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Article Abstract Selection Calendar 2012


Confocal microscopy images showing the morphological changes between ON- and OFF-cells. Quiescent VSMCs elongate and become spindle-shaped as evidenced by Phalloidin (a); Vinculin has a peri-nuclear distribution that seems more polarised in ON and more abundant in OFF

Proteomics changes in adhesion molecules: a driving force for vascular smooth muscle cell phenotypic switch Silvia Rocchiccioli,a Nadia Ucciferri,ab Laura Comelli,a Maria Giovanna Trivella,a Lorenzo Cittia and Antonella Cecchettiniyab

Mol. BioSyst., 2012, 8, 1052–1059 ascular smooth muscle cells (VSMCs), if activaV 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 approach was proposed to highlight factors modulated during VSMC activation. Twenty proteins, differentially 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 activation, their roles and interactions.

a Institute of Clinical Physiology, CNR, Via Moruzzi 1, 56124, Pisa, Italy b Department of Human Morphology and Applied Biology,Pisa, Italy y Department of Human Morphology and Applied Biology, University of Pisa, Italy. This work was presented at the 6th Annual National Conference of the Italian Proteomics Association held in Turin on 21–24th June 2011. Electronic supplementary information (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.

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



e sought to investigate whether combining left ventricular (LV) volumes, regional wall motion abnormalities, and scar tissue extent obtained by cardiac magnetic resonance (CMR) improves risk stratification of patients with previous myocardial infarction (MI). Methods and results In 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 defibrillator 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 index .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 cardiac events [hazard ratio (HR) Âź 0.112, P , 0.01 and

HR Âź 0.261, P , 0.05] than those with three factors. The cumulative event-rate estimated at 4 years was 29.6% in patients with all three factors, 7.7% in those with one or two factors, and 3.5% in patients with none of these factors. Conclusion A multiparametric CMR approach, which includes the measure of scar tissue extent, LV end-diastolic volume and regional wall motion abnormalities, improves risk stratification of patients with previous MI

Eur Heart J 2012

1 CNR, Institute of Clinical Physiology, G. Monasterio Foundation, Via Moruzzi, 1, 56124, Pisa, Italy; 2 Clinical and Experimental Department of Medicine and Pharmacology, University of Messina, Messina, Italy; 3 Fondazione Toscana G. Monasterio, CNR, Regione Toscana, Pisa, Italy





Distribution of flow mediated dilationeperipheral arterial tone (FMD-PAT) in controls and cerebral autosomal 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 ackground and purpose CADASIL (cerebral autosomal 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 altered in CADASIL patients with respect to controls.


Methods Vasoreactivity was studied by a non-invasive pletismographic method in 49 mildly disabled CADASIL patients (30-65 years, 58% male, Rankin scale 2) and 25 controls. 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). Results Patients 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 controls (1.88 (1.57 to 2.43) vs 2.08 (1.81 to 2.58); p=0.126)

but 17 CADASIL patients (35%) had FMD-PAT scores below the fifth percentile 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 FMDPAT below the fifth percentile in CADASIL patients. Conclusions The impaired vasoreactivity observed in CADASIL patients highlights the fact that both endothelial and smooth muscle functional alterations may already be present in mildly disabled subjects. The improvement in vascular function could be a new target for pharmacological trials in CADASIL patients.

J Neurol Neurosurg Psychiatry 2012;83:268e274

1 CNR Clinical Physiology Institute, Cardiovascular Department, Niguarda Caâ&#x20AC;&#x2122; Granda Hospital, Milan, Italy 2 Institute of Translational Pharmacology, CNR, Rome, Italy 3 Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy 4 Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy 5 Department of Neurological, Neurosurgical and Behavioural Sciences, University of Siena, Siena, Italy 6 Center for Experimental Neurological 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





Star plot of measured metabolites in the 3-way connected 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, postadsorptive resting state, diabetes 1 and diabetes 2 simulating conditions in the 3-way connected culture.

Glucose and Fatty Acid Metabolism in a 3 Tissue In-Vitro Model Challenged with Normo-and Hyperglycaemia Elisabetta Iori1, Bruna Vinci2,3, Ellen Murphy1, Maria Cristina Marescotti1, Angelo Avogaro1,Arti Ahluwalia2,3

utrient balance in the human body is maintained N through systemic signaling between different cells and tissues. Breaking down this circuitry to its most basic elements and reconstructing the metabolic network in-vitro provides a systematic method to gain a better understanding of how cross-talk between the organs contributes to the whole body metabolic profile and of the specific role of each different cell type. To this end, a 3-way connected culture of hepatocytes, adipose tissue and endothelial cells representing a simplified model of energetic substrate metabolism 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 concentrations 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 systemâ&#x20AC;&#x2122;s metabolic profile changes dramatically in the presence of high concentrations of glucose, and that these changes are mo-

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 conditions, indicating, respectively, endothelial injury and proinflammatory stress in the challenged 3-way system.

PLos ONE April 2012; 7 e34704

1 Division of Metabolic Diseases, Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy 2 Centro Interdipartimentale di Ricerca E. Piaggi0, University of Pisa, Pisa, Italy 3 CNR Institute of Clinical Physiology, Pisa, Italy



Features of a generic hammerhead ribozyme binding (large arrow) its target substrate. Synthetic hammerhead 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 Sites for trans-Acting Minimal Hammerhead Ribozymes Alberto Mercatanti , Caterina Lande , and Lorenzo Citti

rans-acting hammerhead ribozymes are challenT ging tools for diagnostic, therapeutic, and biosensoristic purposes, owing to their specificity, efficiency,

Methods Mol Biol. 2012; 848:337-56

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 suitable target sites.

The aim of this chapter is to describe ALADDIN, â&#x20AC;&#x153;SeArch computing tooL for hAmmerheaD ribozyme DesIgN,â&#x20AC;? 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.

CNR Institute of Clinical Physiology, Pisa, Italy




Prevalence of airway obstruction in a) the general population 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 prevalence values range from 22% to 46.6%, with a median value of 29.9% (GOLD criteria). NHANES: National Health and Nutrition Examination Survey; ERS: European 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#

to raise public awareness of the importance Iblenoforder early detection of airway obstruction and to enamany people who had not been tested previously to have their lung function measured, the European Lung Foundation and the European Respiratory Society (ERS) organised a spirometry testing tent during the annual ERS Congresses in 2004–2009.

Spirometry was performed during the ERS Congresses in volunteers; all participants answered a simple, brief questionnaire on their descriptive characteristics, 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). Airway obstruction was present in 12.4% of investigated subjects according to LLN criteria and 20.3% according to GOLD criteria.

Through multinomial logistic regression analysis, age, smoking habits and asthma were significant risk factors for airway obstruction. 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 current smokers and 2.8 (2.2–3.6) for reported asthma diagnosis. In addition to being a useful advocacy tool, the spirometry tent represents an unusual occasion for early detection of airway obstruction in large numbers of city residents with an important public health perspective.

Eur Respir J. 2012

1 Pulmonary Environmental Epidemiology Unit, CNR Institute of Clinical Physiology, Pisa * For affilation details, refer to the Acknowledgements section. # These contributors are listed in the Acknowledgements section.




High resolution CT positive for interstitial lung disease

Lung ultrasound for the screening of interstitial lung disease 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 high 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 interstitial syndrome.


Objective To evaluate whether LUS is reliable in the screening of ILD in patients with SSc. Methods Fifty-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. Results At HRCT, ILD was detected in 88% of the SSc population and in 41% of the very early SSc population. A significant difference in the number of B-lines was found

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 sensitivity and negative predictive value of 100% in both SSc and very early SSc. Conclusions ILD may be detected in patients with very early SSc. The presence of B-lines at LUS examination correlates with ILD at HRCT. LUS is very sensitive for detecting ILD even in patients with a diagnosis of very early SSc. The use of LUS as a screening tool for ILD may be feasible to guide further investigation with HRCT.

Ann Rheumat Dis 2012

1 Department of Biomedicine, Division of Rheumatology AOUC, Excellence Centre for Research, Transfer and High Education DENOthe, University of Florence, Florence, Italy 2 Institute of Clinical Physiology, National Council of Research, Pisa, Italy 3 Department of Medicine, Division of Medicine AOUC, University of Florence, Florence, Italy 4 Diagnostic and Interventional Radiology, University of Pisa, Pisa, Italy


Annual Mortality Rate Annual mortality in the group of patients with known coronary artery disease (CAD) and suspected CAD separated on the basis of presence (+) or absence (-) of ischemia at SE and CFR on left anterior descending artery 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 he 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).


JACC 2012; Vol.5, No.1 1:1079–85

BACKGROUND CFR evaluated using pulsed Doppler echocardiography testing on left anterior descending artery is the state-of-the-art method during vasodilatory stress echocardiography. CONCLUSIONS CFR 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 echocardiography with a normal CFR confers an annual risk of death <?>1% in both patient groups.

* Cardiology Division, Campo di Marte Hospital, Lucca, Italy; † Cardiology Division, Umberto I° Hospital, Mestre-Venice, Italy; ‡ Cardiology Division, Cesena Hospital, Cesena, Italy; § CNR, Institute of Clinical Physiology, Pisa, Italy.


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

Echographic detectability of optoacoustic signals from low-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 o 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, nanoparticle stability, and imaging procedure safety.


Results Laser irradiation at 30 mJ/cm2 for 20 seconds resulted 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 concentration 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 optimized optoacoustic effectiveness. The tested GNRs also exhibited high biocompatibility over the entire considered concentration range.

Conclusion An optimal configuration for GNRenhanced optoacoustic imaging was experimentally determined, demonstrating in particular its feasibility with a conventional echographic device. The proposed approach can be easily extended to quantitative performance evaluation of different contrast agents for optoacoustic imaging.

Int J Nanomedicine 2012;7:4373-89

1 National Research Council, Institute of Clinical Physiology, Lecce, Italy; 2 National Nanotechnology Laboratory of CNR-NANO, Lecce, Italy; 3 University of Salento, Department of Engineering for Innovation, Lecce, Italy; 4 Italian Institute of Technology Center for Biomolecular Nanotechnology (CBN-IIT), Arnesano, Italy; 5 University of Salento, Department of Mathematics and Physics ‘Ennio De Giorgi’, Lecce, Italy

Step back from the edge EMBO 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 surrender to 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 be more 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. Zoppè Scientific Vizualization Unit, Institute of Clinical Physiology (CNR), Pisa, Italy REFERENCES 1. Geuens G (2012) Le Monde Diplomatique May

2. Palma JG (2009) Cambridge J Econ 33: 829–869

O C T O B E R /

An example of microneurographic recording of sympathetic 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 vascular tone, is usually acquired simultaneously with heart rate (in yellow) and beat-to-beat blood pressure (in green).

Sympathetic regulation of vascular function in health and disease Rosa M. Bruno1,2,Lorenzo Ghiadoni1, Gino Seravalle 3, Raffaella Dellâ&#x20AC;&#x2122;Oro4, Stefano Taddei1 and Guido Grassi 4,5

he sympathetic nervous system (SNS) is known T to play a pivotal role in short- and long-term regulation of different functions of the cardiovascular

system. In the past decades in creasing evidence demonstrated that sympathetic neural control is involved not only in the vasomotor control of small resistance 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 regulating 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 function. In healthy subjects, muscle sympathetic nerve activity (MSNA) appears to be related to surrogate markers of endothelial function, and an acute incre-

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 human studies is scanty. In humans large artery stiffness has been associated with increased sympathetic 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 autonomic regulation by impairing carotid baroreflex sensitivity.

Front Physiol. 2012;3:284

1 Department of Internal Medicine, University of Pisa, Italy 2 Institute of Clinical PhysiologyCNR, Pisa, Italy 3 Istituto Auxologico Italiano, Milan, Italy 4 Clinica Medica, Dipartimento di Medicina Clinica, Prevenzione e Biotecnologie Sanitarie, UniversitĂ  Milano-Bicocca, Ospedale San Gerardo, Monza, Milan, Italy 5 Istituto a Carattere Scientifico IRCCS Multimedica, Sesto SanGiovanni, Milan, Italy

O C T O B E R /

Carotid diameter is calculated as the distance between mediaeadventitia interfaces. Systolic and diastolic vessel diameters are detected for each cardiac cycle and distension 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 o evaluate local carotid stiffness (CS) and intima-medial thickness (C-IMT) in hypertensive patients with different cardiovascular risk profile, using a new user-friendly ultrasound-based system, previously validated vs. RF-based echotracking device.


