Carotid artery disease: Novel pathophysiological mechanisms identified by gene-expression profiling of peripheral blood

AbstractObjectThe pathogenesis of carotid artery stenosis (CAS) as well as the mechanisms underlying the different localisation of the atherosclerotic lesions remains poorly understood. We used microarray technology to identify novel systemic mediators that could contribute to CAS pathogenesis.Moreover, we compared gene-expression profile of CAS with that of patients affected by abdominal aortic aneurysm (AAA), previously published by our group.Methods and resultsBy global gene-expression profiling in a pool of 10 CAS patients and 10 matched controls, we found 82 genes differentially expressed. Validation study in pools used for profiling and replication study in larger numbers of CAS patients (n = 40) and controls (n = 40) of 14 genes by real-time polymerase chain reaction (RT-PCR) confirmed microarray results. Fourteen out of 82 genes were similarly expressed in AAA patients. Gene ontology analysis identified a statistically significant enrichment in CAS of differentially expressed transcripts involved in immune response and oxygen transport. Whereas alteration of oxygen transport is a common tract of the two localisations, alteration of immune response in CAS and of lipid metabolic process in AAA represents distinctive tracts of the two atherosclerotic diseases.ConclusionsWe describe the systemic gene-expression profile of CAS, which provides an extensive list of potential molecular markers

Influence of eNOS Gene Polymorphisms on Carotid Atherosclerosis

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On-Treatment Platelet Reactivity is a Predictor of Adverse Events in Peripheral Artery Disease Patients Undergoing Percutaneous Angioplasty

Objectives: Few data are available on the association between a different entity of platelet inhibition on antiplatelet treatment and clinical outcomes in patients with peripheral artery disease (PAD). The aim of this study was to evaluate the degree of on-treatment platelet reactivity, and its association with ischaemic and haemorrhagic adverse events at follow up in PAD patients undergoing percutaneous transluminal angioplasty (PTA). Methods: In this observational, prospective, single centre study, 177 consecutive patients with PAD undergoing PTA were enrolled, and treated with dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. Platelet function was assessed on blood samples obtained within 24 h from PTA by light transmission aggregometry (LTA) using arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists of platelet aggregation. High on-treatment platelet reactivity (HPR) was defined by LTA ≥ 20% if induced by AA, and LTA ≥ 70% if induced by ADP. Follow up was performed to record outcomes (death, major amputation, target vessel re-intervention, acute myocardial infarction and/or myocardial revascularisation, stroke/TIA, and bleeding). Results: HPR by AA and HPR by ADP were found in 45% and 32% of patients, respectively. During follow up (median duration 23 months) 23 deaths (13%) were recorded; 27 patients (17.5%) underwent target limb revascularisation (TLR), two (1.3%) amputation, and six (3.9%) myocardial revascularisation. Twenty-four patients (15.6%) experienced minor bleeding. On multivariable analysis, HPR by AA and HPR by ADP were independent predictors of death [HR 3.8 (1.2–11.7), p =.023 and HR 4.8 (1.6–14.5), p =.006, respectively]. The median value of LTA by ADP was significantly lower in patients with bleeding complications than in those without [26.5% (22–39.2) vs. 62% (44.5–74), p <.001). LTA by ADP ≤ 41% was independently associated with bleeding HR 14.6 (2.6–24.0), p =.001] on multivariable analysis. Conclusions: In this study a high prevalence of on-clopidogrel and aspirin high platelet reactivity was found, which was significantly associated with the risk of death. Conversely, a low on-clopidogrel platelet reactivity was associated with a higher risk of bleeding. These results document that the entity of platelet inhibition is associated with both thrombotic and bleeding complications in PAD patients

Loss of CD147 results in impaired epithelial cell differentiation and malformation of the meibomian gland

