Background: The appetite-stimulating hormone ghrelin is a fundamental regulator of human energy metabolism. A series of studies support the notion that long-term appetite and weight regulation may be already programmed in early life and it could be demonstrated that the intrauterine environment affects the ghrelin system of the offspring. Animal studies have also shown that intrauterine programming of orexigenic systems persists even until adolescence/adulthood. Methods: We hypothesized that plasma ghrelin concentrations in adulthood may be associated with the intrauterine exposure to cigarette smoke. We examined this hypothesis in a sample of 19-year-olds followed up since birth in the framework of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study of the long-term outcome of early risk factors. Results: As a main finding, we found that ghrelin plasma concentrations in young adults who had been exposed to cigarette smoke in utero were significantly higher than in those without prenatal smoke exposure. Moreover, individuals with intrauterine nicotine exposure showed a significantly higher prevalence of own smoking habits and lower educational status compared to those in the group without exposure. Conclusion: Smoking during pregnancy may be considered as an adverse intrauterine influence that may alter the endocrine-metabolic status of the offspring even until early adulthood.

Background: Given the increasing number of military deployments in modern forces and the high individual and social costs of substance use disorders, the risk of substance use (alcohol, nicotine, illegal drugs) and substance use disorders (abuse, dependence) associated with deployment and deployment-related stressful experiences is an important area of research. Main questions in this area are: Are deployment and deployment-related stressful experiences associated with problematic substance use patterns and substance use disorders? Are there high-risk groups for deploymentrelated increases in substance use and the occurrence of substance use disorders? Do other mental disorders such as posttraumatic stress disorder play a role for the risk of substance use disorders? This dissertation thesis aims to contribute to these questions. The thesis is based on a research program in German military personnel deployed to Afghanistan. The program includes a crosssectional and a prospective-longitudinal study component. In the cross-sectional component, a random, stratified sample of 1483 was assessed twelve months after return from deployment. As a control group, 889 never deployed soldiers were also assessed. In the prospective-longitudinal component, another sample of 358 male soldiers was assessed directly before and twelve months following deployment. Information about substance use and substance use disorders was obtained using a standardized diagnostic interview. Deployment-related stressful experiences and other relevant variables were assessed with additional scales and questionnaires. Based on this study program, the following research questions were addressed: (1) Do deployed and never deployed soldiers differ regarding the prevalence of problematic substance use patterns (alcohol, nicotine, illegal drugs) and substance use disorders (alcohol, nicotine)? (2) How are soldiers with deployment-related changes in alcohol use characterized? (3) Are posttraumatic stress disorder symptoms related to the risk for substance use disorders (alcohol, nicotine)? (4) Are soldiers with prior mood and anxiety disorders at higher risk for the onset of substance use disorders (alcohol, nicotine) following deployment-related stressful experiences? Main results: Regarding these research questions, the following main results were observed: (1) Deployed and never deployed do not differ considerably regarding the prevalence of substance use and substance use disorders. (2) There was evidence for both deployment-related increases and decreases in alcohol use in specific subgroups. Compared to soldiers with a stable consumption, soldiers with increased alcohol use were characterized by lower ranks, less acceptance, less social support, more sleeping problems after deployment and more deployment-related negative cognitions. Soldiers with deployment-related decreases in alcohol use were characterized by fewer posttraumatic stress disorders symptoms prior deployment and less childhood emotional neglect. (3) Posttraumatic stress disorder symptoms were related to the risk for substance use disorders. These associations were partially attributable to other comorbid mental disorders. However, several posttraumatic stress disorder symptoms were related to substance use disorders above the contribution of comorbidity. (4) Specific constellations of prior mood and anxiety disorders and high degrees of certain deploymentrelated stressful experiences predicted the onset of alcohol use disorders. Conclusions: Based on these findings it can be concluded that German soldiers deployed to Afghanistan do not have an overall elevated risk for substance use and substance use disorders. However, several subgroups with a deployment-related increase in substance use and substance use disorders could be identified for specific substances. These subgroups include soldiers with low ranks, low social support and other mental disorders, of which several posttraumatic stress disorder symptoms might be particularly relevant. In addition, soldiers who experience mood and anxiety disorders prior to deployment as well as high degrees of specific deployment-related stressful experiences might be at higher risk for the onset of alcohol use disorders. It is also noteworthy that some soldiers show a deployment-related decrease in alcohol consumption. These findings might contribute to an improved identification of high-risk groups and suggest targets for possible interventions and preventive efforts. Because of some limitations, mainly regarding crosssectional designs and limited statistical power, some observed associations have to be interpreted with caution. Further prospective studies in high-risk populations or larger samples are necessary to replicate and extend the suggested findings. Moreover, the generalizability of findings to non-military samples and other types of stressful experiences should be investigated. These investigations might help to further reduce the prevalence of excessive substance use and substance use disorders.:Content Zusammenfassung 10 Summary 13 0 Preface 15 1 General introduction 16 1.1 Substance use and substance use disorders 16 1.2 Stressful experiences 23 1.3 Stressful experiences and substance use in deployed military personnel 28 2 Aims 34 3 Methods 36 3.1 Design 36 3.2 Sampling 37 3.3 Study instruments 38 4 Substance use and substance use disorders in recently deployed and never deployed soldiers 40 4.1 Abstract 40 4.2 Introduction 41 4.3 Methods 43 4.4 Results 47 4.5 Discussion 52 5 Predictors of changes in daily alcohol consumption in the aftermath of military deployment 57 5.1 Abstract 57 5.2 Introduction 58 5.3 Methods 60 5.4 Results 64 5.5 Discussion 68 6 Associations between lifetime PTSD symptoms and current substance use disorders using a five-factor model of PTSD 73 6.1 Abstract 73 6.2 Introduction 74 6.3 Methods 78 6.4 Results 80 6.5 Discussion 85 7 Stress exposure and the risk for the onset of alcohol use disorders and nicotine dependence: The role of prior internalizing disorders 89 7.1 Abstract 89 7.2 Introduction 90 7.3 Methods 92 7.4 Results 96 7.5 Discussion 103 7.6 Conclusions 105 8 General discussion 106 8.1 Summary of main findings 106 8.2 Discussion of main findings 109 8.3 Critical discussion of methodology 117 8.4 Practical implications 120 8.5 Directions for future research 122 9 Conclusion 125 10 References 126 11 Appendix 157 / Hintergrund: Das Risiko für den Konsum psychotroper Substanzen (Alkohol, Nikotin, illegale Drogen)und das Auftreten von Substanzstörungen (Missbrauch, Abhängigkeit) im Zusammenhang mit Belastungen in militärischen Einsätzen ist angesichts der Zunahme militärischer Einsätze sowie der hohen individuellen und sozialen Kosten von Substanzstörungen ein Forschungsthema von hoher Relevanz. Wichtige Fragen sind dabei: Stehen Auslandseinsätze generell im Zusammenhang mit problematischen Konsummustern und Substanzstörungen? Gibt es bestimmte Risikogruppen für Anstiege im Substanzkonsum und das Auftreten von Substanzstörungen? Welche Rolle spielen andere psychische Störungen, wie z.B. die posttraumatische Belastungsstörung (PTBS), für das Auftreten einer Substanzstörung? Diese Dissertationsschrift behandelt verschiedene Aspekte dieser Fragestellungen auf der Grundlage eines Forschungsprogramms zur psychischen Gesundheit bei in Afghanistan eingesetzten deutschen Soldaten. Das Programm umfasste eine querschnittliche und eine prospektiv-longitudinale Studie. In der Querschnittstudie wurde eine randomisierte, stratifizierte Stichprobe von 1483 Soldaten zwölf Monate nach Rückkehr aus einem Einsatz in Afghanistan untersucht. Als Kontrollgruppe wurden zudem 889 Soldaten untersucht, welche niemals im Einsatz waren. In der prospektiv-longitudinalen Studie wurde eine weitere Stichprobe von 358 männlichen Soldaten unmittelbar vor und zwölf Monate nach Einsatzrückkehr aus Afghanistan untersucht. Information zu Substanzkonsum und Substanzstörungen nach DSM-IV wurden mittels standardisierter diagnostischer Interviews erfasst. Einsatzbezogene belastende Ereignisse und andere relevante Variablen wurden mit zusätzlichen Skalen und Fragebögen erhoben. Auf Basis dieses Studienprogramms wurden unter anderem die folgenden Fragestellungen bearbeitet: (1) Unterscheiden sich Soldaten mit und ohne Auslandseinsatz hinsichtlich der Prävalenz von kritischen Konsummustern (Alkohol, Nikotin, illegale Drogen) und Substanzstörungen (Alkohol, Nikotin)? (2) Durch welche Merkmale sind Soldaten mit einsatzbezogenen Veränderungen im Alkoholkonsum gekennzeichnet? (3) Sind Symptome der PTBS mit dem Risiko für Substanzstörungen (Alkohol, Nikotin) assoziiert? (4) Haben Soldaten mit bereits vor dem Einsatz bestehenden Angst- und affektiven Störungen ein höheres Risiko für das Auftreten einer Substanzstörung (Alkohol, Nikotin) nach belastenden Einsatzereignissen? Hauptergebnisse: In Bezug auf diese Fragestellungen ergaben sich folgende Ergebnisse: (1) Soldaten mit und ohne Auslandseinsatz unterschieden sich kaum hinsichtlich der Prävalenz von Substanzkonsum und Substanzstörungen. (2) Allerdings ergaben sich Hinweise auf Zu-, wie auch Abnahmeeffekte im Alkoholkonsum in unterschiedlichen Subgruppen. Soldaten mit einem Anstieg im Alkoholkonsum waren im Vergleich zu Soldaten mit stabilem Konsum durch einen niedrigeren Dienstgrad, ein geringeres Ausmaß an Akzeptanz, weniger soziale Unterstützung, mehr Schlafprobleme nach Einsatzrückkehr sowie ein höheres Ausmaß an negativen einsatzbezogenen Bewertungen gekennzeichnet. Bei Soldaten mit einer einsatzbezogenen Reduktion im Alkoholkonsum fanden sich weniger PTBS-Symptome vor dem Einsatz sowie ein geringeres Ausmaß an emotionaler Vernachlässigung in der Kindheit. (3) Es gab Zusammenhänge zwischen PTBS-Symptomen und Substanzstörungen, die jedoch teilweise durch andere komorbide psychische Störungen erklärt werden konnten. Allerdings blieben einige PTBS-Symptome über andere komorbide Störungen hinaus mit Substanzstörungen assoziiert. (4) Bestimmte Konstellationen von bereits vor dem Einsatz bestehenden Angst- und affektiven Störungen sagten bei hohem Ausmaß an einigen einsatzbezogenen Belastungen das Auftreten einer Störung durch Alkoholkonsum vorher. Schlussfolgerungen: Auf Grundlage dieser Befunde lässt sich schlussfolgern, dass in Afghanistan eingesetzte Bundeswehrsoldaten kein generell erhöhtes Risiko für kritische Konsummuster und das Auftreten von Substanzstörungen aufweisen. Allerdings konnten Subgruppen identifiziert werden, die in Bezug auf bestimmte Substanzen ein erhöhtes Risiko für einen erheblichen Anstieg im Substanzkosum oder das Auftreten einer Substanzstörung haben. Dazu gehören unter anderem Soldaten mit niedrigen Dienstgrad, geringer sozialer Unterstützung und anderen psychischen Störungen, wobei bestimmte Symptome der posttraumatischen Belastungsstörung von besonderer Relevanz sein könnten. Zudem scheint das Risiko für Störungen durch Alkoholkonsum bei Soldaten erhöht, bei denen bereits vor dem Einsatz Angst- und affektive Störungen auftraten und die gleichzeitig ein hohes Ausmaß an bestimmten Einsatzbelastungen erleben. Bemerkenswert ist aber auch, dass einige Soldaten nach dem Einsatz eine erhebliche Reduktion des Alkoholkonsums aufweisen. Die Befunde könnten zu einer verbesserten Identifikation von Risikogruppen beitragen und Ansatzpunkte für mögliche Interventionen und präventive Maßnahmen liefern. Aufgrund einiger Limitationen, die vor allem querschnittliche Designs und eine eingeschränkte statistische Power betreffen, sollten einige der beobachteten Zusammenhänge vorsichtig interpretiert werden. Weitere prospektive Untersuchungen an größeren Stichproben sowie Hochrisikokohorten sind nötig, um die Befunde zu replizieren und zu erweitern. Weiter sollte die Übertragbarkeit der Befunde auf nichtmilitärische Stichproben unter Einbezug anderer Arten von belastenden Ereignissen untersucht werden. Diese Untersuchungen könnten langfristig zur Senkung von problematischen Substanzkonsum und Substanzstörungen beitragen.:Content Zusammenfassung 10 Summary 13 0 Preface 15 1 General introduction 16 1.1 Substance use and substance use disorders 16 1.2 Stressful experiences 23 1.3 Stressful experiences and substance use in deployed military personnel 28 2 Aims 34 3 Methods 36 3.1 Design 36 3.2 Sampling 37 3.3 Study instruments 38 4 Substance use and substance use disorders in recently deployed and never deployed soldiers 40 4.1 Abstract 40 4.2 Introduction 41 4.3 Methods 43 4.4 Results 47 4.5 Discussion 52 5 Predictors of changes in daily alcohol consumption in the aftermath of military deployment 57 5.1 Abstract 57 5.2 Introduction 58 5.3 Methods 60 5.4 Results 64 5.5 Discussion 68 6 Associations between lifetime PTSD symptoms and current substance use disorders using a five-factor model of PTSD 73 6.1 Abstract 73 6.2 Introduction 74 6.3 Methods 78 6.4 Results 80 6.5 Discussion 85 7 Stress exposure and the risk for the onset of alcohol use disorders and nicotine dependence: The role of prior internalizing disorders 89 7.1 Abstract 89 7.2 Introduction 90 7.3 Methods 92 7.4 Results 96 7.5 Discussion 103 7.6 Conclusions 105 8 General discussion 106 8.1 Summary of main findings 106 8.2 Discussion of main findings 109 8.3 Critical discussion of methodology 117 8.4 Practical implications 120 8.5 Directions for future research 122 9 Conclusion 125 10 References 126 11 Appendix 157

Human decision making is closely related to reward processing because many decisions rely to a certain degree on the evaluation of different outcome values. Reward-based decisions can be health-related, for example if someone has to compare the outcome value of the instant reward of smoking a cigarette to that of the long term goal of keeping well and fit. Such comparisons do not only rely on the nominal value of the alternatives but also on devaluation of rewards over time. The value of being healthy at older age might outweigh the value of smoking a cigarette but since the payoff of the health-outcome will be delayed, humans tend to decrease the value of this option. Therefore in this example one might choose the immediate reward of smoking a cigarette. The proclivity to devaluate the value of rewards over time has been widely investigated with experimental intertemporal choice tasks, in which subjects have to choose between smaller sooner rewards and larger later rewards. A stronger individual devaluation proclivity (i.e. discounting rate) has been reported to be related to addiction. Research in neuroeconomics has suggested the competing neurobehavioural decision systems (CNDS) theory, proposing that an imbalance between an executive (cortical prefrontal brain areas) and an impulsive (i.e. subcortical areas, such as ventral striatum (VS), amygdala) system in the brain leads to steeper discounting and a higher risk for addiction. Additionally, temporal discounting has been proposed as a transdisease process, i.e., “a process that occurs across a range of disorders, making findings from one disorder relevant to other disorders” (Bickel, Jarmolowicz, Mueller, Koffarnus, & Gatchalian, 2012, Abstract). Thus, the CNDS theory and temporal discounting might also have implications for other health-related behaviour than substance use. So far many factors have been shown to be associated with higher discount rates: for instance, adolescent age, lower intelligence and nicotine dependence. Further, it has been shown that adolescents are at highest risk to start smoking. On the other hand a higher education level has been shown to be associated to lower rates of smoking. Thus, it seems likely that a higher discount rate might be one reason why adolescents experiment with smoking, why lower education is associated to nicotine addiction and why dependent smokers are not successful in smoking cessation. But relatively little is known about the neural processes behind these variables, which could be also seen as exemplary risk- and protective factors regarding addiction. The 3 studies of the thesis at hand were conducted to extend the knowledge about neural processes associated to age, intelligence and smoking in their relation to intertemporal choice. The task was chosen because of its relevance for addiction and a variety of health-related behaviour. The first study was conducted to explore the neural correlates of age related differences between adolescents at age 14 and young adults during intertemporal choices. Additionally, the roles of discounting and choice consistency were investigated. Although adoles-cents discounted delayed rewards more steeply than adults, neural processing of reward value did not differ between groups, when controlling reward values for the individual discount rates. However, a higher discount rate was related to a lower responsivity in the ventral striatum to delayed rewards, independent of age. Concerning decision making, adolescents exhib-ited a lower consistency of choices and less brain activity in a parietal network than adults (i.e. posterior and inferior parietal regions). Thus, reward value processing might be more sensitive to the discount rate than to chronological age. Lower consistency of intertemporal choices might indicate ongoing maturation of parietal brain areas from adolescence to young adulthood. The