Dose reduction of epoetin-alpha in the prevention of chemotherapy-induced anaemia.

INTRODUCTION: Anaemia during chemotherapy is often left untreated. Erythropoiesis-stimulating agents are frequently used to treat overt anaemia. Their prophylactic use, however, remains controversial and raises concerns about cost-effectiveness. