6 Zusammenfassung Marianne Reinboth Bioverfügbarkeit des Flavonols Quercetin beim Hund Veterinär-Physiologisches Institut der Veterinärmedizinischen Fakultät der Universität Leipzig Eingereicht im Juni 2010 79 Seiten, 20 Abbildungen, 6 Tabellen, 211 Literaturangaben, 1 Anhang Schlüsselwörter: Quercetin, Bioverfügbarkeit, Hund, absolute Bioverfügbarkeit, Isoquercitrin, Rutin, Flavonole Für das pflanzliche Flavonol Quercetin werden vielfältige gesundheitsfördernde Wirkungen postuliert, so auch bei Hunden. Über die Bioverfügbarkeit des Flavonols bei dieser Spezies liegen bislang jedoch keinerlei Daten vor. Daher hatte diese Arbeit das Ziel, Bioverfügbarkeit und pharmakokinetische Parameter von Quercetin und wichtigen Quercetinglycosiden bei Hunden nach deren Verabreichung mit einer Testmahlzeit in einer praxisrelevanten Dosierung von 10 mg/kg Körpermasse zu untersuchen. Dazu erhielten 9 adulte Beagles beiderlei Geschlechts das zuckerfreie \"Aglycon\" Quercetin bzw. seine Glycoside Isoquercitrin (Quercetin-3-O-Glucosid) und Rutin (Quercetin-3-O-Glucorhamnosid) in jeweils äquimolarer Dosierung in einer Testmahlzeit verabreicht. Anschließend wurden Blutproben über einen Zeitraum von bis zu 72 Stunden entnommen und mittels HPLC die Konzentrations-Zeitverläufe der Metaboliten im Blutplasma, die Bioverfügbarkeit sowie weitere pharmakokinetische Parameter bestimmt. Weiterhin wurde die absolute Bioverfügbarkeit von Quercetin aus dem Vergleich einer oralen mit einer intravenösen Applikation bestimmt. Der weitaus größte Teil der Plasmametaboliten von Quercetin sowie seiner beiden Glycoside bestand aus glucuronidierten bzw. sulfatierten Quercetinkonjugaten. Nicht konjugiertes Quercetin-Aglycon kam nur in einem Anteil von etwa 20 % vor. Neben Quercetin machten seine Metaboliten Isorhamnetin und Kämpferol weniger als 10 % aller im Plasma zirkulierenden Flavonole aus. Die absolute Bioverfügbarkeit von Quercetin betrug nur etwa 4 %. Die relative Bioverfügbarkeit aus dem 3-O-Glucosid Isoquercitrin war mehr als doppelt so hoch wie aus dem Aglycon, die maximalen Plasmaspiegel lagen aber auch hier unter 1 µmol/l. Sowohl nach Aufnahme von Quercetin als auch nach Isoquercitrin kam es zu einer relativ schnellen Absorption aus dem Dünndarm mit einem ersten Plasmapeak ungefähr eine Stunde nach der Ingestion. Vier Stunden nach Aufnahme der beiden Flavonole trat ein zweiter Plasmapeak auf, der in der Regel höher als der erste ausfiel. Dies deutet auf einen enterohepatischen Kreislauf der über die Galle ausgeschiedenen Metaboliten hin. Nach Aufnahme von Rutin kam es zu einer verzögerten Absorption, da eine Deglycosylierung durch bakterielle Glycosidasen im Dickdarm Voraussetzung für die Absorption des Flavonols ist. Maximale Plasmakonzentrationen wurden im Mittel erst 11 Stunden nach Ingestion dieses Glycosids erreicht. Die maximalen Plasmakonzentra-tionen nach Rutin waren geringer als nach Quercetin oder Isoquercitrin, jedoch war die mittlere Verweildauer der Plasmametaboliten mit 18 Stunden auch wesentlich länger. Im Unterschied zu anderen Spezies war die relative Bioverfügbarkeit von Rutin gegenüber Quercetin nicht verringert. Obwohl Rutin eine relativ gute Quercetinquelle für Hunde zu sein scheint, muss bei der Einschätzung möglicher In-vivo-Wirkungen die relativ geringe Bioverfügbarkeit sowie die intensive Metabolisierung seines Aglycons Quercetin berücksichtigt werden.:1 Einleitung 1 2 Literaturübersicht 3 2.1 Funktionen von Flavonoiden in Pflanzen 3 2.2 Biosynthese und