Evaluation von Effektivität und Sicherheit der niederfrequenten, transkraniellen Ultraschalltherapie beim Schlaganfall

In den westlichen Ländern nimmt die Zahl der Schlaganfall-Patienten stetig zu und zählt mittlerweilernzu einer der häufigsten Todesursachen. Derzeit ist die Rekanalisationstherapie mit demrnFibrinolytikum rt-PA die einzig zugelassene Therapie. Die Rekanalisationsrate ist oftmals inkomplettrnund aufgrund von möglichen Blutungskomplikationen die Therapie nicht bei allen Patientenrnmöglich. Daher ist es wichtig, Alternativtherapieansätze (z.B. Ultraschallthrombolyse) zurnentwickeln. Blutgerinnsel können mit Hilfe von Ultraschall in Schwingung gebracht und sornlysiert oder die Wirkung von rt-PA verstärkt werden. Die vorliegende Arbeit hatte die Evaluationrnvon Bioeffekten von 60 kHz Ultraschall an gesundem und ischämischem Hirngewebe zum Ziel.rnNeben tierexperimentellen Methoden kamen auch molekular-biologische Techniken zur Anwendung.rnDie erste Studie beschäftigte sich mit der Wirkung von 60 kHz (Intensität: 0,2 W/cm2 undrnDuty Cycle 50%) auf ischämisches Hirngewebe (permanent ischämisch und nach Reperfusion).rnLediglich nach Reperfusion und Ultraschallbehandlung war das Läsionsvolumen signifikantrnerhöht, so dass von einer besonderen Vulnerabilität des Hirngewebes nach Reperfusionrnauszugehen ist (Penumbraschädigung). In der neurologischen Beurteilung der Tiere zeigte sichrnbei allen Tieren mit permanenter Okklusion und etwa einem Drittel der Tiere nach Reperfusionrnund Ultraschallbehandlung eine Hörminderung. In der anschließenden Studie wurde diernUltraschallintensität erniedrigt und der Duty Cycle variiert. In einer publizierten in vitro Studiernkonnte die zunehmende Lyserate mit steigendem Duty Cycle nachgewiesen werden. DiernAuswertung ergab eine Abhängigkeit des Läsionsvolumens von der Länge des Duty Cycles. Derrndritte Teil der Arbeit befasst sich mit der Wirkung von Ultraschall auf die Genexpression. Hierzurnwurden gesunde Ratten mit Ultraschall verschiedener Frequenzen (60 kHz, 488 kHz und 3 MHz)rntranskraniell behandelt und 4 h bzw. 24 h nach der Behandlung getötet. Proben von ischämischenrnTieren dienten als positive Kontrollen. Aufgrund von Literaturrecherchen wurden mehrerernKandidatengene ermittelt. Die Messung der Ischämieproben ergab eine weitgehende Übereinstimmungrnmit der Literatur. Die Messungen an den mit 60 kHz behandelten Proben ergabenrnkaum Anzeichen für eine differenzielle Genregulation. Die Frequenz von 488 kHz zeigte diernmeisten Regulationen, gefolgt von der Behandlung mit 3 MHz. Dieses Ergebnis lässt vermuten,rndass es sich bei den detektierten Veränderungen um protektive Mechanismen handelt, da diesernFrequenzen bislang im Tierversuch als nebenwirkungsarm beschrieben wurden. Die Auswertungrnvon 60 kHz-Proben mit Affymetrix Arrays ergab lediglich einige wenige differentiell regulierternGene. Die Array-Experimente konnten nicht durch qPCR-Messungen bestätigt werden.

