Tagungsbericht: "Hier sitze ich wieder in meiner Klause": Johann Gottfried Seume (1763 - 1810) und Leipzig

Tagungsbericht: Veranstalter: Urs Meyer/ Gabi Pahnke, Johann-Gottfried-Seume-Gesellschaft zu Leipzig e.V.; Ludwig Stockinger, Universität Leipzig Datum, Ort: 03.06.2010-05.06.2010, Leipzig Bericht von: Urs Meyer, Universität Fribourg: Obgleich Johann Gottfried Seume (1763-1810) bis heute vor allem als der "Spaziergänger nach Syrakus", als Reisender fern seiner Heimat, in Erinnerung geblieben ist, war der sozialkritische Schriftsteller, Dichter und Publizist der Spätaufklärung auch überzeugter sächsischer Landsmann – und bisweilen sogar heimwehkrank nach seiner "Vaterstadt" Leipzig. Immer wieder trieb es ihn fort aus seiner Heimat, doch kehrte er auch immer wieder zurück. Damit drängt es sich auf, Seumes Verhältnis zu Leipzig, zu der Stadt, in der er über 25 Jahre seines Lebens verbrachte, zum Gegenstand einer Tagung zu machen, die im Rahmen von Feierlichkeiten zum 200. Todestag des Dichters in Leipzig stattfand

Cytochrome P450 enzymes

No abstract availabl

Prenatal exposure to infection: a primary mechanism for abnormal dopaminergic development in schizophrenia

Rationale: Prenatal exposure to infection is a notable environmental risk factor in the development of schizophrenia. One prevalent hypothesis suggests that infection-induced disruption of early prenatal brain development predisposes the organism to long-lasting structural and functional brain abnormalities. Many of the prenatal infection-induced functional brain abnormalities appear to be closely associated with imbalances in the mesocorticolimbic dopamine system in adult life, suggesting that disruption of functional and structural dopaminergic development may be at the core of the developmental neuropathology associated with psychosis-related abnormalities induced by prenatal exposure to infection. Objectives: In this review, we integrate recent findings derived from experimental models in animals with parallel research in humans which supports this hypothesis. We thereby highlight the developmental perspective of abnormal DA functions following in-utero exposure to infection in relation to the developmental and maturational mechanisms potentially involved in schizophrenia. Results: Experimental investigations show that early prenatal immune challenge can lead to the emergence of early structural and functional alterations in the mesocorticolimbic DA system, long before the onset of the full spectrum of psychosis-associated behavioral and cognitive abnormalities in adulthood. Conclusions: Dopaminergic mal-development in general, and following prenatal immune activation in particular, may represent a primary etiopathological mechanism in the development of schizophrenia and related disorders. This hypothesis differs from the view that dopaminergic abnormalities in schizophrenia may be secondary to abnormalities in other brain structures and/or neurotransmitter systems. The existence of primary dopaminergic mechanisms may have important implications for the identification and early treatment of individuals prodromally symptomatic for schizophreni

Warum reagiert mein Patient anders auf dieses Medikament? : Pharmakogenomik und personalisierte Medizin in der Praxis

Inter- und intraindividuelle Variabilität in der Arzneimittelwirkung ist häufig. Die Ursachen dieser Unterschiede sind vielseitig und bei jedem Patienten in verschiedener Kombination vorhanden. Hauptursachen sind genetische Diversität und wechselnde Umweltfaktoren wie Ernährung,andere Arzneimittel und "Lifestyle". Variabilität kann die Pharmakokinetik, z.B. den Arzneimittelabbau, oder die Pharmakodynamik, d.h. den Wirkungsmechanismus eines Medikamentes betreffen. Diese individuellen Unterschiede im Ansprechen auf ein Medikament sind ein wichtiger Teil des Konzeptes der "Personalisierten Medizin" mit dem Anspruch, für jeden Patienten eine massgeschneiderte Therapie anzuwenden, d.h. das für seine persönliche Problematik richtige Medikament in der richtigen Dosierung. Durchbrüche in den Technologien der Genomik haben dazu geführt, dass vor allem die genetische Variation der Arzneimittelwirkung besser untersucht werden kann. Diese Studien haben zu molekulargenetischen Tests geführt, die die Wirksamkeit oder das Risiko unerwünschter Nebenwirkungen besser voraussagen können. Am häufigsten wird die "Personalisierte Medizin" heute in der Krebstherapie oder bei HIV Infektionen angewandt, zunehmend aber auch in anderen therapeutischen Gebieten. Die heute bekannten Situationen, die auch für die Praxis von Bedeutung sein können, werden hier zusammengefasst. Patienten der Internet-Generation sind besser informiert über ihre Krankheit und über die Therapie, die sie erhalten. Zunehmend werden auch Patienten in der Praxis mit bereits vorhandenen Informationen zu ihrer Gensequenz oder gewissen Gentests erscheinen

Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency

Previous work has demonstrated that the function of extrahepatic cytochrome P450 CYP1A1 is dependent on the availability of heme. CYP1A1 is involved in the activation of polyaromatic hydrocarbons. In the present study we used a transgenic mouse model with chronic impairment of heme synthesis - female porphobilinogen deaminase-deficient (PBGD-/-) mice - to investigate the effects of limited heme in untreated and β-naphthoflavone (β-NF)-treated animals on the function of CYP1A1 in brain. The heme content of PBGD-/- mice was diminished in the liver and brain compared to wild types. In the liver, partial heme deficiency led to less potent induction of CYP1A1 mRNA after β-NF treatment. In the brain, CYP1A1 protein was detected not only at the endoplasmic reticulum (ER), but also in the cytosol of PBGD-/- mice. Furthermore, 7-deethylation of ethoxyresorufin, an indicator of CYP1A1 metabolic activity, could be restored by heme in cytosol of PBGD-/- mouse brain. Independent of the genotype, we found only one cyp1a1 gene product, indicating that the cytosolic appearance of CYP1A1 most likely did not originate from mutant alleles. We conclude that heme deficiency in the brain leads to incomplete heme saturation of CYP1A1, which causes its improper incorporation into the ER membrane and persistence in the cytosol. It is suggested that diseases caused by relative heme deficiency, such as hepatic porphyrias, may lead to impaired hemoprotein function in brai

Disruption of the US pre-exposure effect and latent inhibition in two-way active avoidance by systemic amphetamine in C57BL/6 mice

Rationale: Pre-exposure to either one of the two to-be-associated stimuli alone is known to reduce the efficiency of the learning of their association when they are subsequently paired explicitly. In classical conditioning, pre-exposure to the conditioned stimulus (CS) gives rise to latent inhibition (LI); and pre-exposure to the unconditioned stimulus (US) results in the US pre-exposure effect (USPEE). Considerable evidence supports an important role of central dopamine in the regulation and modulation of LI; it has been suggested that the USPEE may be similarly controlled by dopamine, but this parallelism has only been directly demonstrated in the conditioned taste aversion paradigm. Objective: The present study tested this hypothesis by comparing the efficacy of systemic amphetamine treatment to affect the expression of LI and the USPEE in a two-way active avoidance paradigm. Methods: C57BL/6 male mice were tested in active avoidance using a tone CS and a foot-shock US. Twenty-four hours before, they were pre-exposed to 100 presentations of the CS or the US, or to the test apparatus only. Amphetamine (2.5mg/kg) or saline was administered before stimulus pre-exposure and conditioned avoidance test, in which the mice learned to avoid the shock by shuttling in response to the tone. Results: Amphetamine disrupted both stimulus pre-exposure effects, thus, lending further support to the hypothesis that the USPEE is similar to LI in its sensitivity to dopamine receptor agonist. Hence, the USPEE paradigm may represent a valuable addition to the study of dopamine-sensitive processes of selective learning currently implicated in LI and Kamin blockin

Prenatal and postnatal maternal contributions in the infection model of schizophrenia

