University of PaviaPavia

Italy

University of PaviaPavia

Italy
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Pistono C.,University of PaviaPavia | Osera C.,University of PaviaPavia | Boiocchi C.,University of PaviaPavia | Mallucci G.,National Neurological Institute &ldquo | And 3 more authors.
Pharmacological Research | Year: 2017

Multiple Sclerosis (MS) is a chronic pathology affecting the Central Nervous System characterized by inflammatory processes that lead to demyelination and neurodegeneration. In MS treatment, disease modifying therapies (DMTs) are essential to reduce disease progression by suppressing the inflammatory response responsible for promoting lesion formation. Recently, in addition to the classical injectable DMTs like Interferons and Glatiramer acetate, new orally administered drugs have been approved for MS therapy: dimethyl fumarate, teriflunomide and fingolimod. These drugs act with different mechanisms on the immune system, in order to suppress the harmful inflammatory process. An additional layer of complexity is introduced by the influence of polymorphic gene variants in the Human Leukocyte Antigen region on the risk of developing MS and its progression. To date, pharmacogenomic studies have mainly focused on the patient's response following admission of injectable drugs. Therefore, greater consideration must be made to pharmacogenomics with a view to developing more effective and personalized therapies. This review aims to shed light on the mechanism of action of the new oral drugs dimethyl fumarate, teriflunomide and fingolimod, taking into account both the importance of immunogenetics in drug response and pharmacogenomic studies. © 2017 Elsevier Ltd


PubMed | Connectivity, University of Pavia, University of PaviaPavia and Santi Paolo e Carlo Hospital of Milan Milan
Type: | Journal: Frontiers in human neuroscience | Year: 2016

The


Mori G.,University of PaviaPavia | Chiarelli L.R.,University of PaviaPavia | Esposito M.,University of PaviaPavia | Makarov V.,Russian Academy of Sciences | And 28 more authors.
Chemistry and Biology | Year: 2015

Summary To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target. © 2015 The Authors.


PubMed | University of Pavia, University Paris - Sud and University of PaviaPavia
Type: | Journal: Frontiers in human neuroscience | Year: 2016

Gait initiation (GI) involves passing from bipedal to unipedal stance. It requires a rapid movement of the center of foot pressure (CoP) towards the future swing foot and of the center of mass (CoM) in the direction of the stance foot prior to the incoming step. This anticipatory postural adjustment (APA) allows disengaging the swing leg from the ground and establishing favorable conditions for stepping. This study aimed to describe the neuro-mechanical process that underlies the goal-directed medio-lateral (ML) APA. We hypothesized that controlled knee flexion of the stance leg contributes to the initial ML displacement of the CoP and to the calibration of the first step. Fourteen subjects initiated gait starting from three different initial stance widths of 15 cm (Small), 30 cm (Medium), and 45 cm (Large). Optoelectronic, force platform and electromyogram (EMG) measurements were performed. During APA, soleus activity diminished bilaterally, while tibialis anterior (TA) activity increased, more so in the stance leg than in the swing leg, and to a larger extent with increasing initial stance width. Knee flexion of the stance leg was observed during APA and correlated with the ML CoP displacement towards the swing leg. ML CoP and CoM displacements during APA increased with increasing stance width. The activity of stance-leg TA was correlated with the degree of knee flexion. Swing-leg tensor fasciae latae (TFL) was also active during APA. Across subjects, when stance-leg tibialis activity was low, TFL activity was large and vice versa. The modulation of the ML CoP position during APA allowed the gravity-driven torque to place the CoM just lateral to the stance foot during step execution. Accordingly, the gravity-driven torque, the ML CoM velocity during step execution, and the step width at foot contact (FC) were lower in the Small and greater in the Large condition. Consequently, the position of the stepping foot at FC remained close to the sagittal plane in all three conditions. Conclusively, coordinated activation of hip abductors and ankle dorsiflexors during APA displaces the CoP towards the swing leg, and sets the contact position for the swing foot.


Meloni M.F.,Ospedale Valduce | Smolock A.,University of Wisconsin - Madison | Cantisani V.,University of RomeRome | Bezzi M.,University of RomeRome | And 6 more authors.
European Journal of Radiology | Year: 2015

Abstract Image-guided percutaneous ablation techniques are increasingly being used for the treatment of malignant tumors of the liver and kidney. Contrast enhanced ultrasound (CEUS) is a real-time dynamic imaging technique that plays an important role in the pre-, intra-, and post-procedural management of these patients. This review will focus on the role of CEUS in the evaluation of patients undergoing treatment with percutaneous ablation for hepatic or renal tumors. © 2015 Elsevier Ireland Ltd.