Milk and dairy products: evaluation of bioactive components by analytical techniques

Milk and dairy products are important source of bioactive compounds useful to satisfy the nutritional and physiological needs of any newborns of mammalian species and useful to guarantee adequate growth and development of infants as well as provide a complete nourishment of adults. Physico-chemical, nutritional and organoleptic properties of the main constituents and the “minor” components have a crucial role in the quality of milk and milk products. Although in the past decades dietary milk fat was often regarded as harmful for the human health, recent researches suggest that milk contains specific fatty acids with nutritional and physiological health benefits. For these reasons, a major attention is given to the quantity and quality of total fat intake. In the recent years, as a result of the new concept of multifunctional agriculture and the changing behaviours about diet, consumer demands in favor of high-quality, security and safety dairy products are increased. Moreover, milk proteins and milk-derived bioactive peptides are recognized to have a high nutritive value, several health-promoting functional activities and excellent technological properties. Accordingly, growing interest in the development of functional dairy products and preparation of infant formulae for babies who cannot be breast-fed, has been give in order to meet the specific consumer’s requests. This manuscript presents the main results obtained during my PhD research aimed to evaluate the main bioactive lipids and proteins in milk and dairy products using innovative analytical techniques. The experimental section of this manuscript is divided in two sections where are reported the main results obtained during my research activities on dairy products and human milks in order to characterize their bioactive compounds for functional food applications.

Evaluation of energy level to be absorbed by tractor ROPS: Actual Tests, Simulation and Computation

A highly dangerous situations for tractor driver is the lateral rollover in operating conditions. Several accidents, involving tractor rollover, have indeed been encountered, requiring the design of a robust Roll-Over Protective Structure (ROPS). The aim of the thesis was to evaluate tractor behaviour in the rollover phase so as to calculate the energy absorbed by the ROPS to ensure driver safety. A Mathematical Model representing the behaviour of a generic tractor during a lateral rollover, with the possibility of modifying the geometry, the inertia of the tractor and the environmental boundary conditions, is proposed. The purpose is to define a method allowing the prediction of the elasto-plastic behaviour of the subsequent impacts occurring in the rollover phase. A tyre impact model capable of analysing the influence of the wheels on the energy to be absorbed by the ROPS has been also developed. Different tractor design parameters affecting the rollover behaviour, such as mass and dimensions, have been considered. This permitted the evaluation of their influence on the amount of energy to be absorbed by the ROPS. The mathematical model was designed and calibrated with respect to the results of actual lateral upset tests carried out on a narrow-track tractor. The dynamic behaviour of the tractor and the energy absorbed by the ROPS, obtained from the actual tests, showed to match the results of the model developed. The proposed approach represents a valuable tool in understanding the dynamics (kinetic energy) and kinematics (position, velocity, angular velocity, etc.) of the tractor in the phases of lateral rollover and the factors mainly affecting the event. The prediction of the amount of energy to be absorbed in some cases of accident is possible with good accuracy. It can then help in designing protective structures or active security devices.

Essays in Industrial Organization and Information Technology

Chapter 1 studies how consumers’ switching costs affect the pricing and profits of firms competing in two-sided markets such as Apple and Google in the smartphone market. When two-sided markets are dynamic – rather than merely static – I show that switching costs lower the first-period price if network externalities are strong, which is in contrast to what has been found in one-sided markets. By contrast, switching costs soften price competition in the initial period if network externalities are weak and consumers are more patient than the platforms. Moreover, an increase in switching costs on one side decreases the first-period price on the other side. Chapter 2 examines firms’ incentives to invest in local and flexible resources when demand is uncertain and correlated. I find that market power of the monopolist providing flexible resources distorts investment incentives, while competition mitigates them. The extent of improvement depends critically on demand correlation and the cost of capacity: under social optimum and monopoly, if the flexible resource is cheap, the relationship between investment and correlation is positive, and if it is costly, the relationship becomes negative; under duopoly, the relationship is positive. The analysis also sheds light on some policy discussions in markets such as cloud computing. Chapter 3 develops a theory of sequential investments in cybersecurity. The regulator can use safety standards and liability rules to increase security. I show that the joint use of an optimal standard and a full liability rule leads to underinvestment ex ante and overinvestment ex post. Instead, switching to a partial liability rule can correct the inefficiencies. This suggests that to improve security, the regulator should encourage not only firms, but also consumers to invest in security.

Safety, Security And safeguards In GEN IV sodium fast reactors

This work presents first a study of the national and international laws in the fields of safety, security and safeguards. The international treaties and the recommendations issued by the IAEA as well as the national regulations in force in France, the United States and Italy are analyzed. As a result of this, a comparison among them is presented. Given the interest of the Japan Atomic Energy Agency for the aspects of criminal penalties and monetary, also the Japanese case is analyzed. The main part of this work was held at the JAEA in the field of proliferation resistance (PR) and physical protection (PP) of a GEN IV sodium fast reactor. For this purpose the design of the system is completed and the PR & PP methodology is applied to obtain data usable by designers for the improvement of the system itself. Due to the presence of sensitive data, not all the details can be disclosed. The reactor site of a hypothetical and commercial sodium-cooled fast neutron nuclear reactor system (SFR) is used as the target NES for the application of the methodology. The methodology is applied to all the PR and PP scenarios: diversion, misuse and breakout; theft and sabotage. The methodology is applied to the SFR to check if this system meets the target of PR and PP as described in the GIF goal; secondly, a comparison between the SFR and a LWR is performed to evaluate if and how it would be possible to improve the PR&PP of the SFR. The comparison is implemented according to the example development target: achieving PR&PP similar or superior to domestic and international ALWR. Three main actions were performed: implement the evaluation methodology; characterize the PR&PP for the nuclear energy system; identify recommendations for system designers through the comparison.

Investigations on asymptotic safety of metric, tetrad and Einstein-Cartan gravity

Among the different approaches for a construction of a fundamental quantum theory of gravity the Asymptotic Safety scenario conjectures that quantum gravity can be defined within the framework of conventional quantum field theory, but only non-perturbatively. In this case its high energy behavior is controlled by a non-Gaussian fixed point of the renormalization group flow, such that its infinite cutoff limit can be taken in a well defined way. A theory of this kind is referred to as non-perturbatively renormalizable. In the last decade a considerable amount of evidence has been collected that in four dimensional metric gravity such a fixed point, suitable for the Asymptotic Safety construction, indeed exists. This thesis extends the Asymptotic Safety program of quantum gravity by three independent studies that differ in the fundamental field variables the investigated quantum theory is based on, but all exhibit a gauge group of equivalent semi-direct product structure. It allows for the first time for a direct comparison of three asymptotically safe theories of gravity constructed from different field variables. The first study investigates metric gravity coupled to SU(N) Yang-Mills theory. In particular the gravitational effects to the running of the gauge coupling are analyzed and its implications for QED and the Standard Model are discussed. The second analysis amounts to the first investigation on an asymptotically safe theory of gravity in a pure tetrad formulation. Its renormalization group flow is compared to the corresponding approximation of the metric theory and the influence of its enlarged gauge group on the UV behavior of the theory is analyzed. The third study explores Asymptotic Safety of gravity in the Einstein-Cartan setting. Here, besides the tetrad, the spin connection is considered a second fundamental field. The larger number of independent field components and the enlarged gauge group render any RG analysis of this system much more difficult than the analog metric analysis. In order to reduce the complexity of this task a novel functional renormalization group equation is proposed, that allows for an evaluation of the flow in a purely algebraic manner. As a first example of its suitability it is applied to a three dimensional truncation of the form of the Holst action, with the Newton constant, the cosmological constant and the Immirzi parameter as its running couplings. A detailed comparison of the resulting renormalization group flow to a previous study of the same system demonstrates the reliability of the new equation and suggests its use for future studies of extended truncations in this framework.

