bluuebunny/crossref_metadata_2025 huggingface dataset:
Value of serum glycated albumin and high-sensitivity C-reactive protein levels in the prediction of presence of coronary artery disease in patients with type 2 diabetes
Authors: Pu Li Jin , Lu Lin , Xu Xue Wei , Zhang Rui Yan , Zhang Qi , Zhang Jian Sheng , Hu Jian , Yang Zheng Kun , Ding Feng Hua , Chen Qiu Jin , Lou Sheng , Shen Jie , Fang Dan Hong , Shen Wei Feng
Published: December 2006

Background

Coronary artery disease (CAD) is a major vascular complication of diabetes mellitus and reveals high mortality. Up to 30% of diabetic patients with myocardial ischemia remain asymptomatic and are associated with worse prognosis compared to non-diabetic counterpart, which warrants routine screening for CAD in diabetic population. The purpose of this study was to evaluate the clinical value of serum glycated albumin and high-sensitivity C-reactive protein (hs-CRP) levels in predicting the presence of CAD in patients with type 2 diabetes.

Methods

Three hundred and twenty-four patients with type 2 diabetes were divided into two groups based on presence (CAD group, n = 241) or absence (control group, n = 83) of angiographically-documented CAD (lumen diameter narrowing ≥70%). Serum levels of glycated albumin and hs-CRP as well as serum concentrations of glucose, lipids, creatinine, blood urea nitrogen and uric acid were measured in both groups. Predictors of CAD were determined using multivariate logistic regression model and receiver-operating characteristic (ROC) curves.

Results

Serum glycated albumin and hs-CRP levels were significantly increased in diabetic patients with CAD. Multivariate regression analysis revealed that male gender, age, serum levels of glycated albumin, hs-CRP, creatinine and lipoprotein (a) were independent predictors for CAD. Areas under the curve of glycated albumin and hs-CRP and for regression model were 0.654 (95%CI 0.579–0.730, P < 0.001), 0.721 (95%CI 0.658–0.785, P < 0.001) and 0.824 (95% CI 0.768–0.879, P < 0.001), respectively. The optimal values of cut-off point were 18.7% (sensitivity 67.9%, specificity 60.0%) for glycated albumin and 5.2 mg/l (sensitivity 72.2%, specificity 60.0%) for hs-CRP to predict CAD. Logistic regression model was defined as: P/(1-P) = EXP(-1.5 + 1.265 gender + 0.812 age + 1.24 glycated albumin + 0.953 hs-CRP + 0.902 lipoprotein(a) + 1.918 creatinine). The optimal probability value for predicting CAD in type 2 diabetic patients was 0.648 (sensitivity 82.3%, specificity 68.6%).

Conclusion

Serum glycated albumin and hs-CRP levels were significantly elevated in patients with type 2 diabetes and CAD. The logistic regression model incorporating with glycated albumin, hs-CRP and other major risk factors of atherosclerosis may be useful for screening CAD in patients with type 2 diabetes.
Medical science, culture, and truth
Authors: Gillett Grant
Published: December 2006

There is a fairly closed circle between culture, language, meaning, and truth such that the world of a given culture is a world understood in terms of the meanings produced in that culture. Medicine is, in fact, a subculture of a powerful type and has its own language and understanding of the range of illnesses that affect human beings. So how does medicine get at the truth of people and their ills in such a way as to escape its own limited constructions? There is a way out of the closed circle implicit in the idea of a praxis and the engagement with reality that is central to it and the further possibility introduced by Jacques Lacan that signification is never comprehensive in relation to the subject's encounter with the real. I will explore both of these so as to develop a conception of truth that is apt for the knowledge that arises in the clinic.
Classification methods for the development of genomic signatures from high-dimensional data
Authors: Moon Hojin , Ahn Hongshik , Kodell Ralph L , Lin Chien-Ju , Baek Songjoon , Chen James J
Published: December 2006

Personalized medicine is defined by the use of genomic signatures of patients to assign effective therapies. We present Classification by Ensembles from Random Partitions (CERP) for class prediction and apply CERP to genomic data on leukemia patients and to genomic data with several clinical variables on breast cancer patients. CERP performs consistently well compared to the other classification algorithms. The predictive accuracy can be improved by adding some relevant clinical/histopathological measurements to the genomic data.
Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2–/– mice
Authors: Wareing Mark D , Lyon Ashley , Inglis Chandra , Giannoni Francesca , Charo Israel , Sarawar Sally R
Published: December 2006

Influenza virus infections induce chemokines and cytokines, which regulate the immune response. The chemokine receptor CCR2 plays an important role in macrophage recruitment and in the development of T1 immunity. In the present study, we addressed the role of CCR2 in influenza A virus infection. CCR2 knockout (−/−) mice are protected against influenza A virus infection, despite delayed recruitment of macrophages. We show that low-dose influenza infection of CCR2−/− mice leads to increased neutrophilia between Days 5 and 10 after infection and decreased monocyte/macrophage and CD4+ T cell recruitment to the lungs between Days 5 and 7 after infection. These changes in leukocyte recruitment did not result from or cause increased viral titers or delayed viral clearance. Neutrophilia in the lungs correlated with increased keratinocyte-derived chemokine (KC) and/or MIP-2 expression in CCR2−/− mice between Days 5 to 10 after infection, although the kinetics of neutrophil recruitment was not altered. MIP-2 mRNA and protein expression was increased three- to fivefold, and KC protein levels were increased two- to threefold in CCR2−/− compared with CCR2 wild-type mice at Day 5 after infection. This preceded the peak neutrophil influx, which occurred 7 days after infection. In vitro studies confirmed that MIP-2 and KC accounted for neutrophil chemotactic activity in the bronchoalveolar lavage. CCR2 deficiency also resulted in increased MIP-1α, MIP-1β, MCP-1, and IFN-inducible protein 10 and decreased RANTES mRNA expression. Furthermore, IL-6 and TNF-α cytokine production were elevated after infection. These studies suggest that CCR2 plays a multifactorial role in the development of the immune response to influenza.
Structural and Functional Genetic Disorders of the Great Vessels and Outflow Tracts
Authors: BEE KATHARINE J. , WILKES DAVID , DEVEREUX RICHARD B. , LERMAN BRUCE B. , DIETZ HARRY C. , BASSON CRAIG T.
Published: December 2006

Abstract:  Development of the aorta and pulmonary artery is a complex process involving multiple molecular genetic pathways that modulate morphogenesis of the outflow tracts and the anastomosis of branch vessels. Recent genetic studies of the cardiovascular system demonstrate that congenital and adult onset progressive disorders of the great vessels such as aneurysms are components of generalized vascular, cardiac, and extracardiovascular syndromes. Current paradigms suggest that aortic disease is founded in patterning anomalies of the conotruncus that occur in utero. These aberrations can be consequences of genetic aberrations in transcriptional regulation of signal transduction both within and outside the developing great vessels.
Diffusion of Alexa Fluor 488‐Conjugated Dendrimers in Rat Aortic Tissue
Authors: CHO BRENDA S. , ROELOFS KAREN J. , MAJOROS ISTVAN J. , BAKER JAMES R. , STANLEY JAMES C. , HENKE PETER K. , UPCHURCH GILBERT R.
Published: December 2006

Abstract:  In this study, the distribution of labeled dendrimers in native and aneurysmal rat aortic tissue was examined. Adult male rats underwent infrarenal aorta perfusion with generation 5 (G5) acetylated Alexa Fluor 488‐conjugated dendrimers for varying lengths of time. In a second set of experiments, rats underwent aortic elastase perfusion followed by aortic dendrimer perfusion 7 days later. Aortic diameters were measured prior to and postelastase perfusion, and again on the day of harvest. Aortas were harvested 0, 12, or 24 h postperfusion, fixed, and mounted. Native aortas were harvested and viewed as negative controls. Aortic cross‐sections were viewed and imaged using confocal microscopy. Dendrimers were quantified (counts/high‐powered field). Results were evaluated by repeated measures ANOVA and Student's t‐test. We found that in native aortas, dendrimers penetrated the aortic wall in all groups. For all perfusion times, fewer dendrimers were present as time between dendrimer perfusion and aortic harvest increased. Longer perfusion times resulted in increased diffusion of dendrimers throughout the aortic wall. By 24 h, the majority of the dendrimers were through the wall. Dendrimers in aneurysmal aortas, on day 0 postdendrimer perfusion, diffused farther into the aortic wall than controls. In conclusion, this study documents labeled dendrimers delivered intra‐arterially to native rat aortas in vivo, and the temporal diffusion of these molecules within the aortic wall. Increasing perfusion time and length of time prior to harvest resulted in continued dendrimer diffusion into the aortic wall. These preliminary data provide a novel mechanism whereby local inhibitory therapy may be delivered locally to aortic tissue.
Hypoxia at the Site of Abdominal Aortic Aneurysm Rupture Is Not Associated with Increased Lactate
Authors: CHOKE EDWARD , COCKERILL GILLIAN W. , DAWSON JOSEPH , CHUNG YUEN‐LI , GRIFFITHS JOHN , WILSON RICHARD W. , LOFTUS IAN M. , THOMPSON MATTHEW M.
Published: December 2006

Abstract:  The mechanisms of hypoxia‐mediated aneurysm wall weakening and rupture are unknown. During hypoxia, strategies to maintain cellular ATP levels include increasing glycolysis (glycolytic strategy) or decreasing ATP consumption (metabolic depression). This study demonstrated that compared to anterior aneurysm sac, rupture edge overexpressed hypoxia‐inducible factor‐1‐α (marker of hypoxia) and showed no significant difference in levels of combined ADP and ATP or lactate (glycolytic end product). Further studies are needed to confirm whether hypoxic AAA cells adapt through metabolic depression rather than glycolysis. The downregulation of protein synthesis during such metabolic depression may be a factor in hypoxia‐mediated wall weakening.
Gene Expression Profile of Abdominal Aortic Aneurysm Rupture
Authors: CHOKE EDWARD , THOMPSON MATTHEW M. , JONES ALUN , TORSNEY EVELYN , DAWSON JOSEPH , LAING KENNETH , NASR HOSAAM , LOFTUS IAN M. , COCKERILL GILLIAN W.
Published: December 2006

Abstract:  To search for novel transcriptional pathways that are activated in abdominal aortic aneurysm rupture, cDNA microarrays were used to compare global mRNA expression at the aneurysm rupture edge to anterior sac, and selected results were confirmed using quantitative real‐time‐polymerase chain reaction (QRT‐PCR). This study identified apoptosis, angiogenesis, and inflammation as potentially important participants during the process of aneurysm rupture.
Increased Angiogenesis at the Site of Abdominal Aortic Aneurysm Rupture
Authors: CHOKE EDWARD , COCKERILL GILLIAN W. , DAWSON JOSEPH , WILSON RICHARD W. , JONES ALUN , LOFTUS IAN M. , THOMPSON MATTHEW M.
Published: December 2006

Abstract:  Abdominal aortic aneurysm (AAA) rupture is associated with elevated levels of matrix metalloproteinase (MMP). Medial neovascularization is a known characteristic of established AAAs and involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell proliferation and migration. This study evaluated the extent of neovascularization in abdominal aortic aneurysm rupture. Results indicated upregulation of proangiogenic cytokines and increased medial neovascularization at the aneurysm rupture edge compared with paired aneurysm anterior sac. Further investigations into the role of angiogenesis in aneurysm rupture may open novel therapeutic avenues to prevent aneurysm rupture.
AAA Disease
Authors: DALMAN RONALD L. , TEDESCO MAUREEN M. , MYERS JONATHON , TAYLOR CHARLES A.
Published: December 2006

Abstract:  Abdominal aortic aneurysm (AAA) is a common and frequently lethal disease of older Americans. No medical therapy has been proven effective in retarding progression of small AAAs prior to surgical repair. With the emerging ability of magnetic resonance (MR) flow imaging and MR‐based computational analysis to define aortic hemodynamic conditions, and bio‐imaging strategies to monitor aortic inflammation real time in vivo, the opportunity now exists to confirm the potential value of medical interventions such as supervised exercise training as first line therapy for small AAA disease.
Circulating Cytokines in Patients with Abdominal Aortic Aneurysms
Authors: DAWSON JOE , COCKERILL GILLIAN , CHOKE EDWARD , LOFTUS IAN , THOMPSON MATT M.
Published: December 2006

Abstract:  Studies suggest that aneurysm‐derived cytokines perpetuate the cycle of inflammation and proteolysis that is the pathological hallmark of abdominal aortic aneurysms (AAA). As interleukin (IL)‐6 is an independent risk factor for cardiovascular mortality, such cytokines may also have important systemic effects. The purpose of this study was to investigate the effect of aneurysm repair on circulating levels of cytokines. Inflammatory cytokines were measured in 99 patients with AAA and 100 patients who had undergone AAA repair in the past. There was a significant reduction in IL‐10 in the postoperative group, and a nonsignificant trend toward reduction in IL‐6 and CRP in the postoperative group. Subgroup analysis of the postoperative group revealed significantly lower levels of IL‐6 and CRP in the open group compared to endovascular aneurysm repair (EVAR). These results suggest that aneurysm repair may have an effect upon chronic levels of circulating inflammatory cytokines, and that the type of repair may exert some influence.
Is There a Role for the Macrophage 5‐Lipoxygenase Pathway in Aortic Aneurysm Development in Apolipoprotein E–Deficient Mice?
Authors: FUNK COLIN D. , CAO RICHARD YANG , ZHAO LEI , HABENICHT ANDREAS J.R.
Published: December 2006

Abstract: Activation of the 5‐lipoxygenase (5‐LO) pathway leads to the biosynthesis of proinflammatory leukotriene (LT) lipid mediators in macrophages, mast cells, and other inflammatory cell types. A recent surge in interest in this pathway within the cardiovascular system has arisen from a variety of exciting findings using genetic, pathological specimen, and biochemical approaches in humans and mice. We found that a subset of CD68‐positive macrophages, localized within the adventitial layer of apolipoprotein E (apo E)‐deficient mice, expressed 5‐LO and that these cells represented a significant cellular component of aortic aneurysms induced by an atherogenic diet containing cholate. Surprisingly, almost no 5‐LO‐expressing cells were observed in atherosclerotic lesions in the same mice. Correspondingly, lesion size in the fat‐fed mice did not depend on 5‐LO gene expression but aneurysm incidence was reduced in the absence of the 5‐LO pathway. We are currently exploring the potential mechanisms for 5‐LO/LT involvement in aneurysm pathogenesis and if this pathway might come into play in other models such as induction by angiotensin II.
Current Status of Endovascular Repair of Infrarenal Abdominal Aortic Aneurysms in the Context of 50 Years of Conventional Repair
Authors: HERTZER NORMAN R.
Published: December 2006

Abstract:  The operative risk for conventional open repair of nonruptured infrarenal abdominal aortic aneurysms (AAAs) has steadily declined during the past several decades to the point that open procedures now can be done with a mortality rate of approximately 2% at tertiary referral centers. Nevertheless, population‐based studies suggest that the mortality rate for open AAA repair remains nearly 7% in many communities, a finding that undoubtedly is influenced by a substantial risk for unfavorable outcomes in patients who represent less than ideal candidates for major abdominal operations on the basis of advanced age and the medical comorbidities that so often accompany it. Endovascular aneurysm repair (EVAR) is a landmark contribution to the management of such patients and has been associated with significant overall reductions in the operative mortality rate in statewide and national audits. This early advantage of EVAR comes at the price of a unique set of complications, secondary interventions, and related expenses, however, and randomized clinical trials of EVAR versus open repair have not yet demonstrated differences in survival or quality of life within 4 years of follow‐up. Data from the Nationwide Inpatient Sample and other sources indicate that the mortality rate for open AAA repair appears to be less than 2% in patients who are 65 years of age or younger. This low operative risk may not justify exposure to whatever incidence of late complications the current generation of endografts may prove to have during the relatively long survival times that can be anticipated for these patients.
Arterial Aneurysms in HIV Patients
Authors: TILSON M.D. , WITHERS L.
Published: December 2006