Struktur von Flavonoiden 4 2.3 Flavonoidwirkungen im menschlichen und tierischen Organismus 7 2.3.1 Antioxidative Eigenschaften 10 2.3.2 Wirkungen auf Enzyme und Transportproteine des Arzneistoffwechsels 12 2.4 Bioverfügbarkeit und Stoffwechsel des Flavonols Quercetin 13 2.4.1 Bioverfügbarkeit von Quercetin 13 2.4.2 Einfluss des Futters 15 2.4.3 Einfluss des Glycosylierungsmusters 16 2.4.4 Intestinale Absorption und Metabolismus 18 2.4.5 Einfluss der intestinalen Mikroflora 21 2.4.6 Bindung an Plasmaproteine 22 2.4.7 Gewebeverteilung 23 2.4.8 Exkretion 24 2.5 Zielsetzung 25 3 Tiere, Material und Methoden 26 3.1 Versuchstiere und Haltungsbedingungen 26 3.2 Verwendete Flavonole 27 3.3 Durchführung des Tierversuchs 28 3.3.1 Allgemeine Durchführung der Versuche 28 3.3.2 Bioverfügbarkeit von Quercetin und Rutin (je 30 mg/kg KM) 29 3.3.3 Absolute Bioverfügbarkeit von Quercetin 30 3.3.4 Relative Bioverfügbarkeit verschiedener Quercetinglycoside 31 3.4 Probenaufarbeitung 31 3.5 HPLC 33 3.5.1 Methodenvalidierung und -kalibrierung 34 3.5.2 Berechnung der pharmakokinetischen Parameter 40 3.5.3 Statistische Auswertung 41 4 Ergebnisse 42 4.1 Bioverfügbarkeit von Quercetin und Rutin (je 30 mg/kg KM) 42 4.1.1 Quercetin-Aglycon 42 4.1.2 Rutin 46 4.2 Absolute Bioverfügbarkeit Quercetin 48 4.3 Relative Bioverfügbarkeit verschiedener Quercetinglycoside 52 4.3.1 Quercetin-Aglycon 53 4.3.2 Rutin 56 4.3.3 Isoquercitrin 57 5 Diskussion 62 5.1 Zielsetzung der Studie 62 5.2 Methodische Aspekte 62 5.2.1 Auswahl der Versuchstiere und Versuchsanordnung 62 5.2.2 Wahl der Testmahlzeit 63 5.2.3 Einfluss der Zeitpunkte für die Probennahme auf die Berechnung der Verfügbarkeit 64 5.2.4 Analysemethode 65 5.3 Plasmametaboliten von Quercetin 66 5.4 Absolute Bioverfügbarkeit von Quercetin 69 5.5 Relative Bioverfügbarkeit verschiedener Quercetinglycoside 70 5.5.1 Isoquercitrin 70 5.5.2 Rutin 71 5.6 Bezug der pharmakokinetischen Daten zu potentiellen In-vivo-Wirkungen 73 5.7 Schlussfolgerungen 75 6 Zusammenfassung 76 7 Summary 78 8 Literaturverzeichnis 80 9 Anhang 102 9.1 HPLC-Chemikaien 102 9.2 Validierung der HPLC-Methode 103 Danksagung 109 / 7 Summary Marianne Reinboth Bioavailability of the Flavonol Quercetin in Dogs Institute of Physiology of the Faculty of Veterinary Medicine, University of Leipzig Submitted in June 2010 79 pages, 20 figures, 6 tables, 211 references, 1 appendix Keywords: quercetin, bioavailability, dog, absolute bioavailability, isoquercitrin, rutin, flavonols The plant flavonol quercetin is supposed to exert multiple health-related effects in dogs. To date no information on its bioavailability in this particular species is avai-lable. This study intended to investigate bioavailability and pharmacokinetics of quercetin and certain quercetin glycosides in dogs after ingestion of a test meal sup-plemented with a quercetin dose equivalent to 10 mg/kg body weight. Nine adult beagle dogs of both sexes received the aglycon quercetin (sugarfree) or its glycosides isoquercitrin (quercetin-3-O-glucoside) and rutin (quercetin-3-O-glucorhamnoside) in equimolar amounts together with a test meal. Blood samples were taken over a period of up to 72 hours; bioavailability and pharmacokinetics were calculated from the HPLC-derived plasmaconcentration-time-curves. Absolute bioavailability was calculated by comparing an oral to an intravenous administration of quercetin. The majority of analysed plasma metabolites were glucuronidated and sulfated con-jugates of quercetin. Non-conjugated