Article Abstract SelectionCalendar 2012

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YConfocal microscopy images showing the morpholo-gical changes between ON- and OFF-cells. Quiescent VSMCs elongate and become spindle-shaped as eviden-ced by Phalloidin (a); Vinculin has a peri-nuclear di-stribution that seems more polarised in ON and more abundant in OFF

Proteomics changes in adhesion molecules: a driving forcefor vascular smooth muscle cell phenotypic switch

Silvia Rocchiccioli,a Nadia Ucciferri,ab Laura Comelli,a Maria Giovanna Trivella,a Lorenzo Cittia and Antonella Cecchettiniyab

Vascular smooth muscle cells (VSMCs), if activa-ted by growth factors as a consequence of vessel

injuries, acquire the ability to proliferate and migrate thus contributing to the formation of neointima and atherosclerotic plaque.In this study, a gel-free and label-free proteomic ap-proach was proposed to highlight factors modulated during VSMC activation. Twenty proteins, differen-tially expressed between quiescent and activated cells, were identified. A constellation of elements, that move together and are closely and functionally related, was visualized. The great majority of them are involved in cell migration and in adhesion formation, suggesting a pivotal role of these protein complexes on the phenotypic modulation. This study represents a first step to ascertain the precise actors of cell ac-tivation, their roles and interactions.

Mol. BioSyst., 2012, 8, 1052–1059

a Institute of Clinical Physiology, CNR, Via Moruzzi 1, 56124, Pisa, Italy

b Department of Human Morpho-logy and Applied Biology,Pisa, Italy

y Department of Human Morpho-logy and Applied Biology, Univer-sity of Pisa, Italy.

This work was presented at the 6th Annual National Conference of the Italian Proteomics Asso-ciation held in Turin on 21–24th June 2011.

Electronic supplementary infor-mation (ESI) available. See DOI: 10.1039/c2mb05470a

Delayed enhancement images in patient with previous anterior myocardial infarction. It is clear the presence of a white zone, in the endocardium of the meddle and distal segments of the anterior wall and septum.

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Scar extent, left ventricular end-diastolic volume and wall motion abnormalities identify high-risk patients with previous myocardial infarction: a multiparametric approach for progno-stic stratification

Gianluca Di Bella1,2, Valeria Siciliano1, Giovanni Donato Aquaro3, Sabrina Molinaro1, Massimo Lombardi1, Scipione Carerj2, Patrizia Landi1, Daniele Rovai1,3, and Alessandro Pingitore1,3

AIMS

We sought to investigate whether combining left ventricular (LV) volumes, regional wall motion

abnormalities, and scar tissue extent obtained by car-diac magnetic resonance (CMR) improves risk stratifi-cation of patients with previous myocardial infarction (MI).

MeThodS And ReSuLTSIn 231 consecutive patients (age 64+11 years, males 89%) with previous MI, we quantified LV volumes and regional wall motion abnormalities by cine CMR, and measured the extent of the infarction scar by late gadolinium enhancement (LGe). during follow-up (median, 3.2 years) cardiac events (cardiac death or appropriate intra-cardiac defibrilla-tor shocks) occurred in 19 patients. After adjustment for age, an extent of LGe .12.7%, an LV end-diastolic volume .105 mL/m2, and a wall motion score in-dex .1.7 were independent associated with adverse cardiac events at multivariate analysis (P , 0.05, P , 0.001, and P, 0.01, respectively). The patients with none of these factors, and those with one or two factors, showed a lower risk of car-diac events [hazard ratio (hR) ¼ 0.112, P , 0.01 and

Eur Heart J2012

1 CNR, Institute of Clinical Physio-logy, G. Monasterio Foundation, Via Moruzzi, 1, 56124, Pisa, Italy;

2 Clinical and Experimental De-partment of Medicine and Phar-macology, University of Messina, Messina, Italy;

3 Fondazione Toscana G. Monaste-rio, CNR, Regione Toscana, Pisa, Italy

hR ¼ 0.261, P , 0.05] than those with three factors.The cumulative event-rate esti-mated at 4 years was 29.6% in pa-tients with all three factors, 7.7% in those with one or two factors, and 3.5% in patients with none of these factors.

ConCLuSIonA multiparametric CMR appro-ach, which includes the measure of scar tissue extent, LV end-dia-stolic volume and regional wall motion abnormalities, improves risk stratification of patients with previous MI

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HDistribution of flow mediated dilationeperipheral arte-rial tone (FMD-PAT) in controls and cerebral autoso-mal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients. Each subject is represented by an open circle; CADASIL patients on statins are represented by filled circles.

Impaired vasoreactivity in mildly disabled CAdASIL patients

Jonica Campolo,1 Renata De Maria,1 Marina Frontali,2 Franco Taroni,3 Domenico Inzitari,4 Antonio Federico,5 Silvia Romano,6 Emanuele Puca,7Caterina Mariotti,3 Chiara Tomasello,3 Leonardo Pantoni,4 Francesca Pescini,4 Maria Teresa Dotti,5 Maria Laura Stromillo,5 Nicola De Stefano,5 Alessandra Tavani,8 Oberdan Parodi1

ABSTRACT

Background and purpose CAdASIL (cerebral autoso-mal dominant arteriopathy with subcortical infarcts and

leukoencephalopathy) is a rare genetic disease caused by noTCh3 gene mutations. A dysfunction in vasoreactivity has been proposed as an early event in the pathogenesis of the disease. The aim of this study was to verify whether endothelium dependent and/or independent function is al-tered in CAdASIL patients with respect to controls.

MeThodS Vasoreactivity was studied by a non-invasive pletismo-graphic method in 49 mildly disabled CAdASIL patients (30-65 years, 58% male, Rankin scale 2) and 25 con-trols. endothelium dependent vasodilatation was assessed by reactive hyperaemia (flow mediated dilation-peripheral arterial tone (FMd-PAT)) and endothelium independent vasoreactivity by glyceryl trinitrate (GTn) administration (GTn-PAT).

ReSuLTSPatients and controls showed comparable age, gender and cardiovascular risk factor distribution. GTn-PAT values were significantly lower in CAdASIL patients (1.54 (1.01 to 2.25)) than in controls (1.89 (1.61 to 2.59); p=0.041). FMd-PAT scores did not differ between patients and con-trols (1.88 (1.57 to 2.43) vs 2.08 (1.81 to 2.58); p=0.126)

J Neurol Neurosurg Psy-chiatry 2012;83:268e274

1 CNR Clinical Physiology Institute, Cardiovascular Department, Ni-guarda Ca’ Granda Hospital, Milan, Italy

2 Institute of Translational Pharma-cology, CNR, Rome, Italy

3 Fondazione IRCCS Istituto Neurolo-gico Carlo Besta, Milan, Italy

4 Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy

5 Department of Neurological, Neu-rosurgical and Behavioural Sciences, University of Siena, Siena, Italy

6 Center for Experimental Neurolo-gical Therapy, S Andrea Hospital, University of Rome, La Sapienza, Rome, Italy

7 Neurovascular Treatment Unit, University of Rome, La Sapienza, Rome, Italy

8 Department of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

but 17 CAdASIL patients (35%) had FMd-PAT scores below the fifth per-centile of controls. FMd-PAT and GTn-PAT values correlated both in controls (rho=0.648, p<0.001) and CAdASIL patients (rho=0.563, p<0.001). By multivariable logistic regression for clinical and laboratory variables, only GTn-PAT (oR 0.39, 95% CI 0.15 to 0.97; p=0.044) was independently associated with FMd-PAT below the fifth percentile in CAdASIL patients.

ConCLuSIonSThe impaired vasoreactivity obser-ved in CAdASIL patients highlights the fact that both endothelial and smooth muscle functional alterations may already be present in mildly di-sabled subjects. The improvement in vascular function could be a new target for pharmacological trials in CAdASIL patients.

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Star plot of measured metabolites in the 3-way con-nected cultures. Fractional variation in GLU (glucose), FFA, GLY (glycerol), LAC (lactate), ALA (L-alanine), IL-6 and E-SEL (E-selectin) at 48 H in fasting, post-adsorptive resting state, diabetes 1 and diabetes 2 simula-ting conditions in the 3-way connected culture.

Glucose and Fatty Acid Metabolism in a 3 Tissue In-VitroModel Challenged with normo-and hyperglycaemia

Elisabetta Iori1, Bruna Vinci2,3, Ellen Murphy1, Maria Cristina Marescotti1, Angelo Avogaro1,Arti Ahluwalia2,3

nutrient balance in the human body is maintained through systemic signaling between different

cells and tissues. Breaking down this circuitry to its most basic elements and reconstructing the metabo-lic network in-vitro provides a systematic method to gain a better understanding of how cross-talk betwe-en the organs contributes to the whole body meta-bolic profile and of the specific role of each different cell type. To this end, a 3-way connected culture of hepa-tocytes, adipose tissue and endothelial cells repre-senting a simplified model of energetic substrate me-tabolism in the visceral region was developed.The 3-way culture was shown to maintain glucose and fatty acid homeostasis in-vitro. Subsequently it was challenged with insulin and high glucose con-centrations to simulate hyperglycaemia. The aim was to study the capacity of the 3-way culture to maintain or restore normal circulating glucose concentrations in response to insulin and to investigate the effects these conditions on other metabolites involved in glucose and lipid metabolism.The results show that the system’s metabolic profile changes dramatically in the presence of high concen-trations of glucose, and that these changes are mo-