Abstract:  There is growing literature on the subject of aneurysmal degeneration of arteries in patients who are infected with HIV. A patient recently seen at our medical center with an aneurysm of the carotid artery stimulated our interest in reviewing the mechanisms by which HIV may initiate or predispose to these pathologies. There are at least three major possibilities: (1) immunodeficiency allows bacteria that are known to cause mycotic aneurysms to proliferate without immune restraint; (2) one or more of the HIV envelope proteins sufficiently resemble one or more artery‐specific‐antigenic proteins (ASAPs) that may trigger an autoimmune response (molecular mimicry); and (3) the HIV virus itself infects arterial‐resident cells that maintain the integrity of the load‐bearing matrix. The computational searches reported here suggest that the ASAP, matrix cell adhesion molecule‐1 (Mat‐CAM‐1), has a high degree of similarity to known ligands for HIV envelope proteins gp41 and gp120. No similarities of Mat‐CAM‐1 to the HIV envelope glycoproteins were detected. Accordingly, among the possibilities for explaining the HIV/aneurysm connection, direct infection of aortic fibroblasts by the HIV virus is more likely to be the pathogenetic mechanism than the process of molecular mimicry.
Abdominal Aortic Aneurysm as a Complex Multifactorial Disease
Authors: PEARCE WILLIAM H. , SHIVELY VERA P.
Published: December 2006

Abstract:  The role of matrix metalloproteinases (MMPs) in the pathogenesis of abdominal aortic aneurysm (AAA) has focused on the degradation of the extracellular matrix (ECM). The new frontier of MMP biology involves the role of MMPs in releasing cryptic fragments and neoepitopes from the ECM and the impact of MMPs on the regulation of the inflammatory response. The ECM is a complex structure, much more important than an inert scaffold. Both MMP‐2 and MMP‐9 expose a cryptic epitope that controls angiogenesis. MMPs inhibit angiogenesis through the release of endostatin, endorepellin, arresten, canstatin, and tumstatin. Other breakdown products of the ECM include fragments of fragmin and elastin degradation products (EDPs). In addition, the ECM contains embedded vascular endothelial growth factor (VEGF) and transforming growth factor‐beta (TGF‐β). Inflammation is a complex, highly regulated system that involves the identification of injury or infection, response to the injury or infection, repair and healing, and return to normal homeostasis. In some instances, the inflammatory process leads to a pathologic process that is damaging to the host. MMPs play an important role in the control of the inflammatory response through the modification of proinflammatory cytokines, chemokines, and shedding of membrane receptors. Genetic association studies have been performed to help determine the genetic risk associated with certain single nucleotide polymorphisms (SNPs) However, because of the variability in the patient populations and the size of the population, it is difficult to draw any conclusions from these studies. While the etiology of AAA remains unknown, understanding of the inflammatory process and its regulatory points will develop new strategies for the treatment of AAA. Perhaps one difficulty with understanding the pathogenesis of AAA is the lack of precise definition of the phenotype.
Female Gender Attenuates Cytokine and Chemokine Expression and Leukocyte Recruitment in Experimental Rodent Abdominal Aortic Aneurysms
Authors: SINHA INDRANIL , CHO BRENDA S. , ROELOFS KAREN J. , STANLEY JAMES C. , HENKE PETER K. , UPCHURCH GILBERT R.
Published: December 2006

Abstract:  Female gender appears to be protective in the development of abdominal aortic aneurysms (AAAs). This study sought to identify gender differences in cytokine and chemokine expression in an experimental rodent AAA model. Male and female rodent aortas were perfused with either saline (control) or elastase to induce AAA formation. Aortic diameter was determined and aortic tissue was harvested on postperfusion days 4 and 7. Cytokine and chemokine gene expression was examined using focused gene arrays. Immunohistochemistry was used to quantify aortic leukocyte infiltration. Data were analyzed by Student's t‐tests and ANOVA.
Elastase‐perfused female rodents developed significantly smaller aneurysms compared to males by day 7 (93 ± 10% vs. 201 ± 25%, P= 0.003). Elastase‐perfused female aortas exhibited a fivefold decrease in expression of the BMP family and ligands of the TNF superfamily compared to males. In addition, the expression of members of the TGF β and VEGF families were three to fourfold lower in female elastase‐perfused aortas compared to males. Multiple members of the interleukin, CC chemokine receptor, and CC ligand families were detectable in only the male elastase‐perfused aortas. Female elastase‐perfused aortas demonstrated a corollary twofold lower neutrophil count (females: 17.5 ± 1.1 PMN/HPF; males: 41 ± 5.2 neutrophils/HPF, P= 0.01) and a 1.5‐fold lower macrophage count (females: 12 ± 1.1 macrophages/HPF; males: 17.5 ± 1.1 macrophages/HPF, P= 0.003) compared to male elastase‐perfused aortas.
This study documents decreased expression of multiple cytokines and chemokines and diminished leukocyte trafficking in female rat aortas compared to male aortas following elastase perfusion. These genes may contribute to the gender disparity seen in AAA formation.
Regression of Abdominal Aortic Aneurysm by Inhibition of c‐Jun N‐Terminal Kinase in Mice
Authors: YOSHIMURA KOICHI , AOKI HIROKI , IKEDA YASUHIRO , FURUTANI AKIRA , HAMANO KIMIKAZU , MATSUZAKI MASUNORI
Published: December 2006

Abstract:  Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c‐Jun N‐terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)‐9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaCl2, which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECM biosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl2‐induced AAA. Furthermore, SP600125 treatment after the establishment of AAA caused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II‐induced AAA in ApoE‐null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.
Matrix Metalloproteinase‐2
Authors: THOMPSON MATT , COCKERILL GILLIAN
Published: December 2006

Abstract:  The pathogenesis of abdominal aortic aneurysm (AAAs) involves progressive cycles of proteolysis and inflammation, the product of proteolysis driving subsequent inflammation. Little is yet known about the initiating events. We review the specific literature examining the possibility that MMP‐2 may be the initial catalyst. Histologically, elastolysis is one of the earliest observable events in aneurysm genesis. Matrix metalloproteinase‐2 (MMP‐2), as the dominant gelatinase differentially expressed in aneurysmal tissue and cells derived from aneurysms, would be a good candidate. We report the results of in vivo and in vitro experiments, which lend support to the importance of MMP‐2 as an aneurysmal initiator.
Increasing Evidence for Immune‐Mediated Processes and New Therapeutic Approaches in Abdominal Aortic Aneurysms—A Review
Authors: DUFTNER CHRISTINA , SEILER RÜDIGER , DEJACO CHRISTIAN , FRAEDRICH GUSTAV , SCHIRMER MICHAEL
Published: December 2006

Abstract:  Animal models for abdominal aortic aneurysms (AAAs), immunogenetical and pathophysiological studies support the importance of immune‐mediated processes in the pathogenesis of AAA disease. Neutrophils, natural killer (NK) cells, monocytes/macrophages, and proinflammatory cytokines are involved in the complex and dynamic tissue remodeling of the AAA vessel wall. Our group showed an increased prevalence of circulating interferon‐γ (IFN‐γ) producing CD28− T cells especially in smaller AAAs, thus supporting the concept of a T cell‐mediated pathophysiology of AAAs, especially during the early development of AAAs. Further research should now assess the possible benefit of anti‐inflammatory therapeutic approaches in AAA patients, especially with small AAAs.
The Long‐Term Relationship of Wall Stress to the Natural History of Abdominal Aortic Aneurysms (Finite Element Analysis and Other Methods)
Authors: FILLINGER MARK
Published: December 2006

Abstract:  For the past four decades, abdominal aortic aneurysm (AAA) rupture risk has been estimated using maximum aneurysm diameter. Although this works relatively well in general, clinicians know that some aneurysms rupture at an unusually small size, while others grow to exceptionally large sizes without rupture. We have demonstrated that finite element analysis (FEA) of AAA wall stress using three‐dimensional computed tomography (CT) reconstructions is better than diameter for differentiating AAAs near the time of rupture, and that wall stress is superior to AAA diameter for predicting rupture risk in patients under observation. This article summarizes our current work, future areas of investigation, and issues related to “translational” research for FEA of aortic aneurysms.
Aortic Aneurysm, Thoracoabdominal Aneurysm, Juxtarenal Aneurysm, Fenestrated Endografts, Branched Endografts, and Endovascular Aneurysm Repair
Authors: GREENBERG ROY K.
Published: December 2006

Abstract:  The development of endovascular devices to treat aneurysms that abut or involve the visceral vessels has occurred in an effort to reduce the significant procedural morbidity and mortality associated with conventional repair. To accomplish this, three systems have been trialed. The first technique was developed to treat juxtarenal aneurysms and involves the placement of customized fenestrations strategically placed within the fabric of the graft. These are aligned with the ostia of the visceral vessels incorporated by the repair and supplemented by the placement of a balloon expandable stent. In a similar fashion, aneurysms that involve the visceral vessels can be treated with a fenestrated graft where the fenestration is reinforced with a nitinol ring. This is then mated with a balloon‐expandable stentgraft, allowing the devices to seal at the level of the nitinol ring. An alternative means of incorporating the visceral vessels is to use directional branches where one or more additional limbs (typically 8 mm) are anastomosed to the aortic graft, through which access into the visceral vessel is attained. Mating stentgrafts for the later design can be of a self‐expanding or balloon expandable nature. The experience with fenestrated devices is mature and associated with a low perioperative mortality (<2%) without many long‐term complications. The treatment of thoracoabdominal aneurysms with branches has provided us with optimism regarding the technique, but results are only short term in nature. Further device development is ongoing and dissemination of this technology is now occurring in Europe, Australia and Canada.
Global Expression Profiles in Human Normal and Aneurysmal Abdominal Aorta Based on Two Distinct Whole Genome Microarray Platforms
Authors: LENK GUY M. , TROMP GERARD , SKUNCA MAGDALENA , GATALICA ZORAN , BERGUER RAMON , KUIVANIEMI HELENA
Published: December 2006

Abstract:  Abdominal aortic aneurysms (AAA) are the thirteenth cause of death in the United States. The etiology of the disease is yet largely unknown, although several environmental risk factors (e.g., smoking) have been identified and the search for finding genetic risk factors has been initiated. The purpose of our study was to gain insight into the pathobiology of AAA by determining which genes are expressed in the abdominal aorta under either the diseased or normal states, thereby generating the whole‐genome‐wide expression profiles for these conditions.
Identification of c‐Jun N‐Terminal Kinase as a Therapeutic Target for Abdominal Aortic Aneurysm
Authors: YOSHIMURA KOICHI , AOKI HIROKI , IKEDA YASUHIRO , FURUTANI AKIRA , HAMANO KIMIKAZU , MATSUZAKI MASUNORI
Published: December 2006

