Background: Specialized adult care of phenylketonuria (PKU) patients is of increasing importance. Adult outpatient clinics for inherited errors of metabolism can help to achieve this task, but experience is limited. Ten years after establishment of a coordinated transition process and specialised adult care for inherited metabolic diseases, adult PKU care was evaluated with respect to metabolic control, therapy satisfaction, life satisfaction, sociodemographic data, economical welfare as well as pregnancy outcome. Methods: All PKU patients transferred from paediatric to adult care between 2005 and 2015 were identified. A retrospective data analysis and a cross-sectional survey in a sub-cohort of 30 patients including a questionnaire for assessing quality of life (FLZm) were performed as a single-centre investigation at the metabolic department of the University Hospital Leipzig, Germany. For statistical analysis, Mann-Whitney-U-test, t-test for independent samples, ANOVA and chi square test were used as appropriate. Results: 96 PKU patients (56 females/40 males; median age 32 years, range 18–62) were included. In the last 3-year period, 81 % of the transferred patients still kept contact to the adult care centre. Metabolic control was stable over the evaluation period and dried blood phenylalanine concentrations mostly remained within the therapeutic range (median 673.0 μmol/l, range 213.0–1381.1). Sociodemographic data, economical welfare and life satisfaction data were comparable to data from the general population. However, differences could be revealed when splitting the cohort according to time of diagnosis and to management during childhood. 83 % of the PKU adults were satisfied with the transition process and current adult care. 25 completed pregnancies were supervised; three newborns, born after unplanned pregnancy, showed characteristic symptoms of maternal PKU syndrome. Conclusions: Continuous care for adult PKU patients in a specialized outpatient clinic is successful, leading to good to satisfactory metabolic control and social outcomes. Uninterrupted good metabolic treatment throughout childhood and adolescence positively influences educational, professional and economic success in later life. Further effort in specialized paediatric and adult metabolic care is needed to prevent loss of follow-up and to support the recommended life-long treatment and/or care.

Die Schwangerschaft ist ein komplexes Phänomen, bei dem es zu einer Interaktion zwischen dem mütterlichen Immunsystem und dem Fetus kommt. An der feto-maternalen Grenze kommt es zur Auslösung einer inflammatorischen Reaktion, die für eine normale Implantation und Schwangerschaft notwendig ist. Allerdings kann eine exzessive Entzündungsreaktion zu Schwangerschaftskomplikationen wie dem immunologisch vermittelten Sponatanabort füh-ren. Das zytoprotektive Enzym Hämoxygenase-1 (HO-1) spielt eine sehr wichtige Rolle bei der Kontrolle inflammatorischer Reaktionen. Inwiefern HO-1 für das Gelingen und Bestehen einer Schwangerschaft unabdingbar ist, wurde bisher nicht untersucht. Unsere Hypothese ist, dass HO-1 eine bedeutsame Rolle während der Schwangerschaft spielt. Die Beantwortung dieser wichtigen Frage ist deshalb Hauptziel dieser Dissertation. Es konnte gezeigt werden, dass eine spezifische Hochregulation des HO-1 Moleküls mittels Gentherapie in einem Mausmodell für Spontanabort zur signifikanten Reduktion der Abortra-te führte. Dieser protektive Effekt war mit einer erhöhten Th2/Th1 Zytokinen-Ratio und mit verminderter Apoptose assoziiert. Ein weiteres Teilziel dieser Arbeit bestand darin, die Rolle des HO-1 Moleküls während der Plazentation zu untersuchen. Dafür wurde eine Trophoblastenstammzelllinie benutzt, die in der Lage ist, zu Riesenzellen zu differenzieren. Die mittels Zinkprotoporphyrin (ZnPPIX) induzierte Expressionssuppression von HO-1 führte zur Verminderung der Überlebensrate von Trophoblastenstammzellen und zur Hemmung von deren Ausdifferenzierung in Trophoblastenriesenzellen. Um die Rolle des HO-1 Moleküls in anderen Schwangerschaftsprozessen zu untersuchen, wurden Hämoxygenase-1 defiziente (Hmox1-/-) Mäuse benutzt. Da die Verpaarung von Hmox1-/- Mäuse zu keinem erfolgreichen Abkömmling führt, war ein weiteres Teilziel dieser Arbeit gewesen, den zu Grunde liegenden Mechanismus aufzuklären. Es zeigte sich, dass Hmox1-/- Weibchen im Vergleich zu den Hmox1+/+ Weibchen weniger Oozyten produzieren. Auch konnten die Hmox1-/- Oozyten weniger erfolgreich als die Hmox1+/+ Oozyten fertili-ziert werden. Verschiedene Verpaarungsexperimente mit Hmox1+/+, Hmox1+/- und Hmox1-/- Mäusen ergaben einen indirekt proportionalen Zusammenhang zwischen HO-1 Expression und Aborthäufigkeit. Die hier gewonnenen Daten deuten daraufhin, dass HO-1 eine entscheidene Rolle in der Schwangerschaft spielt. Die gewonnenen Erkenntnisse tragen zum Verständnis der Pathologie des immunologisch vermittelten Spontaborts bei und können darüber hinaus helfen neue Be-handlungsstrategien gegen diese gefürchtete Schwangerschaftskomplikation zu entwickeln. / Mammalian pregnancy is a parabiotic union of two genetically different individuals, the fetus and the mother. At the feto-maternal interface, inflammatory processes can occur due to an immune reaction against alloantigens. It is known that some degree of systemic or uterine inflammation is necessary for both normal implantation and pregnancy. However, if this in-flammation becomes too excessive it can cause pregnancy complications such as abortion. Heme oxygenase-1 (HO-1), the enzyme responsible for the degradation of free heme, plays a key role in inflammatory processes. Viewing pregnancy mainly as an inflammatory process had led us to the idea that HO-1 may play an important role in pregnancy. Therefore, the main aim of this work was to analyze the role of HO-1 in the different processes related to preg-nancy by means of functional studies employing in vivo as well as in vitro models. First, we could show that a specific up-regulation of HO-1 in abortion-prone animals by means of an adenoviral vector is able to reduce the abortion rate. This HO-1 up-regulation improved pregnancy outcome by up-regulating the Th2/Th1 cytokines ratio and protecting tissues from apoptosis, suggesting an important role of HO-1 in pregnancy. In a second part of the work, we aimed to analyze the role of HO-1 in placentation. For that, a trophoblast stem cell line capable of differentiate into trophoblast giant cells was used. Inter-estingly, a down-regulation of HO-1 by means of ZnPPIX led to diminished survival of the trophoblast stem cells. Furthermore, these cells were unable to differentiate into trophoblast giant cells in the absence of HO-1, strongly suggesting a crucial role of HO-1 in placentation. Finally, a closer look into the role of HO-1 in pregnancy was performed by using heme oxy-genase-1 deficient mice (Hmox1-/- mice). Interestingly, Hmox1-/- females produce much less oocytes than wild type females. Analyses of the ovaries of both types of females showed dif-ferences in follicle development. Furthermore, when fertilized in vitro, a significant diminu-tion in the fertilization rate of Hmox1-/- oocytes when compared to Hmox1+/+ oocytes was found. Since the mating of Hmox1-/- mice does not yield progeny, we also aimed to clarify whether this is due to problems in the female, in the male or in both. For this, different mating combinations of mice partially or totally deficient in Hmox1 were performed. The analysis of the pregnancy outcome showed that, the less HO-1 in the combination, the higher the fetal rejection. In summary, a central role of HO-1 in different processes of reproduction could be demon-strated in this work which helps understanding the mechanisms behind pregnancy success.

Background: Maternal perinatal mental health has been shown to be associated with adverse consequences for the mother and the child. However, studies considering the effect of DSM-IV anxiety disorders beyond maternal self-perceived distress during pregnancy and its timing are lacking. Aims: To examine the role of maternal anxiety disorders with an onset before birth and self-perceived distress during pregnancy for unfavourable maternal, obstetric, neonatal and childhood outcomes. Study design: DSM-IV mental disorders and self-perceived distress of 992 mothers as well as obstetric, neonatal and childhood outcomes of their offspring were assessed in a cohort sampled from the community using the Munich-Composite International Diagnostic Interview. Logistic regression analyses revealed associations (odds ratios) between maternal anxiety disorders and self-perceived distress during pregnancy with maternal depression after birth and a range of obstetric, neonatal and childhood psychopathological outcomes. Results: Lifetime maternal anxiety disorders were related to offspring anxiety disorders, but not to offspring externalizing disorders. Analyses focussing on maternal DSM-IV anxiety disorders before birth yielded associations with incident depression after birth. In addition, self-perceived distress during pregnancy was associated with maternal depression after birth, preterm delivery, caesarean section, separation anxiety disorder, ADHD, and conduct disorder in offspring. Conclusion: Findings confirm the transmission of anxiety disorders from mother to offspring. Apart from maternal anxiety, self-perceived distress during pregnancy also emerged as a putative risk factor for adverse outcomes. The finding that maternal anxiety disorders before birth yielded less consistent associations, suggests that self-perceived distress during pregnancy might be seen as a putative moderator/mediator in the familial transmission of anxiety.

Wie für viele andere Zivilisationskrankheiten werden auch für Atherosklerose und dadurch verursachte Erkrankungen wie Herzinfarkt oder Schlaganfall die Weichen mitunter schon vor der Geburt gestellt. Pränatale oder fetale Programmierung heißt der Mechanismus, durch den negative Umweltbedingungen während der Schwangerschaft, allen voran der Einfluss von Stresshormonen, auf die Entwicklung des Fetus wirken und die Prädisposition für spätere Erkrankungen schaffen können (SCHWAB 2009, SECKL 2001). Ziel der vorliegenden Arbeit war es, die Auswirkungen von Stress während der Schwangerschaft auf den Fettstoffwechsel der Nachkommen unter besonderer Berücksichtigung bekannter Herz-Kreislauf-Risikofaktoren zu untersuchen. Zu diesem Zweck wurde 28 Weißbüschelaffen (F0) während der Trächtigkeit eine Woche lang täglich Dexamethason (DEX) – ein synthetisches Glucocorticoid (GC), welches die Plazentaschranke passieren kann (TEGETHOFF et al. 2009) – oral verabreicht (BEINDORFF et al. 2006, EINSPANIER et al. 2006c). Die drei weiblichen Folgegenerationen DEX F1 (n = 5), DEX F2 (n = 6) und DEX F3 (n = 3) dieser Tiere wurden untersucht, wobei sich die Medikamentengabe auf die F0-Generation beschränkte und alle weiteren Trächtigkeiten ungestört verliefen. Im Alter von 3,3 bis 5,6 Jahren (DEX F1) bzw. von Geburt an bis 1,5 Jahre (DEX F2, DEX F3) wurden die Tiere wöchentlich gewogen. In Blutproben wurden einerseits Fettsäuren (FS), andererseits Cholesterol (CHOL), Triglyceride (TG) und Lipoproteine gemessen, wobei zwei Methoden – enzymatische Analyse nach Ultrazentrifugation und direkter Assay – zum Einsatz kamen. Alle Resultate wurden denen gesunder Kontrolltiere ähnlichen Alters (n = 12) gegenübergestellt. Die Körpermasse unterschied sich zu keinem Zeitpunkt signifikant zwischen den Nachkommen der mit DEX behandelten Tiere und den Kontrollgruppen. Entweder gab es keinen programmierten Effekt auf das Gewicht oder er wurde durch individuelle Schwankungen, möglicherweise verstärkt durch erhöhte Stressempfindlichkeit oder Hyperaktivität der DEX-Nachkommen (FRENCH et al. 2004, SCHWAB 2009) und damit einhergehende Tendenz zur Gewichtsabnahme (KAPLAN und SHELMIDINE 2010) maskiert. Beide Methoden zur Untersuchung des Lipoproteinprofils erschienen für Weißbüschelaffen geeignet und können für zukünftige Untersuchungen empfohlen werden. Bei den Kontrollgruppen fiel auf, dass ältere Tiere u. a. signifikant mehr LDL- und VLDL-CHOL, aber signifikant weniger HDL-TG und n3-FS hatten als jüngere, was auf ein wie beim Menschen mit dem Alter steigendes Herz-Kreislauf-Risiko (CARLSSON et al. 2010) schließen lässt. Sowohl DEX F2 als auch DEX F3 wiesen signifikant höhere Konzentrationen von LDL-CHOL, signifikant niedrigere Werte von HDL-TG, mehr Gesamt-CHOL sowie einen höheren Quotienten CHOL : HDL-CHOL im Blutplasma auf als die Kontrolltiere. Diese Parameter gehören zu den in der humanmedizinischen Diagnostik genutzten Herz-Kreislauf-Risikofaktoren und die Veränderungen weisen auf eine erhöhte Auftrittswahrscheinlichkeit kardiovaskulärer Erkrankungen hin (KANNEL et al. 1994, LUSIS et al. 2004, NCEP 2002). Zusätzlich fielen bei DEX F1, DEX F2 und DEX F3 im Vergleich zu den Kontrollen signifikant erniedrigte Gehalte an n3-FS auf, die u. a. für ihre antiphlogistische und kardioprotektive Wirkung bekannt sind (ALONSO et al. 2003, CALDER 2004, KINSELLA et al. 1990). Pränatale GC-Behandlung rief demzufolge über Veränderungen im Fettstoffwechsel ein erhöhtes Risiko für Herz-Kreislauf-Erkrankungen bei ihren weiblichen Nachkommen F1 bis F3 hervor. Dies lässt auf epigenetische Effekte schließen, welche in weiterführenden Untersuchungen genauer erforscht werden sollten. / As for many other civilization diseases, the way for atherosclerosis and hence heart attack and stroke can be paved even before birth. The mechanism by which negative environmental circumstances, first of all the influence of stress hormones, can alter the development of the fetus and cause a predisposition for diseases later in life is called prenatal or fetal programming (SCHWAB 2009, SECKL 2001). The aim of the present study was to investigate the consequences of stress during pregnancy on lipid metabolism of the offspring with special regard to known cardiovascular risk factors. Therefore, 28 common marmosets (F0) were given dexamethasone (DEX) – a synthetic glucocorticoid (GC) with the ability to pass the placenta easily (TEGETHOFF et al. 2009) – orally, once daily for one week during gestation (BEINDORFF et al. 2006, EINSPANIER et al. 2006c). The three female filial generations DEX F1 (n = 5), DEX F2 (n = 6) and DEX F3 (n = 3) of those monkeys were investigated. Only the F0 generation was treated with DEX, while all of the following pregnancies remained undisturbed. At the age of 3.3 up to 5.6 years (DEX F1) and from birth until 1.5 years (DEX F2, DEX F3), respectively, the animals were weighed weekly. Blood samples were analyzed on the one hand for fatty acids (FA), on the other hand for cholesterol (CHOL), triglycerides (TG) and lipoproteins using two different methods – enzymatic analysis after ultracentrifugation and direct assay. All results were compared to those of healthy controls of similar age (n = 12). Body mass of the offspring of dams prenatally treated with DEX was not significantly different from that of the controls at any point of time. Either there was no programming effect on weight or it was masked by individual fluctuations, maybe potentiated by hyperactivity or a higher sensitivity to stress of the DEX offspring (FRENCH et al. 2004, SCHWAB 2009) and hence a tendency to loose weight (KAPLAN and SHELMIDINE 2010). Both methods for lipoprotein analysis seemed to be suitable for the common marmoset and can be recommended for future investigations. In the controls, older animals showed significantly more LDL and VLDL CHOL, but significantly less HDL TG and n3 FA than younger ones, which points out to a cardiovascular risk rising with age as in humans (CARLSSON et al. 2010). DEX F2 and DEX F3 had significantly higher concentrations of LDL CHOL, significantly lower levels of HDL TG, more total CHOL and a higher ratio of CHOL : HDL CHOL in blood plasma than the controls. Those parameters are well-known human medicine cardiovascular risk factors and the aberrations detected indicate a higher probability of developing cardiovascular diseases (KANNEL et al. 1994, LUSIS et al. 2004, NCEP 2002). Additionally, compared to the controls, all DEX generations F1 to F3 showed significantly lower levels of n3 FA, which are known for their antiinflammatory and cardioprotective effects amongst others (ALONSO et al. 2003, CALDER 2004, KINSELLA et al. 1990). Consequently, prenatal treatment with GC caused an increased risk for cardiovascular diseases in the female offspring F1 up to F3 via alteration of lipid metabolism. This points out to epigenetic effects, which require further investigation.

The associations between maternal smoking and nicotine dependence and patterns of smoking and nicotine dependence in offspring were examined in a large community-based sample of adolescents. Data were derived from baseline and 4-year follow-up assessments of 938 respondents aged 14–17 years at the outset of the Early Developmental Stages of Psychopathology (EDSP) study, a prospective-longitudinal community study of adolescents and young adults and their parents respectively. Smoking and nicotine dependence in respondents were assessed using the Munich Composite International Diagnostic Interview (DSM-IV algorithms). Diagnostic information about smoking behavior in mothers was collected by independent direct diagnostic interviews with the mothers. In comparison to children of non- or occasionally smoking mothers, children of regularly smoking and nicotine-dependent mothers had higher probabilities of using tobacco as well as of developing nicotine dependence. For all ages under consideration, survival analyses revealed a higher cumulative lifetime risk of regular smoking and nicotine dependence among these children. Maternal smoking during pregnancy seems to represent an additional risk for these outcomes in children, specifically with regard to the risk of developing nicotine dependence. Associations were comparable for sons and daughters. Our findings show that maternal smoking predicts escalation of smoking, development of nicotine dependence, and stability of smoking behavior in children. Implications for specific intervention and prevention efforts are discussed.

Background: Maternal perinatal mental health has been shown to be associated with adverse consequences for the mother and the child. However, studies considering the effect of DSM-IV anxiety disorders beyond maternal self-perceived distress during pregnancy and its timing are lacking. Aims: To examine the role of maternal anxiety disorders with an onset before birth and self-perceived distress during pregnancy for unfavourable maternal, obstetric, neonatal and childhood outcomes. Study design: DSM-IV mental disorders and self-perceived distress of 992 mothers as well as obstetric, neonatal and childhood outcomes of their offspring were assessed in a cohort sampled from the community using the Munich-Composite International Diagnostic Interview. Logistic regression analyses revealed associations (odds ratios) between maternal anxiety disorders and self-perceived distress during pregnancy with maternal depression after birth and a range of obstetric, neonatal and childhood psychopathological outcomes. Results: Lifetime maternal anxiety disorders were related to offspring anxiety disorders, but not to offspring externalizing disorders. Analyses focussing on maternal DSM-IV anxiety disorders before birth yielded associations with incident depression after birth. In addition, self-perceived distress during pregnancy was associated with maternal depression after birth, preterm delivery, caesarean section, separation anxiety disorder, ADHD, and conduct disorder in offspring. Conclusion: Findings confirm the transmission of anxiety disorders from mother to offspring. Apart from maternal anxiety, self-perceived distress during pregnancy also emerged as a putative risk factor for adverse outcomes. The finding that maternal anxiety disorders before birth yielded less consistent associations, suggests that self-perceived distress during pregnancy might be seen as a putative moderator/mediator in the familial transmission of anxiety.

Objective: The aim of this study was to examine changes in perceived social support from early pregnancy to 2 years postpartum and to test whether these changes (a) differ between mothers and fathers or (b) vary as a function of the Big Five personality traits. - Background: Higher peripartum social support in (expectant) mothers and fathers has been associated with fewer complications during pregnancy and delivery as well as better parental and offspring health. - Methods: Prospective-longitudinal data from two regional-epidemiological samples from Germany were used: MARI (N = 396, including n = 293 mothers and n = 103 fathers) and DREAM (N = 2,819, including n = 1,689 mothers and n = 1,130 fathers). The Big Five personality traits were assessed during pregnancy in MARI as well as 8 weeks after the anticipated birth date in DREAM with short forms of the Big Five Inventory. Perceived social support was assessed during pregnancy, 4 months postpartum, and 16 months postpartum in MARI as well as during pregnancy, 14 months postpartum, and 2 years postpartum in DREAM using the short version of the Social Support Questionnaire. - Results: Multilevel analyses revealed that perceived social support decreased across the peripartum period, and this decrease did not differ between mothers and fathers. More extraverted, emotionally stable, agreeable, conscientious, and open parents perceived higher levels of social support across the peripartum period. The peripartum decrease of perceived social support was smaller in parents who were more extraverted. - Conclusion: Our findings suggest that especially extraversion plays an important role for high and stable levels of perceived social support across the peripartum period. - Implications: Particularly highly introverted parents might profit from targeted social support interventions.

Hintergrund: Traumatische Erfahrungen in Kindheit und Jugend sowie über die Lebensspanne werden mit negativen Auswirkungen auf die psychische und physische Gesundheit der betroffenen Person in Verbindung gebracht. Chronischer Stress und traumatische Erfahrungen stehen zudem im Zusammenhang mit Veränderungen des körpereigenen Stresssystems. Diese Auswirkungen können über die betroffene Person hinaus auch die nächste Generation beeinflussen und deren Entwicklung beeinträchtigen. Während der Schwangerschaft ist intergenerationale Transmission über biologische Pfade denkbar. Daher soll untersucht werden, ob sich mütterliche und kindliche Haarcortisolkonzentration (HCC) als Marker für chronisches Stressgeschehen infolge von traumatischen Erfahrungen der Mütter verändert. Hypothesen: 1. Es wurde angenommen, dass es Unterschiede in der HCC zwischen traumatisierten und nicht traumatisierten Müttern und ihren Kindern gibt. 2. Zudem wurden Zusammenhänge erwartet zwischen dem Ausmaß der Traumatisierung und HCC bei Müttern und Kindern. 3. Es wurde angenommen, dass Kinder traumatisierter Mütter 14 Monate nach Geburt mehr Entwicklungsdefizite zeigen und 4. der Zusammenhang zwischen Traumatisierungserfahrung der Mütter und Entwicklungsoutcome der Kinder über mütterliches und/oder kindliches HCC mediiert wird. Methode: Traumatische Erfahrungen in Kindheit und Jugend wurden erfasst über den Childhood Trauma Questionnaire (CTQ); traumatische Erfahrungen über die Lebens-spanne über die Posttraumatic Diagnostic Scale (PDS). Cortisol wurde über Haaranalysen bei 301 Müttern und 210 Kindern untersucht – die Haarproben der Mütter wurden max. 6 Wochen vor Geburt entnommen, die der Kinder bis zu drei Wochen postpartal, um die intrauterine Glucocorticoidregulation abzubilden. Mittels Einfaktorieller Varianzanalysen wurde auf Unterschiede in der HCC zwischen Müttern mit und ohne traumatischer Vorerfahrung getestet. Korrelationsanalysen wurden eingesetzt, um Zusammenhänge zwischen dem Ausmaß der Traumaerfahrung und der HCC, sowie zwischen dem Schweregrad der Traumatisierung und dem Entwicklungsoutcome der Kinder zu untersuchen. Eine Mediationsanalyse diente bei einer kleineren Stichprobe, die durch den späteren Messzeitpunkt resultierte (261 Mütter und 187 Kinder), dazu, 14 Monate nach Geburt, zu prüfen, ob HCC als Mediator für kindliches Entwicklungsoutcome – gemessen über den Ages and Stages Questionnaire (ASQ––3), angenommen werden kann. Ergebnisse: Es zeigte sich ein signifikanter Unterschied hinsichtlich der langfristig integrierten HCC der Mütter, in Abhängigkeit vom Erleben traumatischer Erfahrungen über die Lebensspanne. Hierbei wiesen die Mütter mit mindestens einem traumatischen Ereignis über die Lebensspanne höhere HCC–Werte auf als nicht traumatisierte Mütter. Je schwerer die mütterliche Traumatisierung im Kindes– und Jugendalter war, desto höher war die mütterliche HCC–Konzentration. Bei den Kindern zeigten sich keine signifikanten Unterschiede im HCC. Ein signifikanter Zusammenhang zwischen dem Maß an Traumatisierung in Kindheit und Jugend der Mütter und kindlichen Entwicklungsoutcomes konnte nur bezüglich eines verbesserten Problemlöseverhaltens der Kinder nachgewiesen werden. Weder die mütterliche noch die kindliche HCC konnte als Mediator zwischen mütterlicher Traumatisierung und kindlichem Entwicklungsoutcome bestätigt werden. Schlussfolgerungen: Das Erleben traumatischer Erfahrungen in Kindheit und Jugend und auch über die Lebensspanne scheint Veränderungen in der Stressbiologie der Mütter, nicht aber ihrer Kinder, nach sich zu ziehen. Kinder traumatisierter Mütter zeigten in der Untersuchung keine auffälligen HCC–Konzentrationen und keine Beeinträchtigungen in ihrer Entwicklung 14 Monate nach Geburt. Zukünftige Studien sind erforderlich, die eine transgenerationale Weitergabe von Traumaerfahrungen über einen längeren Zeitraum und auch unter Berücksichtigung der psychischen Gesundheit der Nach-kommen berücksichtigen. / Background: Traumatic experiences in childhood and adolescence as well as across the lifespan are associated with negative effects on mental and physical health of the affected individual. Chronic stress and traumatic experiences have also been related to changes in the body's stress system. These effects may extend beyond the affected individual to the next generation, potentially impacting their development. During pregnancy transgenerational effects may occur via biological pathways. Thus, we investigate whether maternal and child hair cortisol concentrations (HCC) as a marker for chronic stress events altered following maternal traumatic experiences. Hypotheses : 1. Differences in HCC were assumed between traumatised and non–traumatised mothers and their children. 2. In addition, correlations were expected between the extent of traumatisation and HCC in mothers and children. 3. It was assumed that children of traumatised mothers show more developmental deficits 14 months after birth and 4. that the connection between the traumatisation experience of the mothers and the developmental outcome of the children was mediated by maternal and/or child HCC. Method: Traumatic experiences in childhood and adolescence were assessed by the Childhood Trauma Questionnaire (CTQ); traumatic experiences across the lifespan by the Posttraumatic Diagnostic Scale (PDS). Cortisol was analysed in hair samples of 301 mothers and 210 children – the hair samples of the mothers were taken max. 6 weeks before birth, those of the children up to three weeks postpartum, in order to map intrauterine glucocorticoid regulation. Single–factor analyses of variance were used to test for differences in HCC between mothers with and without previous traumatic experience. Correlational analyses were utilized to investigate associations between the extent of trauma experience and HCC as well as between severity of traumatization and child developmental outcomes. Mediation analysis was used in a smaller sample, resulting from the later measurement time (261 mothers and 187 children) to test, 14 months after birth, whether HCC can be assumed to be a mediator of child developmental outcome – measured via the Ages and Stages Questionnaire (ASQ–3). Results: There was a significant difference in the long–term integrated HCC of the mothers, depending on the existence of traumatic experiences over the life span. Here, mothers with at least one traumatic event over the lifespan had higher HCC levels than non–traumatised mothers. The higher the severity of maternal traumatization in child-hood and adolescence, the higher the maternal HCC concentration. There were no significant differences in HCC among the children. A significant correlation between the level of trauma in childhood and adolescence of the mothers and child developmental outcomes could only be demonstrated with regard to improved problem–solving behavior of the children. Neither maternal nor child HCC could be confirmed as a mediator between maternal traumatization and child developmental outcome. Conclusions: Experiencing traumatic experiences in childhood and adolescence and also across the lifespan seems to result in changes in the stress biology of mothers, but not of their children. Children of traumatized mothers showed no noticeable HCC concentrations and no impairments in the study with regard to their development 14 months after birth. Future studies are needed that consider transgenerational transmission of trauma experiences over time and also examine the mental health of offspring.

Background: The slaughter of pregnant cattle and the fate of the foetuses are relatively new subjects in the field of animal welfare. The Scientific Committee on Veterinary Measures relating to Public Health (SCVPH), however, does not believe this topic to be a critical issue because of the hitherto supposed rare occurrence of this practice. Some previous studies though, contradict this assessment, emphasising its relevance to animal welfare. With regard to the heterogeneous study design of previous investigations, the objective of this study is to evaluate the current situation concerning the slaughter of pregnant cattle in different German abattoirs. Additionally, the prevalence was assessed semi-quantitatively on the basis of a cross-sectional, voluntary and anonymous survey that was conducted amongst senior veterinary students of the University of Leipzig from 2010 until 2013. Results: Of 255 evaluable questionnaires, 157 (63.6 %) mention the slaughter of pregnant cattle, corresponding to 76.9 % of all visited abattoirs. Slaughter of pregnant cattle is reported often (>10 % of females) in 6 (3.8 %), frequently (1–10 % of females) in 56 (35.7 %), and rarely (<1 % of females) in 95 (60.5 %) of all cases (n = 157) respectively. About 50 % of these animals were reported to be in the second or third stage of gestation. 15 (10.6 %) of 142 questionnaires providing information about the foetus, state that the foetus showed visible vital signs after the death of the mother, but in one case the foetus was euthanized subsequently. Conclusions: The results show that the slaughter of pregnant cattle is a common and widespread practice in German abattoirs. The SCVPH’s assumption that pregnant cattle are only slaughtered in rare exceptional cases can no longer be maintained. The high proportion of foetuses in the second and third gestational stage must also be considered. In this context the implementation of suitable studies and detailed analysis of the current situation is indispensable to ensure the high standards in animal welfare in Germany and Europe.

Das Metabolische Syndrom (MetSyn) ist gekennzeichnet durch eine Kombination verschiedener kardiovaskulärer Risikofaktoren: Glukoseintoleranz, Adipositas, Dyslipidämie sowie arterielle Hypertonie. Es gilt beim Menschen als eine der Hauptursachen für Herzkreislauferkrankungen und befindet sich weltweit auf enormem Vormarsch. Die Weichen für die Erkrankung werden zum Teil schon vor der Geburt durch eine veränderte Umwelt in utero gestellt. So können Stress oder eine Glukokortikoidbehandlung während der Schwangerschaft zu einem veränderten Phänotyp des Embryos/Fetus führen - mit Konsequenzen für das gesamte spätere Leben. Dieses Phänomen wird als pränatale Programmierung bezeichnet. Neben diesen epigenetischen Effekten spielen u. a. auch geschlechtsabhängige Faktoren eine Rolle für das Risiko, am MetSyn zu erkranken. Die vorliegende Arbeit befasst sich mit den Auswirkungen einer Glukokortikoidbehandlung in der frühen Trächtigkeit sowie dem Einfluss des Geschlechts auf kardiovaskuläre Risikofaktoren im Erwachsenenalter. Als Modelltier für die Studie wurde der Weißbüschelaffe eingesetzt. In einem 2002 stattgefundenen Vorversuch im Deutschen Primatenzentrum in Göttingen wurde tragenden Tieren (F0) eine Woche lang täglich oral Dexamethason verabreicht. Dieses synthetische Glukokortikoid kann die Plazentaschranke passieren. Die drei folgenden in Leipzig gehaltenen Generationen DexF1/2/3W (weibliche Tiere, n = 4/6/2) und DexF2/3M (männliche Tiere, n = 2/4) gingen in die Untersuchung ein. Tiere, die keine Nachkommen der F0-Generation darstellten, bildeten jeweils eine weibliche (ControlW, n = 11) und eine männliche (ControlM, n = 15) Kontrollgruppe und wurden ebenfalls herangezogen, um die Auswirkungen des Geschlechts auf die untersuchten Parameter zu ermitteln. Es wurde ein oraler Glukosetoleranztest (OGTT) durchgeführt (inklusive der Erfassung der Insulinwerte), der Quantitative Insulin Sensitivity Check Index (QUICKI – Maß für die Insulinsensitivität) berechnet sowie Lipidstoffwechselparameter bestimmt. Außerdem fanden wöchentlich Erfassungen des Körpergewichts statt. In mehreren Sitzungen pro Tier wurde der Blutdruck gemessen. Die statistische Auswertung erfolgte mittels Mann-Whitney-U-Test für unabhängige Stichproben. Unterschiede mit einer Irrtumswahrscheinlichkeit p ≤ 0,05 wurden als signifikant angesehen. Im OGTT wies DexF1W im Vergleich zu ControlW 120 Minuten nach oraler Glukoseapplikation eine signifikant niedrigere Insulinkonzentration auf. Da nach 30 und 120 Minuten auch die Glukosekonzentration signifikant erniedrigt war, ist jedoch nicht von einer klinischen Relevanz auszugehen. Weitere Auswirkungen der Dexamethasonapplikation auf die F1- bis F3-Generation konnten nicht beobachtet werden. Beim Vergleich der weiblichen und männlichen Nachkommen unbehandelter Weißbüschelaffen fiel auf, dass weibliche Tiere signifikant höhere Insulinkonzentrationen und damit eine signifikant größere Insulin-AUC (Fläche unter der Kurve) im OGTT zeigten. Ihr QUICKI war signifikant niedriger. Hyperinsulinämie und niedriger QUICKI stellen Symptome einer gestörten Glukoseregulation dar. Die weiblichen Tiere zeigten außerdem eine signifikante Erhöhung hinsichtlich Körpergewicht, VLDL-Triglycerid- und folglich Plasmatriglyceridkonzentrationen. Ihre HDL-Cholesterolwerte waren signifikant niedriger. Diese Kombination einer Hypertriglyceridämie mit niedrigem HDL-Cholesterol wird als atherogene Dyslipidämie bezeichnet. Eine gestörte Glukosehomöostase, eine Adipositas sowie eine atherogene Dyslipidämie stellen kardiovaskuläre Risikofaktoren und wichtige Komponenten des MetSyn dar. Zusammenfassend lässt sich sagen, dass beim Weißbüschelaffen eine Glukokortikoidbehandlung während der frühen Trächtigkeit nicht zum MetSyn der F1- bis F3-Generationen im Erwachsenenalter führte. Hingegen ergab die Untersuchung auf ein geschlechtsabhängiges Erkrankungsrisiko eine eindeutige Prädisposition bei den weiblichen Tieren. Die zu Grunde liegenden Mechanismen dieses Phänomens bleiben Gegenstand weiterer Untersuchungen. / The metabolic syndrome (MetSyn) consists of a cluster of metabolic disorders, characterized by glucose intolerance, obesity, dyslipidemia and hypertension. In humans, it is a major cause for cardiovascular disease. Its worldwide prevalence is increasing. The way for the disease can be paved even before birth. An adverse intrauterine environment due to prenatal stress or an iatrogenic overexposure of the fetus to glucocorticoids can lead to an altered phenotype with consequences for later life. This phenomenon is called prenatal programming. In addition gender specific factors play a leading role for the risk of developing MetSyn. The aim of the present study was to investigate the influence of a glucocorticoid application in early pregnancy and gender on cardiovascular risk factors in adulthood. The common marmoset was used as model species. In a preliminary experiment (2002) at the german primate centre (Göttingen) animals (F0) were orally treated with dexamethasone for one week during early pregnancy. Dexamethasone is a synthetic glucocorticoid that can pass the placental barrier. The following three generation offspring, reared in Leipzig, DexF1/2/3W (female animal, n = 4/6/2) and DexF2/3M (male animal, n = 2/4) were regarded. Animals that were no descendants of the F0 generation built a female (ControlW, n = 11) and a male (ControlM, n = 15) control group and were also regarded for gender-specific risk for MetSyn. An oral glucose tolerance test (OGTT) was carried out (including measurements of insulin concentration), the Quantitative Insulin Sensitivity Check Index (QUICKI – measure of insulin sensitivity) was calculated and parameters of lipid metabolism were investigated. Furthermore, all animals were weighed weekly and blood pressure was monitored at a series of meetings. Statistical analysis was performed by Mann-Whitney-U-Test for independent samples. The level of significance was defined at p ≤ 0.05. DexF1W in comparison to ControlW had a significantly lower insulin concentration 120 minutes after glucose application in the OGTT and a significantly lower glucose concentration 30 and 120 minutes after reaching the sugar solution. These findings did not seem to be clinically relevant. Apart from that, no consequences could be determined in the F1-3 generation offspring after dexamethasone treatment in pregnancy. Regarding gender comparison of untreated common marmosets, female animals had significantly higher insulin concentrations in OGTT and therefore a significantly greater insulin AUC (area under the curve). QUICKI was significantly lower. Hyperinsulinemia and a low QUICKI are symptoms of an impaired glucose regulation. Furthermore, the female animals showed an increase in body weight, VLDL triglycerides and therefore total triglycerides. HDL cholesterol was significantly lower. Hypertriglyceridemia in combination with low HDL cholesterol is called atherogenic dyslipidemia. A disturbed glucose homeostasis, obesity and an atherogenic dyslipidemia are cardiovascular risk factors and important components of MetSyn. In summary, dexamethasone applied in early pregnancy did not lead to metabolic syndrome in the F1-F3 generation offspring of common marmoset in adulthood. However, the female gender was associated with a higher risk of developing the disease. The underlying mechanisms require further investigation.