Design and synthesis of multipotent drugs: application to Alzheimer's disease and benign prostatic hyperplasia

The aim of this thesis was to synthesize multipotent drugs for the treatment of Alzheimer’s disease (AD) and for benign prostatic hyperplasia (BPH), two diseases that affect the elderly. AD is a neurodegenerative disorder that is characterized, among other factors, by loss of cholinergic neurons. Selective activation of M1 receptors through an allosteric site could restore the cholinergic hypofunction, improving the cognition in AD patients. We describe here the discovery and SAR of a novel series of quinone derivatives. Among them, 1 was the most interesting, being a high M1 selective positive allosteric modulator. At 100 nM, 1 triplicated the production of cAMP induced by oxotremorine. Moreover, it inhibited AChE and it displayed antioxidant properties. Site-directed mutagenesis experiments indicated that 1 acts at an allosteric site involving residue F77. Thus, 1 is a promising drug because the M1 activation may offer disease-modifying properties that could address and reduce most of AD hallmarks. BPH is an enlargement of the prostate caused by increased cellular growth. Blockade of α1-ARs is the predominant form of medical therapy for the treatment of the symptoms associated with BPH. α1-ARs are classified into three subtypes. The α1A- and α1D-AR subtypes are predominant in the prostate, while α1B-ARs regulate the blood pressure. Herein, we report the synthesis of quinazoline-derivatives obtained replacing the piperazine ring of doxazosin and prazosin with (S)- or (R)-3-aminopiperidine. The presence of a chiral center in the 3-C position of the piperidine ring allowed us to exploit the importance of stereochemistry in the binding at α1-ARs. It turned out that the S configuration at the 3-C position of the piperidine increases the affinity of the compounds at all three α1-AR subtypes, whereas the configuration at the benzodioxole ring of doxazosin derivatives is not critical for the interaction with α1-ARs.

Nanotechnology control of self organized biomolecules and biomaterials for medical research

Nanotechnology entails the manufacturing and manipulation of matter at length scales ranging from single atoms to micron-sized objects. The ability to address properties on the biologically-relevant nanometer scale has made nanotechnology attractive for Nanomedicine. This is perceived as a great opportunity in healthcare especially in diagnostics, therapeutics and more in general to develop personalized medicine. Nanomedicine has the potential to enable early detection and prevention, and to improve diagnosis, mass screening, treatment and follow-up of many diseases. From the biological standpoint, nanomaterials match the typical size of naturally occurring functional units or components of living organisms and, for this reason, enable more effective interaction with biological systems. Nanomaterials have the potential to influence the functionality and cell fate in the regeneration of organs and tissues. To this aim, nanotechnology provides an arsenal of techniques for intervening, fabricate, and modulate the environment where cells live and function. Unconventional micro- and nano-fabrication techniques allow patterning biomolecules and biocompatible materials down to the level of a few nanometer feature size. Patterning is not simply a deterministic placement of a material; in a more extended acception it allows a controlled fabrication of structures and gradients of different nature. Gradients are emerging as one of the key factors guiding cell adhesion, proliferation, migration and even differentiation in the case of stem cells. The main goal of this thesis has been to devise a nanotechnology-based strategy and tools to spatially and temporally control biologically-relevant phenomena in-vitro which are important in some fields of medical research.

Efficient ultrasonic signal processing techniques for aided medical diagnostics

Ultrasound imaging is widely used in medical diagnostics as it is the fastest, least invasive, and least expensive imaging modality. However, ultrasound images are intrinsically difficult to be interpreted. In this scenario, Computer Aided Detection (CAD) systems can be used to support physicians during diagnosis providing them a second opinion. This thesis discusses efficient ultrasound processing techniques for computer aided medical diagnostics, focusing on two major topics: (i) Ultrasound Tissue Characterization (UTC), aimed at characterizing and differentiating between healthy and diseased tissue; (ii) Ultrasound Image Segmentation (UIS), aimed at detecting the boundaries of anatomical structures to automatically measure organ dimensions and compute clinically relevant functional indices. Research on UTC produced a CAD tool for Prostate Cancer detection to improve the biopsy protocol. In particular, this thesis contributes with: (i) the development of a robust classification system; (ii) the exploitation of parallel computing on GPU for real-time performance; (iii) the introduction of both an innovative Semi-Supervised Learning algorithm and a novel supervised/semi-supervised learning scheme for CAD system training that improve system performance reducing data collection effort and avoiding collected data wasting. The tool provides physicians a risk map highlighting suspect tissue areas, allowing them to perform a lesion-directed biopsy. Clinical validation demonstrated the system validity as a diagnostic support tool and its effectiveness at reducing the number of biopsy cores requested for an accurate diagnosis. For UIS the research developed a heart disease diagnostic tool based on Real-Time 3D Echocardiography. Thesis contributions to this application are: (i) the development of an automated GPU based level-set segmentation framework for 3D images; (ii) the application of this framework to the myocardium segmentation. Experimental results showed the high efficiency and flexibility of the proposed framework. Its effectiveness as a tool for quantitative analysis of 3D cardiac morphology and function was demonstrated through clinical validation.

La normativa tecnica sul software medical device: analisi del rischio ed impatto sulle aziende sanitarie

Quadro normativo sui Dispositivi Medici e la sua evoluzione (2007/47,UNI CEI EN ISO 14971). Software DM: processo di certificazione,gestione di reti IT medicali, ruoli e responsabilità (CEI 80001-1). Casi d'uso: Linee guida: MEDDEV e linee guida svedesi più relativi esempi applicabili alle aziende sanitarie.

Development of an X-ray spectrometric system and feasibility tests of Silicon Drift Detector for medical and space applications

The thesis work concerns X-ray spectrometry for both medical and space applications and is divided into two sections. The first section addresses an X-ray spectrometric system designed to study radiological beams and is devoted to the optimization of diagnostic procedures in medicine. A parametric semi-empirical model capable of efficiently reconstructing diagnostic X-ray spectra in 'middle power' computers was developed and tested. In addition, different silicon diode detectors were tested as real-time detectors in order to provide a real-time evaluation of the spectrum during diagnostic procedures. This project contributes to the field by presenting an improved simulation of a realistic X-ray beam emerging from a common X-ray tube with a complete and detailed spectrum that lends itself to further studies of added filtration, thus providing an optimized beam for different diagnostic applications in medicine. The second section describes the preliminary tests that have been carried out on the first version of an Application Specific Integrated Circuit (ASIC), integrated with large area position-sensitive Silicon Drift Detector (SDD) to be used on board future space missions. This technology has been developed for the ESA project: LOFT (Large Observatory for X-ray Timing), a new medium-class space mission that the European Space Agency has been assessing since February of 2011. The LOFT project was proposed as part of the Cosmic Vision Program (2015-2025).

Skin tissue engineering: medical problems and technological solutions.

In questo elaborato si affrontano problematiche cliniche legate ai traumi gravi della cute in cui è necessario intervenire chirurgicamente per ripristinare una situazione normale: si approfondisce lo studio della fisiologia del tessuto, la classificazione dei gradi delle ustioni della pelle, la guarigione delle ferite e la meccanica della cute. Il trapianto di tessuto autologo costituisce la soluzione più efficace e con minori complicazioni. Tuttavia il paziente potrebbe non presentare una superficie di cute disponibile sufficientemente estesa, per cui si ricorre ad altri metodi. In primo luogo, si effettuano degli allotrapianti di tessuto di donatore cadavere prelevati secondo le normative vigenti e conservati attraverso le varie tecniche, il cui sviluppo ha consentito una durata di conservazione maggiore; mentre la glicerolizzazione abbatte al 100% il rischio di trasmissione di patologie e lo sviluppo di microorganismi, la crioconservazione preserva la vitalità del tessuto. La chirurgia utilizzata per queste operazioni si avvale di tecnologie innovative come la Tecnologia a Pressione Negativa. Un'alternativa necessaria per sopperire all'ingente richiesta di tessuto di donatore sono i sostituti cutanei, che presentano un grande potenziale per il futuro. Per eliminare totalmente il rischio di rigetto sarebbe necessario personalizzare il costrutto utilizzando cellule autologhe, ma la ricerca è stata rallentata da minori investimenti da parte dell'industria biomedica, che si è maggiormente focalizzata sulla realizzazione di prodotti utilizzabili da un più ampio raggio di pazienti. Per queste ragioni, l'ingegneria tissutale della cute ha trovato più ampio campo di applicazione nel sistema dei test in vitro. A tale scopo sono stati creati dei protocolli certificati per testare la corrosività, la irritabilità e la vitalità del tessuto cutaneo, quali EpiDerm, EpiSkin e SkinEthic che si avvalgono dell'uso del metodo MMT e della spettrofotometria, che è diventata un supporto fondamentale per le scienze biologiche.

Eye-trauma: Event driven control software for gesture recognition in medical simulation

Il progetto Eye-Trauma si colloca all'interno dello sviluppo di un simulatore chirurgico per traumi alla zona oculare, sviluppato in collaborazione con Simulation Group in Boston, Harvard Medical School e Massachusetts General Hospital. Il simulatore presenta un busto in silicone fornito di moduli intercambiabili della zona oculare, per simulare diversi tipi di trauma. L'utilizzatore è chiamato ad eseguire la procedura medica di saturazione tramite degli strumenti chirurgici su cui sono installati dei sensori di forza e di apertura. I dati collezionati vengono utilizzati all'interno del software per il riconoscimento dei gesti e il controllo real-time della performance. L'algoritmo di gesture recognition, da me sviluppato, si basa sul concetto di macchine a stati; la transizione tra gli stati avviene in base agli eventi rilevati dal simulatore.

Medical Malpractice in Public Healthcare Systems: An Empirical Investigation of Scheduled Damages

In the last decades, medical malpractice has been framed as one of the most critical issues for healthcare providers and health policy, holding a central role on both the policy agenda and public debate. The Law and Economics literature has devoted much attention to medical malpractice and to the investigation of the impact of malpractice reforms. Nonetheless, some reforms have been much less empirically studied as in the case of schedules, and their effects remain highly debated. The present work seeks to contribute to the study of medical malpractice and of schedules of noneconomic damages in a civil law country with a public national health system, using Italy as case study. Besides considering schedules and exploiting a quasi-experimental setting, the novelty of our contribution consists in the inclusion of the performance of the judiciary (measured as courts’ civil backlog) in the empirical analysis. The empirical analysis is twofold. First, it investigates how limiting compensations for pain and suffering through schedules impacts on the malpractice insurance market in terms of presence of private insurers and of premiums applied. Second, it examines whether, and to what extent, healthcare providers react to the implementation of this policy in terms of both levels and composition of the medical treatments offered. Our findings show that the introduction of schedules increases the presence of insurers only in inefficient courts, while it does not produce significant effects on paid premiums. Judicial inefficiency is attractive to insurers for average values of schedules penetration of the market, with an increasing positive impact of inefficiency as the territorial coverage of schedules increases. Moreover, the implementation of schedules tends to reduce the use of defensive practices on the part of clinicians, but the magnitude of this impact is ultimately determined by the actual degree of backlog of the court implementing schedules.

Advanced aspects of radiation protection in the use of particle accelerators in the medical field

In this work, the well-known MC code FLUKA was used to simulate the GE PETrace cyclotron (16.5 MeV) installed at “S. Orsola-Malpighi” University Hospital (Bologna, IT) and routinely used in the production of positron emitting radionuclides. Simulations yielded estimates of various quantities of interest, including: the effective dose distribution around the equipment; the effective number of neutron produced per incident proton and their spectral distribution; the activation of the structure of the cyclotron and the vault walls; the activation of the ambient air, in particular the production of 41Ar, the assessment of the saturation yield of radionuclides used in nuclear medicine. The simulations were validated against experimental measurements in terms of physical and transport parameters to be used at the energy range of interest in the medical field. The validated model was also extensively used in several practical applications uncluding the direct cyclotron production of non-standard radionuclides such as 99mTc, the production of medical radionuclides at TRIUMF (Vancouver, CA) TR13 cyclotron (13 MeV), the complete design of the new PET facility of “Sacro Cuore – Don Calabria” Hospital (Negrar, IT), including the ACSI TR19 (19 MeV) cyclotron, the dose field around the energy selection system (degrader) of a proton therapy cyclotron, the design of plug-doors for a new cyclotron facility, in which a 70 MeV cyclotron will be installed, and the partial decommissioning of a PET facility, including the replacement of a Scanditronix MC17 cyclotron with a new TR19 cyclotron.

The medical management after surgery for advanced heart failure

The aim of the Research of this Ph D Project is to improve the medical management after surgery for advanced heart failure, both after left ventricular assist devices (LVAD) implantation, and after heart transplantation in the long-term. Regarding heart transplantation (HTx), the Research Project is focused on diagnostics, classification, prevention and treatment of cardiac allograft vasculopathy (CAV), and on treatment of post-HTx cancers; the results are presented in the first part of this Thesis. In particular, the main aspect investigated are the prognostic role of information derived from coronary angiography, coronary tomography and intravascular ultrasound, and the different sensitivity of these techniques in predicting outcomes and in diagnosing CAV. Moreover, the role of mTOR inhibitors on CAV prevention or treatment is investigated, both alone and in combination with different anti-CMV prevention strategies, as well as the impact of mTOR inhibitors on clinical outcomes in the long term. Regarding LVAD, the main focus is on the role of transthoracic echocardiography in the management of patients with a continuous-flow, centrifugal, intrapericardial pump (HVAD, Heartware); this section is reported in the second part of this Thesis. The main aspects investigated are the use of echocardiography in patients with HVAD device and its interaction with the information derived from pump curves' analysis in predicting aortic valve opening status, a surrogate of the condition of support provided by the LVAD.

Design and fluid dynamic analysis of a custom drip chamber in a medical disposable device

Negli ultimi anni, parallelamente allo sviluppo di calcolatori elettronici sempre più performanti, la fluidodinamica computazionale è diventata uno strumento di notevole utilità nell’analisi dei flussi e nello sviluppo di dispositivi medici. Quando impiegate nello studio di flussi di fluidi fisiologici, come il sangue, il vantaggio principale delle analisi CFD è che permettono di caratterizzare il comportamento fluidodinamico senza dover eseguire test in-vivo/in-vitro, consentendo quindi notevoli vantaggi in termini di tempo, denaro e rischio derivante da applicazioni mediche. Inoltre, simulazioni CFD offrono una precisa e dettagliata descrizione di ogni parametro di interesse permettendo, già in fase di progettazione, di prevedere quali modifiche al layout garantiranno maggiori vantaggi in termini di funzionalità. Il presente lavoro di tesi si è posto l’obiettivo di valutare, tramite simulazioni CFD, le performances fluidodinamiche del comparto sangue “camera venosa” di un dispositivo medico monouso Bellco impiegato nella realizzazione di trattamenti di emodialisi. Dopo una panoramica del contesto, è presentata una breve descrizione della disfunzione renale e dei trattamenti sostitutivi. Notevole impegno è stato in seguito rivolto allo studio della letteratura scientifica in modo da definire un modello reologico per il fluido non-Newtoniano preso in considerazione e determinarne i parametri caratteristici. Il terzo capitolo presenta lo stato dell’arte delle apparecchiature Bellco, rivolgendosi con particolare attenzione al componente “cassette” del dispositivo monouso. L’analisi fluidodinamica del compartimento “camera venosa” della cassette, che sarà presa in considerazione nei capitoli quinto e sesto, si inserisce nell’ambito della riprogettazione del dispositivo attualmente in commercio: il quarto capitolo si incentra sul suo nuovo design, ponendo specifico interesse sul layout della camera venosa di nuova generazione. Per lo studio dei flussi che si sviluppano internamente ad essa ci si è avvalsi del modulo CFD del software COMSOL multiphysics® (versione 5.0); la definizione del modello implementato e della tipologia di studio effettuato sono presi in considerazione nel quinto capitolo. Le problematiche di maggior impatto nella realizzazione di un trattamento di emodialisi sono l’emolisi e la coagulazione del sangue. Nell'evenienza che si verifichino massivamente occorre infatti interrompere il trattamento con notevoli disagi per il paziente, per questo devono essere evitate. Nel sesto capitolo i risultati ottenuti sono stati esaminati rivolgendo particolare attenzione alla verifica dell’assenza di fenomeni che possano portare alle problematiche suddette.

Online health information seeking in the context of the medical consultation in Switzerland

A growing number of patients search for medical information on the Internet. Understanding how they use the Internet is important, as this might impact their health, patient-practitioner roles, and general health care provision. In this article, we illustrate the motives of online health information seeking in the context of the doctor-patient relationship in Switzerland. We conducted semistructured interviews with patients who searched for health information online before or after a medical consultation. Findings suggest that patients searched for health information online to achieve the goals of preparing for the consultation, complementing it, validating it, and/or challenging its outcome. The initial motivations for online health information seeking are identified in the needs for acknowledgment, reduction of uncertainty, and perspective. Searching health information online was also encouraged by personal and contextual factors, that is, a person's sense of self-responsibility and the opportunity to use the Internet. Based on these results, we argue that online health information seeking is less concerned with what happens during the consultation than with what happens before or after it, in the sociocultural context.

Predictors of chemotherapy patients' intentions to engage in medical error prevention

Patients can make contributions to the safety of chemotherapy administration but little is known about their motivations to participate in safety-enhancing strategies. The theory of planned behavior was applied to analyze attitudes, norms, behavioral control, and chemotherapy patients' intentions to participate in medical error prevention.

Work-related behavior and experience patterns and predictors of mental health in German physicians in medical practice

Background and Objectives: Work-related stress and burnout among physicians are of increasing relevance. The aim of this study was to investigate work-related behavior and experience patterns and predictors of mental health of physicians working in medical practice in Germany. Methods: We surveyed a stratified, random sample of 900 physicians from different specialties. The questionnaire included the standardized instruments Work-related Behavior and Experience Pattern (AVEM) and the Short Form-12 Health Survey (SF-12). Results: Only one third of physicians reported high or very high general satisfaction with their job, but 64% would choose to study medicine again. Only 18% of physicians presented a healthy behavior and experience pattern. Almost 40% presented a pattern of reduced motivation to work, 21% were at risk of overexertion, and 22% at risk for burnout. Willingness to study medicine again, fulfilled job expectations, professional years, marital status, and behavior patterns were significant predictors of mental health and accounted for 35.6% of the variance in mental health scores. Job-related perceptions also had a significant effect on burnout. Conclusions: The strong influence of work-related perceptions suggests a need for realistic expectation management in medical education, as well as support in stress management and coping strategies during medical training.