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UML diagram synthesis techniques

Damiano Torre, Yvan Labiche, Marcela Genero, Maria Teresa Baldassarre, Maged Elaasar
2018 Proceedings of the 10th International Workshop on Modelling in Software Engineering - MiSE '18  
Context: The Unified Modeling Language (UML), with its 14 different diagram types, is the de-facto standard modeling language for object-oriented modeling and documentation. Since the various UML diagrams describe different aspects of one, and only one, software under development, they are not independent but strongly depend on each other in many ways. In other words, diagrams must remain consistent. Dependencies between diagrams can become so intricate that it is sometimes even possible to
more » ... hesize one diagram on the basis of others. Support for synthesizing one UML diagram from other diagrams can provide the designer with significant help, thus speeding up the design process, decreasing the risk of errors, and guaranteeing consistency among the diagrams. Objective: The aim of this article is to provide a comprehensive summary of UML synthesis techniques as they have been described in literature to date in order to obtain an extensive and detailed overview of the current research in this area. Method: We have performed a Systematic Mapping Study by following well-known guidelines. We selected ten primary studies by means of a search with seven search engines performed on October 2, 2013. Results: Various results are worth mentioning. First it appears that researchers have not frequently published papers concerning UML synthesis techniques since 2004 (with the exception of two papers published in 2010). Only half of the UML diagram types are involved in the synthesis techniques we discovered. The UML diagram type most frequently used as the source for synthesizing another diagram is the sequence diagram (66.7%), and the most synthesized diagrams are the state machine diagram (58.3%) and the class diagram (25%). Conclusion: The fact that we did not obtain a large number of primary studies over a 14 year period (only ten papers) indicates that synthesizing a UML diagram from other UML diagrams is not a particularly active line of research. Research on UML diagram synthesis is nevertheless relevant since synthesis techniques rely on or enforce diagram consistency, and studying UML diagram consistency is an active line of research. Another result is that research is needed to investigate synthesis techniques for other types of UML diagrams than those involved in our primary studies.
doi:10.1145/3193954.3193957 dblp:conf/icse/TorreLGBE18 fatcat:iqqk6o3dwjcsfmfgxujjgf4z2q

Statin pharmacogenomics: pursuing biomarkers for predicting clinical outcomes

Joseph P Kitzmiller, Philip F Binkley, Saurabh R Pandey, Adam M Suhy, Damiano Baldassarre, Katherine Hartmann
2013 Discovery Medicine  
Indicated for treating hyperlipidemias and for the prevention of cardiovascular disease (CVD), statins rank among the most commonly prescribed drug classes. While statins are considered to be highly effective in preventing atherosclerotic events, a substantial portion of treated patients still progress to overt CVD. Genetic factors are thought to contribute substantially to treatment outcome. Several candidate genes have been associated with statin dose requirements and treatment outcomes, but
more » ... clinically relevant pharmacogenomics test to guide statin therapy has not yet emerged. Here we define basic pharmacogenomics terminology, present strong candidate genes (CETP, HMGCR, SLCO1B1, ABCB1, and CYP3A4/5), and discuss the challenges in developing much-needed statin pharmacogenomics biomarkers for predicting treatment outcomes.
pmid:23911231 pmcid:PMC4039562 fatcat:sqzot4xm2fbbdout7ez42hwscu

Non-invasive imaging of atherosclerosis regression with magnetic resonance to guide drug development

Paolo Raggi, Damiano Baldassarre, Simon Day, Eric de Groot, Z.A. Fayad
2016 Atherosclerosis  
Slowing of progression and inducing the regression of atherosclerosis with medical therapy have been shown to be associated with an extensive reduction in risk of cardiovascular events. This proof of concept was obtained with invasive angiographic studies but these are, for obvious reasons, impractical for sequential investigations. Non-invasive imaging has henceforth replaced the more cumbersome invasive studies and has proven extremely valuable in numerous occasions. Because of excellent
more » ... ducibility and no radiation exposure, magnetic resonance imaging (MRI) has become the non-invasive method of choice to assess the efficacy of anti-atherosclerotic drugs. The very high accuracy of this technology is particularly helpful in rare diseases where the small number of affected patients makes the conduct of outcome-trials in large cohorts impractical. With MRI it is possible to assess the extent, as well as the composition, of atherosclerotic plaques and this further enhances the utility of this technology.
doi:10.1016/j.atherosclerosis.2016.06.028 pmid:27341753 fatcat:c3queotwwzai5k2hoo4qhd7enu

Old and new oral anticoagulants: Food, herbal medicines and drug interactions

Alessandro Di Minno, Beatrice Frigerio, Gaia Spadarella, Alessio Ravani, Daniela Sansaro, Mauro Amato, Joseph P. Kitzmiller, Mauro Pepi, Elena Tremoli, Damiano Baldassarre
2017 Blood reviews  
The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter
more » ... dications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications. Introduction Until recently, the vitamin K antagonists (VKAs) were the only oral anticoagulant agents available, and warfarin remains the most commonly prescribed oral anticoagulant worldwide. Its indications include a wide range of clinical conditions from prevention of cardioembolic ischemic stroke to deep venous thrombosis and pulmonary embolism. Anticoagulants are used in patients with a history of atrial fibrillation or flutter, recent major surgery or immobility, heart valve replacement, ischemic stroke or other thrombotic event [1]. Warfarin has significant variability in dose-response across individuals and a narrow therapeutic window (the international normalized ratio [PT-INR] value must remain between 2.0 and 3.0 for most indications) [2]. Clinical outcomes are highly correlated with the amount of time patient's PT-INR values are maintained in range [3]. Patients with an average individual time in therapeutic range > 70% are considered to be at a low risk of a major hemorrhagic or thrombotic event [4]. Frequent monitoring of PT-INR lab values and dose adjustments, therefore, are necessary for safe and efficacious use of warfarin [5]. Likewise, patient instruction and identification of factors leading to over-or under-anticoagulation are critical [6; 7]. When combined with low-dose aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or clopidogrel, warfarin acts cumulatively, and risk of bleeding is significantly increased [8; 9]. VKAs are among the medications with the highest incidence of drug-related life-threatening events [1] and top the list of interactions with foods, herbal supplements, prescribed drugs and over-thecounter medications [10; 11]. Interactions resulting in over-or under-anticoagulation drastically increase the risk of major hemorrhagic or thrombotic event. Direct oral anticoagulants (DOACs), approved for the prevention and treatment of venous thromboembolism and of systemic and cerebral embolism in atrial fibrillation [12], are poised to replace warfarin for stroke prevention [13]. As their anticoagulant effect is more predictable and stable (i.e., less influenced by interactions with foods, herbal supplements, prescribed drugs and over-the-counter medications), DOACs should prove safer and less problematic compared to the VKAs [14]. Clinical studies of venous and arterial thromboprophylaxis suggest that routine laboratory monitoring is not necessary with thrombin inhibitors or Factor Xa inhibitors. However, ACCEPTED MANUSCRIPT
doi:10.1016/j.blre.2017.02.001 pmid:28196633 fatcat:scsk62xnunfhxdlompj2vhhqki

Time course of forearm arterial compliance changes during reactive hyperemia

Damiano Baldassarre, Mauro Amato, Carlo Palombo, Carmela Morizzo, Linda Pustina, Cesare R. Sirtori
2001 American Journal of Physiology. Heart and Circulatory Physiology  
Baldassarre, Damiano, Mauro Amato, Carlo Palombo, Carmela Morizzo, Linda Pustina, and Cesare R. Sirtori. Time course of forearm arterial compliance changes during reactive hyperemia.  ... 
doi:10.1152/ajpheart.2001.281.3.h1093 pmid:11514275 fatcat:gvr5aseecfegdpk3abd23miqse