Epidemiological studies have indicated that the risk of schizophrenia is enhanced by prenatal maternal infection with viral or bacterial pathogens. Recent experimentation in rodents has yielded additional support for a causal relationship between prenatal immune challenge and the emergence of psychosis-related abnormalities in brain and behaviour in later life. However, little is known about the putative roles of maternal postnatal factors in triggering and modulating the emergence of psychopathology following prenatal immunological stimulation. Here, we aimed to dissect the relative contributions of prenatal inflammatory events and postnatal maternal factors in precipitating juvenile and adult psychopathology in the resulting offspring with a cross-fostering design. Pregnant mice were exposed to the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 5mg/kg, intravenously), or vehicle treatment on gestation day 9, and offspring born to PolyI:C- and vehicle-treated dams were then simultaneously cross-fostered to surrogate rearing mothers, which had either experienced inflammatory or vehicle treatment during pregnancy. Prenatal PolyI:C administration did not affect the expression of latent inhibition (LI) at a juvenile stage of development, but led to the post-pubertal emergence of LI disruption in both aversive classical and instrumental conditioning regardless of the postnatal rearing condition. In addition, deficits in conditioning as such led to a pre- and post-pubertal loss of LI in prenatal control animals that were adopted by PolyI:C-treated surrogate mothers. Our findings thus indicate that the adoption of prenatally immune-challenged neonates by control surrogate mothers does not possess any protective effects against the subsequent emergence of psychopathology in adulthood. At the same time, however, the present study highlights for the first time that the adoption of prenatal control animals by immune-challenged rearing mothers is sufficient to precipitate learning disabilities in the juvenile and adult offsprin

Chronic clozapine treatment improves prenatal infection-induced working memory deficits without influencing adult hippocampal neurogenesis

Background: Converging evidence indicates that prenatal exposure to immune challenge can induce long-term cognitive deficits relevant to schizophrenia. Such cognitive impairments may be related to deficient hippocampal neurogenesis at adult age. Objectives: In the present study, we sought evidence for the possibility that chronic treatment with the reference atypical antipsychotic drug clozapine may improve prenatal infection-induced cognitive dysfunctions by stimulating adult hippocampal neurogenesis. Methods: This hypothesis was tested in a well-established mouse model of prenatal immune challenge which is based on prenatal administration of the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C). Results: We found that maternal PolyI:C (5mg/kg, i.v.) exposure on gestation day 17 led to significant spatial working memory impairment and reduced hippocampal neurogenesis in the resulting offspring at adult age. The latter effect was apparent in postmortem immunohistochemical analyses of the cell proliferation marker bromodeoxyuridine and the microtubule-associated protein doublecortin, a marker of newborn neuronal cells. Chronic (3weeks) administration of clozapine (5mg/kg/day, i.p.) significantly improved the prenatal PolyI:C-induced working memory deficits, while at the same time, it negatively affected working memory performance in adult offspring born to control mothers. These bidirectional cognitive effects of clozapine were not paralleled by concomitant effects on adult hippocampal neurogenesis. Conclusions: Our findings do not support the hypothesis that the atypical antipsychotic drug clozapine may influence cognitive functions by acting on adult neurogenesis in the hippocampus, regardless of whether the drug is administered to subjects with or without a neurodevelopmental predisposition to adult neuropatholog

PARENCHYMAL CELLS FROM ADULT RAT LIVER IN NONPROLIFERATING MONOLAYER CULTURE : I. Functional Studies

Parenchymal cells from adult rat liver have been established in primary monolayer culture. Donor animals are subjected to a partial hepatectomy and, 4 days later, cells are prepared by collagenase perfusion of the regenerated liver. The hepatic parenchymal cells, separated from nonparenchymal material and suspended in serum-free medium, are placed in plastic tissue culture dishes, where they form a monolayer within 24 h. The monolayer cells exhibit minimal mitotic activity and demonstrate several major metabolic functions characteristic of liver in vivo; these include albumin synthesis and secretion, gluconeogenesis from 3-carbon precursors, responsiveness to insulin and glucagon, glycogen synthesis, and activity of two microsomal enzymes. These functions are present in the monolayer cells for several days at activities similar to those observed in the liver in vivo. The findings indicate that hepatic parenchymal cells in this monolayer system are viable and behave in many respects like normal adult rat liver