Die von Tumorzellen exzessiv exprimierte Laktat-Dehydrogenase 5 (LDH-A) ist das Schlüssel-Enzym für den katalytischen Stoffwechsel um Pyruvat in Laktat unter Gewinnung von Energie umzuwandeln. Bei LDH handelt es sich um einen wichtigen prognostischen Marker für die Einstufung der Aggressivität und die Behandlung von Tumoren. Ziel dieser Arbeit war es, das Wissen um die Funktion des Genproduktes von LDH-A (LDH-V) in Bezug auf die Proliferation von Tumorzellen, die Expression Angiogenese-Gene, maligne Konversion von Tumoren und die Metastasierung zu vertiefen. Zusätzlich sollte die Rolle von LDH auf die Genexpression HIF-regulierter Proteine, die das Überleben von Tumorzellen und vor allem der Glykolyse fördern, untersucht werden. Hierfür wurden LDH-A knockdown-Klone von dem murinen B16F10 Melanom und Lewis Lung Karzinom sowie dem humanem HT29 Kolonkarzinom generiert und in vitro und in vivo in den drei verschiedenen Tumormodellen untersucht. Der knockdown von LDH-A führte in vitro zu einer Hemmung der Proliferation in Lewis Lung und B16F10, während bei HT29 Tumorzellen kein solcher Effekt beobachtet werden konnte. Interessanterweise ließen sich nicht bei allen drei Zelllinien die durch limitierte LDH Aktivität ausgelösten Effekte auf die in vitro Proliferation auf das Tumorwachstum in vivo übertragen: Das Wachstum der Lewis Lung als auch der HT29 Tumoren in vivo war durch die Reduktion von LDH-A drastisch vermindert, während die Größe der B16F10 Tumoren davon nicht beeinflusst war. Es konnte gezeigt werden, dass B16F10 Tumoren unter LDH Suppression verstärkt VEGF exprimieren. Dadurch waren diese Zellen in vivo in der Lage, durch verstärkte Vaskularisierung des Tumors der durch LDH-A knockdown ausgelösten Hemmung des Tumorwachstums zu entkommen. Bei Lewis Lung Tumorzellen hingegen, führte die Unterdrückung von LDH-V zu einer beeinträchtigten Glukoseaufnahme unter normoxischen sowie hypoxischen Bedingungen. Die reduzierte Aufnahme von Glukose hatte in vivo, in einer vielschichtigen komplexen Struktur, deutlich größere Auswirkungen als auf einer eindimensionalen Zellkulturschale. Die Ergebnisse der vorliegenden Arbeit liefern neue Erkenntnisse zur Rolle von LDH-V während der Tumorprogression und können als Grundlage für zukünftige, neue Therapiestrategien bei Krebspatienten dienen. / LDH is an important prognostic marker in cancer staging and therapy. High serum LDH activity is associated with poor patient prognosis in different tumor types. LDH-A has been shown to play a major role in tumor malignancy, but the molecular mechanism behind this role is only starting to be understood. The objective of this work was to broaden our knowledge about the role of LDH-A gene product (LDH-V) in tumor cell proliferation, angiogenesis-related gene expression, tumor malignancy and metastasis. Herein, LDH-A shRNA knockdown clones of murine B16F10 melanoma, Lewis Lung carcinoma and human HT29 colon carcinoma were generated to uncover the molecular mechanisms between diminished ability of metabolizing pyruvate to lactate and tumor cell growth in vitro and in vivo. In this study, a significant correlation between tumor weight and serum LDH in in vivo tumor models was found, which additionally correlated with the in vitro LDH secretion. In vitro, suppression of LDH-A led to anti-proliferative effects in Lewis Lung and B16F10 tumor cells, while having no effect on HT29 cells. Interestingly, the consequence of limiting LDH activity in vitro did not show a direct correlation to the in vivo anti-tumor effects in LDH-deficient tumors: B16F10 tumor growth was unaffected by silencing LDH-A, while Lewis Lung and HT29 demonstrated a drastic reduction in tumor growth in vivo. B16F10 tumors were found to have increased VEGF expression upon LDH knockdown, and therefore were able to compensate the tumor growth inhibition-driven by LDH deficiency through increased tumor vascularization in vivo. In contrast, LDH-V suppressed Lewis Lung cells demonstrated an impeded glucose uptake ability under normoxic and hypoxic conditions. Subsequently, a genome-wide gene expression analysis and functional assays of LDH-A deficient and control HT29 clones revealed potential new oncogenic features of LDH-A in tumor migration and invasion as well as a feedback loop to HIF1alpha. In summary, the collective data presented in this thesis provide new insights of LDH-V in tumor progression and therapeutic strategies for the treatment of cancer.

Positive Interaktionen zwischen jüngeren und älteren Erwachsenen scheinen gefährdet, da Untersuchungen einen Mangel an Einfühlungsvermögen gegenüber älteren Menschen nahelegen. Eine Reihe von Faktoren könnte für die Verringerung oder Abwesenheit von Empathie von jüngere Erwachsenen verantwortlich sein: Studie 1 betrachtete die Wirkung von Gesichtsfalten und Stereotypen auf die Dekodierung und Imitation von emotionalen Gesichtsausdrücken und fand heraus, dass Imitationsreaktionen für ältere Erwachsene auftraten, trotz des Einflusses von Falten und Stereotypen auf die Dekodierung. Studie 2 untersuchte den Einfluss des affiliativen Kontextes in Interaktionen zwischen jungen und alten Erwachsenen und nahm an, dass der Emotionsausdruck per se (freudig vs. ärgerlich) sowie die Beziehung zwischen Beobachter und Darsteller (Eigengruppe vs. Fremdgruppe) sich auf Gesichtsmimikry in lebensechten Interaktionen auswirken. Es konnte gezeigt werden, dass Mimikry für freudige Ausdrücke älterer Erwachsener während der beiden emotionalen Ereignisse (freudig vs. ärgerlich) stattfand. Allerdings war Mimikry im freudigen Ereignis stärker gegenüber jungen Erwachsenen im Vergleich zu älteren Erwachsenen ausgeprägt, wohingegen keine Unterschiede in Mimikry im ärgerlichen Ereignis auftraten. Studie 3 untersuchte empathischen Fähigkeiten von älteren im Vergleich zu jüngeren Erwachsenen und fand keine Unterschiede in der affektiven Empathie, obwohl die Dekodierung einiger Emotionen bei den älteren Teilnehmern reduziert war. Insgesamt zeigen die Ergebnisse, dass affektive empathische Reaktionen gegenüber älteren Menschen unabhängig von der reduzierten Akkuratheit der Emotionseinschätzung sowie vom affiliativen Kontext im Wesentlichen intakt sind und dass ältere Erwachsene die über gleichen affektiven Fähigkeiten verfügen. Somit liefert diese Arbeit einen positiveren Ausblick für intergenerationale Interaktionen als bisher gedacht. / Positive interactions between younger and older adults seem to be at risk as previous research suggests a lack of empathy to the elderly. A number of elements might be accountable for the reduction or absence of empathy by younger adults: Study 1 focused on the effect of wrinkles and stereotypes on decoding accuracy and facial mimicry of emotional facial expressions. It revealed that wrinkles and stereotypes have an impact on decoding accuracy, however facial mimicry reactions to the emotion expressions of older adults were present regardless of those decoding biases. Study 2 focused on the affiliative context of interactions between younger and older adults, and suggested that the type of emotion display (happy vs. angry) as well as the observer’s relationship to the expresser (in-group vs. out-group member) impacted on facial mimicry in real-life interactions. It revealed that mimicry of happy expressions of older adults was present during the two emotional events (happy and angry). However, mimicry of younger compared to older adults was stronger in the happy event, whereas no difference occurred in mimicry in the angry event. Study 3 investigated empathic capabilities of older compared to younger adults and found no differences in affective empathy, although decoding accuracy was reduced for some emotions in the older participant sample. Collectively, these results indicate that affective empathic responding via facial mimicry toward the elderly is essentially intact regardless of reduced decoding accuracy for older faces and affiliative context. They further indicate that older adults possess the same affective capabilities as younger adults. In sum, this work provides a more positive outlook for intergenerational interactions than previously suggested.

Background: The consideration of impairment plays a crucial role in detecting significant mental health problems in children whose symptoms do not meet diagnostic criteria. The assessment of impairment may be particularly relevant when only short screening instruments are applied in epidemiological surveys. Furthermore, differences between childrens’ and parents’ perceptions of present impairment and impairing symptoms are of interest with respect to treatment-seeking behaviour. Objectives: The objectives were to assess parent- and self-reported impairment due to mental health problems in a representative sample of children and adolescents; to describe the characteristics of highly impaired children with normal symptom scores; and to investigate the associations between symptoms in different problem areas and impairment. Methods: The mental health module of the German Health Interview and Examination Survey for Children and Adolescents (the BELLA study) examined mental health in a representative sub-sample of 2,863 families with children aged 7–17. Self-reported and parent-reported symptoms of mental health problems and associated impairment were identified by the extended version of the strengths and difficulties questionnaire (SDQ) in children 11 years and older. Results: Considerable levels of distress and functional impairment were found with 14.1% of the boys and 9.9% of the girls being severely impaired according to the parental reports. However, self-reported data shows a reversed gender-difference as well as lower levels of severe impairment (6.1% in boys; 10.0% in girls). Six percent of the sampled children suffer from pronounced impairment due to mental health problems but were not detected by screening for overall symptoms. Childrens’ and parents’ reports differed in regard to the association between reported symptom scores and associated impairment with children reporting higher impairment due to emotional problems. Conclusions: The assessment of impairment caused by mental health problems provides important information beyond the knowledge of symptoms and helps to identify an otherwise undetected high risk group. In the assessment of impairment, gender-specific issues have to be taken into account. Regarding the systematic differences between childrens’ and parents’ reports in the assessment of impairment, the child’s perspective should be given special attention.

Background: Cannabis use is considered a component cause of psychotic illness, interacting with genetic and other environmental risk factors. Little is known, however, about these putative interactions. The present study investigated whether an urban environment plays a role in moderating the effects of adolescent cannabis use on psychosis risk. Method: Prospective data (n=1923, aged 14–24 years at baseline) from the longitudinal population-based German Early Developmental Stages of Psychopathology cohort study were analysed. Urbanicity was assessed at baseline and defined as living in the city of Munich (1562 persons per km2; 4061 individuals per square mile) or in the rural surroundings (213 persons per km2; 553 individuals per square mile). Cannabis use and psychotic symptoms were assessed three times over a 10-year follow-up period using the Munich version of the Composite International Diagnostic Interview. Results: Analyses revealed a significant interaction between cannabis and urbanicity [10.9% adjusted difference in risk, 95% confidence interval (CI) 3.2–18.6, p=0.005]. The effect of cannabis use on follow-up incident psychotic symptoms was much stronger in individuals who grew up in an urban environment (adjusted risk difference 6.8%, 95% CI 1.0–12.5, p=0.021) compared with individuals from rural surroundings (adjusted risk difference −4.1%, 95% CI −9.8 to 1.6, p=0.159). The statistical interaction was compatible with substantial underlying biological synergism. Conclusions: Exposure to environmental influences associated with urban upbringing may increase vulnerability to the psychotomimetic effects of cannabis use later in life.

The frequency of social dysfunctions in a general population sample and in different diagnostic groups was investigated by using the Social Interview Schedule (SIS). Based on the results of the general population sample, several of the a priori derived cut-off scores of the SIS were modified. The analysis of the general population sample revealed sex-specific relationships between age and different aspects of social functioning. Especially for younger women significantly more objective social restrictions, were found due to the burden of multiple role responsibilities. With regard to different diagnostic subgroups including patients and mostly untreated cases from the community sample with Affective Disorders and Anxiety Disorders, results indicate that the degree of social impairment and dysfunctions and the degree of satisfaction with different role areas are strongly dependent on type of disorder and on former treatment status. Specific findings are: (1) The highest number of social impairments and dysfunctions were found in cases and patients with affective syndromes and in schizophrenic patients, but not in schizoaffective patients. (2) Management difficulties and dissatisfaction in intimate relationships were primarily found in depressed women. (3) Unlike anxiety patients, anxiety cases, although mostly chronically ill, had significantly less objective impairments and a lower rate of dissatisfaction than depressed cases. The results are discussed with special reference to the possible key role of depression for the development of social dysfunctions, as measured by the SIS. (4) Problems were, however, acknowledged concerning the use of the SIS with severely disturbed chronic schizophrenic patients.

This article reports the results of a cross-national investigation of patterns of comorbidity between substance use and psychiatric disorders in six studies participating in the International Consortium in Psychiatric Epidemiology. In general, there was a strong association between mood and anxiety disorders as well as conduct and antisocial personality disorder with substance disorders at all sites. The results also suggest that there is a continuum in the magnitude of comorbidity as a function of the spectrum of substance use category (use, problems, dependence), as well as a direct relationship between the number of comorbid disorders and increasing levels of severity of substance use disorders (which was particularly pronounced for drugs). Finally, whereas there was no specific temporal pattern of onset for mood disorders in relation to substance disorders, the onset of anxiety disorders was more likely to precede that of substance disorders in all countries. These results illustrate the contribution of cross-national data to understanding the patterns and risk factors for psychopathology and substance use disorders.

Background: In many countries, buprenorphine and methadone are licensed for the maintenance treatment (MT) of opioid dependence. Despite many short-term studies, little is known about the long-term (12-month) effects of these treatments in different settings, i.e. primary care-based (PMC) and specialized substitution centers (SSCs). Objectives: To describe over a period of 12 months: (1) mortality, retention and abstinence rates; (2) changes in concomitant drug use, somatic and mental health; and (3) to explore differences between different types of provider settings. Methods: 12-Month prospective-longitudinal naturalistic study with four waves of assessment in a prevalence sample of N= 2694 maintenance patients, recruited from a nationally representative sample of N= 223 substitution physicians. Results: The 12-month retention rate was 75%; the mortality rate 1.1%. 4.1% of patients became “abstinent” during follow-up. 7% were referred to drug-free addiction treatment. Concomitant drug use decreased and somatic health status improved. No significant improvements were observed for mental health and quality of life. When controlling for initial severity, small PMC settings revealed better retention, abstinence and concomitant drug use rates. Conclusion: The study underlines the overall 12-month effectiveness of various forms of agonist MT. Findings reveal relatively high retention rates, low mortality rates, and improvements in most 12-month outcome domains, except for mental health and quality of life. PMC settings appear to be a good additional option to improve access to MTs.