Relationship between Influenza Vaccination Coverage Rate and COVID-19 Outbreak: An Italian Ecological Study

Mauro Amato, José Pablo Werba, Beatrice Frigerio, Daniela Coggi, Daniela Sansaro, Alessio Ravani, Palma Ferrante, Fabrizio Veglia, Elena Tremoli, Damiano Baldassarre
2020 Vaccines  
The lack of specific vaccines or drugs against coronavirus disease 2019 (COVID-19) warrants studies focusing on alternative clinical approaches to reduce the spread of this pandemic disease. In this study, we investigated whether anti-influenza vaccination plays a role in minimizing the diffusion of COVID-19 in the Italian population aged 65 and over. Methods: Four COVID-19 outcomes were used: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence, hospitalizations for
more » ... -19 symptoms, admissions to intensive care units for reasons related to SARS-CoV-2, and deaths attributable to COVID-19. Results: At univariate analyses, the influenza vaccination coverage rates correlated negatively with all COVID-19 outcomes (Beta ranging from -134 to -0.61; all p < 0.01). At multivariable analyses, influenza vaccination coverage rates correlated independently with SARS-CoV-2 seroprevalence (Beta (95% C.I.): -130 (-198, -62); p = 0.001), hospitalizations for COVID-19 symptoms (Beta (95% C.I.): -4.16 (-6.27, -2.05); p = 0.001), admission to intensive care units for reasons related to SARS-CoV-2 (Beta (95% C.I.): -0.58 (-1.05, -0.12); p = 0.017), and number of deaths attributable to COVID-19 (Beta (95% C.I.): -3.29 (-5.66, -0.93); p = 0.010). The R2 observed in the unadjusted analysis increased from 82% to 159% for all the considered outcomes after multivariable analyses. Conclusions: In the Italian population, the coverage rate of the influenza vaccination in people aged 65 and over is associated with a reduced spread and a less severe clinical expression of COVID-19. This finding warrants ad hoc studies to investigate the role of influenza vaccination in preventing the spread of COVID-19.
doi:10.3390/vaccines8030535 pmid:32947988 pmcid:PMC7563271 fatcat:feyvpicsfnajjbdwcxedg6aaka

Potentially Spurious Correlations Between Arterial Size, Flow-Mediated Dilation, and Shear RateNovelty and Significance

Fabrizio Veglia, Mauro Amato, Marta Giovannardi, Alessio Ravani, Calogero C. Tedesco, Beatrice Frigerio, Daniela Sansaro, Elena Tremoli, Damiano Baldassarre
2014 Hypertension  
Tedesco 1 , Beatrice Frigerio 1 , Daniela Sansaro 1 , Elena Tremoli 1,2 and Damiano Baldassarre 1,Centro Cardiologico Monzino IRCCS, Milan, Italy 2 Dipartimento di Scienze Farmacologiche e Biomolecolari  ... 
doi:10.1161/hypertensionaha.114.03608 pmid:25245392 fatcat:sxsx4ohjezgjvlhfihmwujgwsi

Assessment and Relevance of Carotid Intima-Media Thickness (C-IMT) in Primary and Secondary Cardiovascular Prevention

Alessio Ravani, Jose Werba, Beatrice Frigerio, Daniela Sansaro, Mauro Amato, Elena Tremoli, Damiano Baldassarre
2015 Current pharmaceutical design  
Interventions aimed to prevent cardiovascular diseases (CVD) are more effective if administered to subjects carefully selected according to their CVD risk. Usually, this risk is evaluated on the basis of the presence and severity of conventional vascular risk factors (VRFs); however, atherosclerosis, the main pathologic substrate of CVD, is not directly revealed by VRFs. The measurement of the arterial wall, using imaging techniques, has increased the early identification of individuals prone
more » ... develop atherosclerosis and to quantify its changes over time. B-mode ultrasound is a technique which allows a non-invasive assessment of the arterial wall of peripheral arteries (e.g. extracranial carotid arteries), and provides measures of the intima-media thickness complex (C-IMT) and additional data on the occurrence, localization and morphology of plaques. Being an independent predictor of vascular events, C-IMT has been considered as a tool to optimize the estimation of CVD risk but this application is still a matter of debate. Though the technique is innocuous, relatively inexpensive and repeatable, its use in the clinical practice is limited by the lack of standardized protocols and clear guidelines. This review outlines the rationale for the potential use of C-IMT in the stratification of cardio-and cerebro-vascular risk and discusses several topics related to the measurement of this variable, which are still controversial among experts of the field.
doi:10.2174/1381612820666141013121545 pmid:25312737 pmcid:PMC5388799 fatcat:wevt2fcv3jhexlb3v477gm6l44

