262,248 research outputs found
In vitro studies and in vivo evaluation of novel diamidines for 2nd stage sleeping sickness
No full textSummary:
African sleeping sickness is one of the most neglected tropical diseases. Transmitted by the tsetse fly it exclusively occurs in sub-Saharan Africa. It is caused by two different parasite subspecies causing two different forms of African sleeping sickness. Trypanosoma brucei gambiense is prevalent in West and Central Africa while Trypanosoma brucei rhodesiense is prevalent in East and South Africa. Sleeping sickness is classified in two main stages. In the first stage, the parasites reside in the lymph and blood system. In the second stage, the parasites additionally infect the brain. Untreated sleeping sickness is fatal. Drugs are available for this fearsome disease, however, most of them are old and have many drawbacks, such as severe adverse effects, treatment failures and complicated treatment schedules, which is a problem in remote rural areas where the disease primarily occurs.
African sleeping sickness is a communicable disease that can be controlled. In 1998, there were an estimated 300,000 cases. By 2012 the prevalence has decreased to about 30,000, by different control measures such as vector control, improved surveillance and free drug distribution. Elimination seems possible, but safe and effective drugs are needed to reach this goal. One of the current drugs is the diamidine pentamidine which is in use since the early 1940s. However, it works only in patients with first stage disease and it has to be injected.
The Consortium for Parasitic Drug Development (CPDD) was founded in the year 2000 to find novel diamidines with better characteristics than the existing drugs. We improved oral absorption, which makes it possible to use pills instead of injections, and central nervous system (CNS) penetration. One compound (pafuramidine) has been tested in patients with first stage infections. It was the first compound that cured sleeping sickness orally, which is of great help for rural areas. Unfortunately, pafuramidine caused kidney and liver problems, and it did not cure second stage infections. In the meantime, we have identified superior compounds especially for the second stage.
As described in Chapter 3, two compounds, the prodrugs DB868 and DB844, given orally, cured all mice with CNS infections. However, both prodrugs were too toxic at the high doses required to cure both stages in monkeys. Nevertheless, DB868 is a good candidate drug to cure first stage sleeping sickness by an oral treatment, as demonstrated in mice and monkeys with first stage infections. Chapter 4 shows data of another CNS potent prodrug, DB1227 which was, however, less effective than DB868 in CNS infected mice.
Chapters 3, 7, 8 and 9 deal with two unmasked diamidines, DB829 and 28DAP010, which were highly effective in mice with second stage infections after i.p. injection. This was unexpected since diamidines are rather unlikely to cross the blood brain barrier in sufficient concentrations by diffusion. These two diamidines may penetrate into the brain by specific transporter proteins. The advantage of the two diamidines is that both cure with a short treatment course which could shorten the time of hospitalization of the patients. We have already tested DB829 in monkeys with promising results. It was safe and effective at low doses and a short treatment schedule in monkeys with second stage disease. 28DAP010 seems to be similarly effective as DB829 on both T. brucei subspecies in vitro and in mouse models.
In Chapter 6 we established a new in vitro method to measure the kinetics of drug action on pathogenic protozoa on a real time basis. We exploited the capacity of viable cells to produce heat and measured the heat flow using microcalorimetry. 28DAP010 inhibited the heat production of trypanosome cultures faster than DB829. The parasite clearance time of 28DAP010 was also faster than of DB829 in mice. The required effective treatment duration was still similar in mice with single dose for first stage and 5 days for second stage infections.
Upcoming efficacy studies will reveal if 28DAP010 is as curative in monkeys as DB829 and toxicity studies of 28DAP010 and DB829 side by side will shed light on their toxicity profile. These studies will help to select the better of these two compounds as a clinical drug candidate for the treatment of second stage sleeping sickness. ---------- Zusammenfassung: Die Afrikanische Schlafkrankheit ist eine Tropenkrankheit, welche durch die Tsetsefliege übertragen wird und daher ausschliesslich im tropischen Afrika vorkommt. Sie gehört zu den vernachlässigsten Krankheiten überhaupt und wird deshalb auch “vergessene Seuche“ genannt. Der Erreger ist ein einzelliger Parasit. Es gibt zwei verschiedene Unterarten, die zu etwas unterschiedlichen Schlafkrankheitsformen führen. Ohne wirksame Medikamentenbehandlung sind beide Formen tödlich. Trypanosoma brucei gambiense kommt nur in West- und Zentralafrika vor, während Trypanosoma brucei rhodesiense in Ost- und Südafrika zu finden ist. Der Krankheitsverlauf kann in zwei Stadien unterteilt werden. Im ersten Stadium findet man die Parasiten im Blut- und Lymphsystem und im zweiten Stadium zusätzlich im Gehirn. Zwar gibt es für diese Krankheit Medikamente, jedoch sind die meisten davon veraltet, haben ausgeprägte Nebenwirkungen und sind wegen Rückfällen oder der komplizierten und aufwendigen Behandlung problematisch.
Die Bekämpfung der Afrikanischen Schlafkrankheit ist möglich. 1998 gab es geschätzt etwa 300.000 Krankheitsfälle. Durch verbesserte Überwachung mit anschliessender medizinischer Behandlung der Infizierten, kostenlose Medikamentenverteilung und Vektorkontrolle, liess sich die Krankheit auf etwa 30.000 Krankheitsfälle im Jahr 2012, eindämmen. Für eine Eliminierung sind wirksame und verträgliche Medikamente notwendig. Ein Diamidin, das schon seit den frühen 40-er Jahren eingesetzt wird ist Pentamidin. Es wirkt noch heute, aber nur in Patienten die sich im ersten Stadium befinden, zudem muss es injiziert werden.
Im Jahr 2000 wurde das Konsortium CPDD, für die Entwicklung neuer Wirkstoffe zur Behandlung parasitärer Erkrankungen, vor allem für die Schlafkrankheit, gegründet. Neuartige Diamidine mit verbesserten Eigenschaften wurden gesucht und es war uns möglich, die orale Bioverfügbarkeit und die Bluthirnschrankengängigkeit, chemisch zu verbessern. Pafuramidin, war einer der neuen Wirkstoffe, das erste oral einzunehmende Medikament gegen Schlafkrankheit, das im Menschen getestet wurde. Ein orales Medikament hat grosse Vorteile für diese Krankheit, die hauptsächlich in abgelegenen Gebieten Afrikas vorkommt, wo ein ausgebautes Gesundheitssystem oft fehlt.
Pafuramidin heilte nur das erste Schlafkrankheitsstadium und dabei wurden Leber- und Nieren-Unverträglichkeiten festgestellt. Während der klinischen Studie testeten wir weitere Diamidine und fanden verbesserte Substanzen, vor allem bezüglich der Wirksamkeit des zweiten Krankheitsstadiums. Kapitel 3 und 4 beschreibt die wirksamsten Moleküle, die das Zweitstadium bei oraler Verabreichung heilten. Diese Moleküle, DB844, DB868, DB1227, aber auch das Pafuramidin sind Medikamenten-vorstufen (Prodrugs). Diese wurden entwickelt, um die orale Aufnahme und Gehirn-gängigkeit zu verbessern. Die aktivsten waren DB868 und DB844 in Mäusen, jedoch zeigten beide Moleküle toxische Wirkungen im Affen ohne dabei ausreichend die Gehirninfektion zu heilen. Dennoch war DB868 im Affenmodell deutlich besser verträglich als Pafuramidin und ist somit ein guter Ersatzkandidat für eine orale Wirkstoffentwicklung fürs erste Stadium.
Unerwartet konnten wir jedoch zwei Diamidine (ohne Vorstufenergänzung) identifizieren, die ebenfalls Mäuse mit Gehirninfektionen heilten. Da Diamidine unter physiologischen Bedingungen protoniert sind, ist es unwahrscheinlich, dass sie durch die Bluthirnschranke diffundieren. Möglicherweise werden sie über spezifische Mechanismen ins Gehirn transportiert. Kapitel 3, 7, 8 und 9 befassen sich mit den beiden aktivsten Diamidinen, DB829 und 28DAP010. Ihre hohe Wirkung und die kurze Behandlungszeit nach parenteraler Verabreichung (i.p. oder i.m) sind vielversprechend. DB829 war gut verträglich und wirksam bei niedrigen Dosen und heilte die infizierten Affen mit dem zweiten Krankheitsstadium bereits bei einer 5-tägigen Behandlung. In vitro und im Mausmodel war 28DAP010 auf beide Trypanosomen Unterarten ähnlich wirksam wie DB829.
Um die Wirkungszeit neuer Substanzen auf Trypanosomen zu testen, entwickelten wir eine neue Methode, die in Kapitel 6 beschrieben wird. Dabei nutzten wir die Eigenschaft der Zellen, Wärme zu produzieren und massen diese mit einem Kalorimeter auf Echtzeit. 28DAP010 reduzierte die Wärmeentwicklung einer Trypanosomenkultur deutlich schneller als DB829. Auch in infizierten Mäusen wirkte 28DAP010 schneller. Die Behandlungsdauer und Dosierung war bei beiden Diamidinen trotzdem vergleichbar. Eine Einzeldosis heilte das erste und eine 5-tägige Behandlung das zweite Stadium in Mäusen.
Weitere Studien sind nötig, um die Wirksamkeit von 28DAP010 im Affenmodel zu überprüfen und die Verträglichkeit beider Diamidine zu analysieren. Diese Ergebnisse werden zeigen, welches der bessere klinische Kandidat für die Behandlung des zweiten Schlafkrankheitsstadiums sein wird
User experience as a method for reducing consumption in domestic buildings
No full textThe thesis presents a use of a domestic building's automation system with a serious game embedded in it, as a method to motivate inhabitants to conserve resources.Green Building InnovationBuilding TechnologyArchitectur
Towards truly sustainable cities? Assessing the contribution of intelligent and knowledge city programmes
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Towards Intelligently-Sustainable Cities? Assessing the contribution of Intelligent and Knowledge City Programmes to the Achievement of Urban Sustainability
No full textReliability Forecasting for Simulation-based Workforce Planning
No full textThe problem owner of the present study is a consulting company that provides simulation-based workforce planning advice to a big manufacturing firm XYZ. The latter pertains the number of engineers of various skill levels that are needed for the repair of health care equipment in hospitals of a large country. The prediction of machine failures (reliability forecasting) is a crucial input to the simulations that affects the quality of the business advice. Currently, the problem owner follows a reliability forecasting approach based on lifetime models following the HPP [1]. Nevertheless, this practice has several limitations as: i) the predictive performance is not always satisfactory due to data overfitting (Liang, 2011), ii) real-world systems do not generally comply with the HPP traits (Kurien, Sekhon & Chawla, 1993), namely constant failure rates of a memoryless failure process, while reliability is non-linear and complex due to a bunch of factors (Chatterjee & Bandopadhyay, 2012). In the view of the above, the problem owner needs to increase the efficiency of workforce planning that will finally lead to cost savings for firm XYZ. It is believed that a more efficient planning can be achieved through the improvement of the forecasting approach. Forecasting should fulfil certain requirements, namely it should predict the failure patterns of multiple machines, at an acceptable level of accuracy, with a high degree of automation. Thus, the study’s research objective is defined as: to provide an automated forecasting framework that detects and predicts the failure patterns of multiple machines with acceptable accuracy. For achieving the research objective, firstly, a clarification of the forecasting requirements is done through a semi-structured interview with the problem owner. Among others, it is clarified that accuracy is the hourly absolute deviation between the actual and the forecasted inter-failure time of a machine (MAE), and it concerns only its next failure (one-step ahead forecasting). Additionally, for a bunch of reasons, two different levels of acceptable accuracy are defined, the 1st with minimum accuracy of 120h (1 working week), and the 2nd of 2160h (1 quarter). Secondly, the identification of the most promising forecasting approach that can fulfil the given requirements is done through a literature review. Time series forecasting is found to be the most promising approach as it: i) outperforms reliability models that follow the NHPP in terms of accuracy (Ho & Xie, 1998; Dindarloo & Siami-Irdermoosa, 2015; Fan & Fan, 2015), ii) is able for automated and large-scale application (Wagner et al., 2011). Subsequently, a case study, which pertains reliability forecasting of radiation treatment machines maintained by firm XYZ, is conducted in order to evaluate the time series approach. The reliability metric of Time-Between-Failures (TBF) is used for forecasting, whilst the time series cross-validation method is employed for its evaluation. The time series approach followed is based on the use of three parametric methods (ARIMA, Exponential Smoothing, Optimized Theta) and two artificial neural networks (FFNN, RGMDH) applied on the machine group level (2 groups) and on the individual machine level (5 machines). In this context, experimentations take place under both full and adjusted for outliers data conditions. Moreover, the related repair data, expressed by Time-To-Repair (TTR) and by a dummy variable that represents the use of spare items, is used in the TBF forecasting with ARIMAX models. The case study demonstrates that: i) on the machine group level, the series are white noise involving that the failure process is memoryless and failure patterns cannot be detected, ii) on the individual machine level, the best performing forecast model of every machine examined satisfies the 2nd level of acceptable accuracy. The MAE error metric of the best forecast model for each machine examined is substantially less than 2160h. Thus, the present study has succeeded in its objective. The reliability forecasting framework produced constitutes a holistic approach to the prediction of machine failures, as with its various and at a degree, complementary methods can deal with all the basic types of failure data (e.g. autocorrelations, seasonality, trend, non/linearity, etc.) The framework formed is provided to the problem owner allowing for the transformation of the workforce planning of firm XYZ from an annual to a quarterly basis. The recommendations for the problem owner as well as for future research are: first, the execution of experimental simulations with a planning horizon of 3 months in order to evaluate the possible cost savings for firm XYZ. Second, the collection of new relevant to machine failures data (e.g. machine utilization, purchase date), and third, the extension and evaluation of the forecasting framework with the inclusion of these new data and/or with new methods (e.g. hybrid, FFNN with external covariates) and techniques (e.g. time series clustering). Fourth, the application and re-evaluation of the reliability forecasting framework formed when the failure data of 2016 become available. Fifth, the use of failure behavior’s variability as a stakeholder management tool when the problem owner deals with forecasting projects. Last, the use of the time series cross-validation method for the evaluation of forecast models and the great amount of attention on the potential existence of outliers in the dataset. On reflection, the contribution of the present thesis is multi-dimensional. First, a holistic and multi-method reliability forecasting framework that can deal with almost any failure process has been produced. This framework can be used in relevant projects as it can be extended and adjusted to the conditions of each project. Second, the aforementioned framework has been built though a state-of-the-art analytical forecasting process that can also be used by the problem owner in different projects. Third, there is a clear potential for cost savings for firm XYZ if workforce planning is adjusted in a quarterly horizon. Fourth, there is a knowledge contribution to the performance of various time series methods (e.g. Optimized Theta, RGMDH) in the context of reliability forecasting. Fifth, there is a clear contribution to the increase of the domain knowledge of reliability forecasting in health care equipment in general, and in radiation treatment machines in particular. Last, it has been highlighted that the initial evaluation of the variability of the failure behavior of a set of machines can serve as a stakeholder management tool as regards the final forecasting deliverable.Technology, Policy and ManagementMulti Actor SystemsM.Sc. in Engineering and Policy Analysis (EPA
Quasi?Experimental Evaluation Method for a Serious Game’s Learning Efficacy
No full textBackground: The increase in elaborateness of serious games has resulted in a more and more prominent use in business environments, their use has grown dramatically. Due to this growing interest; Shell has requested, in 2009, the development of the serious game Hazard Recognition, a single player 3D simulation of a Shell drilling site. Motive: The development of Hazard Recognition has reached completion, but due to the absence of experimental evidence that Hazard Recognition contributes to learning, adoption into Shell lacks. In order to collect this evidence, an evaluation study has been proposed. Complication: Mayer et al. (2012) are in the midst of development of an overarching framework for the evaluation of serious games. However, there is no off-the shelve method available for the evaluation of a serious game’s learning efficacy. Therefore, this study’s research question is: “What is an appropriate method, which can operate in the Comprehensive Evaluation Framework (Mayer et al., 2012), for the evaluation of a serious game’s learning efficacy and the contributing factors?” Method: Literature research has provided for the necessary academic foundations for the development of the evaluation method. Successively, a quasi-experimental experiment shaped the context of application and testing of this method. The experiment was the evaluation of Hazard Recognition’s learning efficacy. The result of this experiment showed that Hazard Recognition achieves learning efficacy. Results: An appropriate conceptual method for the evaluation of a serious game’s learning efficacy, within the context of Mayer’s Comprehensive Evaluation Framework, has been laid down. The learning efficacy of a serious game is defined as the ability of the learning intervention to achieve its learning objectives. This can be mapped and measured by evaluating the movement of students through Burch’s Competence Model (1970s). This requires to map the position of the student on the two axes (conscious and competence) by the measurement of self-perceived competences (conscious) and objective performance (competence). For these measurements there has been formulated an experiment setup with various requirements and constructs for the measurement methods have been developed. The case study, which consisted of the evaluation of Hazard Recognition’s learning efficacy, showed that both the developed conceptual model, as the developed measurement methods are valid.SEPAMSystems EngineeringTechnology, Policy and Managemen
Protecting Animals 36: Author Witi Ihimaera
No full textIn this very special episode of Knowing Animals I am joined by beloved New Zealand author Witi Ihimaera. Witi has written many books featuring nonhuman animals. He offers us a non-colonial lens through which to think about the human/nonhuman relationship
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
Djelatnost ruskih arhitekata emigranata u Hrvatskoj i Jugoslaviji (1920.-1980.)
No full textU pregledu arhitektonske djelatnosti emigranata iz Rusije ovom se prilikom aktualizira rad graditelja iz drugih jugoslavenskih sredina u hrvatskim gradovima, kao i doprinos zagrebačkih diplomanata arhitekture ostvaren izvan granica Hrvatske. Unutar prve skupine graditelja izdvojili su se Andrej Papkov, Andrej Ševcov, Viktor Zelinski i Valerij Staševski, dok su se u drugoj afirmirali Vsevolod Tatarinov, Leonid Makšejev, Viktor Zalevski, Irina Nepokojčickaja i Fedor Wenzler
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