Methods We investigated a population with different cardiovascular risk: 45 healthy normotensives (NT), 90 non-diabetic hypertensives (HT), and 48 patients with hypertension and type-2 diabetes (DM). Framingham risk factor score (FRS) was calculated. 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). Results CS, 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

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 correlated with age. Determinants of aortic and carotid stiffness were identified by multivariate stepwise analysis. Conclusions The proposed B-mode ultrasoundbased system is a reliable and userfriendly method that could serve to investigate the predictive value of CS for cardiovascular events in future large clinical studies.

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


Positron emission tomography (PET) images showing the distribution of the glucose analogue 18F-2-fluoro2-deoxyglucose (18FDG) in the non-stimulated and food-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

he ongoing epidemics of obesity is one main health T 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 addiction. Here, we review the contributions provided by the use of positron emission tomography to the current understanding 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 foods 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 behavior 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.

Though these same regions are similarly involved in drug abusers and game-addicted individuals, any direct resemblance may be an oversimplification, especially as the heterogeneities between studies and the prevalent exclusion of sensitive groups still limit a coherent interpretation of the findings. Further work is required to comprehensively tackle the multifaceted phenotype of obesity and identify the role of food dependency in its pathophysiology.

Obes Facts. 2012;5:155-164

a Institute of Clinical Physiology, National Research Council (CNR), Pisa b Endocrinology Unit, Department of Clinical Medicine, S. OrsolaMalpighi Hospital and C.R.B.A, Alma Mater University of Bologna, Bologna , Italy


Flowchart of population. CHD: coronary heart disease.MC: cardiomyopathy. V: valvular disease. I: arterial hypertension. A: arrhythmias. Other: other cardiac disease 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 everal 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 cardiometabolic risk factor. The aim of the study was to evaluate the independent impact of overweight and obesity on long-term mortality in a large cohort of patients with heart disease (HD).


Methods The study included 10,446 patients hospitalized in the last three decades for ischemic (60%) or nonischemic 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 categories (≤65 and >65 years). Considering that survival in HD patients has improved after the introduction of revascularization, beta-blockers, ACE inhibitors, and statins, the relationship was re-examined separately in patients hospitalized before and after 1990. Results Diabetes, hyperuricemia, hypertension, glycaemia, and triglyceridemia increased across BMI groups. During follow-up (73±59 months) there were 1707 all-cause de-

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

Int J Cardiol. 2012 Oct 16

Conclusions No 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 different effect of obesity onset in old vs. young age cannot be ruled out.

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


Positron emission tomography (PET) images showing the distribution of the glucose analogue 18F-2-fluoro2-deoxyglucose (18FDG) in the skeletal muscle and subcutaneous adipose tissue of the thighs during euglycemic insulin stimulation ď&#x20AC;ĄTransaxial view of the thigh ď&#x20AC;¤Coronal 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 mpaired adipose tissue (AT) blood flow hasbeenimplicated in the pathogenesis of insulin resistance in obesity. Insulin and bradykinin are meal-stimulated promoters of AT blood flow and glucose metabolism.


Objective: We tested whether blood flow regulates glucose metabolism 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. Design Perfusionandglucose metabolism in theATof the thighswerestudied by positron emission tomography and H215O(flow tracer) and 18F-2-fluoro-2-deoxyglucose. Study I included five subjects in whom positron emission 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 imaging protocol was performed during euglycemic hyperinsulinemia.

Results Bradykinin alone doubled fasting AT blood flow without modifying glucose uptake. Hyperinsulinemia increasedATblood flow (P0.05) similarly in leanandobese individuals. In the lean group, bradykinin increased 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 impaired (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). Conclusion AT blood flow is not an independent regulator of AT glucose metabolism. 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.

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

Š Institute of Clinical Physiology 2013 Graphic Design by Luca Serasini / IFC-CNR Multimedia Team

IFC CNR Article Abstract Selection 2012