Plasma cysteine and glutathione are independent markers of postmethionine load endothelial dysfunction

Oberdan Parodi, Benedetta De Chiara, Damiano Baldassarre, Marina Parolini, Raffaele Caruso, Linda Pustina, Guido Parodi, Jonica Campolo, Valentina Sedda, Francesco Baudo, Cesare Sirtori
2007 Clinical Biochemistry  
Objectives: Oxidative stress caused by acute hyperhomocysteinemia impairs endothelial function in human arteries. We sought to identify markers of endothelial dysfunction during methionine-induced hyperhomocysteinemia. Design and methods: 35 subjects underwent flow-mediated dilation (FMD) of the brachial artery by high-resolution ultrasonography and fasting blood samples before and 3 h postmethionine load (PML). Clinical, conventional biochemical, and redox status (plasma total and reduced
more » ... ysteine, glutathione, cysteine, cysteinylglycine, ascorbic acid, α-tocopherol, free malondialdehyde, blood glutathione) data were sequentially entered into an univariate and multivariate stepwise linear regression analysis to evaluate their relation with the dependent variable FMD. Results: Median [interquartile range] FMD decreased from 4.1% [2.8-6.3] to 3.2% [0.7-4.3] PML (P= 0.02). At the multivariate analysis PML total cysteine (β= −0.008, P= 0.002) and glutathione (β =0.21, P = 0.005) were the only independent variables associated with FMD after methionine, adjusted for baseline FMD. Conclusions: Elevated plasma total cysteine and decreased plasma total glutathione levels were associated with abnormal FMD PML. Cysteine and glutathione are stronger markers of endothelial dysfunction than clinical and all other biochemical variables explored.
doi:10.1016/j.clinbiochem.2006.08.017 pmid:17056026 fatcat:jws6no3iqfcwvge2ps7d5iqw2e

Aortic Valve Sclerosis in High-Risk Coronary Artery Disease Patients

Veronika A. Myasoedova, Stefano Genovese, Laura Cavallotti, Alice Bonomi, Mattia Chiesa, Jeness Campodonico, Maurizio Rondinelli, Nicola Cosentino, Damiano Baldassarre, Fabrizio Veglia, Mauro Pepi, Francesco Alamanni (+3 others)
2021 Frontiers in Cardiovascular Medicine  
Current knowledge regarding the relationship between aortic valve sclerosis (AVSc), cardiovascular risk factors, and mortality in patients with known coronary artery disease (CAD) is still unclear. The present study aimed at investigating the prevalence of AVSc as well as its association with long-term all-cause mortality in high-risk CAD patients that has never been explored in large cohorts thus far.Methods and Results: In this retrospective and observational cohort study we enrolled
more » ... CAD patients, hospitalized at Centro Cardiologico Monzino (CCM), Milan, Italy, between January 2006 and December 2016. The morphology and function of the aortic valve were assessed from the recorded echocardiographic images to evaluate the presence of AVSc, defined as a non-uniform thickening of the aortic leaflets with no consequences on hemodynamics. Data on 5-year all-cause mortality was retrieved from a Regional database. Of the 5,489 patients initially screened, 4,938 (mean age 67 ± 11 years, 3,954 [80%] men) were enrolled in the study. In the overall population, AVSc was detected in 2,138 (43%) patients. Multivariable LASSO regression revealed that age, female gender, diabetes mellitus, previous MI, and left ventricular ejection fraction were independently associated with AVSc. All-cause mortality (adjusted hazard ratio: 1.29, 95%CI: 1.05–1.58) was significantly higher in AVSc than in non-AVSc patients.Conclusions: AVSc is frequently detected in high-risk CAD patients and is associated with long-term mortality. Our findings corroborate the hypothesis that AVSc is an underestimated marker of systemic cardiovascular risk. Thus, AVSc detection may be used to improve long-term risk stratification of high-risk CAD patients.
doi:10.3389/fcvm.2021.711899 fatcat:2jgmvylrgbdjrhssbbn2b6h3u4