quercetin aglycon comprised only 20 %. Be-sides quercetin, its metabolites isorhamnetin and kaempferol made up less than 10 % of all circulating metabolites. The absolute bioavailability of quercetin was only 4 %. The relative bioavailability of quercetin from isoquercitrin was more than twice as high than from the aglycon, but even there maximal plasma concentrations were generally less than 1 μmol/l. Absorption from the small intestine was rather fast with a first plasma peak after 1 hour after ingestion of quercetin or isoquercitrin. A second, generally higher plasma peak occurred 4 hours after ingestion. This suggests an in-tensive enterohepatic recycling of biliary secreted metabolites. Absorption was significantly delayed after ingestion of rutin due to the necessity of bacterial deglycosilation in the large intestine. Plasma concentrations peaked only after 11 hours. Plasma concentrations after rutin were lower than after quercetin or isoquercitrin, but mean residence time of plasma metabolites was as long as 18 hours after rutin ingestion. Consequently, a once daily feeding of dogs with rutin might lead to relatively constant plasma metabolite concentrations. In contrast to other species, bioavailability from rutin was not smaller than that from quercetin. Although rutin seems to be a relative good quercetin source for dogs, estimations about potential in-vivo-effects of quercetin have to take into consideration its low bioavailabilty and intensive metabolism.:1 Einleitung 1 2 Literaturübersicht 3 2.1 Funktionen von Flavonoiden in Pflanzen 3 2.2 Biosynthese und Struktur von Flavonoiden 4 2.3 Flavonoidwirkungen im menschlichen und tierischen Organismus 7 2.3.1 Antioxidative Eigenschaften 10 2.3.2 Wirkungen auf Enzyme und Transportproteine des Arzneistoffwechsels 12 2.4 Bioverfügbarkeit und Stoffwechsel des Flavonols Quercetin 13 2.4.1 Bioverfügbarkeit von Quercetin 13 2.4.2 Einfluss des Futters 15 2.4.3 Einfluss des Glycosylierungsmusters 16 2.4.4 Intestinale Absorption und Metabolismus 18 2.4.5 Einfluss der intestinalen Mikroflora 21 2.4.6 Bindung an Plasmaproteine 22 2.4.7 Gewebeverteilung 23 2.4.8 Exkretion 24 2.5 Zielsetzung 25 3 Tiere, Material und Methoden 26 3.1 Versuchstiere und Haltungsbedingungen 26 3.2 Verwendete Flavonole 27 3.3 Durchführung des Tierversuchs 28 3.3.1 Allgemeine Durchführung der Versuche 28 3.3.2 Bioverfügbarkeit von Quercetin und Rutin (je 30 mg/kg KM) 29 3.3.3 Absolute Bioverfügbarkeit von Quercetin 30 3.3.4 Relative Bioverfügbarkeit verschiedener Quercetinglycoside 31 3.4 Probenaufarbeitung 31 3.5 HPLC 33 3.5.1 Methodenvalidierung und -kalibrierung 34 3.5.2 Berechnung der pharmakokinetischen Parameter 40 3.5.3 Statistische Auswertung 41 4 Ergebnisse 42 4.1 Bioverfügbarkeit von Quercetin und Rutin (je 30 mg/kg KM) 42 4.1.1 Quercetin-Aglycon 42 4.1.2 Rutin 46 4.2 Absolute Bioverfügbarkeit Quercetin 48 4.3 Relative Bioverfügbarkeit verschiedener Quercetinglycoside 52 4.3.1 Quercetin-Aglycon 53 4.3.2 Rutin 56 4.3.3 Isoquercitrin 57 5 Diskussion 62 5.1 Zielsetzung der Studie 62 5.2 Methodische Aspekte 62 5.2.1 Auswahl der Versuchstiere und Versuchsanordnung 62 5.2.2 Wahl der Testmahlzeit 63 5.2.3 Einfluss der Zeitpunkte für die Probennahme auf die Berechnung der Verfügbarkeit 64 5.2.4 Analysemethode 65 5.3 Plasmametaboliten von Quercetin 66 5.4 Absolute Bioverfügbarkeit von Quercetin 69 5.5 Relative Bioverfügbarkeit verschiedener Quercetinglycoside 70 5.5.1 Isoquercitrin 70 5.5.2 Rutin 71 5.6 Bezug der pharmakokinetischen Daten zu potentiellen In-vivo-Wirkungen 73 5.7 Schlussfolgerungen 75 6 Zusammenfassung 76 7 Summary 78 8 Literaturverzeichnis 80 9 Anhang 102 9.1 HPLC-Chemikaien 102 9.2 Validierung der HPLC-Methode 103 Danksagung 109

This thesis investigates the connections between henselian valuations and absolute Galois groups. There are fundamental links between these: On one hand, the absolute Galois group of a field often encodes information about (henselian) valuations on that field. On the other, in many cases a henselian valuation imposes a certain structure on an absolute Galois group which makes it easier to study. We are particularly interested in the question of when a field admits a non-trivial parameter-free definable henselian valuation. By a result of Prestel and Ziegler, this does not hold for every henselian valued field. However, improving a result by Koenigsmann, we show that there is a non-trivial parameter-free definable valuation on every henselian valued field. This allows us to give a range of conditions under which a henselian field does indeed admit a non-trivial parameter-free definable henselian valuation. Most of these conditions are in fact of a Galois-theoretic nature. Throughout the thesis, we discuss a number of applications of our results. These include fields elementarily characterized by their absolute Galois group, model complete henselian fields and henselian NIP fields of positive characteristic, as well as PAC and hilbertian fields.

In this thesis we consider three different problems in the domain of portfolio optimisation. The first problem we consider is that of selecting an Absolute Return Portfolio (ARP). ARPs are usually seen as financial portfolios that aim to produce a good return regardless of how the underlying market performs, but our literature review shows that there is little agreement on what constitutes an ARP. We present a clear definition via a three-stage mixed-integer zero-one program for the problem of selecting an ARP. The second problem considered is that of designing a Market Neutral Portfolio (MNP). MNPs are generally defined as financial portfolios that (ideally)exhibit performance independent from that of an underlying market, but, once again, the existing literature is very fragmented. We consider the problem of constructing a MNP as a mixed-integer non-linear program (MINLP) which minimises the absolute value of the correlation between portfolio return and underlying benchmark return. The third problem is related to Exchange-Traded Funds (ETFs). ETFs are funds traded on the open market which typically have their performance tied to a benchmark index. They are composed of a basket of assets; most attempt to reproduce the returns of an index, but a growing number try to achieve a multiple of the benchmark return, such as two times or the negative of the return. We present a detailed performance study of the current ETF market and we find, among other conclusions, constant underperformance among ETFs that aim to do more than simply track an index. We present a MINLP for the problem of selecting the basket of assets that compose an ETF, which, to the best of our knowledge, is the first in the literature. For all three models we present extensive computational results for portfolios derived from universes defined by S&P international equity indices with up to 1200 stocks. We use CPLEX to solve the ARP problem and the software package Minotaur for both our MINLPs for MNP and an ETF.

Our work falls within the field of high resolution spectroscopy of gas phase molecules in the far-, mid- and near-infrared ranges. Its guiding line are absorption spectral intensities, dealt with experimentally and theoretically. In particular, we developed in our laboratory the field of intensities measurements of vibration-rotation lines using Fourier transform spectrometers, with a precision of about 0.5 % and an accuracy of 2-4 % for chemically stable species. We study chemically stable (CO2, N2O, C2H6, OCS, C2H2) and unstable (HOCl, HCOOH et HNO3) compounds. We also measure infrared absorption cross section spectra for CFC replacements. Some of our measured intensities, of direct interest for the study of planetary atmospheres, are now incorporated in international spectroscopic databases. Others are used to develop global theoretical models of molecules, in relationship with intra-molecular dynamics./Nos travaux de recherches relèvent de la spectroscopie à haute résolution de molécules en phase gazeuse dans les domaines de l’infrarouge lointain, moyen et proche. Ils ont pour ligne directrice les intensités spectrales d’absorption, abordées expérimentalement et théoriquement. Nous avons en particulier développé dans notre laboratoire le domaine de la mesure d’intensités d’absorption de raies de vibration-rotation à l’aide de spectromètres à transformée de Fourier. Nous réalisons ces mesures avec une précision d’environ 0.5 % et une exactitude d'environ 2-4 % pour les espèces chimiquement stables. Nous étudions des composés chimiquement stables (CO2, N2O, C2H6, OCS, C2H2) et instables (HOCl, HCOOH et HNO3). Nous mesurons également des spectres de sections efficaces d’absorption infrarouge pour des substituts des chlorofluorocarbures (CFC). Certaines de nos mesures d’intensité, d’intérêt direct pour l’étude d’atmosphères planétaires, sont aujourd’hui incorporées dans les bases de données spectroscopiques internationales. D’autres sont utilisées pour développer des modèles théoriques globaux de molécules, en liaison avec la dynamique intramoléculaire.

An employee is usually entitled to representation in a disciplinary hearing. The question arises whether this representation includes legal representation or whether it is limited to representation by union representatives or a fellow employee? An employee's right to legal representation will in most cases be determined by a collective agreement, the employment contract or a disciplinary code. Over the years the Courts have indicated that they are not prepared to grant an absolute right to legal representation in disciplinary enquiries. Yet in some cases the courts found legal representation to be a sine qua non for a fair hearing and an intrinsic part of natural justice. It seems that the conclusion that can be drawn from this research is that legal representation might soon become a requirement for a fair disciplinary hearing in serious and complex matters. This research looks at numerous decisions both in die public and private sector before and after 1994. The right to legal representation is also discussed in the light of a fair hearing. The various advantages and disadvantages of legal representation are briefly examined. It is argued that all employees should be granted legal representation in complex and serious matters where the employee is likely to be dismissed. It is thus said that all presiding officers should be granted a discretion to allow legal representation in serious and complex matters. / Thesis (LL.M. (Labour Law))--North-West University, Potchefstroom Campus, 2006.

