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Biodisponibilità e farmacocinetiche nello studio del profilo farmacologico di molecole ad azione cannabinoidergica
Get PDFThe curative properties of Cannabis sativa L. have been known for ages, but only in the last years interesting pharmaceutical properties have been reported for both synthetic and natural compounds having high affinity towards CB1 and/or CB2 cannabinoid receptors. In particular Rimonabant and other pyrazole derivatives have been widely studied for their CB1 antagonism in different in vitro and in vivo models. The lead compound Rimonabant (SR14176A or Acomplia®) has been initially employed in human as anti-obesity drug, but unfortunately EMA was constrained to block its sales according to the evidence of related
adverse effects, particularly increased incidence of depression and suicidality. However interest in cannabinoid drug discovery is actually marked, especially toward the obtainment of new CB1 and/or CB2 ligands. In order to evaluate structure-activity relationship due to the modification of the different substituents at both C4 and C5 positions of the pyrazole core, new series of cannabinoid pyrazole derivatives have been obtained. Molecular structures have been investigated by Infrared Spettroscopy, Nuclear Magnetic Resonance and Mass Spectrometry. Two of CB1 antagonist compounds, NESS014A and NESS006A, were obtained and characterized by CB1 affinity of 14.3 and 35.0 nM, respectively (expressed as Ki). To evaluate the effect of the chemical structure of the compounds on the blood and brain barrier permeability, bioanalytical methods based on high-performance liquid
chromatography tandem mass spectrometry (HPLC/MS/MS) in both rat brain and blood were developed and validated. To investigate their adsorbition, distribution, metabolism
and elimination (ADME), pharmacokinetic analysis were carried out by Compartimental Analysis at different time: pre-dose and from 2 to 1440 minutes post-dose after NESS014A
and NESS006A acute infusion
Fire resistance of Laminated Veneer Lumber (LVL) and Cross-Laminated Timber (XLAM) elements
Get PDFEngineering design of timber structures in fire conditions is crucial to ensure high safety levels. Wood is subjected to degradation under fire exposure therefore its thermal
and mechanical behaviours change. Timber design must take the decrease of timber performance into account to calculate structural elements that can carry external loads
also if exposed to high temperatures. Analytical and numerical approaches can be adopted in fire design practice.
This research investigates the fire behaviour of laminated veneer lumber elements and cross-laminated timber panels. The study focused on some research questions regarding the fire resistance of unprotected and protected timber structural elements, the possibility to predict accurately the fire behaviour of timber elements through numerical
modelling, and the accuracy of analytical estimations of fire resistance using simplified design methods.
Experimental tests of small and large specimens exposed to fire on one or more sides and subjected to different types and levels of load were performed. The results highlight the good performance of timber structural elements in fire conditions. The collected data were used to validate two- and three-dimensional models implemented in the general purpose finite element code Abaqus. Thermal and mechanical analyses were carried out to estimate the temperature distribution within unprotected and protected cross-sections of different sizes, the fire resistance and the displacement of timber elements loaded in-plane and out-of-plane. Further, parametric studies assuming different timber properties-temperature relationships were also performed. The proposed numerical modelling can be used to investigate the fire behaviour of timber members made of other wood-based products and subjected to different loads and fire conditions. Experimental and numerical results were compared with analytical predictions obtained by using simplified design methods proposed by current codes of practice and recent research proposals. Numerical and analytical methods provide overall acceptable estimations of fire behaviour of timber members, especially considering the high variability that characterizes the wood material and the experimental tests, in particular the fire tests
Rappresentazione tridimensionale e musealizzazione digitale delle preesistenze archeologiche indagate mediante metodi geofisici
Get PDFThe work analyses the possibilities to use the non-destructives geophysical methods for the reconstruction and the digital visualization of archaeological structures. In addiction to the introduction, conclusions and the theory of the two methods used, which are the GPR and the electrical method, the most important part focuses on the meaning of the musealization of data. The core of the work are the movies on a CD attached to the thesis, that shows a simulation of the navigation of the three sites investigated. The application of geophysical method in archaeological survey has a distinctive features: measures are taken along lines close together and with a instrumentation that allows the digital acquisition in a very dense data. It comes a great number of data which allow the “digital” knowledge of the subsoil. The
organization of all digital data by particular format and the use of appropriate plug-in allow to explore the digital subsoil. This work submits the application of a GPR survey conducted in Pollentia (Maiorca, Spain) and at the Bastione of Santa Caterina in Cagliari (Sardinia - Italy), there is also the virtual representation of the electrical survey carried on the sea (Mothia Island, Sicily, Italy)
Development of alternative methods for toxicological risk assessment based on human Mesenchymal Stem Cells in the framework of REACH
Get PDFPoisoning due to chemicals is generally recognized as a severe health problem. According to the Institute of Medicine (IOM), indeed, more than four million poisoning episodes occur annually in the United States. In order to ensure an adequate protection of human health and the environment, it is essential to evaluate if such products might cause adverse effects under normal and reasonably
foreseeable use, and also to guarantee that reliable quality and adequate information on the adverse effects of exposure to such chemicals is provided. Toxicological testing is therefore an important part of the regulatory safety assessment for chemicals worldwide. Test methods rely largely on animal models, however, the validity of the data obtained in these in vivo tests has been often questioned. Recently many in vitro methods for toxicity testing have been developed as alternatives to whole animal tests, according to the 3Rs approach proposed by Russell and Burch. This research falls within the framework of the risk assessment of chemicals, and specifically in the
framework of the REACH Regulation, giving specific relevance to the 3Rs concept. The activity performed during the PhD, indeed, concerns the development of novel in vitro models in order to test the potential toxicity of drugs and chemicals, following two different lines of research, both of them based for the first time on the use of human Mesenchymal Stem Cells (MSCs) isolated from bone marrow. From our best knowledge indeed, both animal and human MSCs have never been adopted for developing in vitro model systems for acute toxicity tests, but their unique proprieties, such as unlimited proliferation ability, plasticity to generate others cell types and even being a more readily available sources of human cells, clearly identify their potential benefits in toxicology. The
first line of research focused on the application of the Neutral Red Uptake (NRU) assay to detect chemical toxicity on human MSCs. Specifically, the aim of this study was to evaluate the applicability of human MSCs as cell line for in vitro cytotoxicity tests to correctly predict LD50 and
the hazard category of chemicals according to the Globally Harmonized System (GHS). By comparing the behavior of human MSCs with the already validated 3T3 and NHK NRU test
methods, the results clearly show that the tested cells can be confidently used to perform in vitro acute toxicity tests. The second line of research, on the contrary, was mainly focused on the research of new in vitro methods in order to test the vascular toxicity of chemicals. It is based on the application of emerging tissue engineering concepts on the field of toxicology. For the moment,
only preliminary studies were conducted, which regarded the application of decellularization techniques to animal blood vessels in order to obtain biological scaffolds. These scaffolds could be subsequently used for recellularization processes using human MSCs, and setting up of perfused in
vitro human toxicity tests
Dust signatures observed in atmospheric aerosols and related to radiative transfer algorithms
Get PDFThe Natural Sources of pollutants, such as Sahara desert dust outbreaks or ashes from vulcanoes, in many cases, could grow the bad air quality forecast and PM limits values measured could exeed the European Law recomendations, in that case the country have to pay to the Community if an evidence of that is a Natural Pollutant is not brought to the European Court. The goal to control air quality could be reached studying the pollution sources, the dispersion with atmospheric model, the chemical reactions occurring and also the study of air depositions.
Exeedences of air quality limit value represent breaches of Community law which can have significant legal consequences for the European Member States. For some existing limit values, such as those in the directive 1999/30/EC (first daughter Directive), an exeedence which is caused by particular natural sources can be ignored for the purpose of ensuring compliance with Community law; article 2.15 of the first daughter directive defines “natural events” as volcanic eruptions, seismic activities, geothermal activities, wild-land fires, high wind events or the
atmospheric resuspension or transport of natural particles from dry regions. The next air quality directive will likely extend this principle to natural (i.e. Non anthropogenic) sources of pollution generally so long as the “natural contribution” can be quantified and documented.