Objective: To examine the hypothesis that the “natural” combination of delusions and hallucinations in psychotic disorders in fact represents a selection of early subclinical hallucinatory experiences associated with delusional ideation, resulting in need for care and mental health service use. Methods: In the Early Developmental Stages of Psychopathology study, a prospective, 10-year follow-up of a representative cohort of adolescents and young adults in Munich, Germany (n = 2524), clinical psychologists assessed hallucinations and delusions at 2 time points (T2 and T3). Analyses compared differences in psychopathology, familial liability for nonpsychotic disorder, nongenetic risk factors, persistence, and clinical outcome between groups characterized by: (1) absence of positive psychotic symptoms, (2) presence of isolated hallucinations, (3) isolated delusions, and (4) both hallucinations and delusions. Results: Delusions and hallucinations occurred together much more often (T2: 3.1%; T3: 2.0%) than predicted by chance (T2: 1.0%; T3: 0.4%; OR = 11.0; 95% CI: 8.1, 15.1). Content of delusions was contingent on presence of hallucinations but modality of hallucinations was not contingent on presence of delusions. The group with both hallucinations and delusions, compared to groups with either delusions or hallucinations in isolation, displayed the strongest associations with familial affective liability and nongenetic risk factors, as well as with persistence of psychotic symptoms, comorbidity with negative symptoms, affective psychopathology, and clinical need. Conclusions: The early stages of psychosis may involve hallucinatory experiences that, if complicated by delusional ideation under the influence of environmental risks and (liability for) affective dysregulation, give rise to a poor prognosis hallucinatory–delusional syndrome.

Background It has long been acknowledged that hearing impairment may increase the risk for psychotic experiences. Recent work suggests that young people in particular may be at risk, indicating a possible developmental mechanism. Method The hypothesis that individuals exposed to hearing impairment in early adolescence would display the highest risk for psychotic symptoms was examined in a prospective cohort study of a population sample of originally 3021 adolescents and young adults aged 14–24 years at baseline, in Munich, Germany (Early Developmental Stages of Psychopathology Study). The expression of psychosis was assessed at multiple time points over a period of up to 10 years, using a diagnostic interview (Munich Composite International Diagnostic Interview; CIDI) administered by clinical psychologists. Results Hearing impairment was associated with CIDI psychotic symptoms [odds ratio (OR) 2.04, 95% confidence interval (CI) 1.10–3.81], particularly more severe psychotic symptoms (OR 5.66, 95% CI 1.64–19.49). The association between hearing impairment and CIDI psychotic symptoms was much stronger in the youngest group aged 14–17 years at baseline (OR 3.28, 95% CI 1.54–7.01) than in the older group aged 18–24 years at baseline (OR 0.82, 95% CI 0.24–2.84). Conclusions The finding of an age-specific association between hearing impairment and psychotic experiences suggests that disruption of development at a critical adolescent phase, in interaction with other personal and social vulnerabilities, may increase the risk for psychotic symptoms.

Background The base rate of transition from subthreshold psychotic experiences (the exposure) to clinical psychotic disorder (the outcome) in unselected, representative and non-help-seeking population-based samples is unknown. Method A systematic review and meta-analysis was conducted of representative, longitudinal population-based cohorts with baseline assessment of subthreshold psychotic experiences and follow-up assessment of psychotic and non-psychotic clinical outcomes. Results Six cohorts were identified with a 3–24-year follow-up of baseline subthreshold self-reported psychotic experiences. The yearly risk of conversion to a clinical psychotic outcome in exposed individuals (0.56%) was 3.5 times higher than for individuals without psychotic experiences (0.16%) and there was meta-analytic evidence of dose–response with severity/persistence of psychotic experiences. Individual studies also suggest a role for motivational impairment and social dysfunction. The evidence for conversion to non-psychotic outcome was weaker, although findings were similar in direction. Conclusions Subthreshold self-reported psychotic experiences in epidemiological non-help-seeking samples index psychometric risk for psychotic disorder, with strong modifier effects of severity/persistence. These data can serve as the population reference for selected and variable samples of help-seeking individuals at ultra-high risk, for whom much higher transition rates have been indicated.