Plasminogen Activator Inhibitor Type-1 Synthesis and mRNA Expression in HepG2 Cells Are Regulated by VLDL

Luigi Sironi, Luciana Mussoni, Livia Prati, Damiano Baldassarre, Marina Camera, Cristina Banfi, Elena Tremoli
1996 Arteriosclerosis, Thrombosis and Vascular Biology  
The effect of VLDL on plasminogen activator inhibitor type 1 biosynthesis in HepGZ cells was investigated. Exposure of HepG2 cells to VLDL (range, 10 to 100 g.g protein per milliliter) for 16 hours resulted in an enhanced release of PAI-I antigen and PAI activity into conditioned medium, accompanied by the accumulation of intracellular triglycerides. By using a monoclonal antibody (IgG C7) specific to the LDL receptor, we showed that the effect of VLDL is mediated by its interaction with the
more » ... receptor. Enhanced PAI-I release was due to increased biosynthesis: PAI-1 mRNA was doubled, mainly because of the efiect on the 2.2-kb PAI-I mRNA rather than the 3.2-kb transcript. Addition of insulin with the VLDL explain the link between PAI-1 and plasma triglyceride levcls, studies in human umbilical vein enclothelial cells have been'r8 The results indicate that VLDL, the major lipoprotein subfraction responsible for further enhanced PAI-I antigen release and PAI-1 mRNA accumulation. The effect of VLDL on steady state levels of PAI-1 mRNA was apparently not due to an increase of gene transcription but to stabilization of both PAI-1 mRNA transcripts. The enhancing effect of VLDL on PAI-1 biosynthesis in HepG2 cells may raise PAI-I antigen levels not only in hypertriglyceridemic states but also in those conditions in which both insulin and VLDL are elevated. (Arterioscler Thromb Vasc Biol. 1996;16:89-96.) Key Words o VLDL r plasminogen activator inhibitor type-l o HepG2 . gene expression r insulin
doi:10.1161/01.atv.16.1.89 pmid:8548432 fatcat:6lffvwk7i5bbjoskkycgt5zls4

CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort

Joseph P. Kitzmiller, Jasmine A. Luzum, Damiano Baldassarre, Ronald M. Krauss, Marisa W. Medina
2014 Pharmacogenetics & Genomics  
Objective Simvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4*22 and the loss-of-function CYP3A5*3, has recently been reported. We aim to determine whether CYP3A4*22 and CYP3A5*3 alleles are associated with increased plasma concentrations of simvastatin lactone (SV) and simvastatin acid (SVA). This is the first report evaluating associations between in-vivo simvastatin concentrations and CYP3A4*22, alone or in a
more » ... ombined CYP3A4/5 genotype-defined classification. Participants and methods Genotypes and simvastatin concentrations were determined for 830 participants (555 Whites and 275 African-Americans) in the Cholesterol and Pharmacogenomics clinical trial with 40 mg/day simvastatin for 6 weeks. Concentrations were determined in 12-h postdose samples. Associations between simvastatin concentrations and CYP3A4*22 and CYP3A5*3 alleles were tested separately and in a combined CYP3A4/5 genotypedefined classification system. Results In Whites, CYP3A4*22 carriers (n = 42) had 14% higher SVA (P = 0.04) and 20% higher SV (P = 0.06) compared with noncarriers (n = 513). CYP3A5*3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4*22 carriers (n = 8) had 170% higher SV (P < 0.01) than noncarriers (n = 267), but no significant difference was detected for SVA. African-American CYP3A5 nonexpressors (n = 28) had 33% higher SV (P = 0.02) than CYP3A5 expressors (n = 247), but no significant difference was detected for SVA. For both races, SV appeared to decrease across the rank-ordered combined CYP3A4/5 genotype-defined groups (poor, intermediate, and extensive metabolizers); however, similar trends were not observed for SVA. Conclusion Genetic variation in CYP3A4 was associated with plasma simvastatin concentrations in self-reported Whites. Genetic variations in CYP3A4 and CYP3A5 were associated with plasma simvastatin concentrations in selfreported African-Americans. Pharmacogenetics and Genomics 24:486-491 Simvastatin concentrations for self-reported African-Americans. Data are presented as median and interquartile range. Plasma concentrations of simvastatin acid and simvastatin lactone are represented by light and dark, respectively. P-values determined using one-way Mann-Whitney U-tests, and only those less than 0.10 are displayed. EM, extensive metabolizer; IM, Intermediate metabolizers; PM, poor metabolizer; RoM, ratio of means. CYP3A4/5 and simvastatin concentrations Kitzmiller et al. 489
doi:10.1097/fpc.0000000000000079 pmid:25051018 pmcid:PMC4160394 fatcat:d3c5s4edsrbg7kn3imus7fz6dq

Pharmacogenomic Biomarkers for the Prediction of Statin Efficacy and Safety
Biomarcatori Farmacogenomici Per La Predizione Di Efficacai E Sicurezza Delle Statine

Damiano Baldassarre, Mauro Amato, Beatrice Frigerio, Gualtiero Columbo, Philip F Binkley, Saurabh R Pandey, Adam M Suhy, Katherine Hartmann, Joseph P Kitzmiller
2013 Giornale italiano dell'arteriosclerosi  
Le malattie cardiovascolari (CV) sono la principale causa di morbilità e mortalità dei paesi industrializzati. Ad esempio, più di un americano su tre è affetto da una qualche forma di malattia CV e un decesso su sei è dovuto alla sola malattia coronarica. I costi sanitari superano i 300 miliardi di dollari all'anno (1). Ne consegue che la malattia CV è senz'altro da considerarsi una delle patologie più diffuse e costose che una nazione debba affrontare. L'efficacia relativamente elevata ed il
more » ... ofilo di scarsi effetti collaterali hanno contribuito a rendere le statine la classe di farmaci di riferimento per la prevenzione degli eventi cardiaci associati alla presenza di iperlipidemie. Ampi studi clinici hanno dimostrato, infatti, che le statine riducono il rischio di eventi vascolari maggiori in modo lineare, con una diminuzione del rischio pari al 20% per ogni riduzione di 1 mmol/L di colesterolo associato alle lipoproteine a bassa densità o LDL (Low-Density Lipoprotein) (2). Ancora oggi, a venticinque anni dall'approvazione della Food and Drug Administration (FDA) americana, le statine restano una pietra miliare del sistema sanitario degli Stati Uniti, con la simvastatina che occupa il terzo posto nella lista dei farmaci più prescritti (3). La risposta alla terapia con statine è tuttavia influenzata da diversi fattori e soprattutto non è universale: alcuni pazienti non raggiungono il target terapeutico, altri sviluppano eventi
pmid:25763360 pmcid:PMC4353572 fatcat:heiusfkjpje4df6i47pozgun6y

Normal Vascular Function Despite Low Levels of High-Density Lipoprotein Cholesterol in Carriers of the Apolipoprotein A-I Milano Mutant