This thesis deals with the instabilities of the incompressible boundary-layer flow thatis induced by a disk rotating in otherwise still fluid. The results presented include bothwork in the linear and nonlinear regime and are derived from direct numerical sim-ulations (DNS). Comparisons are made both to theoretical and experimental resultsproviding new insights into the transition route to turbulence. The simulation codeNek5000 has been chosen for the DNS using a spectral-element method (SEM) witha high-order discretization, and the results were obtained through large-scale paral-lel simulations. The known similarity solution of the Navier–Stokes equations for therotating-disk flow, also called the von K ́arm ́an rotating-disk flow, is reproduced by theDNS. With the addition of modelled small simulated roughnesses on the disk surface,convective instabilities appear and data from the linear region in the DNS are anal-ysed and compared with experimental and theoretical data, all corresponding verywell. A theoretical analysis is also presented using a local linear-stability approach,where two stability solvers have been developed based on earlier work. Furthermore,the impulse response of the rotating-disk boundary layer is investigated using DNS.The local response is known to be absolutely unstable and the global response, onthe contrary, is stable if the edge of the disk is assumed to be at radius infinity. Herecomparisons with a finite domain using various boundary conditions give a globalbehaviour that can be both linearly stable and unstable, however always nonlinearlyunstable. The global frequency of the flow is found to be determined by the Rey-nolds number at the confinement of the domain, either by the edge (linear case) or bythe turbulence appearance (nonlinear case). Moreover, secondary instabilities on topof the convective instabilities induced by roughness elements were investigated andfound to be globally unstable. This behaviour agrees well with the experimental flowand acts at a smaller radial distance than the primary global instability. The sharpline corresponding to transition to turbulence seen in experiments of the rotating diskcan thus be explained by the secondary global instability. Finally, turbulence datawere compared with experiments and investigated thoroughly. / <p>QC 20170203</p>

Significant growth rates are in many times associated with countries embracing the ongoing globalization and openness to the international market of exchanging goods and services as well as ideas and technologies. Many researchers believe that participating in an international economy is a primary source of growth. The question is how strong the relationship between openness and growth is and has interested many researchers. This paper aims to investigate the effects of trade openness on economic growth in the long run and begins from Adam smith`s discussion on absolute advantage and specialization to discussions on trade organizations and policies. This study explores the relationship between trade openness and economic growth using a sample of 3 developed countries over the period (1970 – 2006) in a panel data analysis. The fixed effects model analysis indicates that trade openness has a positive and significant effect on economic growth.

The purpose of this paper is to investigate the integrability, measurability, and summability of certain set functions. The paper is divided into four chapters. The first chapter contains basic definitions and preliminary remarks about set functions and absolute continuity. In Chapter i, the integrability of bounded set functions is investigated. The chapter culminates with a theorem that characterizes the transmission of the integrability of a real function of n bounded set functions. In Chapter III, measurability is defined and a characterization of the transmission of measurability by a function of n variables is provided, In Chapter IV, summability is defined and the summability of set functions is investigated, Included is a characterization of the transmission of summability by a function of n variables.

This work attempts to offer an insight into the problematic of the genus Elettariopsis Baker, the last unrevised genus in the subfamily Alpinioideae (Zingiberaceae). Phylogenetic analyses are performed on ITS, matK and DCS sequence data and correlated with absolute genome size and biogeographical distribution of the samples. Elettariopsis as a genus is found to be weakly supported and strongly supported only with the addition of some species of Amomum Roxb., including the type species A. subulatum. The absolute genome size in this group is greater than in the outgroup represented by members of the Zingiberoideae subfamily. The evidence given by sequence data further suggests that Elettariopsis is divided into two well-supported groups, the "E. curtisii" group and the "E. triloba/E. unifolia" group, each of which contains several well-supported clades. In the analysis of absolute genome size it is shown that the absolute genome size in the "E. triloba/E.unifolia" group is higher than in the "E. curtisii" group. These two groups also differ slightly in their biogeographical distribution, the group G being distributed in only in Vietnam, Laos, and Thailand, while members of group H are also occurring in Singapore and Indonesia (Borneo). Keywords: Zingiberaceae, Elettariopsis, South-East Asia, ITS,...

This diploma thesis compares the Spanish verb system with the Czech one in terms of expressing temporal relations. We use the InterCorp parallel synchronic corpus to examine the Spanish tenses of presente, pretérito imperfecto, pretérito perfecto simple, futuro simple, condicional simple, pretérito perfecto compuesto, pretérito pluscuamperfecto, pretérito anterior, futuro compuesto a condicional compuesto in the indicative mode and also the infinitive verb forms of infinitivo simple, infinitivo compuesto, gerundio simple a gerundio compuesto. We look for the Czech equivalents to the complex temporal meanings of the Spanish verb.