Cascading events triggering industrial accidents: quantitative assessment of NaTech and domino scenarios

The so called cascading events, which lead to high-impact low-frequency scenarios are rising concern worldwide. A chain of events result in a major industrial accident with dreadful (and often unpredicted) consequences. Cascading events can be the result of the realization of an external threat, like a terrorist attack a natural disaster or of “domino effect”. During domino events the escalation of a primary accident is driven by the propagation of the primary event to nearby units, causing an overall increment of the accident severity and an increment of the risk associated to an industrial installation. Also natural disasters, like intense flooding, hurricanes, earthquake and lightning are found capable to enhance the risk of an industrial area, triggering loss of containment of hazardous materials and in major accidents. The scientific community usually refers to those accidents as “NaTechs”: natural events triggering industrial accidents. In this document, a state of the art of available approaches to the modelling, assessment, prevention and management of domino and NaTech events is described. On the other hand, the relevant work carried out during past studies still needs to be consolidated and completed, in order to be applicable in a real industrial framework. New methodologies, developed during my research activity, aimed at the quantitative assessment of domino and NaTech accidents are presented. The tools and methods provided within this very study had the aim to assist the progress toward a consolidated and universal methodology for the assessment and prevention of cascading events, contributing to enhance safety and sustainability of the chemical and process industry.

Nanoparticular iron complex drugs for parenteral administration - physicochemical characterization, biological distribution and pharmacological safety

Iron deficiency is the most common deficiency disease worldwide with many patients who require intravenous iron. Within the last years new kind of parenteral iron complexes as well as generic preparations entered the market. There is a high demand for methods clarifying benefit to risk profiles of old and new iron complexes. It is also necessary to disclose interchangeability between originator and intended copies to avoid severe anaphylactic and anaphylactoid side reaction and assure equivalence of therapeutic effect.rnrnThe investigations presented in this work include physicochemical characterization of nine different parenteral iron containing non-biological complex drugs. rnWe developed an in-vitro assay, which allows the quantification of labile iron in the different complexes and thus it is a useful tool to estimate the pharmaclogical safety regarding iron related adverse drug events. This assay additionally allowed the estimation of complex stability by evaluation of degradation kinetics at the applied conditions.rnrnAn in-ovo study was performed to additionally compare different complexes in respect to body distribution. This in combination with complex stability information allowed the risk estimation of potential local acute and chronic reactions to iron overload.rnrnInformation obtained by the combination of the methods within this work are helpful to estimate the safety and efficacy profile of different iron containing non-biological complex drugs. rnrnPhysicochemical differences between the complexes were demonstrated in respect to size of the inorganic fraction, size and size distribution of the complete particles, structure of the inorganic iron fraction, morphology of the complexes and charge of the complexes. And furthermore significant differences in the biological behavior of different complexes were demonstrated. rnrnThe combination of complex stability and biodistribution as well as the combination of structure, size and stability represent helpful tools for the physicochemical characterization of iron containing non-biological complex drugs and for the estimation of pharmacological safety. This work thus represents an up to date summary of some relevant methods for the characterization of intravenous iron complex drugs in respect to pharmaceutical quality, pharmacological safety and aspects of efficacy. rnrnProspectively, it is worthwhile that the methods within this work will contribute to the development and/or characterization of iron containing nanoparticular formulations with beneficial efficacy and safety profiles.rn

Epicardial ventricular tachycardia ablation a multicenter safety study

The aim of this study was to perform a systematic evaluation of safety and midterm complications after epicardial ventricular tachycardia (VT) ablation.

Evaluation of Current Repair Criteria for Longitudinal Barrier with Crash Damage

To protect motorists and avoid tort liability, highway agencies expend considerable resources to repair damaged longitudinal barriers, such as w-beam guardrails. With limited funding available, though, highway agencies are unable to maintain all field-installed systems in the ideal as-built condition. Instead, these agencies focus on repairing only damage that has a detrimental effect on the safety performance of the barrier. The distinction between minor damage and more severe performance-altering damage, however, is not always clear. This paper presents a critical review of current United States (US) and Canadian criteria on whether to repair damaged longitudinal barrier. Barrier repair policies were obtained via comprehensive literature review and a survey of US and Canadian transportation agencies. In an analysis of the maintenance procedures of 40 US States and 8 Canadian transportation agencies, fewer than one-third of highway agencies were found to have quantitative measures to determine when barrier repair is warranted. In addition, no engineering basis for the current US barrier repair guidelines could be found. These findings underscore the importance of the development of quantitative barrier repair guidelines based on a strong technical foundation.

