8 resultados para Pediatric setting

em AMS Tesi di Dottorato - Alm@DL - Università di Bologna


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The present work tries to display a comprehensive and comparative study of the different legal and regulatory problems involved in international securitization transactions. First, an introduction to securitization is provided, with the basic elements of the transaction, followed by the different varieties of it, including dynamic securitization and synthetic securitization structures. Together with this introduction to the intricacies of the structure, a insight into the influence of securitization in the financial and economic crisis of 2007-2009 is provided too; as well as an overview of the process of regulatory competition and cooperation that constitutes the framework for the international aspects of securitization. The next Chapter focuses on the aspects that constitute the foundations of structured finance: the inception of the vehicle, and the transfer of risks associated to the securitized assets, with particular emphasis on the validity of those elements, and how a securitization transaction could be threatened at its root. In this sense, special importance is given to the validity of the trust as an instrument of finance, to the assignment of future receivables or receivables in block, and to the importance of formalities for the validity of corporations, trusts, assignments, etc., and the interaction of such formalities contained in general corporate, trust and assignment law with those contemplated under specific securitization regulations. Then, the next Chapter (III) focuses on creditor protection aspects. As such, we provide some insights on the debate on the capital structure of the firm, and its inadequacy to assess the financial soundness problems inherent to securitization. Then, we proceed to analyze the importance of rules on creditor protection in the context of securitization. The corollary is in the rules in case of insolvency. In this sense, we divide the cases where a party involved in the transaction goes bankrupt, from those where the transaction itself collapses. Finally, we focus on the scenario where a substance over form analysis may compromise some of the elements of the structure (notably the limited liability of the sponsor, and/or the transfer of assets) by means of veil piercing, substantive consolidation, or recharacterization theories. Once these elements have been covered, the next Chapters focus on the regulatory aspects involved in the transaction. Chapter IV is more referred to “market” regulations, i.e. those concerned with information disclosure and other rules (appointment of the indenture trustee, and elaboration of a rating by a rating agency) concerning the offering of asset-backed securities to the public. Chapter V, on the other hand, focuses on “prudential” regulation of the entity entrusted with securitizing assets (the so-called Special Purpose vehicle), and other entities involved in the process. Regarding the SPV, a reference is made to licensing requirements, restriction of activities and governance structures to prevent abuses. Regarding the sponsor of the transaction, a focus is made on provisions on sound originating practices, and the servicing function. Finally, we study accounting and banking regulations, including the Basel I and Basel II Frameworks, which determine the consolidation of the SPV, and the de-recognition of the securitized asset from the originating company’s balance-sheet, as well as the posterior treatment of those assets, in particular by banks. Chapters VI-IX are concerned with liability matters. Chapter VI is an introduction to the different sources of liability. Chapter VII focuses on the liability by the SPV and its management for the information supplied to investors, the management of the asset pool, and the breach of loyalty (or fiduciary) duties. Chapter VIII rather refers to the liability of the originator as a result of such information and statements, but also as a result of inadequate and reckless originating or servicing practices. Chapter IX finally focuses on third parties entrusted with the soundness of the transaction towards the market, the so-called gatekeepers. In this respect, we make special emphasis on the liability of indenture trustees, underwriters and rating agencies. Chapters X and XI focus on the international aspects of securitization. Chapter X contains a conflicts of laws analysis of the different aspects of structured finance. In this respect, a study is made of the laws applicable to the vehicle, to the transfer of risks (either by assignment or by means of derivatives contracts), to liability issues; and a study is also made of the competent jurisdiction (and applicable law) in bankruptcy cases; as well as in cases where a substance-over-form is performed. Then, special attention is also devoted to the role of financial and securities regulations; as well as to their territorial limits, and extraterritoriality problems involved. Chapter XI supplements the prior Chapter, for it analyzes the limits to the States’ exercise of regulatory power by the personal and “market” freedoms included in the US Constitution or the EU Treaties. A reference is also made to the (still insufficient) rules from the WTO Framework, and their significance to the States’ recognition and regulation of securitization transactions.