Meibomian gland dysfunction is a leading cause of ocular surface disease. However, little is known about the regulatory processes that control the development and maintenance of this sebaceous gland. Here, we identify a novel function for CD147, a transmembrane protein that promotes tissue remodeling through induction of matrix metalloproteinases, in regulating meibocyte differentiation and activity. We found that CD147 localized along basal cells and within discrete membrane domains of differentiated meibocytes in glandular acini containing gelatinolytic activity. Induction of meibocyte differentiation in vitro promoted CD147 clustering and MMP9 secretion, whereas RNAi-mediated abrogation of CD147 impaired MMP9 secretion, concomitant with a reduction in the number of proliferative cells and cytoplasmic lipids. Meibomian glands of CD147 knockout mice had a lower number of acini in both the superior and inferior tarsal plates of the eyelids, and were characterized by loss of lipid-filled meibocytes compared with control mice. Together, our data provide evidence showing that gelatinolytic activity in meibocytes is dependent on CD147, and supports a role for CD147 in maintaining the normal development and function of the meibomian gland

Loss of CD147 results in impaired epithelial cell differentiation and malformation of the meibomian gland

Meibomian gland dysfunction is a leading cause of ocular surface disease. However, little is known about the regulatory processes that control the development and maintenance of this sebaceous gland. Here, we identify a novel function for CD147, a transmembrane protein that promotes tissue remodeling through induction of matrix metalloproteinases, in regulating meibocyte differentiation and activity. We found that CD147 localized along basal cells and within discrete membrane domains of differentiated meibocytes in glandular acini containing gelatinolytic activity. Induction of meibocyte differentiation in vitro promoted CD147 clustering and MMP9 secretion, whereas RNAi-mediated abrogation of CD147 impaired MMP9 secretion, concomitant with a reduction in the number of proliferative cells and cytoplasmic lipids. Meibomian glands of CD147 knockout mice had a lower number of acini in both the superior and inferior tarsal plates of the eyelids, and were characterized by loss of lipid-filled meibocytes compared with control mice. Together, our data provide evidence showing that gelatinolytic activity in meibocytes is dependent on CD147, and supports a role for CD147 in maintaining the normal development and function of the meibomian gland

Casi e materiali di diritto commerciale

Il volume raccoglie i casi trattati nelle esercitazioni di Diritto Commerciale I e II nel corso dell’A.A. 2012/2013. Esso vuole costituire, prima di tutto, per gli studenti che frequentano i corsi di Diritto commerciale uno strumento di approfondimento e conoscenza nel concreto dell’applicazione giurisprudenziale delle principali tematiche affrontate a lezione e una guida per la partecipazione alle esercitazioni; ma ancor più serve agli studenti che, per scelta o per necessità, non frequentano i corsi, in quanto li mette di fronte ad una diversa prospettiva di analisi delle norme e li aiuta a comprendere ragioni e metodi dello studio del Diritto Commerciale, più di quanto potrebbe fare la semplice lettura non guidata dei testi didattici e delle norme. Ciascun caso viene presentato secondo uno schema standard: 1) il provvedimento e gli eventuali atti, sfrondati delle parti non strettamente necessarie agli scopi didattici; 2) i titoletti (che servono a classificare la pronuncia secondo partizioni prefissate, consentendo al lettore di individuare immediatamente l’argomento cui attiene e il principio di diritto affermato); 3) i richiami normativi, che individuano le norme la cui lettura e comprensione è indispensabile allo studio del caso; 4) la massima, che enuncia analiticamente il principio di diritto contenuto nel provvedimento; 5) il commento, che guida il lettore attraverso il ragionamento condotto dal giudice, indicandogli il percorso logico/giuridico e le regole di diritto positivo utilizzate per la soluzione del caso; 6) le indicazioni bibliografiche, volutamente non troppo ampie, giacché si limitano a rimandare ad alcune fonti ulteriori che rappresentano punti di partenza basilari per avviare uno studio analitico di ciascuna tematica. Talvolta al centro dell’approfondimento non è una pronuncia giurisprudenziale, ma un documento, parimenti idoneo ad illuminare aspetti problematici o particolarmente interessanti nella prospettiva dello studio del Diritto commerciale. In questo caso, al documento seguono immediatamente il commento/guida alla lettura e le indicazioni bibliografiche. I temi ruotano intorno ai nuclei fondamentali del diritto commerciale. L’impresa, innanzitutto, nelle sue articolate qualificazioni di impresa commerciale, agricola e artigiana, nonché negli aspetti concorrenziali. Il diritto societario, nella “summa divisio” fra società personali e società di capitali, senza trascurare i problemi che l’approvvigionamento dei mezzi finanziari sul mercato solleva a carico dei risparmiatori. E le procedure concorsuali, declinate soprattutto nel fallimento, che – nonostante la travagliata e sempre incompiuta riforma – resta al centro del sistema concorsuale