Abstract:  Despite the advances in molecular cell biology, identification of a therapeutic target in a given disease still poses a significant challenge. Here we report a strategy for identification of the therapeutic target in abdominal aortic aneurysm (AAA). We screened for various signaling molecules in human AAA samples and identified c‐Jun N‐terminal kinase (JNK) as a prominently activated molecule. The JNK pathway‐oriented transcriptome analyses revealed that activation of JNK leads to enhancement of the activity of matrix metalloproteinases and, concurrently, suppression of the extracellular matrix biosynthesis, suggesting that JNK may represent a novel therapeutic target in AAA.
Multiple Endocrine Neoplasia Type 1 (MEN1): Loss of One MEN1 Allele in Tumors and Monohormonal Endocrine Cell Clusters But Not in Islet Hyperplasia of the Pancreas
Authors: Perren Aurel , Anlauf Martin , Henopp Tobias , Rudolph Thomas , Schmitt Anja , Raffel Andreas , Gimm Oliver , Weihe Eberhard , Knoefel Wolfram T. , Dralle Henning , Heitz Philipp U. , Komminoth Paul , Klöppel Günter
Published: December 2006

Context: The occurrence of multiple small pancreatic endocrine tumors in patients suffering from multiple endocrine neoplasia type 1 (MEN1) represents a unique possibility to study early neoplasms and their potential precursor lesions. To date, it is unknown whether small islet-like endocrine cell clusters found in MEN1 patients are neoplastic or rather hyperplastic. It is also unclear whether microadenomas develop from islets.

Design: We hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Using a technique combining fluorescence in situ hybridization of the MEN1 locus and the centromeric region of chromosome 11q with hormone immunostaining, we examined resection specimens from four MEN1 patients. We focused our investigations on the following: 1) typical microadenomas; 2) monohormonal endocrine cell clusters; 3) endocrine and exocrine structures entrapped in microadenomas; and 4) morphologically normal islets.

Results: Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Our results indicate that monohormonal endocrine cell clusters represent a minute form of microadenomas.

Conclusion: The frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development.
Possible Association between Diabetes and Bisphosphonate-Related Jaw Osteonecrosis
Authors: Khamaisi Mogher , Regev Eran , Yarom Noam , Avni Batia , Leitersdorf Eran , Raz Itamar , Elad Sharon
Published: December 2006

Context: Bisphosphonate-related osteonecrosis (BON) of the jaws is a newly identified condition for which the exact mechanism involved in its pathogenesis remains obscure.

Objective: The objective of the study was to evaluate whether diabetes mellitus (DM) may be a contributing factor in the development of BON.

Design: From 2004 to 2006, 31 patients were diagnosed with BON. The diagnosis of BON was based on the medical and dental history of each patient as well as the observation of clinical signs and symptoms of this pathological process. DM was based on two consecutive fasting blood glucose levels above 7 mmol/liter.

Setting: The study was completed in the Hebrew University-Hadassah Hospital referral center.

Results: Of the 31 patients with BON, 18 (58%) were found to have DM or impaired fasting glucose. The proportion of diabetic patients was much higher than expected relative to the incidence of DM in the general population (14%) and compared with the proportion of diabetic patients in a control group of oncological patients treated with bisphosphonates and without BON (12%) (P = 0.00003).

Conclusions: This finding indicates that DM may be a risk factor for BON and that DM patients treated with bisphosphonates should be carefully monitored. We discuss here the bone metabolic pathways characteristic of DM patients and the way in which these pathways can augment the effects of bisphosphonates.
Identification of potential anti-photoageing algal compounds using an in-vitro model of photoageing
Authors: Debacq-Chainiaux F , Borlon C , De Hertogh B , Remacle J , Morvan P-Y , Vallée R , Toussaint O
Published: December 2006

Stress-induced premature senescence (SIPS) has been proposed as an in-vitro model for testing the long-term effects of stressful events and to find molecules/natural extracts that protect against such stress. Premature senescence of human skin diploid fibroblasts (HDFs) can be induced by repeated subcytotoxic exposure to UVB, with the appearance of so-called biomarkers of senescence such as growth arrest, senescence-associated β-galactosidase activity, senescence-associated gene over-expression and the common 4977-bp mitochondrial DNA deletion. This model of UVB-induced premature senescence has been acknowledged as a robust in-vitro model in photoageing research. In this study, the potential anti-photoageing effects of a series of algal extracts were tested. The appearance of the biomarkers of UVB-induced premature senescence of HDFs was studied with or without algal extracts. One algal extract was shown to be particularly protective against UVB-induced SIPS. The results obtained here reinforce the notion that UVB-induced premature senescence of HDFs can be used to screen potential anti-photoageing compounds.
Haloperidol is an inhibitor but not substrate for MDR1/P-glycoprotein
Authors: Iwaki Koichi , Sakaeda Toshiyuki , Kakumoto Mikio , Nakamura Tsutomu , Komoto Chiho , Okamura Noboru , Nishiguchi Kohshi , Shiraki Takashi , Horinouchi Masanori , Okumura Katsuhiko
Published: December 2006

The involvement of the multidrug resistant transporter MDR1/P-glycoprotein in the penetration of haloperidol into the brain and absorption in the intestine was investigated to examine its role in inter/intra-individual variability, using the porcine kidney epithelial cell line LLC-PK1 and its MDR1-overexpressing transfectant, LLC-GA5-COL150. The inhibitory effect of haloperidol on other MDR1 substrates was also investigated in terms of the optimization of haloperidol-based pharmacotherapy. The transepithelial transport of [3H]haloperidol did not differ between the two cell lines, and vinblastine, a typical MDR1 substrate, had no effect on the transport, suggesting that haloperidol is not a substrate for MDR1, and it is unlikely that MDR function affects haloperidol absorption and brain distribution, and thereby the response to haloperidol. However, haloperidol was found to have an inhibitory effect on the MDR1-mediated transport of [3H]digoxin and [3H]vinblastine with an IC50 value of 7.84 ± 0.76 and 3.60 ± 0.64 μM, respectively, suggesting that the intestinal absorption, not distribution into the brain, of MDR1 substrate drugs could be altered by the co-administration of haloperidol in the clinical setting, although further clinical studies are needed.
Cyto-reduction of neuroendocrine tumours using Sandostatin LAR® in combination with Infergen®: results of a case series
Authors: Wang Hank S , Oh David S , Ohning Gordon V , Pisegna Joseph R
Published: December 2006

Historically, limited trials evaluating biotherapy in treating metastatic neuroendocrine tumours have yielded mixed results. In this study, the efficacy of a novel combination therapy featuring long-acting Sandostatin LAR® plus α-interferon was evaluated. In a prospective case series, 12 patients with unresectable metastatic neuroendocrine tumours refractory to treatment initiated therapy with Infergen® and Sandostatin LAR®. Radiological response was followed serially at 3-month intervals. A biochemical response was considered significant if marker levels decreased by ≥50% compared with baseline. Inhibition of tumour growth lasting for greater than 3 months (mean response 22.6 ± 17.7 months) was seen in eight patients. Complete tumour regression was observed in one patient, lasting for 40 months; three patients exhibited partial tumour regression (mean response 29.3 ± 24.0 months), and four patients maintained a stable tumour response (mean response 13.3 ± 9.2 months). Four patients showed no response to therapy (mean response 5.0 ± 6.0 months). All enrolled patients are alive currently. The biochemical response seen in seven patients did not correlate with the radiological response. These results suggest that the novel combination of long-acting Sandostatin LAR® with an α-interferon may be at least as effective as either combination therapy with short-acting octreotide or monotherapy with Sandostatin LAR®.
Inhibitory effect of apigenin on benzo(a)pyrene-mediated genotoxicity in Swiss albino mice
Authors: Khan Tajdar Husain , Jahangir Tamanna , Prasad Lakshmi , Sultana Sarwat
Published: December 2006

Apigenin, a bioflavonoid, is abundantly present in fruits and vegetables and possesses potential chemopreventive properties against a wide variety of chronic diseases. In this study we investigated the anti-genotoxic effects of apigenin against a known genotoxicant, benzo(a)pyrene (B(a)P) (125 mg kg−1 orally) toxicity in Swiss albino mice. B(a)P administration led to induction of cytochrome P-450 (CYP), aryl hydrocarbon hydroxylase (AHH) and DNA strand breaks (P < 0.001), which was suppressed by apigenin (2.5 and 5 mg kg−1 orally) dose dependently (P < 0.001). B(a)P-induced depletion in the level of reduced glutathione (GSH), quinone reductase (QR) and glutathione-S-transferase (GST) was also shown to be restored by apigenin pre-treatment (P < 0.001). A simultaneous significant and dose-dependent reduction was noted in DNA strand breaks and in-vivo DNA damage (P < 0.001), which gives some insight into restoration of DNA integrity in modulator groups. These results strongly support the protective nature of apigenin against B(a)P-induced toxicity.
Analysis of the mechanism of antinociceptive action of niga-ichigoside F1 obtained from Rubus imperialis (Rosaceae)
Authors: Ardenghi Juliana Vargas , Kanegusuku Márcia , Niero Rivaldo , Filho Valdir Cechinel , Monache Franco Delle , Yunes Rosendo Augusto , De Souza Márcia Maria
Published: December 2006

We have previously verified that niga-ichigoside F1 (NI), a triterpene isolated from Rubus imperialis, exhibits significant and potent antinociceptive action when evaluated in some pharmacological models of pain in mice. This effect was confirmed in other experimental models and also the mechanism of action has been evaluated. The antinociception caused by NI (60 mg kg−1) in both phases of the formalin test was significantly attenuated by intraperitoneal injection of mice with haloperidol (a dopaminergic antagonist, 0.20 mg kg−1) and L-arginine (precursor of nitric oxide, 600 mg kg−1). Regarding the cholinergic system, atropine (a cholinergic antagonist 60 mg kg−1) reverted only the second phase. The effect of NI was not affected by treatment of mice with yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg kg−1). The same pharmacological profile was observed for the administration of naloxone (an opioid receptor antagonist, 1 mg kg−1). On the other hand, intraperitoneal injection caused dose-related and significant effects against glutamate- and capsaicin-induced pain, respectively. In conclusion, the marked antinociception of NI appears to be related to the dopaminergic, cholinergic, glutamatergic, tachykininergic and oxinitrergic systems, supporting the ethnomedical use of Rubus imperialis (Rosaceae).
Cordycepin (3‘-deoxyadenosine) inhibits human platelet aggregation induced by U46619, a TXA2 analogue
Authors: Cho Hyun Jeong , Cho Jae Youl , Rhee Man Hee , Lim Chang Ryul , Park Hwa Jin
Published: December 2006

Cordycepin (3′-deoxyadenosine), which comes from Cordyceps militaris, the Chinese medicinal fungal genus Cordyceps, is known to have anti-tumour activity. In this study, we investigated the novel effect of cordycepin on human platelet aggregation that was induced by U46619, a thromboxane A2 (TXA2) analogue. TXA2 is an aggregation-inducing autacoidal molecule that is produced in various agonist-activated platelets. Cordycepin completely inhibited U46619-induced platelet aggregation and simultaneously reduced cytosolic free Ca2+ ([Ca2+]i), which was increased by U46619 (5 μM) up to 66%. Furthermore, the U46619-stimulated phosphorylation of Ca2+-dependent proteins (20 kDa of a myosin light chain and 47 kDa of pleckstrin) was strongly inhibited by cordycepin. These results suggest that cordycepin may have a beneficial effect on autacoidal TXA2-mediated thrombotic diseases by inhibiting TXA2-induced platelet aggregation via suppression of the Ca2+ level.
Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells
Authors: Ogawa Kazuya , Saito Akira , Matsui Hisanori , Suzuki Hiroshi , Ohtsuka Satoshi , Shimosato Daisuke , Morishita Yasuyuki , Watabe Tetsuro , Niwa Hitoshi , Miyazono Kohei
Published: December 2006

Embryonic stem (ES) cells are self-renewing cells that maintain pluripotency to differentiate into all types of cells. Because of their potential to provide a variety of tissues for use in regenerative medicine, there is great interest in the identification of growth factors that govern these unique properties of ES cells. However, the signaling pathways controlling ES cell proliferation remain largely unknown. Since transforming growth factor β (TGFβ) superfamily members have been implicated in the processes of early embryogenesis, we investigated their roles in ES cell self-renewal. Inhibition of activin-Nodal-TGFβ signaling by Smad7 or SB-431542 dramatically decreased ES cell proliferation without decreasing ES pluripotency. By contrast, inhibition of bone morphogenetic protein (BMP) signaling by Smad6 did not exhibit such effects, suggesting that activin-Nodal-TGFβ signaling, but not BMP signaling, is indispensable for ES cell propagation. In serum-free culture, supplementation of recombinant activin or Nodal, but not TGFβ or BMP, significantly enhanced ES cell propagation without affecting pluripotency. We also found that activin-Nodal signaling was constitutively activated in an autocrine fashion in serum-free cultured ES cells, and that inhibition of such endogenous signaling by SB-431542 decreased ES cell propagation in serum-free conditions. These findings suggest that endogenously activated autocrine loops of activin-Nodal signaling promote ES cell self-renewal.
Centriole/basal body morphogenesis and migration during ciliogenesis in animal cells
Authors: Dawe Helen R. , Farr Helen , Gull Keith
Published: December 2006

Cilia, either motile or immotile, exist on most cells in the human body. There are several different mechanisms of ciliogenesis, which enable the production of many kinds of cilia and flagella: motile and immotile, transient and long-lived. These can be linked to the cell cycle or associated with differentiation. A primary cilium is extended from a basal body analogous to the mitotic centrioles, whereas the several hundred centrioles needed to form the cilia of a multi-ciliated cell can be generated by centriolar or acentriolar pathways. Little is known about the molecular control of these pathways and most of our knowledge comes from ultrastructural studies. The increasing number of genetic diseases linked to dysfunctional cilia and basal bodies has renewed interest in this area, and recent proteomic and cell biological studies in model organisms have helped to shed light on the molecular components of these enigmatic organelles.
C-terminal domains deliver the DNA replication factor Ciz1 to the nuclear matrix
Authors: Ainscough Justin F.-X. , Rahman Faisal Abdel , Sercombe Heather , Sedo Alicia , Gerlach Bjorn , Coverley Dawn
Published: December 2006

Cip1-interacting zinc finger protein 1 (Ciz1) stimulates DNA replication in vitro and is required for mammalian cells to enter S phase. Here, we show that a significant proportion of Ciz1 is retained in nuclear foci following extraction with nuclease and high salt. This suggests that Ciz1 is normally immobilized by interaction with non-chromatin nuclear structures, consistent with the nuclear matrix. Furthermore, matrix-associated Ciz1 foci strikingly colocalize with sites of newly synthesized DNA in S phase nuclei, suggesting that Ciz1 is present in DNA replication factories. Analysis of green fluorescent protein-tagged fragments indicates that nuclear immobilization of Ciz1 is mediated by sequences in its C-terminal third, encoded within amino acids 708-830. Immobilization occurs in a cell-cycle-dependent manner, most probably during late G1 or early S phase, to coincide with its reported point of action. Although C-terminal domains are sufficient for immobilization, N-terminal domains are also required to specify focal organization. Combined with previous work, which showed that the DNA replication activity of Ciz1 is encoded by N-terminal sequences, we suggest that Ciz1 is composed of two functionally distinct domains: an N-terminal replication domain and a C-terminal nuclear matrix anchor. This could contribute to the formation or function of DNA replication factories in mammalian cells.