Validation of a new method for human nerve decellularization: toward a new tool in peripheral nerve reconstructive surgery.

Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. In case of peripheral nerve injury, the first approach is primary neurorrhaphy, which is direct nerve repair with epineural microsutures of the two stumps. However, this is not feasible in case of stump retraction or in case of tissue loss (gap > 2 cm), where the main surgical options are autologous grafts, allogenic grafts, or nerve conduits. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable donor site morbidity and functional deficit. Fresh nerve allografts have therefore become a viable alternative option, but they require immunosuppression, which is often contraindicated. Acellular Nerve Allografts (ANA) represent a valid alternative, they do not need immunosuppression and appear to be safe and effective based on recent studies. The purpose of this study is to propose and develop an innovative method of nerve decellularization (Rizzoli method), conforming to cleanroom requirements in order to perform the direct tissue manipulation step and the nerve decellularization process within five hours, so as to accelerate the detachment of myelin and cellular debris, without detrimental effects on nerve architecture. In this study, the safety and the efficacy of the new method are evaluated in vitro and in vivo by histological, immunohistochemical, and histomorphometric studies in rabbits and humans. The new method is rapid, safe, and cheaper if compared with available commercial ANAs. The present study shows that the method, previously optimized in vitro and in vivo on animal model presented by our group, can be applied on human nerve samples. This work represents the first step in providing a novel, safe, and inexpensive tool for use by European tissue banks to democratize the use of nerve tissue transplantation for nerve injury reconstruction.

Tecniche di progettazione tollerante alle variazioni per circuiti digitali in tecnologie nanometriche

The digital electronic market development is founded on the continuous reduction of the transistors size, to reduce area, power, cost and increase the computational performance of integrated circuits. This trend, known as technology scaling, is approaching the nanometer size. The lithographic process in the manufacturing stage is increasing its uncertainty with the scaling down of the transistors size, resulting in a larger parameter variation in future technology generations. Furthermore, the exponential relationship between the leakage current and the threshold voltage, is limiting the threshold and supply voltages scaling, increasing the power density and creating local thermal issues, such as hot spots, thermal runaway and thermal cycles. In addiction, the introduction of new materials and the smaller devices dimension are reducing transistors robustness, that combined with high temperature and frequently thermal cycles, are speeding up wear out processes. Those effects are no longer addressable only at the process level. Consequently the deep sub-micron devices will require solutions which will imply several design levels, as system and logic, and new approaches called Design For Manufacturability (DFM) and Design For Reliability. The purpose of the above approaches is to bring in the early design stages the awareness of the device reliability and manufacturability, in order to introduce logic and system able to cope with the yield and reliability loss. The ITRS roadmap suggests the following research steps to integrate the design for manufacturability and reliability in the standard CAD automated design flow: i) The implementation of new analysis algorithms able to predict the system thermal behavior with the impact to the power and speed performances. ii) High level wear out models able to predict the mean time to failure of the system (MTTF). iii) Statistical performance analysis able to predict the impact of the process variation, both random and systematic. The new analysis tools have to be developed beside new logic and system strategies to cope with the future challenges, as for instance: i) Thermal management strategy that increase the reliability and life time of the devices acting to some tunable parameter,such as supply voltage or body bias. ii) Error detection logic able to interact with compensation techniques as Adaptive Supply Voltage ASV, Adaptive Body Bias ABB and error recovering, in order to increase yield and reliability. iii) architectures that are fundamentally resistant to variability, including locally asynchronous designs, redundancy, and error correcting signal encodings (ECC). The literature already features works addressing the prediction of the MTTF, papers focusing on thermal management in the general purpose chip, and publications on statistical performance analysis. In my Phd research activity, I investigated the need for thermal management in future embedded low-power Network On Chip (NoC) devices.I developed a thermal analysis library, that has been integrated in a NoC cycle accurate simulator and in a FPGA based NoC simulator. The results have shown that an accurate layout distribution can avoid the onset of hot-spot in a NoC chip. Furthermore the application of thermal management can reduce temperature and number of thermal cycles, increasing the systemreliability. Therefore the thesis advocates the need to integrate a thermal analysis in the first design stages for embedded NoC design. Later on, I focused my research in the development of statistical process variation analysis tool that is able to address both random and systematic variations. The tool was used to analyze the impact of self-timed asynchronous logic stages in an embedded microprocessor. As results we confirmed the capability of self-timed logic to increase the manufacturability and reliability. Furthermore we used the tool to investigate the suitability of low-swing techniques in the NoC system communication under process variations. In this case We discovered the superior robustness to systematic process variation of low-swing links, which shows a good response to compensation technique as ASV and ABB. Hence low-swing is a good alternative to the standard CMOS communication for power, speed, reliability and manufacturability. In summary my work proves the advantage of integrating a statistical process variation analysis tool in the first stages of the design flow.

Image analysis in the morphological and morphometric study of teeth

The subject of this doctoral dissertation concerns the definition of a new methodology for the morphological and morphometric study of fossilized human teeth, and therefore strives to provide a contribution to the reconstruction of human evolutionary history that proposes to extend to the different species of hominid fossils. Standardized investigative methodologies are lacking both regarding the orientation of teeth subject to study and in the analysis that can be carried out on these teeth once they are oriented. The opportunity to standardize a primary analysis methodology is furnished by the study of certain early Neanderthal and preneanderthal molars recovered in two caves in southern Italy [Grotta Taddeo (Taddeo Cave) and Grotta del Poggio (Poggio Cave), near Marina di Camerata, Campania]. To these we can add other molars of Neanderthal and modern man of the upper Paleolithic era, specifically scanned in the paleoanthropology laboratory of the University of Arkansas (Fayetteville, Arkansas, USA), in order to increase the paleoanthropological sample data and thereby make the final results of the analyses more significant. The new analysis methodology is rendered as follows: 1. Standardization of an orientation system for primary molars (superior and inferior), starting from a scan of a sample of 30 molars belonging to modern man (15 M1 inferior and 15 M1 superior), the definition of landmarks, the comparison of various systems and the choice of a system of orientation for each of the two dental typologies. 2. The definition of an analysis procedure that considers only the first 4 millimeters of the dental crown starting from the collar: 5 sections parallel to the plane according to which the tooth has been oriented are carried out, spaced 1 millimeter between them. The intention is to determine a method that allows for the differentiation of fossilized species even in the presence of worn teeth. 3. Results and Conclusions. The new approach to the study of teeth provides a considerable quantity of information that can better be evaluated by increasing the fossil sample data. It has been demonstrated to be a valid tool in evolutionary classification that has allowed (us) to differentiate the Neanderthal sample from that of modern man. In a particular sense the molars of Grotta Taddeo, which up until this point it has not been possible to determine with exactness their species of origin, through the present research they are classified as Neanderthal.

Shallow and deep deformation in northern Apennines region using seismological data

For its particular position and the complex geological history, the Northern Apennines has been considered as a natural laboratory to apply several kinds of investigations. By the way, it is complicated to joint all the knowledge about the Northern Apennines in a unique picture that explains the structural and geological emplacement that produced it. The main goal of this thesis is to put together all information on the deformation - in the crust and at depth - of this region and to describe a geodynamical model that takes account of it. To do so, we have analyzed the pattern of deformation in the crust and in the mantle. In both cases the deformation has been studied using always information recovered from earthquakes, although using different techniques. In particular the shallower deformation has been studied using seismic moment tensors information. For our purpose we used the methods described in Arvidsson and Ekstrom (1998) that allowing the use in the inversion of surface waves [and not only of the body waves as the Centroid Moment Tensor (Dziewonski et al., 1981) one] allow to determine seismic source parameters for earthquakes with magnitude as small as 4.0. We applied this tool in the Northern Apennines and through this activity we have built up the Italian CMT dataset (Pondrelli et al., 2006) and the pattern of seismic deformation using the Kostrov (1974) method on a regular grid of 0.25 degree cells. We obtained a map of lateral variations of the pattern of seismic deformation on different layers of depth, taking into account the fact that shallow earthquakes (within 15 km of depth) in the region occur everywhere while most of events with a deeper hypocenter (15-40 km) occur only in the outer part of the belt, on the Adriatic side. For the analysis of the deep deformation, i.e. that occurred in the mantle, we used the anisotropy information characterizing the structure below the Northern Apennines. The anisotropy is an earth properties that in the crust is due to the presence of aligned fluid filled cracks or alternating isotropic layers with different elastic properties while in the mantle the most important cause of seismic anisotropy is the lattice preferred orientation (LPO) of the mantle minerals as the olivine. This last is a highly anisotropic mineral and tends to align its fast crystallographic axes (a-axis) parallel to the astenospheric flow as a response to finite strain induced by geodynamic processes. The seismic anisotropy pattern of a region is measured utilizing the shear wave splitting phenomenon (that is the seismological analogue to optical birefringence). Here, to do so, we apply on teleseismic earthquakes recorded on stations located in the study region, the Sileny and Plomerova (1996) approach. The results are analyzed on the basis of their lateral and vertical variations to better define the earth structure beneath Northern Apennines. We find different anisotropic domains, a Tuscany and an Adria one, with a pattern of seismic anisotropy which laterally varies in a similar way respect to the seismic deformation. Moreover, beneath the Adriatic region the distribution of the splitting parameters is so complex to request an appropriate analysis. Therefore we applied on our data the code of Menke and Levin (2003) which allows to look for different models of structures with multilayer anisotropy. We obtained that the structure beneath the Po Plain is probably even more complicated than expected. On the basis of the results obtained for this thesis, added with those from previous works, we suggest that slab roll-back, which created the Apennines and opened the Tyrrhenian Sea, evolved in the north boundary of Northern Apennines in a different way from its southern part. In particular, the trench retreat developed primarily south of our study region, with an eastward roll-back. In the northern portion of the orogen, after a first stage during which the retreat was perpendicular to the trench, it became oblique with respect to the structure.

Retrieval of trace gases vertical profile in the lower atmosphere combining. Differential Optical Absorption Spectroscopy with radiative transfer models

The motivation for the work presented in this thesis is to retrieve profile information for the atmospheric trace constituents nitrogen dioxide (NO2) and ozone (O3) in the lower troposphere from remote sensing measurements. The remote sensing technique used, referred to as Multiple AXis Differential Optical Absorption Spectroscopy (MAX-DOAS), is a recent technique that represents a significant advance on the well-established DOAS, especially for what it concerns the study of tropospheric trace consituents. NO2 is an important trace gas in the lower troposphere due to the fact that it is involved in the production of tropospheric ozone; ozone and nitrogen dioxide are key factors in determining the quality of air with consequences, for example, on human health and the growth of vegetation. To understand the NO2 and ozone chemistry in more detail not only the concentrations at ground but also the acquisition of the vertical distribution is necessary. In fact, the budget of nitrogen oxides and ozone in the atmosphere is determined both by local emissions and non-local chemical and dynamical processes (i.e. diffusion and transport at various scales) that greatly impact on their vertical and temporal distribution: thus a tool to resolve the vertical profile information is really important. Useful measurement techniques for atmospheric trace species should fulfill at least two main requirements. First, they must be sufficiently sensitive to detect the species under consideration at their ambient concentration levels. Second, they must be specific, which means that the results of the measurement of a particular species must be neither positively nor negatively influenced by any other trace species simultaneously present in the probed volume of air. Air monitoring by spectroscopic techniques has proven to be a very useful tool to fulfill these desirable requirements as well as a number of other important properties. During the last decades, many such instruments have been developed which are based on the absorption properties of the constituents in various regions of the electromagnetic spectrum, ranging from the far infrared to the ultraviolet. Among them, Differential Optical Absorption Spectroscopy (DOAS) has played an important role. DOAS is an established remote sensing technique for atmospheric trace gases probing, which identifies and quantifies the trace gases in the atmosphere taking advantage of their molecular absorption structures in the near UV and visible wavelengths of the electromagnetic spectrum (from 0.25 μm to 0.75 μm). Passive DOAS, in particular, can detect the presence of a trace gas in terms of its integrated concentration over the atmospheric path from the sun to the receiver (the so called slant column density). The receiver can be located at ground, as well as on board an aircraft or a satellite platform. Passive DOAS has, therefore, a flexible measurement configuration that allows multiple applications. The ability to properly interpret passive DOAS measurements of atmospheric constituents depends crucially on how well the optical path of light collected by the system is understood. This is because the final product of DOAS is the concentration of a particular species integrated along the path that radiation covers in the atmosphere. This path is not known a priori and can only be evaluated by Radiative Transfer Models (RTMs). These models are used to calculate the so called vertical column density of a given trace gas, which is obtained by dividing the measured slant column density to the so called air mass factor, which is used to quantify the enhancement of the light path length within the absorber layers. In the case of the standard DOAS set-up, in which radiation is collected along the vertical direction (zenith-sky DOAS), calculations of the air mass factor have been made using “simple” single scattering radiative transfer models. This configuration has its highest sensitivity in the stratosphere, in particular during twilight. This is the result of the large enhancement in stratospheric light path at dawn and dusk combined with a relatively short tropospheric path. In order to increase the sensitivity of the instrument towards tropospheric signals, measurements with the telescope pointing the horizon (offaxis DOAS) have to be performed. In this circumstances, the light path in the lower layers can become very long and necessitate the use of radiative transfer models including multiple scattering, the full treatment of atmospheric sphericity and refraction. In this thesis, a recent development in the well-established DOAS technique is described, referred to as Multiple AXis Differential Optical Absorption Spectroscopy (MAX-DOAS). The MAX-DOAS consists in the simultaneous use of several off-axis directions near the horizon: using this configuration, not only the sensitivity to tropospheric trace gases is greatly improved, but vertical profile information can also be retrieved by combining the simultaneous off-axis measurements with sophisticated RTM calculations and inversion techniques. In particular there is a need for a RTM which is capable of dealing with all the processes intervening along the light path, supporting all DOAS geometries used, and treating multiple scattering events with varying phase functions involved. To achieve these multiple goals a statistical approach based on the Monte Carlo technique should be used. A Monte Carlo RTM generates an ensemble of random photon paths between the light source and the detector, and uses these paths to reconstruct a remote sensing measurement. Within the present study, the Monte Carlo radiative transfer model PROMSAR (PROcessing of Multi-Scattered Atmospheric Radiation) has been developed and used to correctly interpret the slant column densities obtained from MAX-DOAS measurements. In order to derive the vertical concentration profile of a trace gas from its slant column measurement, the AMF is only one part in the quantitative retrieval process. One indispensable requirement is a robust approach to invert the measurements and obtain the unknown concentrations, the air mass factors being known. For this purpose, in the present thesis, we have used the Chahine relaxation method. Ground-based Multiple AXis DOAS, combined with appropriate radiative transfer models and inversion techniques, is a promising tool for atmospheric studies in the lower troposphere and boundary layer, including the retrieval of profile information with a good degree of vertical resolution. This thesis has presented an application of this powerful comprehensive tool for the study of a preserved natural Mediterranean area (the Castel Porziano Estate, located 20 km South-West of Rome) where pollution is transported from remote sources. Application of this tool in densely populated or industrial areas is beginning to look particularly fruitful and represents an important subject for future studies.