Particle Matters (PM) emissions sources are sea-spray, soil moved by wind, biogenic aerosols, volcanic emissions, forest fires, and anthropogenic sources. The EU legislation give limits for mobile emission, there are many like the Euro X limitation for private cars (gasoline and diesel).
To control the road transport emissions there is a common trend of modification of the engines technology, the reduction of traffic in big city centre, the use of Pb and S free fuel, the promotion of the use of renewable energy and the use of alternative fuel. A cure strategy is post combustion treatment. The aim of this PhD work is to present a new way to approach radiative tranfer on air when dust episodes occurs, and to start a study/work group able to inform, with quality and quantity data, on
natural sources of air pollution, capable to discuss with other governative and regional organizations such as ARPAS (with monitoring in site stations or mobile devices), and POLARIS 's entrerprises, which main topic is dealing with Environmental Science and Air quality. It is globally achieved that dust is part of natural aerosols quantity in air, with dimension from 1 to 10 microns, and could affect both human health, for breath disease, and local climate system, or global as well. Dust could reach Mediterranean and South European countries because of the local meteorology, the source points are often in the Sahara desert. Using Satellites Spectroradiometry we could detect and visualise dust over land and oceans. We used three Modis combination bands into the multispectral data analysis toolkit HYDRA (HYperspectral data viewer for Development if Research Application): a simple algorithm is showed with the help of HYDRA software, that help scientists to see dust easly without any other processed data. A case study is showed over the South West Mediterranean Area, near Tunisia and Lybia, but could be used for any other case and area of the world
Intracluster magnetic fields
Get PDFMagnetic fields are ubiquitous in the Universe. They have been detected in planets, stars, galaxies, groups and clusters of galaxies, and recently also along filaments, in the large scale structure of the Universe. The aim of this PhD thesis is to study magnetic fields in clusters of galaxies in different evolutionary stages. The presence of magnetic fields in the intracluster medium is clearly indicated by the discovery of diffuse synchrotron emission in the central region and in the outskirts of a larger and larger number of galaxy clusters. These sources, called radio halos and relics, are generated by high energy relativistic electrons moving along the flux lines of weak magnetic fields. These magnetic fields are deeply linked to
the dynamical state and the energy transport in the system, and the study of their power spectrum gives information about the energy, the capacity to diffuse, and the ordered motion in the plasma of the relativistic particles. The origin of intracluster magnetic fields is still debated. The most reliable theories suppose a cosmological or a galactic (at z 2-3) origin. In both cases, to match the strengths presently observed, an amplification of the field is required, probably due to cluster formation processes. From the present day observations, intracluster magnetic fields appear to fluctuate over a range of scales and their strength seems to decrease with the distance from the cluster center as a function of the thermal gas density. Merging clusters show low magnetic field central strengths (∼1 μG), while relaxed systems are characterized by higher values (up to some 10 μG). In the radio band, the investigation of the intracluster magnetic field power spectrum can be performed by means of two techniques. Large scale (∼ Mpc) studies can be carried out through the analysis of the emission of large-scale diffuse synchrotron sources. Higher resolution investigations (∼ kpc) are allowed by the analysis of the Faraday rotation of the signal coming from galaxies within or behind galaxy clusters. The coexistence in a galaxy cluster of small and large scales of fluctuation of the magnetic field requires a
combination of the two approaches. In fact, in this way, it is possible to follow with continuity the power spectrum of the magnetic field fluctuations from Mpc scales down to kpc scales. Up to now, a detailed study of the magnetic field power spectrum has been performed just in few galaxy clusters. In this work we present the results we obtained by applying these different approaches and their contri-
bution to the present day knowledge of intracluster magnetic fields. To perform this kind of studies, we analyzed Very Large Array (VLA, New Mexico, USA) multi-
frequency polarimetric data of diffuse radio halos and of discrete sources within or behind galaxy clusters. To constrain the magnetic field fluctuation power spectrum, we compared the observations with the expectations of two- and three-dimensional simulations obtained with the FARADAY software package. The structure of this manuscript is the following. Three main sections can be identified:
in Chapter 1 we introduce clusters of galaxies, with particular care to radio emission originating from
galaxies and diffuse synchrotron sources (radio halos, relics and mini-halos);
in Chapters 2 and 3 we present the contribution of this thesis to the still scanty radio halo statistics
and to the study of radio halo properties. We describe the discovery of six new radio halos and the investigation of the X-ray -radio correlation in systems hosting radio halos both on an individual and on a statistical point of view;
in Chapter 4 we give an overview about intracluster magnetic fields and the main techniques applied for their investigation and we present statistical studies based on the Faraday rotation effect on the polarimetric properties of radio galaxies. The modeling we adopt and its application to the detailed investigation of the magnetic field in two galaxy clusters are described in Chapters 5, 6, and 7. Finally in Chapter 8 we summarize our conclusions.