Fin whale density and distribution estimation using acoustic bearings derived from sparse arrays

D.V.H. and L.T. were funded by the Office of Naval Research (Grant Nos. N00014-14-1-0394 and N00014-16-1-2364). J.L.M.O. and J.A.V. were funded under Grant Nos. N00014-14-1-0397 and N00014-16-1-2860 also from the Office of Naval Research.Passive acoustic monitoring of marine mammals is common, and it is now possible to estimate absolute animal density from acoustic recordings. The most appropriate density estimation method depends on how much detail about animals' locations can be derived from the recordings. Here, a method for estimating cetacean density using acoustic data is presented, where only horizontal bearings to calling animals are estimable. This method also requires knowledge of call signal-to-noise ratios, as well as auxiliary information about call source levels, sound propagation, and call production rates. Results are presented from simulations, and from a pilot study using recordings of fin whale (Balaenoptera physalus) calls from Comprehensive Nuclear-Test-Ban Treaty Organization (CTBTO) hydrophones at Wake Island in the Pacific Ocean. Simulations replicating different animal distributions showed median biases in estimated call density of less than 2%. The estimated average call density during the pilot study period (December 2007-February 2008) was 0.02 calls hr-1 km2 (coefficient of variation, CV: 15%). Using a tentative call production rate, estimated average animal density was 0.54 animals/1000 km2 (CV: 52%). Calling animals showed a varied spatial distribution around the northern hydrophone array, with most detections occurring at bearings between 90 and 180 degrees.PostprintPeer reviewe

Recombination between Polioviruses and Co-Circulating Coxsackie A Viruses: Role in the Emergence of Pathogenic Vaccine-Derived Polioviruses

Ten outbreaks of poliomyelitis caused by pathogenic circulating vaccine-derived polioviruses (cVDPVs) have recently been reported in different regions of the world. Two of these outbreaks occurred in Madagascar. Most cVDPVs were recombinants of mutated poliovaccine strains and other unidentified enteroviruses of species C. We previously reported that a type 2 cVDPV isolated during an outbreak in Madagascar was co-circulating with coxsackieviruses A17 (CA17) and that sequences in the 3′ half of the cVDPV and CA17 genomes were related. The goal of this study was to investigate whether these CA17 isolates can act as recombination partners of poliovirus and subsequently to evaluate the major effects of recombination events on the phenotype of the recombinants. We first cloned the infectious cDNA of a Madagascar CA17 isolate. We then generated recombinant constructs combining the genetic material of this CA17 isolate with that of the type 2 vaccine strain and that of the type 2 cVDPV. Our results showed that poliovirus/CA17 recombinants are viable. The recombinant in which the 3′ half of the vaccine strain genome had been replaced by that of the CA17 genome yielded larger plaques and was less temperature sensitive than its parental strains. The virus in which the 3′ portion of the cVDPV genome was replaced by the 3′ half of the CA17 genome was almost as neurovirulent as the cVDPV in transgenic mice expressing the poliovirus cellular receptor gene. The co-circulation in children and genetic recombination of viruses, differing in their pathogenicity for humans and in certain other biological properties such as receptor usage, can lead to the generation of pathogenic recombinants, thus constituting an interesting model of viral evolution and emergence

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies (GWAS). Methods and Results: Through a meta-analysis of 6 GWAS datasets and a validation study totalling 10,204 cases and 107,766 controls we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches we observed no new associations between the lead AAA SNPs and coronary artery disease, blood pressure, lipids or diabetes. Network analyses identified ERG, IL6R and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA appear to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease