FaSSIF-C, a Cholesterol containing biorelevant intestinal model medium for development and test of oral drug formulations

Biorelevante Medien sind entwickelt worden, um die Bedingungen im Magen-Darm-Trakt vor und nach der Mahlzeit zu imitieren. Mit FaSSIF und FeSSIF wurden Medien eingeführt, die nicht nur die pH- und Puffer-Kapazität des Dünndarms widerspiegeln, sondern auch Lipid und physiologische Tensid-Arten enthalten. Diese Medien (FaSSIF-V2 und FaSSlFmod6.5) wurden für Bioverfügbarkeitstudien in der Medikamentenentwicklung im Laufe der Jahre kontinuierlich weiterentwickelt. Dennoch sind die auf dem Markt verfügbaren Medien immer noch nicht in der Lage, die realen physiologischen Bedingungen zu simulieren. In der jetzigen Zusammensetzung sind nicht alle Kompetenten enthalten, welche natürlicher Weise im Duodenum vorkommen. Darüber hinaus wird nur eine 1:5 Verdünnung von FeSSIF zu FaSSIF angenommen, die individuelle Wasserzufuhr bei Medikamentengabe wird hierdurch jedoch nur eingeschränkt simuliert, obwohl diese von Patient zu Patient schwanken kann. rnZiel dieser Dissertation war die Verbesserung der Vorhersage der Auflösung und Absorption lipophiler Arzneistoffe durch Simulation der Bedingungen im zweiten Teil des Zwölffingerdarms mit neuen biorelevanten Medien, sowie unter Einwirkung zusätzlicher Detergention als Wirkstoffträger. rnUm den Effekt der Verdünnungsrate und Zeit im Dünndarm zu untersuchen, wurde die Entwicklung der Nanopartikel in der Magen-Darm-Flüssigkeit FaSSIFmod6.5 zu verschiedenen Zeitpunkten und Wassergehalten untersucht. Dafür wurden kinetische Studien an verschieden konzentrierten Modellmedien nach Verdünnungssprung untersucht. Das Modell entspricht der Vermischung der Gallenflüssigkeit mit dem Darminhalt bei variablem Volumen. Die Ergebnisse zeigen, dass Art und Größe der Nanopartikel stark von Verdünnung und Einirkungszeit abhängen. rnrnDie menschliche Darmflüssigkeit enthält Cholesterin, welches in allen früheren Modellmedien fehlt. Daher wurden biokompatible und physiologische Modellflüssigkeiten, FaSSIF-C, entwickelt. Der Cholesteringehalt von FaSSIF - 7C entspricht der Gallenflüssigkeit einer gesunden Frau, FaSSIF - 10C der einer gesunden männlichen Person und FaSSIF - 13C der in einigen Krankheitszuständen. Die intestinale Teilchen-Struktur-Untersuchung mit dynamische Lichtstreuung (DLS) und Neutronen-Kleinwinkelstreuung (SANS) ergab, dass die Korngröße von Vesikeln mit zunehmender Cholesterin-Konzentration abnahm. Zu hohe Cholesterin-Konzentration bewirkte zusätzlich sehr große Partikel, welche vermutlich aus Cholesterin-reichen “Disks“ bestehen. Die Löslichkeiten einiger BCS Klasse II Wirkstoffe (Fenofibrat, Griseofulvin, Carbamazepin, Danazol) in diesen neuen Medien zeigten, dass die Löslichkeit in unterschiedlicher Weise mit der Cholesteringehalt zusammen hing und dieser Effekt selektiv für die Droge war. rnDarüber hinaus wurde die Wirkung von einigen Tensiden auf die kolloidale Struktur und Löslichkeit von Fenofibrat in FaSSIFmod6.5 und FaSSIF -7C untersucht. Struktur und Löslichkeit waren Tensid- und Konzentrations-abhängig. Im Falle von FaSSIFmod6.5 zeigten die Ergebnisse eine dreifache Verzweigung der Lösungswege. Im Bereich mittlerer Tensidkonzentration wurde eine Löslichkeitslücke der Droge zwischen der Zerstörung der Galle-Liposomen und der Bildung von Tensid-reichen Mizellen beobachtet. In FaSSIF - 7C, zerstörten Tenside in höherer Konzentration die Liposomenstruktur trotz der allgemeinen Stabilisierung der Membranen durch Cholesterin. rnDie in dieser Arbeit vorgestellten Ergebnisse ergeben, dass die Anwesenheit von Cholesterin als eine fehlende Komponente der menschlichen Darmflüssigkeit in biorelevanten Medien wichtig ist und dazu beitragen kann, das in vivo Verhalten schwerlöslicher Arzneistoffe im Körper besser vorhersagen zu können. Der Verdünnungsgrad hat einen Einfluss auf die Nanopartikel-Struktur und Tenside beeinflussen die Löslichkeit von Medikamenten in biorelevanten Medien: Dieser Effekt ist sowohl von der Konzentration das Tensids abhängig, als auch dessen Typ.rnrn

New markov chain based methods for single and cross-domain sentiment classification

Nowadays communication is switching from a centralized scenario, where communication media like newspapers, radio, TV programs produce information and people are just consumers, to a completely different decentralized scenario, where everyone is potentially an information producer through the use of social networks, blogs, forums that allow a real-time worldwide information exchange. These new instruments, as a result of their widespread diffusion, have started playing an important socio-economic role. They are the most used communication media and, as a consequence, they constitute the main source of information enterprises, political parties and other organizations can rely on. Analyzing data stored in servers all over the world is feasible by means of Text Mining techniques like Sentiment Analysis, which aims to extract opinions from huge amount of unstructured texts. This could lead to determine, for instance, the user satisfaction degree about products, services, politicians and so on. In this context, this dissertation presents new Document Sentiment Classification methods based on the mathematical theory of Markov Chains. All these approaches bank on a Markov Chain based model, which is language independent and whose killing features are simplicity and generality, which make it interesting with respect to previous sophisticated techniques. Every discussed technique has been tested in both Single-Domain and Cross-Domain Sentiment Classification areas, comparing performance with those of other two previous works. The performed analysis shows that some of the examined algorithms produce results comparable with the best methods in literature, with reference to both single-domain and cross-domain tasks, in $2$-classes (i.e. positive and negative) Document Sentiment Classification. However, there is still room for improvement, because this work also shows the way to walk in order to enhance performance, that is, a good novel feature selection process would be enough to outperform the state of the art. Furthermore, since some of the proposed approaches show promising results in $2$-classes Single-Domain Sentiment Classification, another future work will regard validating these results also in tasks with more than $2$ classes.

Homicide-suicide cases in Switzerland and their impact on the Swiss Weapon Law

Homicide followed by the suicide of the offender is a well-known phenomenon. In most cases, it takes place in the context of the so-called "family tragedies." A recent series of such family tragedies in Switzerland prompted an intensive debate in the media and the Swiss government concerning the Swiss Weapon Law, in particular the requirement to keep personal army weapons at home. The present study of Homicide-Suicide cases in Switzerland, thus focuses on the role played by guns, especially military weapons, in such crimes. We investigated retrospectively 75 cases of Homicide-Suicide, comprising 172 individuals and spanning a period of 23 years in western and central Switzerland. Our results show that if guns were used in 76% of the cases, army weapons were the cause of death in 25% of the total. In 28% of the deaths caused by a gunshot, the exact type of the gun and its origin could not be determined. Thus, the majority of Homicide-Suicide cases in Switzerland involve the use of guns. The exact percentage of cases were military weapons were involved could not be defined. In our opinion, a stricter weapons law, restricting access to firearms, would be a factor of prevention of Homicide- Suicide cases in Switzerland.

Escherichia coli variants in periprosthetic joint infection: diagnostic challenges with sessile bacteria and sonication

The diagnostic yield of prosthetic joint-associated infection is hampered by the phenotypic change of bacteria into a sessile and resistant form, also called biofilm. With sonication, adherent bacteria can be dislodged from the prosthesis. Species identification may be difficult because of their variations in phenotypic appearance and biochemical reaction. We have studied the phenotypic, genotypic, and biochemical properties of Escherichia coli variants isolated from a periprosthetic joint infection. The strains were collected from synovial fluid, periprosthetic tissue, and fluid from the explanted and sonicated prosthesis. Isolates from synovial fluid revealed a normal phenotype, whereas a few variants from periprosthetic tissue and all isolates from sonication fluid showed different morphological features (including small-colony variants). All isolates from sonication fluid were beta-galactosidase negative and nonmotile; most were indole negative. Because of further variations in biochemical properties, species identification was false or not possible in 50% of the isolates included in this study. In contrast to normal phenotypes, variants were resistant to aminoglycosides. Typing of the isolates using pulsed-field gel electrophoresis yielded nonidentical banding patterns, but all strains were assigned to the same clonal origin when compared with 207 unrelated E. coli isolates. The bacteria were repeatedly passaged on culture media and reanalyzed. Thereafter, most variants reverted to normal phenotype and regained their motility and certain biochemical properties. In addition, some variants displayed aminoglycoside susceptibility after reversion. Sonication of an explanted prosthesis allows insight into the lifestyle of bacteria in biofilms. Since sonication fluid also reveals dislodged sessile forms, species identification of such variants may be misleading.

The in vitro effects of dexamethasone, insulin and triiodothyronine on degenerative human intervertebral disc cells under normoxic and hypoxic conditions

Degeneration of intervertebral discs (IVD) is one of the main causes of back pain and tissue engineering has been proposed as a treatment. Tissue engineering requires the use of highly expensive growth factors, which might, in addition, lack regulatory approval for human use. In an effort to find readily available differentiation factors, we tested three molecules – dexamethasone, triiodothyronine (T3) and insulin – on human IVD cells isolated after surgery, expanded in vitro and transferred into alginate beads. Triplicates containing 40 ng/ml dexamethasone, 10 nM T3 and 10 µg/ml insulin, together with a positive control (10 ng/mL transforming growth factor (TGF)-beta 1), were sampled weekly over six weeks and compared to a negative control. Furthermore, we compared the results to cultures with optimized chondrogenic media and under hypoxic condition (2% O2). Glycosaminoglycan (GAG) determination by Alcian Blue assay and histological staining showed dexamethasone to be more effective than T3 and insulin, but less than TGF-beta1. DNA quantification showed that only dexamethasone stimulated cell proliferation. qPCR demonstrated that TGF-beta1 and the optimized chondrogenic groups increased the expression of collagen type II, while aggrecan was stimulated in cultures containing dexamethasone. Hypoxia increased GAG accumulation, collagen type II and aggrecan expression, but had no effect on or even lowered cell number. In conclusion, dexamethasone is a valuable and cost-effective molecule for chondrogenic and viability induction of IVD cells under normoxic and hypoxic conditions, while insulin and T3 did not show significant differences.

Novel magnetic iron oxide nanoparticles coated with poly(ethylene imine)-g-poly(ethylene glycol) for potential biomedical application: synthesis, stability, cytotoxicity and MR imaging

Magnetic iron oxide nanoparticles have found application as contrast agents for magnetic resonance imaging (MRI) and as switchable drug delivery vehicles. Their stabilization as colloidal carriers remains a challenge. The potential of poly(ethylene imine)-g-poly(ethylene glycol) (PEGPEI) as stabilizer for iron oxide (γ-Fe₂O₃) nanoparticles was studied in comparison to branched poly(ethylene imine) (PEI). Carrier systems consisting of γ-Fe₂O₃-PEI and γ-Fe₂O₃-PEGPEI were prepared and characterized regarding their physicochemical properties including magnetic resonance relaxometry. Colloidal stability of the formulations was tested in several media and cytotoxic effects in adenocarcinomic epithelial cells were investigated. Synthesized γ-Fe₂O₃ cores showed superparamagnetism and high degree of crystallinity. Diameters of polymer-coated nanoparticles γ-Fe₂O₃-PEI and γ-Fe₂O₃-PEGPEI were found to be 38.7 ± 1.0 nm and 40.4 ± 1.6 nm, respectively. No aggregation tendency was observable for γ-Fe₂O₃-PEGPEI over 12 h even in high ionic strength media. Furthermore, IC₅₀ values were significantly increased by more than 10-fold when compared to γ-Fe₂O₃-PEI. Formulations exhibited r₂ relaxivities of high numerical value, namely around 160 mM⁻¹ s⁻¹. In summary, novel carrier systems composed of γ-Fe₂O₃-PEGPEI meet key quality requirements rendering them promising for biomedical applications, e.g. as MRI contrast agents.

Place for video games : a theoretical and pedagogical framework for multiliteracies learning in English studies

Students are now involved in a vastly different textual landscape than many English scholars, one that relies on the “reading” and interpretation of multiple channels of simultaneous information. As a response to these new kinds of literate practices, my dissertation adds to the growing body of research on multimodal literacies, narratology in new media, and rhetoric through an examination of the place of video games in English teaching and research. I describe in this dissertation a hybridized theoretical basis for incorporating video games in English classrooms. This framework for textual analysis includes elements from narrative theory in literary study, rhetorical theory, and literacy theory, and when combined to account for the multiple modalities and complexities of gaming, can provide new insights about those theories and practices across all kinds of media, whether in written texts, films, or video games. In creating this framework, I hope to encourage students to view texts from a meta-level perspective, encompassing textual construction, use, and interpretation. In order to foster meta-level learning in an English course, I use specific theoretical frameworks from the fields of literary studies, narratology, film theory, aural theory, reader-response criticism, game studies, and multiliteracies theory to analyze a particular video game: World of Goo. These theoretical frameworks inform pedagogical practices used in the classroom for textual analysis of multiple media. Examining a video game from these perspectives, I use analytical methods from each, including close reading, explication, textual analysis, and individual elements of multiliteracies theory and pedagogy. In undertaking an in-depth analysis of World of Goo, I demonstrate the possibilities for classroom instruction with a complex blend of theories and pedagogies in English courses. This blend of theories and practices is meant to foster literacy learning across media, helping students develop metaknowledge of their own literate practices in multiple modes. Finally, I outline a design for a multiliteracies course that would allow English scholars to use video games along with other texts to interrogate texts as systems of information. In doing so, students can hopefully view and transform systems in their own lives as audiences, citizens, and workers.

Curricular Integration of Simulations in Neuroscience - Instructional and Technical Perspectives

In recent years interactive media and tools, like scientific simulations and simulation environments or dynamic data visualizations, became established methods in the neural and cognitive sciences. Hence, university teachers of neural and cognitive sciences are faced with the challenge to integrate these media into the neuroscientific curriculum. Especially simulations and dynamic visualizations offer great opportunities for teachers and learners, since they are both illustrative and explorable. However, simulations bear instructional problems: they are abstract, demand some computer skills and conceptual knowledge about what simulations intend to explain. By following two central questions this article provides an overview on possible approaches to be applied in neuroscience education and opens perspectives for their curricular integration: (i) How can complex scientific media be transformed for educational use in an efficient and (for students on all levels) comprehensible manner and (ii) by what technical infrastructure can this transformation be supported? Exemplified by educational simulations for the neurosciences and their application in courses, answers to these questions are proposed a) by introducing a specific educational simulation approach for the neurosciences b) by introducing an e-learning environment for simulations, and c) by providing examples of curricular integration on different levels which might help academic teachers to integrate newly created or existing interactive educational resources in their courses.

Bovine Staphylococcus aureus: diagnostic properties of specific media

As accurate discrimination between Staphylococcus (S.) aureus and NSA (non-S. aureus staphylococci) involved in bovine mastitis is essential in terms of clinical prognosis and outcome, the aim of this study was to reevaluate the classical bacteriological procedures to identify these agents. Various media and the coagulase tube test were investigated using 116 strains of S. aureus and 115 of NSA, all isolated from cows with spontaneous intramammary infections (IMI). Furthermore, 25 NSA reference strains were analyzed. The study demonstrated that a few media were appropriate for differentiating S. aureus from NSA, provided that the staphylococci were isolated from bovine IMI. Evaluation of hemolysis further revealed that double or incomplete hemolysis are specific for S. aureus and are, therefore, a decisive diagnostic criterion. For strains showing complete hemolysis, maximal discrimination between S. aureus and NSA was observed by subculturing them on CHROMagar Staph. aureus.

The Ethnographic Moment: Event and Debate in Mediatized Fieldwork

This article introduces the term ‘the ethnographic moment’, which takes up and ‘plays’ with the long-disputed ‘ethnographic present’ in anthropology, as an indicator of changing conditions and requirements for ethnography in the context of mass media and mediation. It argues that event and debate, rather than structure and practice, have become pivotal aspects in thinking and conducting fieldwork that has to deal with the ephemeral. At the same time, it tries to show that an unquestioning acceptance of technological advancement and speed of societal change immunizes us to the thinkable absence of media and obscures analysis of lasting states of injustice and inequality, in whose (re-)production they have a stake.

The German business and information technologies project

The Business and Information Technologies (BIT) project strives to reveal new insights into how modern IT impacts organizational structures and business practices using empirical methods. Due to its international scope, it allows for inter-country comparison of empirical results. Germany — represented by the European School of Management and Technologies (ESMT) and the Institute of Information Systems at Humboldt-Universität zu Berlin — joined the BIT project in 2006. This report presents the result of the first survey conducted in Germany during November–December 2006. The key results are as follows: • The most widely adopted technologies and systems in Germany are websites, wireless hardware and software, groupware/productivity tools, and enterprise resource planning (ERP) systems. The biggest potential for growth exists for collaboration and portal tools, content management systems, business process modelling, and business intelligence applications. A number of technological solutions have not yet been adopted by many organizations but also bear some potential, in particular identity management solutions, Radio Frequency Identification (RFID), biometrics, and third-party authentication and verification. • IT security remains on the top of the agenda for most enterprises: budget spending was increasing in the last 3 years. • The workplace and work requirements are changing. IT is used to monitor employees' performance in Germany, but less heavily compared to the United States (Karmarkar and Mangal, 2007).1 The demand for IT skills is increasing at all corporate levels. Executives are asking for more and better structured information and this, in turn, triggers the appearance of new decision-making tools and online technologies on the market. • The internal organization of companies in Germany is underway: organizations are becoming flatter, even though the trend is not as pronounced as in the United States (Karmarkar and Mangal, 2007), and the geographical scope of their operations is increasing. Modern IT plays an important role in enabling this development, e.g. telecommuting, teleconferencing, and other web-based collaboration formats are becoming increasingly popular in the corporate context. • The degree to which outsourcing is being pursued is quite limited with little change expected. IT services, payroll, and market research are the most widely outsourced business functions. This corresponds to the results from other countries. • Up to now, the adoption of e-business technologies has had a rather limited effect on marketing functions. Companies tend to extract synergies from traditional printed media and on-line advertising. • The adoption of e-business has not had a major impact on marketing capabilities and strategy yet. Traditional methods of customer segmentation are still dominating. The corporate identity of most organizations does not change significantly when going online. • Online sales channel are mainly viewed as a complement to the traditional distribution means. • Technology adoption has caused production and organizational costs to decrease. However, the costs of technology acquisition and maintenance as well as consultancy and internal communication costs have increased.

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed "medial degeneration," which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient's age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response.

The New Audiovisual Media Services Directive : Television without Frontiers, Television without Cultural Diversity

After long deliberations, the European Community (EC) has completed the reform of its audiovisual media regulation. The paper examines the main tenets of this reform with particular focus on its implications for the diversity of cultural expressions in the European media landscape. It also takes into account the changed patterns of consumer and business behaviour due to the advances in digital media and their wider spread in society. The paper criticises the somewhat unimaginative approach of the EC to new media and the political (and at times protectionist) considerations behind some of the Directive's provisions.