Monica Gomaraschi, Damiano Baldassarre, Mauro Amato, Sonia Eligini, Paola Conca, Cesare R. Sirtori, Guido Franceschini, Laura Calabresi
2007 Circulation  
Background-Carriers of the apolipoprotein A-I Milano (apoA-I M ) mutant have very low plasma high-density lipoprotein cholesterol (HDL-C) levels but do not show any history of premature cardiovascular disease or any evidence of preclinical vascular disease. HDL is believed to prevent the development of vascular dysfunction, which may well contribute to HDL-mediated atheroprotection. Whether the low HDL level of apoA-I M carriers is associated with impaired vascular function is presently
more » ... Methods and Results-The vascular response to reactive hyperemia, assessed by measuring postischemic increase in forearm arterial compliance, and the plasma concentration of soluble cell adhesion molecules were evaluated in 21 adult apoA-I M carriers, 21 age-and gender-matched nonaffected relatives (control subjects), and 21 healthy subjects with low HDL-C (low-HDL subjects). The average plasma HDL-C and apoA-I levels of apoA-I M carriers were remarkably lower than those of control subjects and significantly lower than those of low-HDL subjects. The postischemic increase in forearm arterial compliance in the apoA-I M carriers was 2-fold greater than in low-HDL subjects and remarkably similar to that of control subjects. Plasma soluble cell adhesion molecule levels were similar in apoA-I M carriers and control subjects but were greater in low-HDL subjects. When incubated with endothelial cells, HDL isolated from apoA-I M carriers was more effective than HDL from control and low-HDL subjects in stimulating endothelial nitric oxide synthase expression and activation and in downregulating tumor necrosis factor-␣-induced expression of vascular cell adhesion molecule-1. Conclusions-Despite their very low HDL levels, apoA-I M carriers do not display typical features of impaired vascular function because of an improved activity of apoA-I M HDL in maintaining endothelial cell homeostasis. (Circulation.
doi:10.1161/circulationaha.107.705657 pmid:17967773 fatcat:5e6mc3ryejdyvf6uehqpqf7e2m

Human Genetic Evidence for Involvement of CD137 in Atherosclerosis

Leif Å Söderström, Karl Gertow, Lasse Folkersen, Maria Sabater-Lleal, Eva Sundman, Yuri Sheikine, Anuj Goel, Damiano Baldassarre, Steve E. Humphries, Ulf de Faire, Hugh Watkins, Elena Tremoli (+4 others)
2014 Molecular Medicine  
Atherosclerosis is an inflammatory disease and the main cause of cardiovascular disease. Inflammation promotes plaque instability and clinical disease, such as myocardial infarction, stroke and peripheral vascular disease. Subclinical atherosclerosis begins with thickening of the arterial intimal layer, and increased intima-media thickness (IMT) in the carotid artery is a widely used measurement of subclinical atherosclerosis. Activation of CD137 (tumor necrosis factor receptor super family 9)
more » ... romotes inflammation and disease development in murine atherosclerosis. CD137 is expressed in human atherosclerosis, but its role is largely unknown. This study uses a genetic approach to investigate CD137 in human atherosclerotic disease. In publicly available data on genotype and gene expression from the HapMap project, the minor T allele of rs2453021, a single nucleotide polymorphism in CD137, was significantly associated with CD137 gene expression. In the PROCARDIS and Wellcome Trust Case Control Consortium (WTCCC) cohorts of 13,029 cases and controls, no significant association was detected between the minor T allele of rs2453021 and risk for coronary artery disease or myocardial infarction. However, in the IMPROVE multicenter study of 3,418 individuals, the minor T allele of rs2453021 was associated with increased IMT of the common carotid artery (CCA), as measured by ultrasonography, with presence of plaque in CCA and with increased incidence of adverse noncardiac vascular events. Taken together, this study shows that the minor T allele of rs2453021 is associated with increased IMT in the CCA and increased risk of incident noncardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis.
doi:10.2119/molmed.2014.00004 pmid:25032953 pmcid:PMC4212009 fatcat:vl7bo3tw4jcljcsljl6mebel3u
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