Molecular bases, pathogenic mechanisms and possible therapeutic approach in Leber's Hereditary Optic Neuropathy

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by a rapid loss of central vision and optic atrophy, due to the selective degeneration of retinal ganglion cells. The age of onset is around 20, and the degenerative process is fast and usually the second eye becomes affected in weeks or months. Even if this pathology is well known and has been well characterized, there are still open questions on its pathophysiology, such as the male prevalence, the incomplete penetrance and the tissue selectivity. This maternally inherited disease is caused by mutations in mitochondrial encoded genes of NADH ubiquinone oxidoreductase (complex I) of the respiratory chain. The 90% of LHON cases are caused by one of the three common mitochondrial DNA mutations (11778/ND4, 14484/ND6 and 3460/ND1) and the remaining 10% is caused by rare pathogenic mutations, reported in literature in one or few families. Moreover, there is also a small subset of patients reported with new putative pathogenic nucleotide changes, which awaits to be confirmed. We here clarify some molecular aspects of LHON, mainly the incomplete penetrance and the role of rare mtDNA mutations or variants on LHON expression, and attempt a possible therapeutic approach using the cybrids cell model. We generated novel structural models for mitochondrial encoded complex I subunits and a conservation analysis and pathogenicity prediction have been carried out for LHON reported mutations. This in-silico approach allowed us to locate LHON pathogenic mutations in defined and conserved protein domains and can be a useful tool in the analysis of novel mtDNA variants with unclear pathogenic/functional role. Four rare LHON pathogenic mutations have been identified, confirming that the ND1 and ND6 genes are mutational hot spots for LHON. All mutations were previously described at least once and we validated their pathogenic role, suggesting the need for their screening in LHON diagnostic protocols. Two novel mtDNA variants with a possible pathogenic role have been also identified in two independent branches of a large pedigree. Functional studies are necessary to define their contribution to LHON in this family. It also been demonstrated that the combination of mtDNA rare polymorphic variants is relevant in determining the maternal recurrence of myoclonus in unrelated LHON pedigrees. Thus, we suggest that particular mtDNA backgrounds and /or the presence of specific rare mutations may increase the pathogenic potential of the primary LHON mutations, thereby giving rise to the extraocular clinical features characteristic of the LHON “plus” phenotype. We identified the first molecular parameter that clearly discriminates LHON affected individuals from asymptomatic carriers, the mtDNA copy number. This provides a valuable mechanism for future investigations on variable penetrance in LHON. However, the increased mtDNA content in LHON individuals was not correlated to the functional polymorphism G1444A of PGC-1 alpha, the master regulator of mitochondrial biogenesis, but may be due to gene expression of genes involved in this signaling pathway, such as PGC-1 alpha/beta and Tfam. Future studies will be necessary to identify the biochemical effects of rare pathogenic mutations and to validate the novel candidate mutations here described, in terms of cellular bioenergetic characterization of these variants. Moreover, we were not able to induce mitochondrial biogenesis in cybrids cell lines using bezafibrate. However, other cell line models are available, such as fibroblasts harboring LHON mutations, or other approaches can be used to trigger the mitochondrial biogenesis.