second study was conducted to reveal the associations between neural processes of decision making and intelligence in adolescents. The results of study 2 revealed networks in the adolescent brain where brain activity was related to crystallised intelligence as well as to intertemporal choice behaviour. Specifically, during decision processing higher crystallised intelligence as well as more consistent decisions were associated with higher brain activity in the posterior parietal cortex. Processing of delayed rewards was also related to crystallised intelligence, i.e. more intelligent adolescents showed higher brain activation in the anterior cingulate cortex (ACC) and the inferior frontal gyrus (IFG), which was in turn related to a lower discount rate. Additionally, associations between the parental education level and crys-tallised intelligence of the adolescent participants of the study and their discount rate were found, indicating that parental education as an environmental factor could be related to a low-er risk for addiction. This protective effect might be mediated by the offspring’s crystallised intelligence and discount rate which are both related to brain activity in parts of the same brain networks (i.e. the IFG). The third study was done to investigate neural processes of intertemporal decisions in smokers and non-smokers. To test whether the effects of smoking on the discount rate are due to chronic or acute nicotine intake, non-smokers were additionally assessed under acute nico-tine administration. Study 3 revealed that the effects of nicotine on intertemporal choice behaviour were related to chronic intake of nicotine in smokers rather than to acute nicotine ad-ministration in non-smokers. Regarding the neural processes, smokers compared to non-smokers showed lower brain activity in the posterior parietal cortex. Comparable but weaker effects were found under acute nicotine in non-smokers. Although acute nicotine administra-tion altered neural processes, behavioural changes might only occur after repeated nicotine intake. However, the study did not preclude that the differences are predrug characteristics. Altogether the studies revealed overlapping neural correlates of intertemporal choices which are related to the individual age, the discount rate, the choice consistency, the individual intelligence as well as acute and chronic nicotine intake. This might provide an integrative view on how inter-individual differences and behaviour during intertemporal choices are based on common neural correlates which in turn might have implications for the development and the maintenance of addiction. Specifically, hyposensitivity towards delayed rewards in the adolescent ventral striatum, which has also been found in smokers compared to non-smokers, is associated with higher discount rates and higher risk for smoking initiation. In contrast, higher activation in the IFG and the ACC in more intelligent individuals during reward value processing might enhance behavioural inhibition and control and, hence, might prevent nicotine addiction. In line with the CNDS theory responsivity in subcortical brain areas (i.e. impulsive system), such as the VS was related to the risk factor of adolescent age, whereas activity in cortical areas (IFG and ACC) was related to the protective factors of high-er crystallised intelligence. Since there was only one study beside the studies of the current thesis reporting results regarding consistency, one can only speculate about implications for health-related behaviour, such as addiction. Consistency might play a role, especially for cessation success. Thus, the findings that adolescents as well as less intelligent individuals were less consistent might point to a higher risk for maintenance of nicotine addiction. The higher brain activity in a fronto-parietal network, which has been shown in studies 1 and 2 in adults as well as in more intelligent adolescents, was related to higher consistency of choices in both studies. Thus, the finding might be a possible neural correlate for the association between the risk factor of ado-lescent age, the protective factor of higher crystallised intelligence, and more consistent deci-sion making. In conclusion the findings of the current thesis contribute to a better understanding of how inter-individual differences and environmental factors might be accompanied by neural processes which in turn might be related to individual development of addiction. Further the results might extend the CNDS theory regarding neural correlates of exemplary risk and pro-tective factors regarding adolescents’ health behaviour and smoking in adults.

To provide background information about previous findings about the prevalence of use, abuse and dependence of various substances (nicotine, alcohol, prescription and illicit drugs) findings of available epidemiological studies in Germany from the 1980s and 1990s are summarized and critically evaluated. Focusing on findings of substance use surveys in adolescents and young adults the review indicates: (a) a considerable number of large scale questionnaire surveys in general population samples documenting the frequency of use and patterns of use of most substances; (b) indications of increasing rates of drug use particularly in East Germany; (c) high rates of illicit drug use, mainly of cannabinoids, but also stimulants and hallucinogens, among young age groups. No data are available from substance use surveys or from clinical epidemiological studies allowing the determination of how frequent substance abuse and substance dependence diagnoses are in the general population or in adolescents and young adults. Priorities for future research to ameliorate this unsatisfactory situation are outlined with emphasis on research in adolescents and young adults.

Background: The use of nicotine-containing tobacco is among the substances with the highest dependence potential. The negative impact and consequences of cigarette use are discussed not only among experts. In contrast, nicotine replacement therapy and user experience are unspecified. Aims: The primary goal of the research was to map the experience of clients of the National Tobacco Quitline Czech Republic with the use of nicotine replacement therapy in the treatment of tobacco addiction. The categories examined include: dosage of replacement nicotine, preferred forms of replacement nicotine, reported adverse effects, and route of administration of replacement nicotine. The study was carried out in order to refine the dosage of nicotine replacement therapy, increase the compliance of nicotine replacement users and increase the quality of services provided by the National Tobacco Quitline Czech Republic. Methods: The study was carried out with the help of a qualitative research methodology. Respondents were selected using the method of intentional selection according to defined properties. Data was created using a structured interview with open-ended questions and semi-structured interviews. The research data were processed using the open coding method and the method of capturing formulas was used...

The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson’s disease.

The thesis investigates the theoretical knowledge about the issue of addictive substances and personal experience with their use for pupils 6. and 8. classes of primary school and for students 2. and 4. year of the grammar school. In the first part of my work, I focused on the definition of basic concepts, the outline of the characters and the possible causes that lead to addiction to drugs, I presented the most commonly used drugs and identified the possibilities of drug prevention. The second part is devoted to a survey in the form of a questionnaire, which directly examines the knowledge and experience with the drug specific age groups of pupils and students. This work could be material for teachers who want to participate in the drug prevention.

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Unter den bösartigen Tumoren hat das Bronchialkarzinom wohl die dramatischste Entwicklung genommen. Die Inzidenz und Mortalität ist in den letzten 15-20 Jahren bei Männern zwar leicht rückläufig, für Frauen ist jedoch ein entgegen gesetzter Trend zu erkennen. Dies wird in erster Linie auf die veränderten Lebensgewohnheiten, wie steigender Zigarettengenuss unter den Frauen, zurückgeführt. Derzeit gibt es in Deutschland circa 20 Millionen Raucher, von denen etwa 140˙000 jährlich an den Folgen ihres Inhalationsrauchens versterben...