Transjugular intravascular ultrasound for the evaluation of hepatic vasculature and parenchyma in patients with chronic liver disease

Background The evaluation of the hepatic parenchyma in patients with chronic liver disease is important to assess the extension, localization and relationship with adjacent anatomical structures of possible lesions. This is usually performed with conventional abdominal ultrasound, CT-scan or magnetic resonance imaging. In this context, the feasibility and the safety of intravascular ultrasound in the liver have not been assessed yet. Methods We tested the safety and performance of an intracardiac echography (ICE) catheter applied by a transjugular approach into the hepatic veins in patients with chronic liver disease undergoing hepatic hemodynamic measurements. Results Five patients were enrolled in this pilot study. The insertion of the ICE catheter was possible into the right and middle, but not into the left hepatic vein. The position of the ICE was followed using fluoroscopy and external conventional ultrasound. Accurate imaging of focal hepatic parenchymal lesions, Doppler ultrasound of surrounding blood vessels and assessment of liver surface and ascites were achieved without complications. Conclusions This study demonstrated that a diagnostic approach using an ICE device inserted in the hepatic veins is feasible, safe and well tolerated. However, it remains for the moment only an experimental investigative tool. Whether ICE adds further information regarding parenchymal lesions and associated vascular alterations as compared to other techniques, needs additional investigation.

Experimental Evaluation of Immediate Recanalization Effect and Recanalization Efficacy of a New Thrombus Retriever for Acute Stroke Treatment In Vivo

BACKGROUND AND PURPOSE: Currently, several new stent retriever devices for acute stroke treatment are under development and early clinical evaluation. Preclinical testing under standardized conditions is an important first step to evaluate the technical performance and potential of these devices. The aim of this study was to evaluate the immediate recanalization effect, recanalization efficacy, thrombus-device interaction, and safety of a new stent retriever intended for thrombectomy in patients with acute stroke. MATERIAL AND METHODS: The pREset thrombectomy device (4 × 20 mm) was evaluated in 16 vessel occlusions in an established swine model. Radiopaque thrombi (10-mm length) were used for visualization of thrombus-device interaction during application and retrieval. Flow-restoration effect immediately after deployment and after 5-minute embedding time before retrieval, recanalization rate after retrieval, thromboembolic events, and complications were assessed. High-resolution FPCT was performed to illustrate thrombus-device interaction during the embedding time. RESULTS: Immediate flow restoration was achieved in 75% of occlusions. An increase or stable percentage of recanalizations during embedding time before retrieval was seen in 56.3%; a decrease, in 12.5%; reocclusion of a previously recanalized vessel, in 18.8%; and no recanalization effect at all, in 12.5%. Complete recanalization (TICI 3) after retrieval was achieved in 93.8%; partial recanalization (TICI 2b), in 6.2%. No distal thromboembolic events were observed. High-resolution FPCT illustrated entrapment of the thrombus between the stent struts and compression against the contralateral vessel wall, leading to partial flow restoration. During retrieval, the thrombus was retained in a straight position within the stent struts. CONCLUSIONS: In this experimental study, the pREset thrombus retriever showed a high recanalization rate in vivo. High-resolution FPCT allows detailed illustration of the thrombus-device interaction during embedding time and is advocated as an add-on tool to the animal model used in this study.

Safety and outcome of patients with an acute ST-elevation myocardial infarction transferred for primary coronary intervention: the Neuchâtel experience

BACKGROUND: Transferring patients with ST-elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI) from a community hospital to a PCI centre has been evaluated in randomised trials and shown to be safe and effective. A prolonged transfer time may restrict the benefit of this strategy. AIM: We sought to assess 1) safety of transfer from Neuchâtel to Berne, 2) time intervals of patients transferred either directly from on-site or after evaluation in the local emergency room, and 3) clinical long-term outcome. METHODS AND RESULTS: 42 patients with STEMI eligible for reperfusion therapy were prospectively included between January 2003 and June 2004. Twenty patients (48%, group 1) were directly transferred to the PCI centre from on-site. Twenty-two were transferred after initial treatment in the local emergency room: 11 patients (26%, group 2) presented spontaneously at the hospital and 11 patients (26%, group 3) were admitted by the rescue team. No major complication occurred during transport. Median transport time was 33 minutes. Median time from first healthcare contact to balloon consisted of 131 minutes in group 1, 158 minutes in group 2 and 174 minutes in group 3. The overall rate of Major Adverse Cardiac Events (MACE) at 6 months amounted to 9.5%. CONCLUSIONS: Transfer for primary PCI of our patients with acute STEMI was safe. Direct transfer from on-site to the PCI centre reduced the time of ischaemia. The overall MACE rate was low.

Effectiveness, safety and cost-effectiveness of homeopathy in general practice - summarized health technology assessment

Introduction: The Health Technology Assessment report on effectiveness, cost-effectiveness and appropriateness of homeopathy was compiled on behalf of the Swiss Federal Office for Public Health (BAG) within the framework of the 'Program of Evaluation of Complementary Medicine (PEK)'. Materials and Methods: Databases accessible by Internet were systematically searched, complemented by manual search and contacts with experts, and evaluated according to internal and external validity criteria. Results: Many high-quality investigations of pre-clinical basic research proved homeopathic high-potencies inducing regulative and specific changes in cells or living organisms. 20 of 22 systematic reviews detected at least a trend in favor of homeopathy. In our estimation 5 studies yielded results indicating clear evidence for homeopathic therapy. The evaluation of 29 studies in the domain 'Upper Respiratory Tract Infections/Allergic Reactions' showed a positive overall result in favor of homeopathy. 6 out of 7 controlled studies were at least equivalent to conventional medical interventions. 8 out of 16 placebocontrolled studies were significant in favor of homeopathy. Swiss regulations grant a high degree of safety due to product and training requirements for homeopathic physicians. Applied properly, classical homeopathy has few side-effects and the use of high-potencies is free of toxic effects. A general health-economic statement about homeopathy cannot be made from the available data. Conclusion: Taking internal and external validity criteria into account, effectiveness of homeopathy can be supported by clinical evidence and professional and adequate application be regarded as safe. Reliable statements of cost-effectiveness are not available at the moment. External and model validity will have to be taken more strongly into consideration in future studies.

Staged surgical therapy of basal cell carcinoma of the head and neck region: an evaluation of 500 procedures

QUESTIONS UNDER STUDY / PRINCIPLES: The surgical therapy of basal cell carcinoma (BCC) is especially demanding in the facial area. This retrospective study was undertaken to evaluate the outcome of staged surgical therapy (SST) of BCC of the head and neck region performed on an interdisciplinary basis at our institution. METHODS: Patients treated for BCC in the head and neck area between 1/1/1997 and 31/12/2001 were included in the study. The lesions were histologically evaluated. Diameter of lesion, number of stages, defect coverage, operation time, and recurrence and infection rates were analysed using descriptive and inferential statistical procedures. RESULTS: 281 patients were included in the study. SST was performed in two stages in 43.7%, in three stages in 12.9% and in four or more stages in 2.7%, depending on the type of tumour and the patient's pretreatment status. The total operating time per lesion averaged one hour. Defect coverage was achieved by direct closure (37.7%), by full thickness skin graft (39.5%), by split skin graft (1.1%), by local flaps (20.3%) or by composite grafts (1.1%). Median follow-up time was 58.5 months. Low rates of recurrence (3.6%) and infection (2%) were observed with this technique. CONCLUSIONS: The staged surgical therapy of basal cell carcinoma evaluated here offers a series of advantages in respect of patient comfort and safety and economy, while allowing precise histological safety with low infection rates and reliable long-term results.