Throughout this thesis we adopt a ΛCDM cosmology with H0 = 71 km s−1 Mpc−1 , Ωm = 0.27, and ΩΛ = 0.73
Cardiovascular implications of endodontic bone disease
Get PDFCardiovascular diseases (CVD) have a complex etiology determined by risk factors, which are in turn associated to a strong genetic component and to environmental factors. In the biological background for the development of CVD, low-grade chronic inflammation plays a role as a pathogenetic determinant of atherosclerosis. Dental infections have been associated with CVD. Periodontal disease is a chronic infection of the supporting tissues of the tooth that can lead to teeth loss. In recent years, a number of reports have demonstrated the possible relationship between periodontal disease and CVD. Apical periodontitis, on the other hand, is the late consequence of an endodontic infection, which is caused by the persistence of coronal caries and involves the root canal system of the tooth. Most of the time, it is a chronic infection. Some studies have found a correlation between a “composite status” of oral health (eg. caries, tooth loss, periodontal disease) and CVD, but only a few of them have addressed the association between apical periodontitis and CVD. The first part of our study consisted in a “state of the art” analysis concerning the relationship between chronic dental infections and CVD. The results of this analysis confirmed that to date, only a few studies, yielding inconclusive findings, have investigated the potential correlation between apical periodontitis (AP) and CVD. So, in the second part of our study (as the first part of a prospective study) the aim was to evaluate, in the absence of CV risk factors, whether subjects with AP were more exposed to the pathogenetic indices of an atherosclerotic lesion. Methods: Forty men between the ages of 20 and 40 years who were free from periodontal disease, CVD, and traditional CV risk factors were enrolled in the study; 20 subjects had AP, and 20 acted as controls. All subjects underwent dental examination and complete cardiac assessment: physical examination, electrocardiogram, conventional and tissue Doppler echocardiography, and measurement of endothelial flow reserve (EFR). The following laboratory parameters were tested: interleukins -1, -2, and -6 (IL-1, IL-2, IL-6), tumor necrosis factor alpha, and asymmetrical dimethylarginine (ADMA). Data were analyzed by using the 2-tailed Student’s t test, Pearson t test (or Spearman t test for nonparametric variables), and multivariate linear regression analysis. Results: Echocardiography revealed no abnormalities in any of the subjects studied. ADMA levels were inversely correlated with EFR (P < .05) and directly correlated with IL-2 (P < .001). Patients with AP presented with significantly
greater blood concentrations of IL-1 (P < .05), IL-2 (P < .01), IL-6 (P < .05), and ADMA (P < .05) and a significant reduction of EFR (P < .05). Conclusions: Increased ADMA levels and their relationship with poor EFR and increased IL-2 might suggest the existence of an early endothelial dysfunction in young adults with AP
La duplice valenza delle aree di ripopolamento attivo di Palinurus Elephas: utili siti di sperimentazione e potenti strumenti gestionali
Get PDFRecent recognition of increased anthropogenic demands and influence on marine resources and ecosystem has led to a strong push for “active” marine conservation (Hockey e Branch, 1997; Lubchenco, 1997). The value of marine protected areas, particularly no‐take marine reserves, and the fundamental importance of understanding marine environments is now jointly recognized by politicians, conservation and management scientists and commercial fishermen. In this context are framed he remarkable results achieved by the establishment of restocking areas (no‐take areas), established in the seas surrounding Sardinia and aimed at improving the state of a resource of high commercial value such as the spiny lobster Palinurus elephas. Despite the fact that Sardinia, along the eastern part of Sicily, has always been one of the Italian regions with the highest productivity of lobster (data IREPA, 2007), in recent years the international community had become increasingly aware that the current management regulations were not longer sufficient to ensure a rational exploitation of the resource. The worrying picture of the state of the resource has therefore made necessary the search for innovative management policies, through the adoption of new management measures, that would lead to the increase of the stock. In this perspective the Ministry of Agriculture before and after the Autonomous Region of Sardinia, in collaboration with the University of Cagliari, have implemented several measures to protect the resource, including in 1998 the establishment of an area of restocking in the central‐western Sardinia. The restocking action of the reserve Pallosu, that now has lasted 14 years (1998‐2011), led to an increase in biomass of the species by 550% compared to 1997, the year before the establishment of the protection. Important results are also the effects recorded in the commercial areas of fishing surrounding the no‐take area in which, as a result of a continuous spillover of specimens (Follesa et al., 2007a,2011), an increase in productivity of the lobster up to a distance of about 6 km from the center of restocking has been highlighted, with the record of signs of this effect up to an area of about 20 km away. The validity of the research undertaken through the activation of restocking areas is
actually witnessed not only by management results but also by the possibility of enhancing of knowledge of the lobster biology, that it proved to be useful in the management of the resource itself. For example, collecting a large amount of data during the breeding season has revealed that the size of the maximum reproductive potential, for Sardinian lobsters, is reached at 75‐85 mm LCS, well below the minimum capture imposed since 2006 by the same European Economic Community (LCS = 90 mm). This appeared a remarkably important result which confirmed the validity of the rules of governance currently imposed in the management of the lobster fishing. The minimum legal size (MTL), in our case, being well in excess of 15 mm compared to the size of the maximum reproductive potential (75 mm LCS), would enable females to have the opportunity to reproduce more than once before reaching the legal size. Protection of the youngest not only through an imposition of a minimum size of capture (MTL) but also of large specimens through the establishment of additional areas of protection and/ or re‐stocking and the introduction of controls on landing would be desirable for a more and better management of the resource. A careful enforcement of the management together with the support of the action exerted by the major areas of
active recovery could undoubtedly improve the management of this important species of great commercial importance in the Mediterranean Sea. It is still to be emphasized that these results are important both from a management
and scientific perspective, they would not have been achieved without the full cooperation of fishermen which believed in this experimentation. We hope that initiatives like the ones of the Autonomous Region of Sardinia that, in
consequence of the positive results achieved in Su Pallosu, has activated in 2009 other 14 restocking areas, can be multiplied in many other Mediterranean areas. Given the
positive result, it is thought that such experiments, together with the management rules currently in force, can contribute to better regulation of the resource in the entire basin
Cell senescence and aging in carcinogenesis and liver repopulation
Get PDFThe studies presented in my thesis delve into the complex relationship between cancer and aging using analytical approaches shared with the field of regenerative medicine. We took advantage of a model of orthotopic cell transplantation to explore the basic question as to whether the contribution of aging to the risk of cancer is, at least in part, related to alterations in the tissue microenvironment. Previous investigations conducted by our research group had revealed that isolated normal hepatocytes form larger clones of daughter cells when transplanted into the liver of old animals as compared to those formed in young recipients. In a relatively simple experiment we then utilized a similar approach to transplant
preneoplastic cells isolated from hepatic nodules into either young or old animals of a syngeneic strain. Results were striking: very limited expansion of transplanted nodular hepatocytes was observed in the liver of young animals, while the same cell preparations grew significantly upon injection into older hosts, with a few cases of progression to hepatocellular carcinoma (HCC).