PLos ONE April 2012; 7 e34704

1 Division of Metabolic Diseases, Department of Clinical and Expe-rimental Medicine, University of Padua, Padua, Italy

2 Centro Interdipartimentale di Ricerca E. Piaggi0, University of Pisa, Pisa, Italy

3 CNR Institute of Clinical Physio-logy, Pisa, Italy

dulated by the presence of insulin.Furthermore, we observed an increase in e-selectin levels in hyperglycaemic conditions and increased IL-6 concentrations in insulin-free-hyperglycaemic con-ditions, indicating, respectively, endothelial injury and proinflam-matory stress in the challenged 3-way system.

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Features of a generic hammerhead ribozyme binding (large arrow) its target substrate. Synthetic hammerhe-ad moiety (bottom) is represented by highlighting its distinctive domains. The target molecule (top) is also shown and its target stretch schematically illustrated. NUH is the cleavage triplet on target sequence. The small arrow represents the cleavage site. The numbering system is conformant to Hertel et al.

A Computational Approach to Predict Suitable Target Sitesfor trans-Acting Minimal hammerhead Ribozymes

Alberto Mercatanti , Caterina Lande , and Lorenzo Citti

Trans-acting hammerhead ribozymes are challen-ging tools for diagnostic, therapeutic, and biosen-

soristic purposes, owing to their specificity, efficiency, and great flexibility of use. one of the main problems in their application is related to the difficulties in the design of active molecules and identifi cation of sui-table target sites.

The aim of this chapter is to describe ALAddIn, “SeArch computing tooL for hAmmerhead ribozyme desIgn,” an open-access tool able to automatically identify suitable cleavage sites and provide a set of hammerhead ribozymes putatively active against the selected target.

ALAddIn is a fast, cheap, helpful, and accurate tool designed to overcome the problems in the design of trans -acting minimal hammerhead ribozymes.

Methods Mol Biol. 2012; 848:337-56

CNR Institute of ClinicalPhysiology, Pisa, Italy

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Prevalence of airway obstruction in a) the general po-pulation and b) smokers aged >= 40 yrs. In the general population, the prevalence values ranged from 15.5% to 24.3%, with a median value of 19.8% (Global Initiative for Chronic Obstructive Lung Disease (GOLD); .......) and from 10.9% to 15.6%, with a median value of 15.3% (lower limit of normal (LLN); ——). In smokers, the pre-valence values range from 22% to 46.6%, with a median value of 29.9% (GOLD criteria). NHANES: National Health and Nutrition Examination Survey; ERS: Eu-ropean Respiratory Society. ¶: spirometric test without bronchodilator; “: spirometric test with bronchodilator.

The european Respiratory Society spirometry tent: a unique form of screening for airway obstruction

Sara Maio1, Duane L. Sherrill*, William MacNee*, Peter Lange*, Ulrich Costabel*, Sven-Erik Dahle´n*, Gerhard W. Sybrecht*, Otto C. Burghuber*, Robin Stevenson*, Philip Tønnesen*, Karl Haeussinger*, Gunilla Hedlin*, Torsten T. Bauer*, Josef Riedler*, Laurent Nicod*, Kai-Ha°kon Carlsen* and Giovanni Viegi1, on behalf of the European Respiratory Society/European Lung Foundation Spirometry Tent working group#

In order to raise public awareness of the importance of early detection of airway obstruction and to ena-

ble many people who had not been tested previously to have their lung function measured, the european Lung Foundation and the european Respiratory So-ciety (eRS) organised a spirometry testing tent during the annual eRS Congresses in 2004–2009.

Spirometry was performed during the eRS Congres-ses in volunteers; all participants answered a sim-ple, brief questionnaire on their descriptive characte-ristics, smoking and asthma. Portable spirometers were freely provided by the manufacturer. nurses and doctors from pulmonary departments of local hospitals/universities gave their service for free. Lower limit of normal (LLn) and Global Initiative for Chronic obstructive Lung disease (GoLd) criteria for diagnosing and grading airway obstruction were used. of 12,448 participants in six congress cities, 10,395 (83.5%) performed acceptable spirometry (mean age 51.0±18.4 yrs; 25.5% smokers; 5.5% asthmatic). Ai-rway obstruction was present in 12.4% of investigated subjects according to LLn criteria and 20.3% accor-ding to GoLd criteria.

Eur Respir J.2012

Through multinomial logistic re-gression analysis, age, smoking habits and asthma were significant risk factors for airway obstruc-tion. Relative risk ratio and 95% confidence interval for LLn stage I, for example, was 2.9 (2.0–4.1) for the youngest age (<=19 yrs), 1.9 (1.2–3.0) for the oldest age (>=80 yrs), 2.4 (2.0–2.9) for cur-rent smokers and 2.8 (2.2–3.6) for reported asthma diagnosis. In addition to being a useful advo-cacy tool, the spirometry tent represents an unusual occasion for early detection of airway ob-struction in large numbers of city residents with an important public health perspective.

1 Pulmonary Environmental Epide-miology Unit, CNR Institute

of Clinical Physiology, Pisa* Foraffilationdetails,refertothe

Acknowledgements section.# These contributors are listed in

the Acknowledgements section.

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High resolution CT positive for interstitial lung disease

Lung ultrasound for the screening of interstitial lungdisease in very early systemic sclerosis

Tatiana Barskova,1* Luna Gargani,2* Serena Guiducci,1 Silvia Bellando Randone,1 Cosimo Bruni,1 Giulia Carnesecchi,1 Maria Letizia Conforti,1 Francesco Porta,1 Alberto Pignone,3 Davide Caramella,4 Eugenio Picano,2 Marco Matucci Cerinic1

BACkGRound

Ahigh percentage of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILd) during

the course of the disease. Promising data have recently shown that lung ultrasound (LuS) is able to detect ILd by the evaluation of B-lines (previously called ultrasound lung comets), the sonographic marker of pulmonary in-terstitial syndrome.

oBjeCTIVeTo evaluate whether LuS is reliable in the screening of ILd in patients with SSc.

MeThodSFifty-eight consecutive patients with SSc (54 women, mean age 51±14 years) who underwent a high resolution CT (hRCT) scan of the chest were also evaluated by LuS for detection of B-lines. of these, 32 patients (29 women, mean age 51±15 years) fulfi lled the criteria for a diagnosis of very early SSc.

ReSuLTSAt hRCT, ILd was detected in 88% of the SSc popu-lation and in 41% of the very early SSc population. A significant difference in the number of B-lines was found

Ann Rheumat Dis2012

1 Department of Biomedicine, Division of Rheumatology AOUC, Excellence Centre for Research, Transfer and High Education DE-NOthe, University of Florence, Florence, Italy

2 Institute of Clinical Physiology, National Council of Research, Pisa, Italy

3 Department of Medicine, Di-vision of Medicine AOUC, Univer-sity of Florence, Florence, Italy

4 Diagnostic and Interventional Radiology, University of Pisa, Pisa, Italy

in patients with and without ILd on hRCT (57±53 vs 9±9; p<0.0001), with a concordance rate of 83%. All discordant cases were false positive at LuS, providing a sensi-tivity and negative predictive value of 100% in both SSc and very early SSc.

ConCLuSIonSILd may be detected in patients with very early SSc. The presence of B-lines at LuS examination cor-relates with ILd at hRCT. LuS is very sensitive for detecting ILd even in patients with a diagno-sis of very early SSc. The use of LuS as a screening tool for ILd may be feasible to guide further investi-gation with hRCT.

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Annual Mortality RateAnnual mortality in the group of patients with known coronary artery disease (CAD) and suspected CAD se-parated on the basis of presence (+) or absence (-) of ischemia at SE and CFR on left anterior descending ar-tery 2 or 2.

Coronary Flow Reserve during dipyridamole Stress echocardiography Predicts Mortality

Lauro Cortigiani, MD,* Fausto Rigo, MD,† Sonia Gherardi, MD,‡ Francesco Bovenzi, MD,* Sabrina Molinaro, BSC,§Eugenio Picano, MD, PHD,§ Rosa Sicari, MD, PHD§

oBjeCTIVeS

The goal of this study was to evaluate the ability of coronary flow reserve (CFR) over regional wall

motion to predict mortality in patients with known or suspected coronary artery disease (CAd).

BACkGRoundCFR evaluated using pulsed doppler echocardio-graphy testing on left anterior descending artery is the state-of-the-art method during vasodilatory stress echocardiography.

ConCLuSIonSCFR on LAd is a strong and independent indicator of mortality, conferring additional prognostic value over wall motion analysis in patients with known or suspected CAd. A negative result on stress echocar-diography with a normal CFR confers an annual risk of death <?>1% in both patient groups.

JACC 2012; Vol.5, No.1 1:1079–85

* Cardiology Division, Campo di Marte Hospital, Lucca, Italy;

† Cardiology Division, Umberto I° Hospital, Mestre-Venice, Italy;

‡ Cardiology Division, Cesena Ho-spital, Cesena, Italy;

§ CNR, Institute of Clinical Physio-logy, Pisa, Italy.

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/1 TEM image of synthesized PEG-coated gold nanorods (scale bar is 100 nm)

echographic detectability of optoacoustic signals fromlow-concentration PeG-coated gold nanorods

Francesco Conversano1, Giulia Soloperto1, Antonio Greco1, Andrea Ragusa1,2, Ernesto Casciaro1, Fernanda Chiriacò1,Christian Demitri3, Giuseppe Gigli2–5, Alfonso Maffezzoli3, Sergio Casciaro1

PuRPoSe

To evaluate the diagnostic performance of gold nanorod (GnR)-enhanced optoacoustic imaging

employing a conventional echographic device and to determine the most effective operative configuration in order to assure optoacoustic effectiveness, nano-particle stability, and imaging procedure safety.

ReSuLTSLaser irradiation at 30 mj/cm2 for 20 seconds resul-ted in the best compromise among the requirements of effectiveness, safety, and nanoparticle stability. Amplitude of GnR-emitted optoacoustic pulses was proportional to both sample volume and concen-tration along each considered propagation direction for all the tested boundary conditions, providing an experimental confirmation of isotropic optoacoustic emission. Average intensity of echographically detected spots showed similar behavior, emphasizing the presence of an “ideal” GnR concentration (100 pM) that opti-mized optoacoustic effectiveness. The tested GnRs also exhibited high biocompatibility over the entire considered concentration range.

Int J Nanomedicine 2012;7:4373-89

1 National Research Council, Insti-tute of Clinical Physiology, Lecce, Italy;

2 National Nanotechnology La-boratory of CNR-NANO, Lecce, Italy;

3 University of Salento, De-partment of Engineering for Innovation, Lecce, Italy;

4 Italian Institute of Technology Center for Biomolecular Nano-

technology (CBN-IIT), Arnesano, Italy;

5 University of Salento, De-partment of Mathematics and Physics ‘Ennio De Giorgi’, Lecce, Italy

ConCLuSIonAn optimal configuration for GnR-enhanced optoacoustic imaging was experimentally determined, demonstrating in particular its fe-asibility with a conventional echo-graphic device. The proposed approach can be easily extended to quantitative performance eva-luation of different contrast agents for optoacoustic imaging.

Step back from the edgeEMBO Rep. 2012;13:772

I generally read Howy Jacobs’s editorials with both interest and amusement, often enjoying his insight into a diverse range of topics. However, with reference to his June 2012 editorial “At the cliff ’s edge” I think he has allowed himself to be completely misled.Howy states that “political leaders are desperately in search of immediate and reliable advice on how best to handle the current financial crisis”, but points out that the advice they have received is next-to-useless because it is so diverse.He argues that “economists remain fundamentally divided over the diagnosis, which does not stop some of them from offering unsolicited

advice,” and concludes that “our colleagues in economics need to be cautious, applying level-headedness and humility in the face of trends that cannot accurately be predicted, let alone shaped by policy.”However, I take issue with his assertion that our political leaders are actively in search of this advice, and that there is no consensus about the course of action needed.In fact, many commentators agree on solutions to the current crisis and the prevention of future ones.The fact that their suggestions have not been acted on suggests a lack of political will or courage, and undue influence on the government of interested parties.These suggestions include: (i) greater regulation of the financial markets, starting with a ‘Tobin tax’ on financial transactions - this would put a brake on the financial games that are the major cause of the crisis; (ii) a major cut to military spending, which is arguably the worst spent money on Earth; (iii) a higher rate of tax on high salaries—up to

92%, following the example of US President Eisenhower in the 1950s; (iv) the separation of commercial banks and financial banks, with different rules and responsibilities for each, as is being undertaken in the UK; (v) the direct provision of money to people - that is, an increase in salaries, a genuine subsistance salary for the unemployed, expanding the public sector, support for small and medium enterprises, support for the green economy - rather than the existing style of ‘quantitative easing’ that passes it to banks who use it to bolster their capital rather than lend it to boost the economy; (vi) a cap on executive pay; and (vii) a cap on the money spent on lobbying governments.Any one of these policies would help those who are suffering most from the crisis by redistributing wealth or modifying behaviour, rather than increasing the wealth and influence of the few, as is the existing trend.I wonder how many of us are truly aware of the extent to which our politicians are personal stakeholders

in the financial world [1]? Why is it that the richest 1% of nearly every population become richer everyday, whereas the rest stagnate or become poorer [2]?I am not trying to say that things are simple, or that everything can be solved quickly and inexpensively. However, politicians should act on behalf of the people, not surrenderto the will of corporations.Growth forever is simply impossible: this is a lesson that biologists could impart to economists.In relation to Howy’s other point, that academic economists should be more careful in making sweeping proposals on the basis of their own pet theories, it follows from my comment that it does not matter what they say anyway, given that EU politicians seem determined to please the markets, rather than supporting their own people.This mindset is most clearly demonstrated by the fact that the success of political agreements is measured primarily in terms of credit ratings, rather than welfare or

other indicators of a nurtured and successful populace.The admission by Barclays Bank - probably only the first of a series - that it manipulatedinterest rates for its own benefit, is yet another indication that banks should bemore strictly regulated by politicians.It is intolerable that the existing situation sees corporations controlling the will of governments, and worse still that politicians seem almost complicit in this arrangement.Walking along the cliff ’s edge, as Howy suggests, will lead to a serious and probably fatal accident. The question is, who should fall: the financial elite, who caused this crisis and continue to grow wealthier from it, or the common man or woman, whose taxes are being absorbed by banks and whose children have a very bleak outlook indeed? Different economists propose different solutions, based on their opinion: which ones to listen to is the responsibility of politicians, and not a decision that should be left to ‘market forces’.

Monica M. ZoppèScientificVizualizationUnit,Institute of Clinical Physiology (CNR), Pisa, Italy

REFERENCES1. Geuens G (2012) Le Monde Diplomatique May2. Palma JG (2009) Cambridge J Econ 33: 829–869

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An example of microneurographic recording of sympathe-tic nerve traffic in the peroneal nerve of an hypertensive

patient. Muscle sympathetic nerve activity (in violet), which represents the main effector of autonomic regulation of va-

scular tone, is usually acquired simultaneously with heart rate (in yellow) and beat-to-beat blood pressure (in green).

Sympathetic regulation of vascular functionin health and disease

Rosa M. Bruno1,2,Lorenzo Ghiadoni1, Gino Seravalle 3, Raffaella Dell’Oro4, Stefano Taddei1 and Guido Grassi 4,5

The sympathetic nervous system (SnS) is known to play a pivotal role in short- and long-term re-

gulation of different functions of the cardiovascular system. In the past decades in creasing evidence de-monstrated that sympathetic neural control is invol-ved not only in the vasomotor control of small resi-stance arteries but also in modulation of large artery function. Sympathetic activity and vascular function, both of which are key factors in the development and prognosis of cardiovascular events and disease, are linked at several levels.evidence from experimental studies indicates that the SnS is critically influenced, at the central and also at the peripheral level, by the most relevant factors re-gulating vascular function, such as nitricoxide (no), reactive oxygen species (RoS), endothelin(eT), the renin-angiotensin system.Additionally, there is indirect evidence of a reciprocal relationship between endothelial function and activity of the SnS. A number of cardiovascular risk factors and diseases are characterized both by increased sympathetic outflow and decreased endothelial fun-ction. In healthy subjects, muscle sympathetic nerve activity (MSnA) appears to be related to surrogate markers of endothelial function, and an acute incre-

Front Physiol.2012;3:284

1 Department of Internal Medicine, University of Pisa, Italy

2 Institute of Clinical Physiology-CNR, Pisa, Italy

3 Istituto Auxologico Italiano, Milan, Italy

4 Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, Universi-tà Milano-Bicocca, Ospedale San Gerardo, Monza, Milan, Italy

5 IstitutoaCarattereScientificoIRCCS Multimedica, Sesto San-Giovanni, Milan, Italy

ase in sympathetic activity has been associated with a decrease in endothelial function in healthy subjects.however, direct evidence of a cause-effect relationship from hu-man studies is scanty. In humans large artery stiffness has been associated with increased sympa-thetic discharge, both in healthy subjects and in renal transplant recipients. Peripheral sympathetic discharge is also able to modulate wave reflection. on the other hand, large artery stiffness can interfere with auto-nomic regulation by impairing ca-rotid baroreflex sensitivity.

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Carotid diameter is calculated as the distance between mediaeadventitia interfaces. Systolic and diastolic vessel diameters are detected for each cardiac cycle and disten-sion is calculated as the mean value of their difference on the last 8 s of the image sequences.

Local carotid stiffness and intima-media thickness assessment by a novel ultrasound-based system in essential hypertension

Chiara Giannarelli a,, Elisabetta Bianchini b, Rosa Maria Bruno a, Armando Magagna a, Linda Landini a, Francesco Faita b,Vincenzo Gemignani b, Giuseppe Penno c, Stefano Taddei a, Lorenzo Ghiadoni a

oBjeCTIVe

To evaluate local carotid stiffness (CS) and intima-medial thickness (C-IMT) in hypertensive patients with diffe-

rent cardiovascular risk profile, using a new user-friendly ultrasound-based system, previously validated vs. RF-based echotracking device.

MeThodSWe investigated a population with different cardiovascular risk: 45 healthy normotensives (nT), 90 non-diabetic hyper-tensives (hT), and 48 patients with hypertension and type-2 diabetes (dM). Framingham risk factor score (FRS) was cal-culated. PWV was assessed by applanation tonometry. The relative stroke change in diameter (dd) and C-IMT were measured on carotid scans. distensibility coefficient (dC) was calculated as dA/(A*dP), where A ¼ diastolic lumen area, dA ¼ stroke change in lumen area, and dP ¼ carotid pulse pressure. CS (m/s) was calculated as (r*dC) 1/2 (r ¼ blood density).

ReSuLTSCS, C-IMT, PWV were significantly increased in hT and dM vs. nT. C-IMT and PWV were significantly higher in dM than hT. dd and dC were significantly lower in hT and dM vs. nT. FRS 10% group showed increased carotid

Atherosclerosis. 2012;223:372-7

a Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy

b Institute of Clinical Physiology, Italian National Research Council, Pisa, Italy

c Department of Endocrinology, University of Pisa, Italy

diameter, C-IMT and CS than the FRS <10%. FRS was (p < 0.001) correlated with CS (r ¼ 0.35); dd (r ¼ 0.36), dC (r ¼ 0.35), C-IMT (r ¼ 0.48), PWV (r ¼ 0.38). CS correlated (p < 0.05) with PWV in the entire population (r ¼ 0.37), in the nT (r ¼ 0.35), in the hT and dM (r ¼ 0.20). PWV (r ¼ 0.50) and CS (r ¼ 0.33) were corre-lated with age. determinants of aortic and carotid stiffness were identified by multivariate stepwise analysis.

ConCLuSIonSThe proposed B-mode ultrasound-based system is a reliable and user-friendly method that could serve to investigate the predictive value of CS for cardiovascular events in future lar-ge clinical studies.

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Positron emission tomography (PET) images showing the distribution of the glucose analogue 18F-2-fluoro-2-deoxyglucose (18FDG) in the non-stimulated and fo-od-stimulated brain

Brain PeT Imaging in obesity and Food Addiction: Current evidence and hypothesis

Patricia Iozzo a Letizia Guiducci a Maria Angela Guzzardi a Uberto Pagotto b

The ongoing epidemics of obesity is one main health concern of the present time. overeating in some

obese individuals shares similarities with the loss of con-trol and compulsive behavior observed in drug-addicted subjects, suggesting that obesity may involve food ad-diction. here, we review the contributions provided by the use of positron emission tomography to the current understan-ding of the cerebral control of obesity and food intake in humans. The available studies have shown that multiple areas in the brain are involved with the reward properties of food, such as prefrontal, orbitofrontal, somatosensory cortices, insula, thalamus, hypothalamus, amygdala, and others. This review summarizes the current evidence, supporting the concepts that:i) regions involved in the somatosensory response to food sight, taste, and smell are activated by palatable fo-ods and may be hyperresponsive in obese individuals, ii) areas controlling executive drive seem to overreact to the anticipation of pleasure during cue exposure, and iii) those involved in cognitive control and inhibitory be-havior may be resistant to the perception of reward after food exposure in obese subjects. All of these features may stimulate, for different reasons, ingestion of highly palatable and energy-rich foods.

Obes Facts. 2012;5:155-164

a Institute of Clinical Physiology, National Research Council

(CNR), Pisab Endocrinology Unit, Department

of Clinical Medicine, S. Orsola-Malpighi Hospital and C.R.B.A, Alma Mater University of Bolo-gna, Bologna , Italy

Though these same regions are si-milarly involved in drug abusers and game-addicted individuals, any direct resemblance may be an oversimpli-fication, especially as the heteroge-neities between studies and the pre-valent exclusion of sensitive groups still limit a coherent interpretation of the findings. Further work is required to comprehensively tackle the mul-tifaceted phenotype of obesity and identify the role of food dependency in its pathophysiology.

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Flowchart of population. CHD: coronary heart disea-se.MC: cardiomyopathy. V: valvular disease. I: arterial hypertension. A: arrhythmias. Other: other cardiac di-sease as pericarditis, miocarditis.

