of site‐specific expression within the arterial tree. Computerized searches show that the genomic origins of Mat‐CAM‐1 and ‐2 are in the so‐called nasopharnygocarcinoma (NPC) gene on chromosome 2, which is a putative oncogene. Expression of the two different gene products from the same genomic sequence requires shifts of reading frame. Further studies will be required to determine whether these proteins are prototypes for a larger family of tissue‐specific matrix proteins arising from alternative transcriptions of the same genomic sequence.
Abdominal Aortic Aneurysm Is a Specific Antigen‐Driven T Cell Disease
Authors: PLATSOUCAS CHRIS D. , LU SONG , NWANESHIUDU IFEYINWA , SOLOMIDES CHARALAMBOS , AGELAN ALEXIS , NTAOULA NEKTARIA , PUREV ENKHTUYA , LI LI PING , KRATSIOS PASCHALIS , MYLONAS EFSTRATIOS , JUNG WEON‐JU , EVANS KYLE , ROBERTS SEAN , LU YANDI , LAYVI RICARDO , LIN WAN LU , ZHANG XIAOYING , GAUGHAN JOHN , MONOS DIMITRIOS S. , OLESZAK EMILIA L. , WHITE JOHN V.
Published: December 2006

Abstract:  To determine whether monoclonal/oligoclonal T cells are present in abdominal aortic aneurysm (AAA) lesions, we amplified β‐chain T cell receptor (TCR) transcripts from these lesions by the nonpalindromic adaptor (NPA)‐polymerase chain reaction (PCR)/V‐β‐specific PCR followed by cloning and sequencing. Sequence analysis revealed the presence of substantial proportions of identical β‐chain TCR transcripts in AAA lesions in 9 of 10 patients examined, strongly suggesting the presence of oligoclonal populations of αβ TCR+ T cells. We have also shown the presence of oligoclonal populations of γδ TCR+ T cells in AAA lesions. Sequence analysis after appropriate PCR amplification and cloning revealed the presence of substantial proportions of identical VγI and VγII TCR transcripts in 15 of 15 patients examined, and of Vδ1 and Vδ2 TCR transcripts in 12 of 12 patients. These clonal expansions were very strong. All these clonal expansions were statistically significant by the binomial distribution. In other studies, we determined that mononuclear cells infiltrating AAA lesions express early‐ (CD69), intermediate‐ (CD25, CD38), and late‐ (CD45RO, HLA class II) activation antigens. These findings suggest that active ongoing inflammation is present in the aortic wall of patients with AAA. These results demonstrate that oligoclonal αβ TCR+ and γδ TCR+T cells are present in AAA lesions. These oligoclonal T cells have been clonally expanded in vivo in response to yet unidentified antigens. Although the antigenic specificity of these T cells remains to be determined, these T cells may play a significant role in the initiation and/or the propagation of the AAA. It appears that AAA is a specific antigen‐driven T cell disease.
Engineering Improvements in Endovascular Devices
Authors: WILLIAMS DAVID M.
Published: December 2006

Abstract: Advances in endovascular treatment of vascular disease have focused on basic and translational research of vascular disease and endovascular devices. Clinical trials serve to establish the safety and efficacy of engineering advances that incorporate this research. Recent position statements by the Food and Drug Administration (FDA) emphasize that research into conducting these trials in a timely and cost‐effective manner (critical path research) is as important to patient care as the engineering advances themselves. This article reviews the recent FDA documents discussing critical path research, highlighting those topics that the FDA emphasizes. Several directions of translational research in which engineering advances may contribute to enhanced device design and improved patient care are reviewed.
Genome‐Wide Approach to Finding Abdominal Aortic Aneurysm Susceptibility Genes in Humans
Authors: KUIVANIEMI HELENA , KYO YOSHIKI , LENK GUY , TROMP GERARD
Published: December 2006

Abstract:  Familial aggregation of abdominal aortic aneurysms (AAAs) is now widely recognized, however, susceptibility genes have not yet been identified. Our approach to find susceptibility genes has been to collect families with AAAs and to perform DNA linkage analyses to identify regions on the human chromosomes that are linked to AAAs and could harbor susceptibility genes for AAAs. We identified 233 families with at least two individuals diagnosed with AAAs. These families had 653 AAA patients and an average of 2.8 cases per family. When evaluating mode of inheritance, 167 (72%) families were consistent with autosomal recessive inheritance, whereas 58 (25%) families were consistent with autosomal dominant inheritance and in 8 families the familial aggregation could be explained by autosomal dominant inheritance with incomplete penetrance. Blood samples from 235 affected relative pairs (ARPs) and their unaffected relatives were collected for DNA isolation and the DNA used for genotyping with highly variable microsatellite markers. We included covariates in the statistical analyses to allow for genetic heterogeneity. The results for chromosomes 19g13 and 4q31 were significant with sex, number of affected first‐degree relatives, and their interaction as covariates. These chromosomal regions contain many plausible candidate genes, and the future research will include more detailed analyses of these positional candidate genes.
Activators of Plasminogen and the Progression of Small Abdominal Aortic Aneurysms
Authors: LINDHOLT JES S.
Published: December 2006

Abstract:  The aim of this study was to examine the role of activating pathways of plasminogen in the natural history of abdominal aortic aneurysms (AAA). To fulfill this objective 70 male patients with small AAA (> 3 cm) were interviewed and examined. Their blood samples were taken at diagnosis. The patients were scanned annually for a minimum period of 1 year and a maximum of 5 years (mean 2.5 years), and referred for surgery if the AAA exceeded 5 cm in diameter. Plasma levels of urokinase‐like plasminogen activator (uPA), tissue‐type plasminogen activator (tPA), plasminogen‐activator‐inhibitor‐1 (PAI‐1), macrophage‐inhibiting factor (MIF), transforming‐growth‐factor‐β1 (TGF‐β1), homocysteine, and serum levels of IgA‐antibodies against Chlamydia pneumoniae (IgA‐CP) and cotinine (a nicotine metabolite) were measured. The annual expansion rate correlated positively with tPA, IgA‐CP, and S‐cotinine; rho = 0.37 (P= 0.004), 0.28 (P= 0.01), and 0.24 (P= 0.04), while PAI‐1, uPA, TGF‐β1, homocysteine, and MIF did not. S‐cotinine and PAI‐1 also correlated positively with tPA, rho = 0.24 (P= 0.04), and 0.33 (P= 0.005). IgA‐CP did not correlate with tPA. By receiver operating characteristics (ROC) curve analysis, tPA showed to be predictive of cases expanding to above 5 cm within the first 5 years with an optimal sensitivity and specificity of 0.73 and 0.71, respectively (P= 0.015). The aortic matrix degradation in AAA may be partly caused by an activation of plasminogen by tPA, but not by uPA, which usually dominates matrix degradation. Smoking seems to be an important factor for this pathway, while the pathway of IgA‐CP seems different.
Genetic Basis of Thoracic Aortic Aneurysms and Dissections
Authors: PANNU HARIYADARSHI , AVIDAN NILI , TRAN‐FADULU VAN , MILEWICZ DIANNA M.
Published: December 2006

Abstract:  Ascending thoracic aortic aneurysms leading to type A dissections (TAAD) have long been known to occur in association with a genetic syndrome such as Marfan syndrome (MFS). More recently, TAAD has also been demonstrated to occur as an autosomal dominant disorder in the absence of syndromic features, termed familial TAAD. Familial TAAD demonstrates genetic heterogeneity, and linkage studies have identified TAAD loci at 5q13‐14 (TAAD1), 11q23 (FAA1), 3p24‐25 (TAAD2), and 16p12.2‐13.13. The genetic heterogeneity of TAAD is reflected by variation in disease in terms of the age of onset, progression, penetrance, and association with additional cardiac and vascular features. The underlying genetic heterogeneity of TAAD is reflected in the phenotypic variation associated with familial TAAD with respect to age of onset, progression, penetrance, and association with additional cardiac and vascular features. Mutations in the TGFBR2 gene have been identified as the cause of disease linked to the 3p24‐25 locus, implicating dysregulation of TGF‐β signaling in TAAD. Mutations in myosin heavy chain (MYH11), a smooth muscle cell‐specific contractile protein, have been identified in familial TAAD associated with patent ductus arteriosus (PDA) linked to 16p12.2‐12.13. The identification of these novel disease pathways has led to new directions for future research addressing the pathology and treatment of TAAD.
Thoracic Aortic Compliance as a Determinant of Rupture of Abdominal Aortic Aneurysms
Authors: RUSSO LUIGI
Published: December 2006

Abstract:  The relative importance of collagen and elastin in formation, expansion, and rupture of abdominal aortic aneurysms (AAAs) has been investigated extensively. Aortic compliance, which is a relevant component of cardiac afterload, is also determined by the relative amount of media proteins in large arteries as well as by pathological arterial processes. The objective of this study was to determine if thoracic aortic compliance was different in patients with ruptured AAAs compared to those undergoing elective AAA repair. The study was carried out in 43 patients with infrarenal AAAs in the postoperative period. The first group (A) included 17 patients undergoing emergency ruptured AAA repair. The second group (B) included 26 patients operated on for an AAA who underwent elective repair. Patients were studied by a noninvasive Doppler echocardiography. Pulse wave velocity (PWV) was determined in the descending thoracic aorta. Results show that patients with electively repaired AAAs had an accelerated pulse wave transmission, typical of an atherosclerotic aorta with a Gaussian distribution (PWV 9.26 m/sec ± 1.27). In contrast, patients with ruptured aneurysms presented in a distribution with three peaks. A striking increase in aortic compliance (41% of patients with PWV<6 m/sec in group A vs. 3% of group B) was observed in patients with ruptured AAAs.
Do Cathepsins Play a Role in Abdominal Aortic Aneurysm Pathogenesis?
Authors: SUKHOVA GALINA K. , SHI GUO‐PING
Published: December 2006

Abstract:  Between 1998 and 1999 we suggested a role for cysteine proteases, particularly cathepsins S and K, in atherosclerosis and abdominal aortic aneurysm (AAA) formation. We also demonstrated the presence and activity of cathepsins S, K, and L in atherosclerotic and aneurysmal lesions in humans. Features unique to this family of extracellular enzymes indicate its likely participation in these vascular diseases. As very potent elastolytic enzymes, cathepsins are strong candidates as key participants in aneurysm development. Importantly, cathepsins express very high elastolytic activity in AAA due to reciprocal correlation with cystatin C, their most abundant endogenous inhibitor. Two opposite processes coexist in aneurysmal tissue: overexpression of elastolytic cathepsins, and severe suppression of cystatin C, probably due to differentially regulated expression and secretion of cathepsins and their inhibitors in response to inflammatory cytokines. Involvement of cathepsins in microvessel formation, a pathophysiological marker of human AAA, and programmed cell death (apoptosis), increases the likelihood of cathepsin participation in AAA formation and growth. We also summarize here results obtained in our and other laboratories that demonstrated reduced atherosclerosis and AAA in in vivo models using mice lacking different cathepsins. Deficiency of cysteine protease inhibitor cystatin C in atherosclerosis‐prone ApoE‐null mice leads to the development of specific features of AAA such as thinning of the tunica media and aortic dilatation. Taken together, such findings in humans in vitro with different cell types and in vivo in genetically altered mice demonstrate the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during atherosclerosis and aortic aneurysm formation.
Pathophysiology of Abdominal Aortic Aneurysms
Authors: THOMPSON ROBERT W. , CURCI JOHN A. , ENNIS TERRI L. , MAO DONGLI , PAGANO MONICA B. , PHAM CHRISTINE T.N.
Published: December 2006

Abstract:  Abdominal aortic aneurysms (AAAs) represent a complex degenerative disorder involving chronic aortic wall inflammation and destructive remodeling of structural connective tissue. Studies using human AAA tissues have helped identify a variety of molecular mediators and matrix‐degrading proteinases, which contribute to aneurysm disease, thereby providing a sound foundation for understanding AAAs; however, these human tissue specimens represent only the “end stage” of a long and progressive disease process. Further progress in understanding the pathophysiology of AAAs is therefore dependent in part on the development and application of effective animal models that recapitulate key aspects of the disease. Based on original studies in rats, transient perfusion of the abdominal aorta with porcine pancreatic elastase has provided a reproducible and robust model of AAAs. More recent applications of this model to mice have also opened new avenues for investigation. In this review, we summarize investigations using the elastase‐induced mouse model of AAAs including results in animals with targeted deletion of specific genes and more general differences in mice on different genetic backgrounds. These studies have helped us identify genes that are essential to the development of AAAs (such as MMP9, IL6, and AT1R) and to reveal other genes that may be dispensable in aneurysm formation. Investigations on mice from different genetic backgrounds are also beginning to offer a novel approach to evaluate the genetic basis for susceptibility to aneurysm development.
Epidemiology of Aortic Aneurysm Repair in the United States from 1993 to 2003
Authors: COWAN JOHN A. , DIMICK JUSTIN B. , HENKE PETER K. , RECTENWALD JOHN , STANLEY JAMES C. , UPCHURCH GILBERT R.
Published: December 2006