PubMed | C Mondino National Neurological Institute Pavia, Connectivity, University of PaviaPavia and C Mondino National Neurological Institutepavia
Type: | Journal: Frontiers in neuroscience | Year: 2016

Alzheimers disease (AD) is a neurodegenerative disorder characterized by a severe derangement of cognitive functions, primarily memory, in elderly subjects. As far as the functional impairment is concerned, growing evidence supports the disconnection syndrome hypothesis. Recent investigations using fMRI have revealed a generalized alteration of resting state networks (RSNs) in patients affected by AD and mild cognitive impairment (MCI). However, it was unclear whether the changes in functional connectivity were accompanied by corresponding structural network changes. In this work, we have developed a novel structural/functional connectomic approach: resting state fMRI was used to identify the functional cortical network nodes and diffusion MRI to reconstruct the fiber tracts to give a weight to internodal subcortical connections. Then, local and global efficiency were determined for different networks, exploring specific alterations of integration and segregation patterns in AD and MCI patients compared to healthy controls (HC). In the default mode network (DMN), that was the most affected, axonal loss, and reduced axonal integrity appeared to compromise both local and global efficiency along posterior-anterior connections. In the basal ganglia network (BGN), disruption of white matter integrity implied that main alterations occurred in local microstructure. In the anterior insular network (AIN), neuronal loss probably subtended a compromised communication with the insular cortex. Cognitive performance, evaluated by neuropsychological examinations, revealed a dependency on integration and segregation of brain networks. These findings are indicative of the fact that cognitive deficits in AD could be associated not only with cortical alterations (revealed by fMRI) but also with subcortical alterations (revealed by diffusion MRI) that extend beyond the areas primarily damaged by neurodegeneration, toward the support of an emerging concept of AD as a disconnection syndrome. Since only AD but not MCI patients were characterized by a significant decrease in structural connectivity, integrated structural/functional connectomics could provide a useful tool for assessing disease progression from MCI to AD.


Bordoni M.,University of PaviaPavia | Meisina C.,University of PaviaPavia | Vercesi A.,University of Cattolica MilanPiacenza | Bischetti G.B.,University of Milan | And 8 more authors.
Soil and Tillage Research | Year: 2016

Hilly slopes cultivated with vineyards are often affected by rainfall-induced shallow landslides that cause destruction and loss of the cultivations. For this reason, the assessment of mechanical contribution from grapevine roots is fundamental for slope stability analyses and consequently for the slope preservation. In this context, our work aims to quantitatively evaluate the soil reinforcement given by grapevine roots. The selected study area (13.4 km2), located in the region of Oltrepò Pavese in Northern Italy, is characterized by a high shallow landslides density and is constituted by vineyards in steep slopes. The tested soils are Haplic Calcisols, Petric Calcisols and Calcic Gleysols, with silt loamy or silty clay loamy textures, from high to very high carbonate content and low organic carbon and nitrogen contents. The rootstock of the grapevine is a combination of Vitis berlandieri and Vitis riparia with root systems, which reach average depths of up to 1.5 m. The grapevine root density (number of roots and Root Area Ratio) is rather variable and is strongly correlated to soil permeability. In fact, the results show that low permeable soils have small number of roots and occur near recent shallow slides. Despite the differences of soil features, type of bedrock, grapevine plants age, vineyards row orientation and season collection, a unique relationship between root diameter and root tensile strength has been identified. Root reinforcement, related to the grapevine root system and evaluated using Fiber Bundle Model, shows the lowest values in correspondence of sites characterized by the lowest soil permeability, as in the study case Calcic Gleysols. The sites with these soil features, actually, are also those most affected by shallow instability in the past, indicating that their great susceptibility to shallow landslides. The results of this study also highlight the role played by different amounts of grapevine root reinforcement on the slope stability during rainfall conditions, which could lead to triggering, on the study area. © 2016 Elsevier B.V.


PubMed | University of PaviaPavia, University of Pavia and Queen's University
Type: | Journal: Frontiers in molecular biosciences | Year: 2016

Historical and current concepts of in vitro fibrillogenesis are considered in the light of disorders in which amyloid is deposited at anatomic sites remote from the site of synthesis of the corresponding precursor protein. These clinical conditions set constraints on the interpretation of information derived from in vitro fibrillogenesis studies. They suggest that in addition to kinetic and thermodynamic factors identified in vitro, fibrillogenesis in vivo is determined by site specific factors most of which have yet to be identified.


Malhotra R.,Harvard University | Bakken K.,Harvard University | D'Elia E.,Hospital Papa Giovanni XXIII | D'Elia E.,University of PaviaPavia | Lewis G.D.,Harvard University
JACC: Heart Failure | Year: 2016

Exercise intolerance, indicated by dyspnea and fatigue during exertion, is a cardinal manifestation of heart failure (HF). Cardiopulmonary exercise testing (CPET) precisely defines maximum exercise capacity through measurement of peak oxygen uptake (VO2). Peak VO2 values have a critical role in informing patient selection for advanced HF interventions such as heart transplantation and ventricular assist devices. Oxygen uptake and ventilatory patterns obtained during the submaximal portion of CPET are also valuable to recognize because of their ease of ascertainment during low-level exercise, relevance to ability to perform activities of daily living, independence from volitional effort, and strong relationship to prognosis in HF. The ability of peak VO2 and other CPET variables to be measured reproducibly and to accurately reflect HF severity is increasingly recognized and endorsed by scientific statements. Integration of CPET with invasive hemodynamic monitoring and cardiac imaging during exercise provides comprehensive characterization of multisystem reserve capacity that can inform prognosis and the need for cardiac interventions. Here, we review both practical aspects of conducting CPETs in patients with HF for clinical and research purposes as well as interpretation of gas exchange patterns across the spectrum of preclinical HF to advanced HF. © 2016 American College of Cardiology Foundation

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