La fusariose des épis, causée majoritairement par le champignon pathogène Fusarium graminearum (Fg), est une des principales maladies du blé tendre (Triticum aestivum). Pendant son cycle infectieux, l’agent pathogène produit des mycotoxines appartenant principalement aux trichothécènes de type B, tel que le déoxynivalénol (DON), qui sont toxiques pour l’homme et l’animal. Plusieurs loci à caractère quantitatif (QTLs) impliqués dans la résistance à la fusariose des épis ont été identifiés. Certains ont été corrélés avec une détoxication de la mycotoxine, principalement par conjugaison du DON en DON-3-O-glucose (D3G), une réaction enzymatique catalysée par des UDP-glucosyltransferases (UGT). Néanmoins, peu d’études ont conduit des analyses fonctionnelles dans des plantes hôtes de la maladie afin de relier directement la glucosylation de la mycotoxine avec la résistance à la maladie in planta, et aucune d’entre elles n'a été effectuée sur des gènes de détoxication du blé tendre. Notre équipe, à l'aide de la céréale modèle Brachypodium distachyon, a démontré que l'UGT Bradi5g03300 est capable de conférer une tolérance au DON par glucosylation en DON 3-O-glucose et qu’elle est impliquée dans l'établissement précoce d'une résistance quantitative à la fusariose des épis. Le présent travail avait pour objectif de transférer les analyses fonctionnelles menées sur la céréale modèle Brachypodium distachyon au blé tendre. Dans une première approche, le gène Bradi5g03300 a été introduit dans la variété de blé Apogée, sensible à la fusariose. Les analyses phénotypiques effectuées sur les lignées de blé transgéniques exprimant constitutivement le gène Bradi5g03300, montrent une résistance plus élevée à la maladie ainsi qu'une tolérance à la mycotoxine par rapport à la lignée contrôle. Parallèlement, en utilisant une approche de synténie entre les génomes de B. distachyon et du blé tendre, nous avons identifié un gène de blé, orthologue au gène Bradi5g03300.La transformation de l’écotype de B. distachyon sensible à la fusariosepar ce gène candidat a été effectuée pour déterminer rapidement sa capacité à conjuguer le DON in planta et son implication dans la résistance à la fusariose. En conclusion, ce projet contribue à accroître les connaissances concernant la relation fonctionnelle entre la glucosylation DON et la résistance à la fusariose dans le blé tendre et à fournir des gènes candidats à inclure dans les processus de sélection. / Fusarium head blight (FHB) caused by fungi of the Fusarium genus is a widespread disease of wheat (Triticum aestivum) and other small-grain cereal crops. The main causal agent of FHB, Fusarium graminearum, can produce mycotoxins mainly belonging to type B trichothecenes, such as deoxynivalenol (DON) that can negatively affect humans, animals and plants. Several quantitative trait loci (QTLs) for resistance to FHB have been identified some of which have been correlated with efficient DON detoxification, mainly through the conjugation of DON into DON-3-O-glucose (D3G), a reaction catalyzedby UDP-glucosyltransferases (UGTs). Nevertheless, only few studies have conducted functional analyses to directly correlate DON glucosylation and resistance in planta and none were performed on wheat UGT gene(s). Our team, using the model cereal species Brachypodium distachyon, has recently demonstrated that the Bradi5g03300 UGT is able to confer tolerance to DON following glucosylation of DON into DON 3-O-glucose and is involved in the early establishment of quantitative resistance to FHB. In the present work, we transferred the functional analyses conducted on the model species Brachypodium distachyon to bread wheat. In a first approach the B. distachyon Bradi5g03300 gene has been introduced through biolistic-mediated transformation in the wheat variety Apogee, susceptible to FHB. The phenotypic analyses conducted on homozygous transgenic wheat constitutively expressing the Bradi5g03300 gene showed that they exhibit higher resistance to FHB as well as increased root tolerance to DON compared to the control line. In parallel, using a synteny approach between B. distachyon and bread wheat genomes we identified a wheat candidate gene orthologous to the B. distachyon Bradi5g03300 gene. This wheat gene after validation through gene expression pattern during wheat infection, was introduced by transformation into B. distachyon to rapidly determine its ability to conjugate DON into D3G in planta and its involvement in FHB resistance. In conclusion, this project contributes to increase the knowledge concerning the functional relationship between DON glucosylation and FHB resistance in wheat and provide candidate genes to include in selection processes.

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<p>Cytochrome P450s (CYPs) are enzymes that are found throughout the three domains of life. They function in the metabolism of endogenous and exogenous compounds. CYPs are extensively studied in mammalian systems due to their importance in drug metabolism and are highly expressed in detoxification organs like the liver and intestine. Fish CYP3s are not well understood. CYP3s have diversified in fish and subfamilies A, B, C and D constitute the CYP3 clade in fish. In this study, CYP3C1, CYP3C2, CYP3C3 and CYP3C4 in zebrafish (<em>Danio rerio</em>) and CYP3B4, CYP3B5 and CYP3B6 in medaka (<em>Orzyias latipes</em>) were quantified in hepatic and extrahepatic organs. CYP3C genes were quantified throughout development. All CYP3B and 3C isoforms were detected in all organs except CYP3B4 in male organs and in female brain. CYP3C1-C3 were maternally acquired and expressed in all embryonic stages. Higher expression of some of the isoforms occurred in the liver and intestine of zebrafish and medaka. This is indicative of a possible role in xenobiotic metabolism. Differences in expression between males and females gonad was observed, suggesting a possible role for estrogen in gene regulation. Further research will contribute to characterizing the upstream response elements in order to understand whether estrogens or other compounds are responsible for CYP3 regulation in fish. This knowledge will contribute to understanding the potential function these unique families of CYPs serve for fish.</p> / Master of Science (MSc)

Metallohydrolases with dinuclear-zinc active sites perform many important biological hydrolytic reactions on a variety of substrates. In this regard, metallo-β-lactamases (mβ1, class B) represent a unique subset of zine hydrolases that hydrolyze the β-lactam ring in several antibiotics. The antibiotic resistance that results from this hydrolysis is becoming an increased threat for the clinical community. These metalloenzymes can hydrolyze a wide range of β-lactam substrates, such as cephamycins and imipenem that are generally resistant t the serine-containing β-lactamases. Therefore, the clinical application of the entire range of antibiotics is severely compromised in bacteria that produce mβls. Due to the lack of information on the mechanism of mβls, to-date, no clinically known inhibitors is there for mβls. In this present study, we synthesized several mono and dizinc complexes as models for the mβls and investigated the differences in their hydrolytic properties. This study supports the assumption that the second zinc in the dinuclear enzymes does not directly involve in the catalysis, but may orient the substrates for hydrolysis and the basic amino acid residues such as Asp and His may activate the zinc-bound water molecules, fulfilling the role of the second zinc in the mononuclear enzymes. The effect of various side chains on the hydrolysis of some commonly used cephalosporin antibiotics by mβl from B.cereus is described. It is shown that the cephalosporins having heterocyclic thiol side chains are more resistance to mβl-mediated hydrolysis than the antibiotics that do not have such side chains. This is partly due to the inhibition of enzyme activity by the thiol moieties eliminated during the hydrolysis. It is also observed that the heterocyclic side chains in pure form inhibit the lactamase activity of mβl as well as its synthetic mimics. The mode of binding of these heterocyclic side chains to the zinc has been analyzed from the crystal structure of the tetranuclear zinc complexes. The theoretical studies suggest that the eliminated heterocyclic thiols undergo a rapid tautomerism to produce the corresponding thiones. These thiones are found to irreversibly inhibit the LPO-catalyzed iodination reaction. The reaction of various thiones with I2 leads to the formation of thione-iodine complexes similar to that of the most commonly used antithyroid drug methimazole(MMI). These observations suggest that some of the latest generation of antibiotics may show negative effects on thyroid gland upon hydrolysis. Synthetic organophosphorus compounds have been used extensively as pesticides and petroleum additives. These compounds are very toxic to mammals and their widespread use in agriculture leads to serious environmental problems. Therfore, degradation of organophosphorus trimesters and remediation of associated contaminated sites are of worldwide concern. In this regards, the bacterial phsophotriesterase (PTE) enzyme plays an important role in degrading a wide range of organophosphorus esters and the active side of PTE has been shown to be very similar to that of mβl. This identification prompted us to check the hydrolysis of phosphotriesters by the mβl and its mimics. It has been observed that the dinuclear zine(II) complexes that do not allow a strong binding of phosphodiestes would be a better PTE mimics.

One of the major outcomes of a genome sequencing project is the availability of amino acid sequences of all the proteins encoded in the genome of the organism concerned. However, most commonly, for a substantial proportion of the proteins encoded in the genome no information in function is available either from experimental studies or by inference on the basis of homology with a protein of known function. Even if the general function of a protein is known, the region of the protein corresponding to the function might be a domain and there may be additional regions of considerable length in the protein with no known function. In such cases the information on function is incomplete. Lack of understanding of the repertoire of functions of proteins encoded in the genome limits the utility of the genomic data. While there are many experimental approaches available for deciphering functions of proteins at the genomic scale, bioinformatics approaches form a good early step in obtaining clues about functions of proteins at the genomic scale (Koonin et al, 1998). One of the common bioinformatics approaches is recognition of function by homology (Bork et al, 1994). If the evolutionary relationship between two proteins, one with known function and the other with unknown function, could be established it raises the possibility of common function and 3-D structure for these proteins(Bork and Gibson, 1996). While this approach is effective its utility is limited by the ability of the bioinformatics approach to identify related proteins when their evolutionary divergence is high leading to low amino acid sequence similarity which is typical of two unrelated proteins (Bork and Koonin, 1998). Use of 3-D structural information, obtained by predictive methods such as fold recognition, has offered approaches towards increasing the sensitivity of remote homology detection 9e.g., Kelley et al, 2000; Shi et al, 2001; Gough et al, 2001). The work embodied in this thesis has the general objective of analysis of evolution of structural features and functions of families of proteins and design of new bioinformatics approaches for recognizing distantly related proteins and their applications. After an introductory chapter, a few chapters report analysis of functional and structural features of homologous protein domains. Further chapters report development and assessment of new remote homology detection approaches and applications to the proteins encoded in two protozoan organisms. A further chapter is presented on the analysis of proteins involved in methylglyoxal detoxification pathways in kinetoplastid organisms. Chapter I of the thesis presents a brief introduction, based on the information available in the literature, to protein structures, classification, methods for structure comparison, popular methods for remote homology detection and homology-based methods for function annotation. Chapter 2 describes the steps involved in the update and improvements made in this database. In addition to the update, the domain structural families are integrated with the homologous sequences from the sequence databases. Thus, every family in PALI is enriched with a substantial volume of sequence information from proteins with no known structural information. Chapter 3 reports investigations on the inter-relationships between sequence, structure and functions of closely-related homologous enzyme domain families. Chapter 4 describes the investigations on the unusual differences in the lengths of closely-related homologous protein domains, accommodation of additional lengths in protein 3-D structures and their functional implications. Chapter 5 reports the development and assessment of a new approach for remote homology detection using dynamic multiple profiles of homologous protein domain families. Chapter 6 describes development of another remote homology detection approach which are multiple, static profiles generated using the bonafide members of the family. A rigorous assessment of the approach and strategies for improving the detection of distant homologues using the multiple profile approach are discussed in this chapter. Chapter 7 describes results of searches made in the database of multiple family profiles (MulPSSM database) in order to recognize the functions of hypothetical proteins encoded in two parasitic protozoa. Chapter 8 describes the sequence and structural analyses of two glyoxalase pathway proteins from the kinetoplastid organism Leishmania donovani which causes Leishmaniases. An alternate enzyme, which would probably substitute the glyoxalase pathway enzymes in certain kinetoplastid organisms which lack the glyoxalase enzymes are also discussed. Chapter 9 summarises the important findings from the various analyses discussed in this thesis. Appendix describes an analysis on the correlation between a measure of hydrophobicity of amino acid residues aligned in a multiple sequence alignment and residue depth in 3-D structures of proteins.

