Remote Construction of N-Heterocycles via 1,4-Palladium Shift-Mediated Double C-H Activation

In the past years, Pd0-catalyzed C(sp3)-H activation provided efficient and step-economical methods to synthesize carbo- and heterocycles via direct C(sp2)-C(sp3) bond formation. We report herein that a 1,4-Pd shift allows access to N-heterocycles which are difficult to build via a direct reaction. It is shown that o-bromo-N-methylanilines undergo a 1,4-Pd shift at the N-methyl group, followed by intramolecular trapping by C(sp2)-H or C(sp3)-H activation at another nitrogen substituent and remote C-C bond formation to generate biologically relevant isoindolines and β-lactams. The product selectivity is influenced by the employed ligand, with NHCs favoring the product of remote C-C coupling against products arising from direct C-C coupling and N-demethylation

Mechanisms of Na+-Ca2+ Exchange Inhibition by Amphiphiles in CardiacMyocytes: Importance of Transbilayer Movement

The membrane lipid environment and lipid signaling pathways are potentially involved in the modulation of the activity of the cardiac Na+-Ca2+ exchanger (NCX). In the present study biophysical mechanisms of interactions of amphiphiles with the NCX and the functional consequences were examined. For this purpose, intracellular Ca2+ concentration jumps were generated by laser-flash photolysis of caged Ca2+ in guinea-pig ventricular myocytes and Na+-Ca2+ exchange currents (INa/Ca) were recorded in the whole-cell configuration of the patch-clamp technique. The inhibitory effect of amphiphiles increased with the length of the aliphatic chain between C7 and C10 and was more potent with cationic or anionic head groups than with uncharged head groups. Long-chain cationic amines (C12) exhibited a cut-off in their efficacy in INa/Ca inhibition. Analysis of the time-course, comparison with the Ni2+-induced INa/Ca block and confocal laser scanning microscopy experiments with fluorescent lipid analogs (C6- and C12-NBD-labeled analogs) suggested that amphiphiles need to be incorporated into the membrane. Furthermore, NCX block appears to require transbilayer movement of the amphiphile to the inner leaflet ("flip”). We conclude that both, hydrophobic and electrostatic interactions between the lipids and the NCX may be important factors for the modulation by lipids and could be relevant in cardiac diseases where the lipid metabolism is altere

Long-term follow-up and residual sequelae after treatment for intracerebral germ-cell tumour in children and adolescents

Background: Information on long-term follow-up of children and adolescents treated for intracerebral germ-cell tumour is scant. We report on the results of a small series of patients treated at a single institution. Patients and methods: Hospital records from 15 patients treated between 1980 and 1998 were reviewed. An attempt was made to correlate sequelae to tumour location and treatment modalities. Results: This cohort constitutes 5.5% of all brain tumours diagnosed at our institution. Histology: 10 germinomas, 2 benign teratomas, 2 malignant teratomas, and one mixed germ-cell tumour. Overall survival was 87%, with a mean follow-up time of 7 years and 8 months. The majority of patients have long-term sequelae involving one or several organ systems. In 66% endocrine, in 47% ophthalmologic, in 60% neuropsycho-logical defects were observed. Endocrine and ophthalmologic sequelae show a correlation to tumour location. Neuropsycho-logical long-term abnormalities are frequent and are associated with cranial irradiation in particular at young age, but less with tumour location, irradiation dose or surgery. Conclusions: Our preliminary data suggest that today intracerebral germinomas and mature teratomas have a good prognosis even when a relapse occurs. The outcome for mixed germ-cell tumours and malignant teratomas is less favourable. Although long-term sequelae are present in the majority of patients, there is some evidence that patients treated after 1990 suffer fewer severe long-term defects, thereby indicating that recent treatment protocols may result in a reduction of sequela

Application of latent growth and growth mixture modeling to identify and characterize differential responders to treatment for COPD

AbstractObjectiveTo explore the utility of applying growth mixture models (GMMs) in secondary analyses of clinical trials to identify sources of variability in data reported by patients with COPD.MethodsAnalyses were performed on data from two 6-month clinical trials comparing indacaterol and open-label tiotropium or blinded salmeterol and the first six months of a 12-month trial comparing indacaterol and blinded formoterol. Latent growth model (LGM) analyses were conducted to explore the response of the SGRQ Symptoms score from baseline to six months and GMM analyses were evaluated as a method to identify latent classes of differential responders.ResultsVariability in SGRQ Symptom scores was found suggesting subsets of patients with differential response to treatment. GMM analyses found subsets of non-responders in all trials. When the responders were analyzed separately from non-responders, there were increased treatment effects (e.g., symptoms score improvement over six months for whole groups: indacaterol=8–12 units, tiotropium=7 units, salmeterol=9 units, formoterol=11 units. Responder subgroup improvement: indacaterol=9–21 units, tiotropium=7 units, salmeterol=10 units, formoterol=20 units). Responders had significantly different baseline SGRQ Symptom scores, smoking history, age, and mMRC dyspnea scores than non-responders.ConclusionsPatients with COPD represent a heterogeneous population in terms of their reporting of symptoms and response to treatment. GMM analyses are able to identify sub-groups of responders and non-responders. Application of this methodology could be of value on other endpoints in COPD and in other disease areas

DNA ploidy and proliferative activity (S-phase) in childhood soft-tissue sarcomas: their value as prognostic indicators.

The value of DNA ploidy as a prognostic indicator is well established in many cancers, but recent studies in childhood rhabdomyosarcoma (RMS) have been contradictory. In a retrospective study of 128 cases of soft-tissue sarcoma (STS) diagnosed since 1980, the prognostic value of clinical, histological and flow cytometric parameters was compared, using univariate and multivariate methods. Eighty-one RMSs, 18 extraosseous Ewing's (EOE)/peripheral neuroectodermal tumours (PNETs) and 29 other non-RMS STSs were histologically and clinically reviewed. Five year actuarial survival was 63.4% for all STSs and 69.4% for RMSs. Paraffin-embedded tissue blocks were available for flow cytometry in 90 cases. Of the RMSs, 65.5% were aneuploid [DNA index (DI) > 1.1] compared with 23% of the EOE/PNETs and 31% of non-RMS STSs. Median S-phase was also significantly higher in RMSs (17.0%) than in other STSs (10.8%) (P = 0.0023). Univariate analysis in RMSs showed that stage, ploidy status, S-phase, site and tumour size all had a significant impact on survival. In multivariate analysis of 59 cases of RMS, one clinical and two flow cytometric parameters were independently associated with poor prognosis. These were stage (IV), nonhyperdiploidy (DI < 1.10 and > 1.8) and a high rate of proliferative activity (S-phase > 14.0%). These results confirm that ploidy and S-phase are important new prognostic indicators in rhabdomyosarcoma

Temporal association between childhood leukaemia and population growth in Swiss municipalities.

The population mixing hypothesis proposes that childhood leukaemia (CL) might be a rare complication of a yet unidentified subclinical infection. Large population influxes into previously isolated rural areas may foster localised epidemics of the postulated infection causing a subsequent increase of CL. While marked population growth after a period of stability was central to the formulation of the hypothesis and to the early studies on population mixing, there is a lack of objective criteria to define such growth patterns. We aimed to determine whether periods of marked population growth coincided with increases in the risk of CL in Swiss municipalities. We identified incident cases of CL aged 0-15 years for the period 1985-2010 from the Swiss Childhood Cancer Registry. Annual data on population counts in Swiss municipalities were obtained for 1980-2010. As exposures, we defined (1) cumulative population growth during a 5-year moving time window centred on each year (1985-2010) and (2) periods of 'take-off growth' identified by segmented linear regression. We compared CL incidence across exposure categories using Poisson regression and tested for effect modification by degree of urbanisation. Our study included 1500 incident cases and 2561 municipalities. The incident rate ratio (IRR) comparing the highest to the lowest quintile of 5-year population growth was 1.18 (95 % CI 0.96, 1.46) in all municipalities and 1.33 (95 % CI 0.93, 1.92) in rural municipalities (p value interaction 0.36). In municipalities with take-off growth, the IRR comparing the take-off period (>6 % annual population growth) with the initial period of low or negative growth (<2 %) was 2.07 (95 % CI 0.95, 4.51) overall and 2.99 (1.11, 8.05) in rural areas (p interaction 0.52). Our study provides further support for the population mixing hypothesis and underlines the need to distinguish take-off growth from other growth patterns in future research

