Bromierte Pyrrol-Alkaloide aus karibischen Schwämmen der Gattung Agelas : Isolierung, Strukturaufklärung und chemische Ökologie

In der vorliegenden Arbeit wurden marine Schwämme der Gattungen Agelas und Stylissa von den Florida Keys und Bahamas untersucht. Dabei lag das Hauptinteresse neben der Isolierung und Strukturaufklärung der Schwamminhaltsstoffe vor allem auf der ökologischen Funktion der Sekundärstoffe. Die Chemie dieser Schwämme ist sehr charakteristisch und wird von bromierten Derivaten der Pyrrol-2-carbonsäure bestimmt. Insgesamt wurden 17 bromierte Pyrrol-Alkaloide isoliert, von denen die Verbindungen N-alpha-(4-Brompyrrolyl-2-carbonyl)-L-homoarginin (isoliert aus Agelas wiedenmayeri), Bromsceptrin (Agelas conifera), N-Methyl-dibromisophakellin (Stylissa caribica), Monobromisophakellin (Agelas sp.) und Sventrin (Agelas sventres) erstmals beschrieben wurden. Die Strukturaufklärung erfolgte mit spektroskopischen Methoden (2D NMR, MS, IR, UV, CD) und durch Vergleich mit literaturbekannten Daten. Im Fall von N-alpha-(4-Brompyrrolyl-2-carbonyl)- L-homoarginin gelang die Bestimmung der absoluten Konfiguration erst nach Synthese der Verbindung und anschließendem Vergleich der CD-Spektren von Naturstoff und synthetischer Verbindung. Insgesamt wurden die Dichlormethan/Methanol-Rohextrakte von 125 Schwämmen der Gattung Agelas, die an verschiedenen Standorten der Bahamas gesammelt wurden, mittels HPLC qualitativ untersucht und die Hauptsekundärmetaboliten quantitativ bestimmt. In sämtlichen Schwämmen konnten Brompyrrol-Alkaloide nachgewiesen werden, wobei sich drei charakteristische Inhaltsstoffmuster zeigten. Während die Rohextrakte von 71 Proben der Schwämme Agelas cervicornis, Agelas clathrodes, Agelas dispar und Agelas wiedenmayeri durch die beiden Alkaloide Oroidin und 4,5-Dibrompyrrol-2-carbonsäure gekennzeichnet sind, bestimmen dimere Pyrrol-Imidazol-Alkaloide vom Sceptrin- und Ageliferin-Typ, wobei Sceptrin stets dominiert, das Inhaltsstoffmuster von 50 untersuchten Proben der Schwämme Agelas cerebrum, Agelas conifera, Agelas dilatata und Agelas sceptrum. Ein drittes Inhaltsstoffmuster wurde für vier Proben des Schwamms Agelas sp. gefunden, welches durch bromierte Pyrrol-Alkaloide vom Phakellin- und Isophakellin-Typ charakterisiert ist. Zur Untersuchung der ökologischen Bedeutung von Brompyrrol-Alkaloiden wurde die fraßabschreckende Wirkung gegenüber Fischen getestet. In Aquarium- und Freilandversuchen konnte gezeigt werden, daß die fraßhemmende Wirkung der Rohextrakte gegenüber Fischen im Fall von Agelas conifera auf bromierte Pyrrol-Alkaloide vom Sceptrin- und Ageliferin-Typ bzw. Isophakellin-Typ für Stylissa caribica zurückzuführen ist. Erstmals wurden Reinsubstanzen vom Sceptrin-, Ageliferin- und Isophakellin-Typ getestet. Sceptrin und N-Methyl-dibromisophakellin sind bei natürlichen Konzentrationen fraßabschreckend. In weiteren ökologischen Untersuchungen konnte gezeigt werden, daß die bromierten Pyrrol-Alkaloide Oroidin, 4,5-Dibrompyrrol-2-carbonsäure und Sceptrin neben einem fraßabschreckenden Potential gegenüber Fischen auch besiedlungshemmend auf Fäulnisbakterien wirken. Bromierte Pyrrol-Alkaloide erfüllen somit mindestens zwei ökologische Funktionen, die das Überleben von Agelas-Schwämmen sichern und sie zu einer der erfolgreichsten Arten in Lebensgemeinschaften karibischer Riffe machen

Comparison of incidence/risk of venous thromboembolism (VTE) among selected clinical and hereditary risk markers: A community-based cohort study

BACKGROUND: Little information is available from community-based long-term VTE cohort studies to compare the absolute thrombosis risk of established clinical and genetic risk factors. MATERIALS AND METHODS: The occurrence of venous thromboembolism (VTE) was observed during a 10-year observation period in the BAvarian ThromboEmbolic Risk (BATER) study, a cohort study of 4337 women (age 18–55 years). We collected data on demographics, reproductive life, lifestyle, conditions/diseases, and particularly potential risk factors for VTE with a self-administered questionnaire. The objective was to present incidence rates of VTE and to show relative risk estimated associated with different clinical and genetic risk factors. RESULTS: 34 new, by diagnostic means confirmed VTE events occurred during the observation time of 32,656 women-years (WY). The overall incidence of VTE was 10.4 per 10(4 )WY. The incidence rates varied markedly among different risk cohorts. The highest incidence was observed in women with previous history of VTE, followed by family history of VTE. None of the measured "genetically-related risk markers" (antithrombin, protein C, FVL, prothrombin mutation, or MTHFR) showed a significant VTE risk. CONCLUSION: Most of the discussed VTE risk factors showed no significant association with the occurrence of new VTEs due to smallness of numbers. Only first-degree family history of VTE and own history of a previous VTE event depicted a significant association with future VTE. Clinical information seems to be more important to determine future VTE risk than genetically related laboratory tests

Sex, sport, IGF-1 and the community effect in height hypothesis

We test the hypothesis that differences in social status between groups of people within a population may induce variation in insulin-like growth factor-1(IGF-1) levels and, by extension, growth in height. This is called the community effect in height hypothesis. The relationship between IGF-1, assessed via finger-prick dried blood spot, and elite level sport competition outcomes were analysed for a sample of 116 undergraduate men and women. There was a statistically significant difference between winners and losers of a competition. Winners, as a group, had higher average pre-game and post-game IGF-1 levels than losers. We proposed this type of difference as a proxy for social dominance. We found no evidence that winners increased in IGF-1 levels over losers or that members of the same team were more similar in IGF-1 levels than they were to players from other teams. These findings provide limited support toward the community effect in height hypothesis. The findings are discussed in relation to the action of the growth hormone/IGF-1 axis as a transducer of multiple bio-social influences into a coherent signal which allows the growing human to adjust and adapt to local ecological conditions

Knowledge Transfer with Citizen Science: Luft-Leipzig Case Study

Community-based participatory research initiatives such as “hackAir”, “luftdaten.info”, “senseBox”, “CAPTOR”, “CurieuzeNeuzen Vlaanderen”, “communityAQ”, and “Healthy Air, Healthier Children” campaign among many others for mitigating short-lived climate pollutants (SLCPs) and improving air quality have reported progressive knowledge transfer results. These research initiatives provide the research community with the practical four-element state-of-the-art method for citizen science. For the preparation-, measurements-, data analysis-, and scientific support-elements that collectively present the novel knowledge transfer method, the Luft-Leipzig project results are presented. This research contributes to science by formulating a novel method for SLCP mitigation projects that employ citizen scientists. The Luft-Leipzig project results are presented to validate the four-element state-of-the-art method. The method is recommended for knowledge transfer purposes beyond the scope of mitigating short-lived climate pollutants (SLCPs) and improving air quality

VTE Risk assessment – a prognostic Model: BATER Cohort Study of young women

BACKGROUND: Community-based cohort studies are not available that evaluated the predictive power of both clinical and genetic risk factors for venous thromboembolism (VTE). There is, however, clinical need to forecast the likelihood of future occurrence of VTE, at least qualitatively, to support decisions about intensity of diagnostic or preventive measures. MATERIALS AND METHODS: A 10-year observation period of the Bavarian Thromboembolic Risk (BATER) study, a cohort study of 4337 women (18–55 years), was used to develop a predictive model of VTE based on clinical and genetic variables at baseline (1993). The objective was to prepare a probabilistic scheme that discriminates women with virtually no VTE risk from those at higher levels of absolute VTE risk in the foreseeable future. A multivariate analysis determined which variables at baseline were the best predictors of a future VTE event, provided a ranking according to the predictive power, and permitted to design a simple graphic scheme to assess the individual VTE risk using five predictor variables. RESULTS: Thirty-four new confirmed VTEs occurred during the observation period of over 32,000 women-years (WYs). A model was developed mainly based on clinical information (personal history of previous VTE and family history of VTE, age, BMI) and one composite genetic risk markers (combining Factor V Leiden and Prothrombin G20210A Mutation). Four levels of increasing VTE risk were arbitrarily defined to map the prevalence in the study population: No/low risk of VTE (61.3%), moderate risk (21.1%), high risk (6.0%), very high risk of future VTE (0.9%). In 10.6% of the population the risk assessment was not possible due to lacking VTE cases. The average incidence rates for VTE in these four levels were: 4.1, 12.3, 47.2, and 170.5 per 10(4 )WYs for no, moderate, high, and very high risk, respectively. CONCLUSION: Our prognostic tool – containing clinical information (and if available also genetic data) – seems to be worthwhile testing in medical practice in order to confirm or refute the positive findings of this study. Our cohort study will be continued to include more VTE cases and to increase predictive value of the model

Progranulin antibodies entertain a proinflammatory environment in a subgroup of patients with psoriatic arthritis

Psoriatic arthritis (PsA) is a distinctive inflammatory arthritis which may typically develop in a subgroup of individuals suffering from psoriasis. We recently described progranulin autoantibodies (PGRN-Abs) in the sera of patients with different autoimmune diseases including seronegative polyarthritis. In the present study we investigated the occurrence of PGRN-Abs in PsA.PGRN-Abs were determined in 260 patients with PsA, 100 patients with psoriasis without arthritic manifestations (PsC) and 97 healthy controls using a recently described ELISA. PGRN plasma levels were determined from subgroups by a commercially available ELISA-kit. Possible functional effects of PGRN-antibodies were analysed in vitro by tumour necrosis factor (TNF)-α mediated cytotoxicity assays using WEHI-S and HT1080 cells.PGRN-Abs were detected with relevant titres in 50/260 (19.23%) patients with PsA, but in 0/100 patients with psoriasis without arthritic manifestations (P = 0.0001). All PGRN-Abs belonged to immunoglobulin G (IgG). PGRN-Abs were significantly more frequent in PsA patients with enthesitis or dactylitis. PGRN-Abs were also more frequent in PsA patients receiving treatment with TNF-α-blockers than in patients treated without TNF-α-blockers (20.8% versus 17.4%; P = 0.016). PGRN plasma levels were significantly lower in PGRN-Ab-positive patients with PsA than in healthy controls and patients with psoriasis without arthritic manifestations (P < 0.001), indicating a neutralizing effect of PGRN-Abs. Moreover cytotoxicity assays comparing PGRN-antibody positive with negative sera from matched patients with PsA, clearly showed a proinflammatory effect of PGRN antibodies.Neutralizing PGRN-Abs occur with relevant titres in a subgroup of patients with PsA, but not in patients without arthritic manifestations (PsC). PGRN-Ab-positive patients had more frequent enthesitis or dactylitis. TNF-α-induced cytotoxicity assays demonstrated that the protective effects of progranulin were inhibited by serum containing PGRN-Abs. This suggests that PGRN-Ab might not only be useful as a diagnostic and prognostic marker, but may provide a proinflammatory environment in a subgroup of patients with PsA

Progranulin antibodies entertain a proinflammatory environment in a subgroup of patients with psoriatic arthritis

Psoriatic arthritis (PsA) is a distinctive inflammatory arthritis which may typically develop in a subgroup of individuals suffering from psoriasis. We recently described progranulin autoantibodies (PGRN-Abs) in the sera of patients with different autoimmune diseases including seronegative polyarthritis. In the present study we investigated the occurrence of PGRN-Abs in PsA.PGRN-Abs were determined in 260 patients with PsA, 100 patients with psoriasis without arthritic manifestations (PsC) and 97 healthy controls using a recently described ELISA. PGRN plasma levels were determined from subgroups by a commercially available ELISA-kit. Possible functional effects of PGRN-antibodies were analysed in vitro by tumour necrosis factor (TNF)-α mediated cytotoxicity assays using WEHI-S and HT1080 cells.PGRN-Abs were detected with relevant titres in 50/260 (19.23%) patients with PsA, but in 0/100 patients with psoriasis without arthritic manifestations (P = 0.0001). All PGRN-Abs belonged to immunoglobulin G (IgG). PGRN-Abs were significantly more frequent in PsA patients with enthesitis or dactylitis. PGRN-Abs were also more frequent in PsA patients receiving treatment with TNF-α-blockers than in patients treated without TNF-α-blockers (20.8% versus 17.4%; P = 0.016). PGRN plasma levels were significantly lower in PGRN-Ab-positive patients with PsA than in healthy controls and patients with psoriasis without arthritic manifestations (P < 0.001), indicating a neutralizing effect of PGRN-Abs. Moreover cytotoxicity assays comparing PGRN-antibody positive with negative sera from matched patients with PsA, clearly showed a proinflammatory effect of PGRN antibodies.Neutralizing PGRN-Abs occur with relevant titres in a subgroup of patients with PsA, but not in patients without arthritic manifestations (PsC). PGRN-Ab-positive patients had more frequent enthesitis or dactylitis. TNF-α-induced cytotoxicity assays demonstrated that the protective effects of progranulin were inhibited by serum containing PGRN-Abs. This suggests that PGRN-Ab might not only be useful as a diagnostic and prognostic marker, but may provide a proinflammatory environment in a subgroup of patients with PsA