Abstract:  The epidemiology of abdominal aortic aneurysm (AAA) disease has been well described over the preceding 50 years. This disease primarily affects elderly males with smoking, hypertension, and a positive family history contributing to an increased risk of aneurysm formation. The aging population as well as increased screening in high‐risk populations has led some to suggest that the incidence of AAAs is increasing. The National Inpatient Sample (1993–2003), a national representative database, was used in this study to determine trends in mortality following AAA repair in the United States. In addition, the impact of the introduction of less invasive endovascular AAA repair was assessed. Overall rates of treated unruptured and ruptured AAAs remained stable (unruptured 12 to 15/100,000; ruptured 1 to 3/100,000). In 2003, 42.7% of unruptured and 8.8% of ruptured AAAs were repaired through an endovascular approach. Inhospital mortality following unruptured AAA repair continues to decline for open repair (5.3% to 4.7%, P= 0.007). Mortality after elective endovascular AAA repair also has statistically decreased (2.1% to 1.0%, P= 0.024) and remains lower than open repair. Mortality rates for ruptured AAAs following repair remain high (open: 46.5% to 40.7%, P= 0.01; endovascular: 40.0% to 35.3%, P= 0.823). These data suggest that the numbers of patients undergoing elective AAA repair have remained relatively stable despite the introduction of less invasive technology. A shift in the treatment paradigm is occurring with a higher percentage of patients subjected to elective endovascular AAA repair compared to open repair. This shift, at least in the short term, appears justified as the mortality in patients undergoing elective endovascular AAA repair is significantly reduced compared to patients undergoing open AAA repair.
Refinements in Mathematical Models to Predict Aneurysm Growth and Rupture
Authors: BERGUER RAMON , BULL JOSEPH L. , KHANAFER KHALIL
Published: December 2006

Abstract:  The growth of aneurysms and eventually their likelihood of rupture depend on the determination of the stress and strain within the aneurysm wall and the exact reproduction of its geometry. A numerical model is developed to analyze pulsatile flow in abdominal aortic aneurysm (AAA) models using real physiological resting and exercise waveforms. Both laminar and turbulent flows are considered. Interesting features of the flow field resulting from using realistic physiological waveforms are obtained for various parameters using finite element methods. Such parameters include Reynolds number, size of the aneurysm (D/d), and flexibility of the aneurysm wall. The effect of non‐Newtonian behavior of blood on hemodynamic stresses is compared with Newtonian behavior, and the non‐Newtonian effects are demonstrated to be significant in realistic flow situations. Our results show that maximum turbulent fluid shear stress occurs at the distal end of the AAA model. Furthermore, turbulence is found to have a significant effect on the pressure distribution along AAA wall for both physiological waveforms. Related experimental work in which a bench top aneurysm model is developed is also discussed. The experimental model provides a platform to validate the numerical model. This work is part of our ongoing development of a patient‐specific tool to guide clinician decision making and to elucidate the contribution of blood flow‐induced stresses to aneurysm growth and eventual rupture. These studies indicate that accurately modeling the physiologic features of real aneurysms and blood is paramount to achieving our goal.
Role of the Renin‐Angiotensin System in the Development of Abdominal Aortic Aneurysms in Animals and Humans
Authors: DAUGHERTY ALAN , RATERI DEBRA L. , CASSIS LISA A.
Published: December 2006

Abstract:  The mediators for the initiation, progression, and rupture of abdominal aortic aneurysms (AAAs) have not been defined. Recent evidence has demonstrated that chronic infusion of angiotensin II via subcutaneously placed osmotic pumps can reproducibly form AAAs in mice. The evolution of AngII‐induced AAAs in these mice is complex. Rapid medial macrophage accumulation precedes transmedial breaks and large lumen expansion, which are restricted to the suprarenal aorta. After this initial phase, there is a more gradual rate of lumen expansion that is progressive with continued AngII exposure. There is extensive aortic remodeling during this gradual expansion phase. An initial prominent thrombus gradually resolves and is replaced by fibrous tissue containing several types of inflammatory cells. At prolonged intervals of AngII infusion, internal aortic diameters of the suprarenal aorta can increase up to fourfold compared to the same region in saline‐infused mice. The extrapolation of these data in mice to the development of human AAAs remains to be determined. However, there are a considerable number of drugs available to potentially test the efficacy of inhibiting the renin‐angiotensin system on the progression of the human disease.
A Summary of the Contributions of the VA Cooperative Studies on Abdominal Aortic Aneurysms
Authors: LEDERLE FRANK A.
Published: December 2006

Abstract:  The Department of Veterans Affairs Cooperative Studies Program has completed two studies on abdominal aortic aneurysm (AAA) and is currently conducting a third. The first, the Aneurysm Detection and Management (ADAM) Study, consisted of both a screening program, which provided information on the prevalence and associations of AAA, and a randomized trial, which found that survival is not improved by repair of small AAA. The second was a prospective observational study to determine the incidence of rupture in patients with large AAA for whom elective repair was not planned due to medical contraindications or patient refusal. AAA in this population had a high risk of rupture, about 10% per year for AAA > 5.5 cm, and 25% within 6 months for AAA larger than 8.0 cm. The third, the Open Versus Endovascular Repair (OVER) Trial, is a multicenter randomized trial comparing long‐term survival following two methods of elective AAA repair.
Genes Predisposing to Rapid Aneurysm Growth
Authors: POWELL J.T.
Published: December 2006

Abstract:  The aim of the study was to investigate the effect of functional polymorphisms in promoters of the MMP‐2 (−1306 C > T), MMP‐3 (−1171 5A > 6A), MMP‐9 (−1562 C > T), MMP‐12 (−82 A > G), TIMP‐1 (−372 C > T), and PAI‐1 (−675 4G > 5G and −847 A > G) genes on the growth rate of small abdominal aortic aneurysms. The patients with small aneurysms were recruited from the surveillance arm of the U.K. Small Aneurysm Trial and monitored for aneurysm growth, mean follow‐up 2.6 years. Mean linear aneurysm growth rates were calculated by flexible modeling. For MMP‐2, MMP‐3, MMP‐9, MMP‐12, and TIMP‐1 polymorphisms there were no clear associations with aneurysm growth. The increased growth rates for patients of 5G5G PAI‐1 genotype were of borderline significance (P= 0.06). However, PAI‐1 haplotype analysis showed that 5G5G/GG patients had significantly faster aneurysm growth (mean 0.46 mm/year faster). There was no evidence that any specific MMP polymorphism had a clinically significant effect on aneurysm growth. However the plasminogen system (via PAI‐1) appears to have a small, but clinically significant, role in aneurysm growth.
Should Usual Criteria for Intervention in Abdominal Aortic Aneurysms Be “Downsized,” Considering Reported Risk Reduction with Endovascular Repair?
Authors: SCHERMERHORN MARC
Published: December 2006

Abstract:  Two randomized trials have demonstrated the safety of waiting until abdominal aortic aneurysm (AAA) diameter reaches 5.5 cm for repair in most patients. Other recent randomized trials have demonstrated lower perioperative mortality and morbidity with endovascular aneurysm repair (EVAR) compared to open surgery. Therefore, it is logical to assume that endovascular repair may change the appropriate threshold for intervention. However, endovascular repair is not as durable as open surgery and is associated with ongoing risks of rupture and reintervention. Decision analysis based on data available in 1998 showed that endovascular repair should not change the threshold for intervention. Since that time retrospective data have emerged to suggest that outcomes with endovascular repair are improved in smaller AAAs, although this may simply represent selection bias and the natural history of small AAAs. Randomized trials are appropriate to determine whether improved endovascular outcomes in small AAAs reduce late rupture and reintervention enough to justify early intervention in patients with appropriate anatomy. In the absence of data from these trials, the threshold for intervention should not be changed.
HLA–DQA Is Associated with Abdominal Aortic Aneurysms in the Belgian Population
Authors: TROMP GERARD , OGATA TORU , GREGOIRE LUCIE , GODDARD KATRINA A.B. , SKUNCA MAGDALENA , LANCASTER WAYNE D. , PARRADO ANTONIO R. , LU QING , SHIBAMURA HIDENORI , SAKALIHASAN NATZI , LIMET RAYMOND , MACKEAN GERALD L. , ARTHUR CLAUDETTE , SUEDA TAIJIRO , KUIVANIEMI HELENA
Published: December 2006

Abstract:  Chronic inflammation and autoimmunity likely contribute to the pathogenesis of abdominal aortic aneurysms (AAAs). The aim of this study was to investigate the role of autoimmunity in the etiology of AAAs using a genetic association study approach with human leukocyte antigen (HLA) polymorphisms (HLA–DQA1, –DQB1, –DRB1 and –DRB3–5 alleles) in 387 AAA cases and 426 controls. We observed an association with the HLA–DQA1 locus among Belgian males, and found a significant difference in the HLA–DQA1*0102 allele frequencies between AAA cases and controls. In conclusion, this study showed potential evidence that the HLA–DQA1 locus harbors a genetic risk factor for AAAs suggesting that autoimmunity plays a role in the pathogenesis of AAAs.
A Biomechanics‐Based Rupture Potential Index for Abdominal Aortic Aneurysm Risk Assessment
Authors: VANDE GEEST JONATHAN P. , DI MARTINO ELENA S. , BOHRA AJAY , MAKAROUN MICHEL S. , VORP DAVID A.
Published: December 2006

Abstract:  Abdominal aortic aneurysms (AAAs) can typically remain stable until the strength of the aortic wall is unable to withstand the forces acting on it as a result of the luminal blood pressure, resulting in AAA rupture. The clinical treatment of AAA patients presents a dilemma for the surgeon: surgery should only be recommended when the risk of rupture of the AAA outweighs the risks associated with the interventional procedure. Since AAA rupture occurs when the stress acting on the wall exceeds its strength, the assessment of AAA rupture should include estimates of both wall stress and wall strength distributions. The present work details a method for noninvasively assessing the rupture potential of AAAs using patient‐specific estimations the rupture potential index (RPI) of the AAA, calculated as the ratio of locally acting wall stress to strength. The RPI was calculated for thirteen AAAs, which were broken up into ruptured (n= 8 and nonruptured (n= 5) groups. Differences in peak wall stress, minimum strength and maximum RPI were compared across groups. There were no statistical differences in the maximum transverse diameters (6.8 ± 0.3 cm vs. 6.1 ± 0.5 cm, p= 0.26) or peak wall stress (46.0 ± 4.3 vs. 49.9 ± 4.0 N/cm2, p= 0.62) between groups. There was a significant decrease in minimum wall strength for ruptured AAA (81.2 ± 3.9 and 108.3 ± 10.2 N/cm2, p= 0.045). While the differences in RPI values (ruptured = 0.48 ± 0.05 vs. nonruptured = 0.36 ± 0.03, respectively; p= 0.10) did not reach statistical significance, the p‐value for the peak RPI comparison was lower than that for both the maximum diameter (p= 0.26) and peak wall stress (p= 0.62) comparisons. This result suggests that the peak RPI may be better able to identify those AAAs at high risk of rupture than maximum diameter or peak wall stress alone. The clinical relevance of this method for rupture assessment has yet to be validated, however, its success could aid clinicians in decision making and AAA patient management.
Toward a Model for Local Drug Delivery in Abdominal Aortic Aneurysms
Authors: GEEST JONATHAN P. VANDE , SIMON BRUCE R. , MORTAZAVI ARIANE
Published: December 2006

Abstract:  The formation of an abdominal aortic aneurysm (AAA) may eventually result in rupture, an event associated with a 50% mortality rate. This work represents a first step toward improving current stress estimation techniques and local transport simulations in AAA. Toward this aim, a computational parametric study was performed on an axisymmetric cylindrical FEM of a 5 cm AAA with a 1.5 cm thick intraluminal thrombus (ILT). Both the AAA wall and ILT were modeled as porohyperelastic PHE materials using estimated values of AAA wall and ILT permeability. While no values for AAA wall permeability could be found in the literature, the value of ILT permeability was taken from a previous investigation by Adolph et al.7 Peak stresses, fluid velocities, and local pore pressure values within the ILT and wall were recorded and analyzed as a function of the cardiac cycle. While peak wall stress values for the PHE models did not largely differ from corresponding solid finite element simulations (186.2 N/cm2 vs. 186.5 N/cm2), the stress in the abluminal region of the ILT increased by 17.4% (7.7 N/cm2 vs. 6.5 N/cm2). Pore pressure values were relatively constant through the ILT while there were significant pore pressure gradients present in the AAA wall. The magnitude of fluid velocities varied in magnitude and direction throughout the cardiac cycle with large fluctuations occurring on the luminal surface. The combination of the patient‐specific PHE AAA FEMs with mass transport simulations will result in spatially and time‐varying concentration distributions within AAA, which may benefit future pharmaceutical treatments of AAA.