Gesellschaftliche Leistungen der biologischen Landwirtschaft

Zusammenfassuung: In diesem Bericht werden die wissenschaftlichen Ergebnisse nationaler und internationaler Studien zu den gesellschaftlichen Leistungen des Biolandbaus zusammengefasst. Als Referenzen werden dabei sowohl die konventionelle wie auch die integrierte Landwirtschaft herangezogen. Es ist den Autoren bewusst, dass alle Landwirtschaftsmethoden in der Schweiz und im Ausland eine grosse Streubreite aufweisen, da der Einfluss der regionalen sozioökonomischen Rahmenbedingungen, der Standortfaktoren, der Betriebsleiter und der unterschiedlichen staatlichen und privaten Regulierungen gross ist. Trotzdem ergeben sich für die verschiedenen Landwirtschaftsmethoden klare Unterschiede, die bei den agrarpolitischen Massnahmen berücksichtigt werden müssen. Bezüglich der positiven Externalitäten weist der Biolandbau klare Mehrleistungen in der Biodiversität auf. Dies sowohl auf der Ebene der Genetik, der Arten und besonders auch der Habitate. Deutlich sind die Mehrleistungen des Biolandbaus auch im Bereich des Humusaufbaus, was eine höhere CO2-Sequestrierung zur Folge hat. Obwohl eine dauerhafte Honorierung der Vermeidung negativer Externalitäten im bisherigen Konzept der Weiterentwicklung des Direktzahlungssystems (WDZ) nicht vorgesehen ist, sind hier die Vorteile der biologischen Landwirtschaft beträchtlich. Dies betrifft die Nährstoff- und Pflanzenschutzmittelverluste in Grund- und Oberflächengewässer sowie in andere Umweltkompartimente, der Verbrauch von nicht erneuerbarer Energie, die Emissionen von Klimagasen und die Belastungen mit Tiermedikamenten. Die nationalen und internationalen Studien zeigen auf, dass der Biolandbau sich besonders durch Systemwirkungen auszeichnet: erhöhte Biodiversität, verbesserter Schutz des Bodens, wirksame Vermeidung von Umweltbelastungen, effiziente Nutzung von natürlichen Ressourcen, geringer Verbrauch nicht erneuerbarer Energie und verbessertes Tierwohl. Dies sind die Effekte von komplexen Response-Massnahmen der Betriebsleiter auf einfach zu kontrollierende Einschränkungen und Verbote. Dadurch entstehen nicht zu unterschätzende Zusatzleistungen und Synergien bei der Erreichung der vom Bund definierten Ziele. Um den Mehrleistungen des Biolandbaus gerecht zu werden, schlagen die Autoren zwei neue Massnahmen vor: 1) Biodiversitätsbeitrag für Acker, Sonderkulturen und intensive Wiesen und 2) CO2-Sequestrationsbeiträge. Damit sind aber die gesellschaftlich wichtigen Mehrleistungen des Biolandbaus noch nicht abgegolten. Bei der Vermeidung negativer Externalitäten werden höhere umweltschutzrelevante Effekte erzielt. Diese können i) durch die Einführung eines negativen Anreizsystems nach dem Polluter-Pays-Principle (z.B. Stickstoffsteuer, CO2 - Abgabe), ii) durch ein höheres Einstiegsniveau bei den Cross-Compliance-Massnahmen für alle Betriebe (ÖLNplus) oder iii) durch einen finanziellen Ausgleich für die Mehrleistungen des Biolandbaus abgegolten werden. Die „Förderung des Biolandbaus“ als systemorientierte Massnahme macht auch nach dem Grundsatz des effizienten Einsatzes von Steuermitteln Sinn und stellt eine kosteneffektive Massnahme dar. Einerseits können damit die deutlich höheren positiven Externalitäten abgegolten werden, andererseits wird die stärkere Vermeidung von negativen Externalitäten genügend berücksichtigt