Effects of man made pollutants on an ecosystem are initiated at the cellular level where a prime determinant for survival of an organism is its ability to metabolise and excrete toxic chemicals or their metabolites, thereby preventing cellular toxicity or damage to germ cell DNA. Cytochrome P450 (CYP) enzymes are responsible (in concert with the remainder of the Ah battery enzymes) for the metabolism of numerous xenobiotics and endogenous compounds, including the metabolic activation of most environmental toxic chemicals and carcinogens. Genetic polymorphisms which affect performance of these enzymatic detoxification systems may alter tolerance to pollutants and thus survival in polluted environments. Alterations in the susceptibility of individuals and the development of resistant populations has arisen by forced selection of populations with variant genes, resulting in increased detoxification capacity. There is evidence for such scenarios of variations in activities of pollutant biotransforming enzymes of fish contributing to survival in polluted estuarine environments and several chemically resistant populations have been identified in the USA and Europe. In fish it has been demonstrated that CYP1A enzyme activity is required to activate some carcinogenic xenobiotics to a metabolic state in which they can form DNA adducts. The mechanism of reduced CYP1A expression in highly contaminated populations may therefore represent resistance to chemical stressors. European flounder (Platichthys flesus) from some waterways which have a long history of severe sedimentary contamination do not show elevated levels of CYP1A. The aim of the current study was to investigate whether any heritable differences were apparent between offspring from parents inhabiting long-term polluted and pristine areas. Flounder were obtained from a highly polluted estuary in the UK and crossed with fish from a relatively pristine environment. Offspring were raised in communal tanks in order to standardise environmental conditions, and allow investigations into the genetic variation of CYP1A. To allow identification of offspring to parental fish, polymorphic microsatellite loci were isolated and characterised for the flounder. Novel cDNA probes to transcription factors in the detoxification pathway (AhR2 and ARNT2) were cloned for flounder, and RT-PCR / Southern blot methods were developed for quantitation of gene transcript levels. A novel method of CYP1A quantification using real-time PCR was developed. PAH and PCB exposure trials were carried out on mixed batch offspring, and CYP1A gene transcript levels assessed using Northern blot and real-time PCR techniques. Offspring were genotyped to their parents using the microsatellites obtained, and CYP1A transcript levels were correlated with clean and polluted areas. CYP1A was further correlated to transcription factor expression, and data are presented. Following exposure to the commercial PCB mixture, Aroclor 1254, CYP1A transcript levels were found to be significantly lower in families whose parents originated from a polluted area. This observation indicates that there is a possible genetic component to variation in CYP1A levels, and that these fish may have acquired a heritable tolerance to polluted areas. The lack of induction, or correlation with CYP1A levels, of AhR2 and ARNT2 expression indicates a possible AhR independent pathway for the metabolism of PCBs in the flounder. © Tom Dixon 2003 http://www.tomdixon.org

Die vorliegende Arbeit beschäftigt sich mit zwei verschiedenen Therapieformen des Alkoholentzugs. Es geht um den Vergleich einer rein somatischen, sechs bis siebentätigen Kurzzeitentgiftung einerseits mit der ca. dreiwöchigen Qualifizierten Entgiftung andererseits. Im Verlauf der letzten Jahre belegten zahlreiche Untersuchungen die Überlegenheit der Qualifizierten Entgiftung (QE) gegenüber der Kurzzeitentgiftung (KE). Allerdings gab es bisher kaum Studien, die zeigen, welche Faktoren eine Teilnahme an der QE begünstigen. Ziel der vorliegenden Arbeit war es daher, patienten- und umweltbezogene Merkmale zu untersuchen, die mit der Qualifizierten Entgiftung assoziiert sind. Zu diesem Zweck erfolgte die retrospektive Auswertung der Krankenakten von 155 Patienten (KE: 99, QE: 56). Anhand eines selbsterstellten Auswertungsbogens wurden 55 Items erhoben. Davon gingen 47 in die Auswertung ein und wurden zunächst hinsichtlich ihres Einflusses auf die gewählte Therapieart untersucht. Anschließend wurden diese Items bezüglich geschlechts- und altersspezifischer Unterschiede beleuchtet. Nach Abschluss der univariaten Analyse erfolgte eine multivariate Analyse, um den unabhängigen Einfluss der Variablen zu prüfen. Da die Untersuchung als retrospektive Aktenauswertung erfolgte, sind die Ergebnisse vorsichtig zu interpretieren. Dennoch konnten zahlreiche Erkenntnisse gewonnen werden, die einen differenzierteren Umgang mit den Patienten ermöglichen und langfristig genutzt werden können, um mehr Patienten in die Qualifizierte Entgiftung zu integrieren. Angesichts der Tatsache, dass es bisher kaum Veröffentlichungen gibt, die zeigen, welche Faktoren eine Teilnahme an der QE begünstigen, liefert die vorliegende Arbeit wichtige neue Erkenntnisse, die gegebenenfalls in prospektiven Studien näher untersucht werden sollten. Unsere Daten zeigen deutlich, dass die Teilnehmer der QE häufiger männlich waren, meist geplant zur Aufnahme kamen, besser sozial integriert und häufig fremdmotiviert waren sowie eine größerer Eigenmotivation aufwiesen. Außerdem zeigten sie weniger Alkoholfolgesyndrome und befanden sich zum Zeitpunkt der Aufnahme in einem besseren Gesundheitszustand. Desweiteren fiel auf, dass Frauen nur sehr selten geplant an einer Qualifizierten Entgiftung teilnahmen, sondern meist nur eine Kurzzeitentgiftung im Rahmen akuter alkoholbedingter Komplikationen oder psychiatrischer Begleiterkrankungen absolvierten. Zusammenfassend lässt sich sagen, dass es nur selten gelang, notfallmäßig aufgenommene Patienten, v.a. Frauen, zur QE zu motivieren. Dies könnte u.a. daran liegen, dass eine sechs- bis siebentägige Entgiftung nicht genügt, um eine ausreichende Rückbildung kognitiver Defizite zu erreichen und eine Motivation zur QE herbeizuführen. Außerdem ist es speziell für Frauen schwierig, sich aufgrund ihres Rollenverständnisses und ihrer Biografie in gemischtgeschlechtlichen Gruppen mit der Alkoholabhängigkeit auseinanderzusetzen. Für die Zukunft wäre es daher wünschenswert, den zeitlichen Rahmen für die Entgiftung zu erweitern und mehr Therapien anzubieten, die speziell auf die Bedürfnisse alkoholabhängiger Frauen ausgerichtet sind. In unserer Klinik waren die Ergebnisse der vorliegenden Studie Anlass, den Anteil der weiblichen Therapeuten in der Qualifizierten Entgiftung zu erhöhen. Wir hoffen, dadurch mehr Frauen für die Teilnahme an der QE zu motivieren und traumatische Biografien in einem geschützten Rahmen aufzuarbeiten. Inwieweit dies langfristig zu einer verstärkten Teilnahme weiblicher Alkoholabhängiger an der QE führt, sollte in weiterführenden Studien geprüft werden. Außerdem sollte versucht werden, das soziale Netz der Patienten und insbesondere die niedergelassenen Haus- und Fachärzte noch stärker in das Suchthilfesystem einzubinden, um eine Qualifizierte Entgiftung langfristig und effektiv vorbereiten zu können. Insgesamt bleibt festzuhalten, dass eine Qualifizierte Entgiftung möglichst frühzeitig erfolgen sollte. Sind bereits Alkoholfolgeschäden, kognitive Defizite und soziale Isolation eingetreten, fällt es zunehmend schwerer Patienten in eine QE zu integrieren.:INHALTSVERZEICHNIS 1 EINLEITUNG 1 1.1 Die Qualifizierte Entgiftung 1 1.2 Grenzen der QE 3 1.3 Entstehung, Aufrechterhaltung und Therapie des Alkoholismus 3 1.3.1 Entstehung und Aufrechterhaltung des Alkoholismus 3 1.3.2 Therapiemotivation und Prognosefaktoren bei alkoholabhängigen Patienten 3 1.3.2.1 Förderung der Motivation 4 1.3.2.2 Faktoren mit positivem Einfluss auf die Beibehaltung der Abstinenz 4 1.3.2.3 Faktoren mit negativem Einfluss auf Therapieverlauf und Prognose der Abhängigkeit 5 1.3.2.4 Weitere Faktoren mit Einfluss auf den Therapieerfolg 6 2 ZIELSETZUNG 7 3 MATERIAL UND METHODE 8 3.1 Therapieverfahren: KE und QE 8 3.2 Die Datenerhebung 10 3.3 Einschlusskriterien 10 3.4 Ausschlusskriterien 11 3.5 Der Auswertungsbogen 12 3.6 Statistische Methoden 12 3.7 Datenschutz 13 4 ERGEBNISSE 14 4.1 Gesamtstichprobe 14 4.2 Vergleich von KE und QE 15 4.2.1 Soziodemografische Faktoren 15 4.2.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 20 4.2.3 Bisherige und zukünftige Therapien 22 4.2.4 Angaben zum Indexaufenthalt 25 4.2.5 Angaben zur Suchtanamnese 29 4.2.6 Angaben zur Therapiemotivation 32 4.2.7 Aufnahme- und entlassungsbezogene Merkmale 35 4.3 Vergleich von Männern und Frauen 39 4.3.1 Soziodemografische Faktoren 39 4.3.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 41 4.3.3 Bisherige und zukünftige Therapien 42 4.3.4 Angaben zum Indexaufenthalt 44 IV Kurzzeitentgiftung und Qualifizierte Entgiftung – eine vergleichende Untersuchung 4.3.5 Angaben zur Suchtanamnese 47 4.3.6 Angaben zur Therapiemotivation 51 4.3.7 Aufnahme- und entlassungsbezogene Merkmale 51 4.4 Vergleich von Patienten, die jünger als 40 Jahre waren mit Patienten, die 40 Jahre oder älter waren 51 4.4.1 Soziodemografische Faktoren 51 4.4.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 54 4.4.3 Bisherige und zukünftige Therapien 55 4.4.4 Angaben zum Indexaufenthalt 55 4.4.5 Angaben zur Suchtanamnese 56 4.4.6 Angaben zur Therapiemotivation 58 4.4.7 Aufnahme- und entlassungsbezogene Merkmale 59 4.5 Übersichtstabelle 59 4.6 Multivariate Analysen 61 5 DISKUSSION 65 5.1 Methodenkritik 65 5.2 Ergebnisse 65 5.2.1 Vergleich von KE und QE 65 5.2.1.1 Soziodemografische Faktoren 65 5.2.1.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 66 5.2.1.3 Bisherige und zukünftige Therapien 67 5.2.1.4 Angaben zum Indexaufenthalt 68 5.2.1.5 Angaben zur Suchtanamnese 70 5.2.1.6 Angaben zur Therapiemotivation 70 5.2.1.7 Aufnahme- und entlassungsbezogene Merkmale 71 5.2.2 Vergleich von Männern und Frauen 73 5.2.2.1 Soziodemografische Faktoren 73 5.2.2.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 74 5.2.2.3 Bisherige und zukünftige Therapien 74 5.2.2.4 Angaben zum Indexaufenthalt 74 5.2.2.5 Angaben zur Suchtanamnese 75 5.2.2.6 Angaben zur Therapiemotivation 76 5.2.2.7 Aufnahme- und entlassungsbezogene Merkmale 76 5.2.3 Vergleich von Patienten, die jünger als 40 Jahre waren mit Patienten, die 40 Jahre oder älter waren 77 5.3 Interpretation der Ergebnisse der multivariaten Analyse 78 5.4 Konsequenzen für Praxis und zukünftige Forschung 79 6 ZUSAMMENFASSUNG 81 7 ABSTRACT 84 V Kurzzeitentgiftung und Qualifizierte Entgiftung – eine vergleichende Untersuchung 8 LITERATURVERZEICHNIS 86 9 ANLAGEN 92 10 SELBSTÄNDIGKEITSERKLÄRUNG 109 11 LEBENSLAUF 110 12 DANKSAGUNG 112 / This study deals with two different forms of alcohol detoxification therapy. A “simple” somatic detoxification program (KE), lasting six to seven days, was compared with a qualified detoxification program (QE) having a duration of approximately 3 weeks. In recent years research has shown that qualified detoxification programs are more effective than simple somatic detoxification. However, so far there have been few publications showing which factors cause patients to take part in QE. Consequently, the aim of our study was to examine patient-related and environmental factors that are associated with the assignment to qualified detoxification. We completed a retrospective analysis of 155 patients´ charts (KE: 99, QE: 56). With the help of a self-made questionnaire, 55 items were evaluated, of which 47 were included into statistical analysis. First, their influence on the type of chosen therapy was examined. Then the same items were tested on gender-specific and age-related differences. After finishing the univariate analysis a multivariate analysis was completed to investigate the independent influence of the variables. This study was designed as a retrospective data analysis, and the results should be interpreted critically. Nevertheless useful information could be gained, that allows dealing with the patients in a more differentiated way. This knowledge can be used to increase the number of patients taking part in qualified detoxification. Considering the fact that so far there have been very few publications, examining which factors support assignment to QE, our study provides important new data which should be further examined in prospective studies. Our data clearly shows that participants of qualified detoxification were mostly male and that their admission to hospital was planned in advance. Moreover, they had a good social network, better motivation for therapy, and were motivated more often to take part in therapy by their social network. They showed less negative consequences as a result of drinking and were in a better state of health at the time of admission. Another remarkable aspect was that women hardly ever took part in a planned QE. Mostly they only did a KE during treatment for acute alcohol-related complications or psychiatric comorbidities. Patients who had been admitted to the hospital as an emergency, especially women, rarely could be motivated to take part in QE. One reason might be that the time frame of 6 to 7 days for somatic detoxification might not be long enough to allow patients to recover from cognitive deficits and to motivate them to take part in QE. Another issue is that, due to their social role and personal history, dealing with their addiction is difficult for women, especially in mixed-gender groups. For the future it would be desirable to extend the time frame for somatic detoxification and to offer more programs that specifically deal with problems of female alcoholics. In our clinic, the results of this study caused us to increase the number of female therapists in our qualified detoxification program. This way we hope to motivate more women to take part in QE and to be able to deal with their personal problems in a protected atmosphere. Whether this will increase participation of female alcoholics in QE should be further examined by future studies. The social network of the patient, general practitioners, and outpatient specialists should be better integrated into treatment programs to successfully prepare patients for participation in QE programs. We believe that patients should take part in qualified detoxification programs early in the course of their disease. Once adverse effects of alcohol abuse, cognitive deficits, and social isolation have occurred, it becomes increasingly difficult to integrate patients into QE.:INHALTSVERZEICHNIS 1 EINLEITUNG 1 1.1 Die Qualifizierte Entgiftung 1 1.2 Grenzen der QE 3 1.3 Entstehung, Aufrechterhaltung und Therapie des Alkoholismus 3 1.3.1 Entstehung und Aufrechterhaltung des Alkoholismus 3 1.3.2 Therapiemotivation und Prognosefaktoren bei alkoholabhängigen Patienten 3 1.3.2.1 Förderung der Motivation 4 1.3.2.2 Faktoren mit positivem Einfluss auf die Beibehaltung der Abstinenz 4 1.3.2.3 Faktoren mit negativem Einfluss auf Therapieverlauf und Prognose der Abhängigkeit 5 1.3.2.4 Weitere Faktoren mit Einfluss auf den Therapieerfolg 6 2 ZIELSETZUNG 7 3 MATERIAL UND METHODE 8 3.1 Therapieverfahren: KE und QE 8 3.2 Die Datenerhebung 10 3.3 Einschlusskriterien 10 3.4 Ausschlusskriterien 11 3.5 Der Auswertungsbogen 12 3.6 Statistische Methoden 12 3.7 Datenschutz 13 4 ERGEBNISSE 14 4.1 Gesamtstichprobe 14 4.2 Vergleich von KE und QE 15 4.2.1 Soziodemografische Faktoren 15 4.2.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 20 4.2.3 Bisherige und zukünftige Therapien 22 4.2.4 Angaben zum Indexaufenthalt 25 4.2.5 Angaben zur Suchtanamnese 29 4.2.6 Angaben zur Therapiemotivation 32 4.2.7 Aufnahme- und entlassungsbezogene Merkmale 35 4.3 Vergleich von Männern und Frauen 39 4.3.1 Soziodemografische Faktoren 39 4.3.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 41 4.3.3 Bisherige und zukünftige Therapien 42 4.3.4 Angaben zum Indexaufenthalt 44 IV Kurzzeitentgiftung und Qualifizierte Entgiftung – eine vergleichende Untersuchung 4.3.5 Angaben zur Suchtanamnese 47 4.3.6 Angaben zur Therapiemotivation 51 4.3.7 Aufnahme- und entlassungsbezogene Merkmale 51 4.4 Vergleich von Patienten, die jünger als 40 Jahre waren mit Patienten, die 40 Jahre oder älter waren 51 4.4.1 Soziodemografische Faktoren 51 4.4.