Sorveglianza dell'influenza aviare: studio di un sistema di rilevazione precoce della circolazione virale in popolazioni di volatili selvatici

The emergency of infection by highly pathogenic avian influenza virus (HPAI) subtype H5N1 has focused the attention of the world scientific community, requiring the prompt provision of effective control systems for early detection of the circulation of low pathogenic influenza H5 viruses (LPAI) in populations of wild birds to prevent outbreaks of highly pathogenic (HPAI) in populations of domestic birds with possible transmission to humans. The project stems from the aim to provide, through a preliminary analysis of data obtained from surveillance in Italy and Europe, a preliminary study about the virus detection rates and the development of mathematical models, an objective assessment of the effectiveness of avian influenza surveillance systems in wild bird populations, and to point out guidelines to support the planning process of the sampling activities. The results obtained from the statistical processing quantify the sampling effort in terms of time and sample size required, and simulating different epidemiological scenarios identify active surveillance as the most suitable for endemic LPAI infection monitoring in wild waterfowl, and passive surveillance as the only really effective tool in early detecting HPAI H5N1 circulation in wild populations. Given the lack of relevant information on H5N1 epidemiology, and the actual finantial and logistic constraints, an approach that makes use of statistical tools to evaluate and predict monitoring activities effectiveness proves to be of primary importance to direct decision-making and make the best use of available resources.

Applicazione di strumenti e metodi per la gestione ambientale di un territorio vasto - Sviluppo di un sistema di gestione ambientale in un ente pubblico secondo lo schema europeo EMAS e analisi di un sistema energetico territoriale

Environmental Management includes many components, among which we can include Environmental Management Systems (EMS), Environmental Reporting and Analysis, Environmental Information Systems and Environmental Communication. In this work two applications are presented: the developement and implementation of an Environmental Management System in local administrations, according to the European scheme "EMAS", and the analysis of a territorial energy system through scenario building and environmental sustainability assessment. Both applications are linked by the same objective, which is the quest for more scientifically sound elements; in fact, both EMS and energy planning are oftec carachterized by localism and poor comparability. Emergy synthesis, proposed by ecologist H.T. Odum and described in his book "Environmental Accounting: Emergy and Environmental Decision Making" (1996) has been chosen and applied as an environmental evaluation tool, in order complete the analysis with an assessment of the "global value" of goods and processes. In particular, eMergy syntesis has been applied in order to improve the evaluation of the significance of environmental aspects in an EMS, and in order to evaluate the environmental performance of three scenarios of future evolution of the energy system. Regarding EMS, in this work an application of an EMS together with the CLEAR methodology for environmental accounting is discussed, in order to improve the identification of the environmental aspects; data regarding environmental aspects and significant ones for 4 local authorities are also presented, together with a preliminary proposal for the integration of the assessment of the significance of environmental aspects with eMergy synthesis. Regarding the analysis of an energy system, in this work the carachterization of the current situation is presented together with the overall energy balance and the evaluation of the emissions of greenhouse gases; moreover, three scenarios of future evolution are described and discussed. The scenarios have been realized with the support of the LEAP software ("Long Term Energy Alternatives Planning System" by SEI - "Stockholm Environment Institute"). Finally, the eMergy synthesis of the current situation and of the three scenarios is shown.

Valutazione dell'efficacia delle procedure di Pushover convenzionali, modali ed adattive applicate a telai piani in c.a. regolari ed irregolari in elevazione.

The research performed during the PhD and presented in this thesis, allowed to make judgments on pushover analysis method about its application in evaluating the correct structural seismic response. In this sense, the extensive critical review of existing pushover procedures (illustrated in chapter 1) outlined their major issues related to assumptions and to hypothesis made in the application of the method. Therefore, with the purpose of evaluate the effectiveness of pushover procedures, a wide numerical investigation have been performed. In particular the attention has been focused on the structural irregularity on elevation, on the choice of the load vector and on its updating criteria. In the study eight pushover procedures have been considered, of which four are conventional type, one is multi-modal, and three are adaptive. The evaluation of their effectiveness in the identification of the correct dynamic structural response, has been done by performing several dynamic and static non-linear analysis on eight RC frames, characterized by different proprieties in terms of regularity in elevation. The comparisons of static and dynamic results have then permitted to evaluate the examined pushover procedures and to identify the expected margin of error by using each of them. Both on base shear-top displacement curves and on considered storey parameters, the best agreement with the dynamic response has been noticed on Multi-Modal Pushover procedure. Therefore the attention has been focused on Displacement-based Adative Pushover, coming to define for it an improvement strategy, and on modal combination rules, advancing an innovative method based on a quadratic combination of the modal shapes (QMC). This latter has been implemented in a conventional pushover procedure, whose results have been compared with those obtained by other multi-modal procedures. The development of research on pushover analysis is very important because the objective is to come to the definition of a simple, effective and reliable analysis method, indispensable tool in the seismic evaluation of new or existing structures.

Use of VEGFR-2 targeted microbubbles (BR55, Bracco imaging) for the early ultrasound evaluation of response to antiangiogenic treatment in a xenograft model of hepatocarcinoma

Aim: To evaluate the early response to treatment to an antiangiogenetic drug (sorafenib) in a heterotopic murine model of hepatocellular carcinoma (HCC) using ultrasonographic molecular imaging. Material and Methods: the xenographt model was established injecting a suspension of HuH7 cells subcutaneously in 19 nude mice. When tumors reached a mean diameter of 5-10 mm, they were divided in two groups (treatment and vehicle). The treatment group received sorafenib (62 mg/kg) by daily oral gavage for 14 days. Molecular imaging was performed using contrast enhanced ultrasound (CEUS), by injecting into the mouse venous circulation a suspension of VEGFR-2 targeted microbubbles (BR55, kind gift of Bracco Swiss, Geneve, Switzerland). Video clips were acquired for 6 minutes, then microbubbles (MBs) were destroyed by a high mechanical index (MI) impulse, and another minute was recorded to evaluate residual circulating MBs. The US protocol was repeated at day 0,+2,+4,+7, and +14 from the beginning of treatment administration. Video clips were analyzed using a dedicated software (Sonotumor, Bracco Swiss) to quantify the signal of the contrast agent. Time/intensity curves were obtained and the difference of the mean MBs signal before and after high MI impulse (Differential Targeted Enhancement-dTE) was calculated. dTE represents a numeric value in arbitrary units proportional to the amount of bound MBs. At day +14 mice were euthanized and the tumors analyzed for VEGFR-2, pERK, and CD31 tissue levels using western blot analysis. Results: dTE values decreased from day 0 to day +14 both in treatment and vehicle groups, and they were statistically higher in vehicle group than in treatment group at day +2, at day +7, and at day +14. With respect to the degree of tumor volume increase, measured as growth percentage delta (GPD), treatment group was divided in two sub-groups, non-responders (GPD>350%), and responders (GPD<200%). In the same way vehicle group was divided in slow growth group (GPD<400%), and fast growth group (GPD>900%). dTE values at day 0 (immediately before treatment start) were higher in non-responders than in responders group, with statistical difference at day 2. While dTE values were higher in the fast growth group than in the slow growth group only at day 0. A significant positive correlation was found between VEGFR-2 tissue levels and dTE values, confirming that level of BR55 tissue enhancement reflects the amount of tissue VEGF receptor. Conclusions: the present findings show that, at least in murine experimental models, CEUS with BR55 is feasable and appears to be a useful tool in the prediction of tumor growth and response to sorafenib treatment in xenograft HCC.