The relevance of these findings is twofold. Firstly, they clearly indicate that preneoplastic cell populations isolated from hepatic nodules are not endowed with any measurable degree of growth autonomy, in that they were unable to form nodules when transferred into the liver of young hosts. Thus, their focal growth is dependent on stimuli originating from the local microenvironment. In this respect they behave like normal hepatocytes. Secondly, it is evident from these results that the microenvironment
of the aged liver is able to foster the growth transplanted syngeneic nodular hepatocytes, again reproducing analogous findings already obtained with normal cells. Having established this fundamental fact, it became important to explore possible biological and underlying molecular mechanisms explaining the growth-promoting nature of the aged liver microenvironment. To this end, intriguing insights came again from the field of regenerative medicine.
Our research group is involved in the characterization of an experimental model of massive liver repopulation through hepatocyte transplantation. This approach was set up in our laboratory and is based on the administration of retrorsine (RS), a naturally occurring alkaloid, as a preconditioning treatment. Rat liver exposed to RS and then transplanted with isolated normal hepatocytes is entirely replaced by
donor-derived cells within a few months. Importantly, transplanted nodular hepatocytes can also selectively expand in the RS-treated liver, rapidly evolving to HCC. Again, neither normal, nor nodular hepatocytes are able to proliferate when injected into the liver of untreated recipients, as already noted above. This pattern of findings is similar to that observed in the aged liver, although the magnitude of the observed phenomena is far greater following exposure to RS. Moreover, it is apparent from the foregoing discussion that the growth of normal and nodular hepatocytes is controlled by fundamentally similar
biological mechanisms, such that carcinogenesis and liver repopulation represent in fact “two sides of the same coin”, as it has been proposed. Given the similarities of biological responses between the RS-treated and the aged liver, we then probed into possible cellular and molecular analogies shared by the two systems. Much to our surprise, it was found that exposure to RS is a powerful inducer of cell senescence in hepatocytes in vivo. As reported in
the preceding section of this report, several markers of cell senescence were expressed by RS-exposed hepatocytes, including senescence-associated β-galactosidase (SA-β-gal), cell hypertrophy, a persistent block in the cell cycle coupled with activation of cell growth pathways. The picture emerging from these findings is that RS treatment, which sets the stage for the selective growth of both normal and nodular transplanted hepatocytes, leading to massive liver repopulation and emergence of HCC, respectively, is also associated with the induction of a senescent phenotype in resident hepatocytes. Such a senescence phenotype is commonly found in aged tissues including the liver, as also shown in our studies. This phenotype is likely to explain, at least in part, the similarities observed between the microenvironments of the aged liver and that of RS-exposed liver. The last section of this thesis describes studies aimed at reversing the RS-induced alterations in the liver microenvironment and, in doing so, at verifying whether this would modulate the growth of preneoplastic lesions promoted by RS. Animals given the genotoxic agent diethylnitrosamine (DENA) followed by RS developed large hepatocyte nodules within a few months. However, the growth of preneoplastic nodules
was significantly delayed in animals receiving hepatocyte transplantation following the DENA+RS regimen. These results represent a proof of principle that an altered microenvironment is indeed a powerful driving force in neoplastic progression; most importantly, they clearly indicate that strategies aimed at “normalizing” such an altered microenvironment might impact on the rate of progression of the neoplastic process
Hizbullāh: da movimento di resistenza a partito di resistenza
Get PDFHizbullāh, the shiite muslim Party of God, was born in Lebanon in the early 1980s in response to the 1982 israeli invasion of Lebanon. The members of the Party of God were trained and organized by 1500 Iranian Revolution Guards, commonly known as the Pasdaran, to wage an guerrilla war
against Israeli Forces. Hizbullāh’s founding principles were its militant resistance to foreign occupation and the
establishment of an Islamic system in Lebanon based upon the ideology derived by ayatollāh Khomeinī in the Iranian Revolution: the wilāyat al-faqīh or “rule of the jurist”.
From 1982 until the present, Hezbollāh’s most visible activity has been its resistance against the Israeli occupation of southern Lebanon, but in the 1990s (within the structure of the Ta’if Agreement) the Party of God has transformed itself from a radical and clandestine militia to a legitimate political party whit a resistance wing, playing an active part in the Lebanese political system. The Party of God has also a highly organized system of health, educational and social organizations that provide services to the impoverished people of Lebanon. The following pages will discuss a review of the Party of God, its political, social and ideological evolution