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Hydrothermal fluids are a fundamental resource for understanding and monitoring volcanic and non-volcanic systems. This thesis is focused on the study of hydrothermal system through numerical modeling with the geothermal simulator TOUGH2. Several simulations are presented, and geophysical and geochemical observables, arising from fluids circulation, are analyzed in detail throughout the thesis. In a volcanic setting, fluids feeding fumaroles and hot spring may play a key role in the hazard evaluation. The evolution of the fluids circulation is caused by a strong interaction between magmatic and hydrothermal systems. A simultaneous analysis of different geophysical and geochemical observables is a sound approach for interpreting monitored data and to infer a consistent conceptual model. Analyzed observables are ground displacement, gravity changes, electrical conductivity, amount, composition and temperature of the emitted gases at surface, and extent of degassing area. Results highlight the different temporal response of the considered observables, as well as the different radial pattern of variation. However, magnitude, temporal response and radial pattern of these signals depend not only on the evolution of fluid circulation, but a main role is played by the considered rock properties. Numerical simulations highlight differences that arise from the assumption of different permeabilities, for both homogeneous and heterogeneous systems. Rock properties affect hydrothermal fluid circulation, controlling both the range of variation and the temporal evolution of the observable signals. Low temperature fumaroles and low discharge rate may be affected by atmospheric conditions. Detailed parametric simulations were performed, aimed to understand the effects of system properties, such as permeability and gas reservoir overpressure, on diffuse degassing when air temperature and barometric pressure changes are applied to the ground surface. Hydrothermal circulation, however, is not only a characteristic of volcanic system. Hot fluids may be involved in several mankind problems, such as studies on geothermal engineering, nuclear waste propagation in porous medium, and Geological Carbon Sequestration (GCS). The current concept for large-scale GCS is the direct injection of supercritical carbon dioxide into deep geological formations which typically contain brine. Upward displacement of such brine from deep reservoirs driven by pressure increases resulting from carbon dioxide injection may occur through abandoned wells, permeable faults or permeable channels. Brine intrusion into aquifers may degrade groundwater resources. Numerical results show that pressure rise drives dense water up to the conduits, and does not necessarily result in continuous flow. Rather, overpressure leads to new hydrostatic equilibrium if fluids are initially density stratified. If warm and salty fluid does not cool passing through the conduit, an oscillatory solution is then possible. Parameter studies delineate steady-state (static) and oscillatory solutions.

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In this research work I analyzed the instrumental seismicity of Southern Italy in the area including the Lucanian Apennines and Bradano foredeep, making use of the most recent seismological database available so far. I examined the seismicity occurred during the period between 2001 and 2006, considering 514 events with magnitudes M ≥ 2.0. In the first part of the work, P- and S-wave arrival times, recorded by the Italian National Seismic Network (RSNC) operated by the Istituto Nazionale di Geofisica e Vulcanologia (INGV), were re-picked along with those of the SAPTEX temporary array (2001–2004). For some events located in the Upper Val d'Agri, I also used data from the Eni-Agip oil company seismic network. I computed the VP/VS ratio obtaining a value of 1.83 and I carried out an analysis for the one-dimensional (1D) velocity model that approximates the seismic structure of the study area. After this preliminary analysis, making use of the records obtained in the SeSCAL experiment, I incremented the database by handpicking new arrival times. My final dataset consists of 15,666 P- and 9228 S-arrival times associated to 1047 earthquakes with magnitude ML ≥ 1.5. I computed 162 fault-plane solutions and composite focal mechanisms for closely located events. I investigated stress field orientation inverting focal mechanism belonging to the Lucanian Apennine and the Pollino Range, both areas characterized by more concentrated background seismicity. Moreover, I applied the double difference technique (DD) to improve the earthquake locations. Considering these results and different datasets available in the literature, I carried out a detailed analysis of single sub-areas and of a swarm (November 2008) recorded by SeSCAL array. The relocated seismicity appears more concentrated within the upper crust and it is mostly clustered along the Lucanian Apennine chain. In particular, two well-defined clusters were located in the Potentino and in the Abriola-Pietrapertosa sector (central Lucanian region). Their hypocentral depths are slightly deeper than those observed beneath the chain. I suggest that these two seismic features are representative of the transition from the inner portion of the chain with NE-SW extension to the external margin characterized by dextral strike-slip kinematics. In the easternmost part of the study area, below the Bradano foredeep and the Apulia foreland, the seismicity is generally deeper and more scattered and is associated to the Murge uplift and to the small structures present in the area. I also observed a small structure NE-SW oriented in the Abriola-Pietrapertosa area (activated with a swarm in November 2008) that could be considered to act as a barrier to the propagation of a potential rupture of an active NW-SE striking faults system. Focal mechanisms computed in this study are in large part normal and strike-slip solutions and their tensional axes (T-axes) have a generalized NE-SW orientation. Thanks to denser coverage of seismic stations and the detailed analysis, this study is a further contribution to the comprehension of the seismogenesis and state of stress of the Southern Apennines region, giving important contributions to seismotectonic zoning and seismic hazard assessment.

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We aimed to evaluate the role of anti-TNF-alpha therapy with infliximab and adalimumab in a cohort of pediatric patients followed by our Center from 2002 to 2012. The cohort of patients examined consisted of 40 patients: 34 with Crohn disease (85%), 5 with ulcerative colitis (12.5%), one with chronic pouchitis after IPAA for ulcerative colitis (2.5%). All patients were treated with the anti-TNF-α biologic agents infliximab and adalimumab. Thirty-six received infliximab therapy: 19/36 received only infliximab, 17/36 received infliximab and then adalimumab due to loss of response to infliximab and steroid dependency; 4 patients received only adalimumab (infliximab-naïve). Anti-TNF treatment was started before 18 years of age in 34 patients: 29 received infliximab and 5 started adalimumab during childhood. Medical charts were reviewed and safety and efficacy of anti-TNF-alpha have been determined in this population.

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Lo studio si pone l'obiettivo di approfondire il tema della valutazione affettiva del setting odontoiatrico in età evolutiva indagando se possa essere modulata da fattori quali: differenze di genere, specifici quadri patologici (Displasia Ectodermica e Patologie Sistemiche Croniche) responsabili di pregresse esperienze odontoiatriche e/o ospedalizzazioni; stato affettivo del bambino, stato affettivo del genitore. Materiali e metodi Studio 1. 85 soggetti [39 (19 maschi e 20 femmine) affetti da PSC e 46 (26 maschi e 20 femmine) soggetti sani] (range di età: 5-14 anni). Sono stati somministrati: un compito di valutazione immagini con 36 immagini (12 a contenuto piacevole, 12 neutro e 12 spiacevole) dallo IAPS e 12 immagini a contenuto odontoiatrico e dei questionari (MCDASf, CFSS-DS, TAD). Studio 2. 45 soggetti (19 maschi affetti da EDs e 26 maschi sani) (range di età: 5-14 anni). Sono stati somministrati: il compito di valutazione immagini precedentemente descritto e i questionari (MCDASf, CFSS-DS, TAD). Studio 3. 104 bambini (64 maschi and 40 femmine) (range di età: 5-14 anni) e uno dei genitori (19 padri and 69 madri). Sono stati somministrati i questionari MCDASf, CFSS-DS, TAD ai bambini e FDPQ, STAI-Y1, Y2-BDI-II ai genitori. Risultati: il contesto odontoiatrico ha una caratterizzazione affettiva distinta rispetto a contesti piacevoli, spiacevoli o neutri; specifici quadri patologici (EDs e PSC) non sembrano modulare il tipo di valutazione affettiva del contesto odontoiatrico; le femmine, attribuiscono al contesto odontoiatrico una valenza significativamente più spiacevole e una maggiore attivazione emotiva rispetto ai maschi; la paura del dolore odontoiatrico del genitore ha una correlazione con l’ansia dei bambini. Conclusione: è importante che l’odontoiatra consideri che la risposta emotiva delle bambine può essere caratterizzata da vissuti di paura con tendenza a comportamenti di allontanamento e valuti se la figura genitoriale rappresenta una risorsa o un elemento disturbante nella corso della seduta stessa.

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Bone metastases are responsible for different clinical complications defined as skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, hypercalcaemia, bone marrow infiltration and severe bone pain requiring palliative radiotherapy. The general aim of these three years research period was to improve the management of patients with bone metastases through two different approaches of translational research. Firstly in vitro preclinical tests were conducted on breast cancer cells and on indirect co-colture of cancer cells and osteoclasts to evaluate bone targeted therapy singly and in combination with conventional chemotherapy. The study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Furthermore the combination Zoledronic Acid + Cisplatin induced a high antitumoral activity in the two triple-negative lines MDA-MB-231 and BRC-230. The p21, pMAPK and m-TOR pathways were regulated by this combined treatment, particularly at lower Cisplatin doses. A co-colture system to test the activity of bone-targeted molecules on monocytes-breast conditioned by breast cancer cells was also developed. Another important criticism of the treatment of breast cancer patients, is the selection of patients who will benefit of bone targeted therapy in the adjuvant setting. A retrospective case-control study on breast cancer patients to find new predictive markers of bone metastases in the primary tumors was performed. Eight markers were evaluated and TFF1 and CXCR4 were found to discriminate between patients with relapse to bone respect to patients with no evidence of disease. In particular TFF1 was the most accurate marker reaching a sensitivity of 63% and a specificity of 79%. This marker could be a useful tool for clinicians to select patients who could benefit for bone targeted therapy in adjuvant setting.

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The gut microbiota (GM) is essential for human health and contributes to several diseases; indeed it can be considered an extension of the self and, together with the genetic makeup, determines the physiology of an organism. In this thesis has been studied the peripheral immune system reconstitution in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (aHSCT) in the early phase; in parallel, have been also explored the gut microbiota variations as one of the of primary factors in governing the fate of the immunological recovery, predisposing or protecting from complications such as the onset of acute graft-versus-host disease (GvHD). Has been demonstrated, to our knowledge for the first time, that aHSCT in pediatric patients is associated to a profound modification of the GM ecosystem with a disruption of its mutualistic asset. aGvHD and non-aGvHD subjects showed differences in the process of GM recovery, in members abundance of the phylum Bacteroidetes, and in propionate fecal concentration; the latter are higher in the pre-HSCT composition of non-GvHD subjects than GvHD ones. Short-chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients and distribute systemically from the gut to blood. For this reason, has been studied their effect in vitro on human DCs, the key regulators of our immune system and the main player of aGvHD onset. Has been observed that propionate and, particularly, butyrate show a strong and direct immunomodulatory activity on DCs reducing inflammatory markers such as chemokines and interleukins. This study, with the needed caution, suggests that the pre-existing GM structure can be protective against aGvHD onset, exerting its protective role through SCFAs. They, indeed, may regulate cell traffic within secondary lymphoid tissues, influence T cell development during antigen recognition, and, thus, directly shape the immune system.

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Pediatric acute myeloid leukemia (AML) is a molecularly heterogeneous disease that arises from genetic alterations in pathways that regulate self-renewal and myeloid differentiation. While the majority of patients carry recurrent chromosomal translocations, almost 20% of childhood AML do not show any recognizable cytogenetic alteration and are defined as cytogenetically normal (CN)-AML. CN-AML patients have always showed a great variability in response to therapy and overall outcome, underlining the presence of unknown genetic changes, not detectable by conventional analyses, but relevant for pathogenesis, and outcome of AML. The development of novel genome-wide techniques such as next-generation sequencing, have tremendously improved our ability to interrogate the cancer genome. Based on this background, the aim of this research study was to investigate the mutational landscape of pediatric CN-AML patients negative for all the currently known somatic mutations reported in AML through whole-transcriptome sequencing (RNA-seq). RNA-seq performed on diagnostic leukemic blasts from 19 pediatric CN-AML cases revealed a considerable incidence of cryptic chromosomal rearrangements, with the identification of 21 putative fusion genes. Several of the fusion genes that were identified in this study are recurrent and might have a prognostic and/or therapeutic relevance. A paradigm of that is the CBFA2T3-GLIS2 fusion, which has been demonstrated to be a common alteration in pediatric CN-AML, predicting poor outcome. Important findings have been also obtained in the identification of novel therapeutic targets. On one side, the identification of NUP98-JARID1A fusion suggests the use of disulfiram; on the other, here we describe alteration-activating tyrosine kinases, providing functional data supporting the use of tyrosine kinase inhibitors to specifically inhibit leukemia cells. This study provides new insights in the knowledge of genetic alterations underlying pediatric AML, defines novel prognostic markers and putative therapeutic targets, and prospectively ensures a correct risk stratification and risk-adapted therapy also for the “all-neg” AML subgroup.