Committed to reform? Pragmatic antitrust enforcement in electricity markets

This thesis is a collection of essays about the instrumental use of commitment decisions to facilitate the completion of the European internal electricity market. European policy can shape markets in many ways, two most evident being regulation and competition enforcement. The interplay between these two instruments attracts a lot of scholarly attention. One of the major concerns in the competition vs. regulation debate is the instrumental use of competition rules. It has been observed that competition enforcement is triggered not only as a response to an anticompetitive harm occurring in the market, but that it sometimes becomes a powerful tool in the European Commission’s hands to pursue regulatory goals. This thesis looks for examples of such instrumentalisation in the context of electricity markets and finds that the Commission is very pragmatic in using all the possible instruments it has at hand to push forward its project of creating the internal electricity market. This includes regulation, competition enforcement and all sorts of political pressure. To the extent that commitment decisions accelerate sector-specific regulation and overcome political deadlocks, they contribute to the Commission’s energy policy goals. However, instrumentalisation of competition rules comes at a certain cost to competition policy, energy policy and, most importantly, to electricity markets themselves. Markets might be negatively affected either indirectly, by application of sector-specific regulation or competition policy building on previous commitment decisions, or directly, through the implementation of inadequate commitments in individual cases. Concluding, commitment decisions generally contributed to achieving the policy objectives of the internal electricity market, but their use for that purpose does not come without cost. Given that this cost is ultimately borne by the internal electricity market, the Commission should take a more balanced approach to the instrumental use of commitment decisions so that it does not do more harm than good.

Application of innovative methods of source apportionment in air contamination assessment

In this work, new tools in atmospheric pollutant sampling and analysis were applied in order to go deeper in source apportionment study. The project was developed mainly by the study of atmospheric emission sources in a suburban area influenced by a municipal solid waste incinerator (MSWI), a medium-sized coastal tourist town and a motorway. Two main research lines were followed. For what concerns the first line, the potentiality of the use of PM samplers coupled with a wind select sensor was assessed. Results showed that they may be a valid support in source apportionment studies. However, meteorological and territorial conditions could strongly affect the results. Moreover, new markers were investigated, particularly focusing on the processes of biomass burning. OC revealed a good biomass combustion process indicator, as well as all determined organic compounds. Among metals, lead and aluminium are well related to the biomass combustion. Surprisingly PM was not enriched of potassium during bonfire event. The second research line consists on the application of Positive Matrix factorization (PMF), a new statistical tool in data analysis. This new technique was applied to datasets which refer to different time resolution data. PMF application to atmospheric deposition fluxes identified six main sources affecting the area. The incinerator’s relative contribution seemed to be negligible. PMF analysis was then applied to PM2.5 collected with samplers coupled with a wind select sensor. The higher number of determined environmental indicators allowed to obtain more detailed results on the sources affecting the area. Vehicular traffic revealed the source of greatest concern for the study area. Also in this case, incinerator’s relative contribution seemed to be negligible. Finally, the application of PMF analysis to hourly aerosol data demonstrated that the higher the temporal resolution of the data was, the more the source profiles were close to the real one.

Temperature Variation Aware Energy Optimization in Heterogeneous MPSoCs

Thermal effects are rapidly gaining importance in nanometer heterogeneous integrated systems. Increased power density, coupled with spatio-temporal variability of chip workload, cause lateral and vertical temperature non-uniformities (variations) in the chip structure. The assumption of an uniform temperature for a large circuit leads to inaccurate determination of key design parameters. To improve design quality, we need precise estimation of temperature at detailed spatial resolution which is very computationally intensive. Consequently, thermal analysis of the designs needs to be done at multiple levels of granularity. To further investigate the flow of chip/package thermal analysis we exploit the Intel Single Chip Cloud Computer (SCC) and propose a methodology for calibration of SCC on-die temperature sensors. We also develop an infrastructure for online monitoring of SCC temperature sensor readings and SCC power consumption. Having the thermal simulation tool in hand, we propose MiMAPT, an approach for analyzing delay, power and temperature in digital integrated circuits. MiMAPT integrates seamlessly into industrial Front-end and Back-end chip design flows. It accounts for temperature non-uniformities and self-heating while performing analysis. Furthermore, we extend the temperature variation aware analysis of designs to 3D MPSoCs with Wide-I/O DRAM. We improve the DRAM refresh power by considering the lateral and vertical temperature variations in the 3D structure and adapting the per-DRAM-bank refresh period accordingly. We develop an advanced virtual platform which models the performance, power, and thermal behavior of a 3D-integrated MPSoC with Wide-I/O DRAMs in detail. Moving towards real-world multi-core heterogeneous SoC designs, a reconfigurable heterogeneous platform (ZYNQ) is exploited to further study the performance and energy efficiency of various CPU-accelerator data sharing methods in heterogeneous hardware architectures. A complete hardware accelerator featuring clusters of OpenRISC CPUs, with dynamic address remapping capability is built and verified on a real hardware.

Sleep motor activity in parkinsonian syndromes at onset: a prospective study to determine potential diagnostic and prognostic markers

Aim of this study is to describe the possible diagnostic value of sleep disturbances in the differential diagnosis of neurodegenerative diseases characterized by parkinsonism at onset. 42 consecutive patients with parkinsonian features and disease duration up to 3 years were included in the BO-ProPark study. Each patient was evaluated twice, at baseline (T0) and 16 months later (T1). Patients were diagnosed as Parkinson disease (PD, 27 patients), PD plus (PD with cognitive impairment/dementia or dysautonomia, 4 patients) and parkinsonian syndrome (PS, 11 patients). All patients underwent a full night video-polysomnography scored by a neurologist blinded to the clinical diagnosis. Sleep efficiency and total sleep time were reduced in all patients; wake after sleep onset was higher in patients with atypical parkinsonisms than in PD patients. No significant differences between groups of patients were detected in other sleep parameters. The mean percentage of epochs with enhanced tonic muscle EMG activity during REM sleep was higher in PD plus and PS than in PD. No difference in phasic muscle EMG activity during REM sleep was seen between the two groups. REM behaviour disorder was more frequent in PD plus and PS than in PD patients. Our data suggest that REM sleep motor control is more frequently impaired at disease onset in patients with PS and PD plus compared to PD patients. The presence of RBD or an enhanced tonic muscle EMG activity in a patient with recent onset parkinsonian features should suggest a diagnosis of atypical parkinsonism, rather than PD. More data are needed to establish the diagnostic value of these features in the differential diagnosis of parkinsonisms. The evaluation of sleep disorders may be a useful tool in the differential diagnosis of parkinsonism at onset.

Indagini forensi in tema di scambio di file pedopornografici mediante software di file sharing a mezzo peer-to-peer

La prova informatica richiede l’adozione di precauzioni come in un qualsiasi altro accertamento scientifico. Si fornisce una panoramica sugli aspetti metodologici e applicativi dell’informatica forense alla luce del recente standard ISO/IEC 27037:2012 in tema di trattamento del reperto informatico nelle fasi di identificazione, raccolta, acquisizione e conservazione del dato digitale. Tali metodologie si attengono scrupolosamente alle esigenze di integrità e autenticità richieste dalle norme in materia di informatica forense, in particolare della Legge 48/2008 di ratifica della Convenzione di Budapest sul Cybercrime. In merito al reato di pedopornografia si offre una rassegna della normativa comunitaria e nazionale, ponendo l’enfasi sugli aspetti rilevanti ai fini dell’analisi forense. Rilevato che il file sharing su reti peer-to-peer è il canale sul quale maggiormente si concentra lo scambio di materiale illecito, si fornisce una panoramica dei protocolli e dei sistemi maggiormente diffusi, ponendo enfasi sulla rete eDonkey e il software eMule che trovano ampia diffusione tra gli utenti italiani. Si accenna alle problematiche che si incontrano nelle attività di indagine e di repressione del fenomeno, di competenza delle forze di polizia, per poi concentrarsi e fornire il contributo rilevante in tema di analisi forensi di sistemi informatici sequestrati a soggetti indagati (o imputati) di reato di pedopornografia: la progettazione e l’implementazione di eMuleForensic consente di svolgere in maniera estremamente precisa e rapida le operazioni di analisi degli eventi che si verificano utilizzando il software di file sharing eMule; il software è disponibile sia in rete all’url http://www.emuleforensic.com, sia come tool all’interno della distribuzione forense DEFT. Infine si fornisce una proposta di protocollo operativo per l’analisi forense di sistemi informatici coinvolti in indagini forensi di pedopornografia.