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 54 4.4.3 Bisherige und zukünftige Therapien 55 4.4.4 Angaben zum Indexaufenthalt 55 4.4.5 Angaben zur Suchtanamnese 56 4.4.6 Angaben zur Therapiemotivation 58 4.4.7 Aufnahme- und entlassungsbezogene Merkmale 59 4.5 Übersichtstabelle 59 4.6 Multivariate Analysen 61 5 DISKUSSION 65 5.1 Methodenkritik 65 5.2 Ergebnisse 65 5.2.1 Vergleich von KE und QE 65 5.2.1.1 Soziodemografische Faktoren 65 5.2.1.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 66 5.2.1.3 Bisherige und zukünftige Therapien 67 5.2.1.4 Angaben zum Indexaufenthalt 68 5.2.1.5 Angaben zur Suchtanamnese 70 5.2.1.6 Angaben zur Therapiemotivation 70 5.2.1.7 Aufnahme- und entlassungsbezogene Merkmale 71 5.2.2 Vergleich von Männern und Frauen 73 5.2.2.1 Soziodemografische Faktoren 73 5.2.2.2 Psychiatrische Nebendiagnosen und Alkoholfolgesyndrome 74 5.2.2.3 Bisherige und zukünftige Therapien 74 5.2.2.4 Angaben zum Indexaufenthalt 74 5.2.2.5 Angaben zur Suchtanamnese 75 5.2.2.6 Angaben zur Therapiemotivation 76 5.2.2.7 Aufnahme- und entlassungsbezogene Merkmale 76 5.2.3 Vergleich von Patienten, die jünger als 40 Jahre waren mit Patienten, die 40 Jahre oder älter waren 77 5.3 Interpretation der Ergebnisse der multivariaten Analyse 78 5.4 Konsequenzen für Praxis und zukünftige Forschung 79 6 ZUSAMMENFASSUNG 81 7 ABSTRACT 84 V Kurzzeitentgiftung und Qualifizierte Entgiftung – eine vergleichende Untersuchung 8 LITERATURVERZEICHNIS 86 9 ANLAGEN 92 10 SELBSTÄNDIGKEITSERKLÄRUNG 109 11 LEBENSLAUF 110 12 DANKSAGUNG 112

Phanerochaete chrysosporium est un champignon forestier faisant partie des organismes saprophytes capables de recycler la matière organique morte. Grâce à l'excrétion de nombreuses enzymes de dégradation, en particulier des lignine peroxydases, il est capable de décomposer la matière végétale dont la lignine, un polymère complexe de composés phénoliques très résistant. L'élimination de la lignine permet la libération des autres composants du bois tels que la cellulose et l'hémicellulose qui peuvent être utilisés dans l'industrie papetière ou pour la production de bioéthanol de deuxième génération. La structure des intermédiaires et produits de dégradation de la lignine est souvent proche de celle denombreux polluants, d'où l'intérêt biotechnologique de P. chrysosporium dans les processus de bioremédiation. Cependant, les systèmes de dégradation engendrent des composés plus ou moins toxiques pour le champignon et contre lesquels il doit faire face. C'est pourquoi il possède un système de détoxication impliquant des enzymes telles que les cytochrome P450 monooxygénases ou encore les glutathion transférases (GST). Les Ure2p forment une classe de GST étendue chez Phanerochaete et d'autres basidiomycètes saprophytes. Leur étude par des approches phylogénétiques, biochimiques, structurales et transcriptomiques a permis de mieux comprendre les mécanismes d'évolution que peut subir une classe d'enzymes potentiellement soumises à une forte pression de sélection / Phanerochaete chrysosporium is a forest fungus being part of saprophytic organisms able to recycle dead organic matter. Thanks to the excretion of numerous wood decaying enzymes, and especially lignin peroxidases, this fungus is able to break down plant material including lignin, a complex polymer of phenolic compounds. Lignin removal allows the release of other wood components such as cellulose and hemicellulose, which can be further used in paper industry or to produce second generation bioethanol. The structure of intermediates and products from lignin decomposition is close to that of numerous pollutants making P. chrysosporium biotechnologically interesting for bioremediation purposes. Moreover, the fungus has to deal with more or less toxic compounds created by degradation mechanisms. It thus presents a detoxification pathway involving enzymes including cytochrome P450 monooxygenases and glutathione transferases (GST). Ure2p enzymes belong to an extended GST class in Phanerochaete genus as well as in other saprophytic basidiomycetes. Their study based on phylogenetic, biochemical, structural and transcriptomic approaches provides a better understanding of evolution mechanisms of a class of enzymes potentially subject to strong selection selection pressure