Interpretation of the “obesity paradox”:A 30-year study in patients with cardiovascular disease

Patricia Iozzo, Giuseppe Rossi, Claudio Michelassi, Patrizia Landi, Clara Carpeggiani *

BACkGRound

Several epidemiological reports indicate that the body ma ss index (BMI) is inversely related with mortality,

in spite of the notion that obesity is a recognized cardio-metabolic risk factor. The aim of the study was to eva-luate the independent impact of overweight and obesity on long-term mortality in a large cohort of patients with heart disease (hd).

MeThodSThe study included 10,446 patients hospitalized in the last three decades for ischemic (60%) or nonische-mic hd and followed-up for 10 years. The relationship between BMI and total or cardiovascular mortality was analyzed in the whole cohort, and in age-stratified cate-gories (≤65 and >65 years). Considering that survival in hd patients has improved after the introduction of reva-scularization, beta-blockers, ACe inhibitors, and statins, the relationship was re-examined separately in patients hospitalized before and after 1990.

ReSuLTSdiabetes, hyperuricemia, hypertension, glycaemia, and triglyceridemia increased across BMI groups. during fol-low-up (73±59 months) there were 1707 all-cause de-

Int J Cardiol.2012 Oct 16

* Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy

aths (47% cardiac). Any relationship between BMI and mortality was lost in the ≤65 age category and in pa-tients hospitalized before 1990, but it persisted in old patients hospitali-zed after 1990. Most significant inde-pendent predictors of mortality in all groups were hyperuricemia, diabetes and impaired ejection fraction.

ConCLuSIonSno independent relationship was found between BMI and mortality in subjects ≤65 years of age.This neutral relationship seems to be partly counteracted by treatment, particularly in old patients. A diffe-rent effect of obesity onset in old vs. young age cannot be ruled out.

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R/3 Positron emission tomography (PET) images showing

the distribution of the glucose analogue 18F-2-fluoro-2-deoxyglucose (18FDG) in the skeletal muscle and subcutaneous adipose tissue of the thighs during eu-glycemic insulin stimulation

Transaxial view of the thighCoronal view (posterior thigh)

The Interaction of Blood Flow, Insulin, and Bradykinin in Regulating Glucose uptake in Lower-Body Adipose Tissue in Lean and obese Subjects

Patricia Iozzo, Antti Viljanen, Maria A. Guzzardi, Hanna Laine, Miikka J. Honka, Ele Ferrannini and Pirjo Nuutila

ConTexT

Impaired adipose tissue (AT) blood flow hasbeenimpli-cated in the pathogenesis of insulin resistance in obesi-

ty. Insulin and bradykinin are meal-stimulated promoters of AT blood flow and glucose metabolism.

oBjeCTIVe:We tested whether blood flow regulates glucose me-tabolism in AT, insulin and bradykinin exert additive effects on AT blood flow and metabolism, and any of these actions explains the insulin resistance observed in obese individuals.

deSIGnPerfusionandglucose metabolism in theATof the thi-ghswerestudied by positron emission tomography and h215o(flow tracer) and 18F-2-fluoro-2-deoxyglucose. Study I included five subjects in whom positron emis-sion tomography imaging was performed in the fasting state during intraarterial infusion of bradykinin in the left leg; the right leg served as a control. Study II included seven lean and eight obese subjects in whom the ima-ging protocol was performed during euglycemic hype-rinsulinemia.

J Clin Endocrinol Metab. 2012;97:E1192-1196

Turku PET Centre (P.I., A.V., M.J.H., P.N.), and Departments of Ophthalmology (A.V.) and Medicine(H.L., P.N.), University of Turku, 20521 Turku, Finland; Institute of Clinical Physiology (P.I., M.A.G.), National Research Council (CNR), 56124 Pisa, Italy; and Department of Medicine (E.F.), University of Pisa School of Medicine, 56127 Pisa, Italy

ReSuLTSBradykinin alone doubled fasting AT blood flow without modifying glucose uptake. hyperinsulinemiaincreasedATblood flow (P0.05) si-milarly in leanandobese individuals. In the lean group, bradykinin incre-ased insulin-mediated AT glucose uptake from 8.6 1.6 to 12.3 2.4 mol/min kg (P 0.038). In the obese group, AT glucose uptake was im-paired (5.0 1.0 mol/min kg, P 0.05 vs. the lean group),and bradykinin did not exert any metabolic action (6.0 0.8 mol/min kg, P 0.01 vs. the lean group).

ConCLuSIonAT blood flow is not an indepen-dent regulator of AT glucose meta-bolism. Insulin is a potent stimulator of AT blood flow, and bradykinin potentiates the hemodynamic and metabolic actions of insulin in lean but not in obese individuals.

© Institute of Clinical Physiology 2013Graphic design by Luca Serasini / IFC-CnR Multimedia Team www.ifc.cnr.it