Super-diversité

Le concept de super-diversité, en cernant les conditions d'un scénario 'avenir optimiste, offre un nouvel éclairage au débat sur l'intégration. Nous sommes à la croisée des chemins. Cette étude comparative internationale montre qu'un avenir souriant se profile dans les villes qui donnent des chances aux enfants de migrants dans l'enseignement et sur le marché du travail. C'est la deuxième génération ayant réussi qui prend l'initiative en matière d'émancipation. Les jeunes ayant un niveau élevé d'éducation propagent l'égalité des hommes et des femmes et le droit individuel à décider de leur sexualité dans leur propre communauté. La perspective de la super-diversité offre un nouveau regard sur la société urbaine. Une perspective où un groupe croissant de citadins est fermement intolérant à l'intolérance et à la limitation des ibertés individuelles. Nous proposons une alternative progressiste aux aspects problématiques du multiculturalisme qui exigeait la tolérance pour toutes les opinions et coutumes culturelles, y compris celles qui semaient l'intolérance vis-à-vis des autres

Superdiversiteit. Een nieuwe visie op integratie

Amsterdam is sinds 2011 een majority-minority city. De autochtone bevolkingsgroep is officieel een minderheid geworden. Superdiversiteit (M. Crul, J. Schneider & F. Lelie 2013) biedt een nieuw vergezicht in het integratiedebat door de voorwaarden te schetsen van een grootstedelijk toekomstscenario van hoop. In de leeftijd onder de vijftien jaar is nog slechts een derde van de jongeren van autochtoon-Nederlandse afkomst. Kortom: grote steden worden superdivers, zowel in Nederland als in andere West-Europese landen. Maar het ontbreekt vooralsnog aan een intellectueel perspectief op deze ontwikkeling.Superdiversiteit biedt een nieuw vergezicht in het integratiedebat door de voorwaarden te schetsen van een grootstedelijk toekomstscenario van hoop. We staan op een kruispunt. Deze internationaal vergelijkende studie laat zien dat in steden waar kinderen van migranten in het onderwijs en op de arbeidsmarkt kansen krijgen zich een hoopvolle toekomst aftekent. De succesvolle tweede generatie neemt daar het voortouw in de emancipatie. Hoog opgeleide jongeren propageren in de eigen gemeenschap de gelijkheid van mannen en vrouwen en het individuele recht op zelfbeschikking met betrekking tot seksualiteit. Het superdiversiteitsperspectief biedt een nieuwe kijk op de stedelijke samenleving. Een perspectief waarin een groeiende groep stedelingen overtuigd intolerant is ten opzichte van intolerantie en beperking van persoonlijke vrijheden. Daarmee dient zich een progressief alternatief aan voor de problematische kanten van het multiculturalisme, dat tolerantie vroeg ten aanzien van álle culturele opvattingen en gewoontes, ook die welke tot intolerantie ten opzichte van anderen leiden

Super-diversity. A new perspective on integration.

__Abstract__ Inhabitants of Dutch descent are no longer a majority in Amsterdam. Professor Maurice Crul addresses the superdivers city in his inaugural lecture. For the first time the people in Amsterdam from Dutch origin are a minority. This brings on the question who should adapt to who? Super-diversity draws a new perspective in the debate on integration. It argues that we are standing at a crossroads. On the one hand the multi-ethnic city is a fact: for the first time the people from Dutch origin are a minority in Amsterdam, just like all the other ethnic groups. On the other hand the idea of the multicultural society is increasingly viewed as naive, since cultural equality opens the door for undesirable cultural habits, like the repression of women. Super-diversity offers a progressive alternative for the failed idea of multiculturalism and the worn-out call from politicians for migrants to adapt to Dutch values. In his view, the key to a successfully diverse society lies in the emancipation of second generation women. Super-diversity carries out a vision of hope. But there is also urgency to it. It shows that an un-emancipated second generation withdraws from society, and is even more conservative than their parents

Nanoparticle–membrane interactions

Engineered nanomaterials have a wide range of applications and as a result, are increasingly present in the environment. While they offer new technological opportunities, there is also the potential for adverse impact, in particular through possible toxicity. In this review, we discuss the current state of the art in the experimental characterisation of nanoparticle-membrane interactions relevant to the prediction of toxicity arising from disruption of biological systems. One key point of discussion is the urgent need for more quantitative studies of nano-bio interactions in experimental models of lipid system that mimic in vivo membranes

Phase I pharmacokinetic and pharmacodynamic study of the prenyl transferase inhibitor AZD3409 in patients with advanced cancer

AZD3409 is an orally active double prodrug that was developed as a novel dual prenyltransferase inhibitor. The formation of the active metabolite AZD3409 acid is mediated by esterases in plasma and cells. The aim of this phase I study was to determine the maximum tolerated dose, toxicities, pharmacokinetics and pharmacodynamics of AZD3409. AZD3409 was administered orally to patients with advanced solid malignancies using an interpatient dose-escalation scheme starting at 500 mg AZD3409 once daily. Twenty-nine patients were treated at seven dose levels. The MTD of part A was defined as 750 mg b.i.d. in the fasted state. Adverse events were mainly gastrointestinal and the severity was on average mild to moderate and reversible. The dose-limiting toxicities were vomiting, diarrhoea and uncontrolled nausea. Pharmacokinetic studies of the prodrug and the active metabolite indicated dose proportionality. Pharmacodynamic studies showed that farnesyltransferase (FTase) was inhibited at all dose levels. In conclusion, chronic oral dosing with AZD3409 is feasible and results in significant inhibition of FTase activity. Pharmacodynamic studies revealed that the maximal FTase inhibition, estimated at 49±11%, appeared to be reached at AZD3409 acid plasma concentrations at which the occurrence of drug-related toxicity was low. This study supports the rationale to implement biological effect studies in clinical trials with biologically active anticancer drugs to define optimal dosing regimens

Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor

The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1-14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5-224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg m-2 given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P = 0.004) and 38.0% (P < 0.001) increased by R115777, respectively. Intermittent dosing of R115777 at a dose of 300 mg b.i.d. for 14 days every 3 weeks is the recommended dose of R115777 in combination with the recommended single-agent irinotecan dose of 350 mg m-2

Non-invasive ventilation (NIV) as an aid to rehabilitation in acute respiratory disease

<p>Abstract</p> <p>Background</p> <p>Non-invasive ventilation (NIV) can increase exercise tolerance, reduce exercise induced desaturation and improve the outcome of pulmonary rehabilitation in patients with chronic respiratory disease. It is not known whether it can be applied to increase exercise capacity in patients admitted with non-hypercapnic acute exacerbations of COPD (AECOPD). We investigated the acceptability and feasibility of using NIV for this purpose.</p> <p>Methods</p> <p>On a single occasion, patients admitted with an acute exacerbation of chronic respiratory disease who were unable to cycle for five minutes at 20 watts attempted to cycle using NIV and their endurance time (T_lim) was recorded. To determine feasibility of this approach in clinical practice patients admitted with AECOPD were screened for participation in a trial of regular NIV assisted rehabilitation during their hospital admission.</p> <p>Results</p> <p>In 12 patients tested on a single occasion NIV increased T_limfrom 184(65) seconds to 331(229) seconds (p = 0.04) and patients desaturated less (median difference = 3.5%, p = 0.029). In the second study, 60 patients were admitted to hospital during a three month period of whom only 18(30)% were eligible to participate and of these patients, only four (7%) consented to participate.</p> <p>Conclusion</p> <p>NIV improves exercise tolerance in patients with acute exacerbations of chronic respiratory disease but the applicability of this approach in routine clinical practice may be limited.</p> <p>Trial registration</p> <p><url>http://www.controlled-trials.com/ISRCTN35692743</url></p

Effect of a farnesyl transferase inhibitor (R115777) on ductal carcinoma in situ of the breast in a human xenograft model and on breast and ovarian cancer cell growth in vitro and in vivo

INTRODUCTION: The ras pathway is essential for cell growth and proliferation. The effects of R115777, a farnesyl transferase inhibitor, were investigated in cancer cell lines expressing varying levels of growth factor receptors and with differing ras status. Effects on tumour xenografts and human ductal carcinoma in situ (DCIS) of the breast in a xenograft mouse model were also tested. METHOD: In vitro, the concentrations required to reduce cell numbers by 50% (50% inhibitory concentration) were established (MDA-MB231, MCF-7, MCF-7/HER2-18, BT-474, SK-BR3 and SKOV3). Human DCIS was implanted in nude mice or, in separate experiments, cultured cells were injected (MDA-MB231, MCF-7/HER2-18, SKOV3) and allowed to form tumours. Proliferation and apoptosis were determined by immunohistochemistry in xenografts and cell tumours. RESULTS: The 50% inhibitory concentrations varied a hundred-fold, from 39 nmol/l (± 26 nmol/l) for SKBR3 to 5.9 μmol/l(± 0.8 μmol/l) for MDA-MB231. In MCF-7/HER2-18 and SKOV3 cells the levels of tumour growth inhibition were approximately 85% and 40%, respectively. There was a significant decrease in the cell turnover index (CTI; proliferation/apoptosis). In MDA-MB 231 with activated k-ras no inhibition was observed. In treated DCIS xenografts proliferation decreased and apoptosis increased. The CTI ratio between the start and 1 and 2 weeks of treatment were 1.99 and 1.50, respectively, for controls and 0.85 (P = 0.005) and 0.75 (P = 0.08) for treated xenografts. CONCLUSION: Treatment with the farnesyl transferase inhibitor reduced cell growth in vitro and cell tumour growth in vivo. In DCIS treatment resulted in a reduced CTI. R115777 is a promising treatment for breast cancer but the relation between effect and growth factor receptor and ras status has to be established

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies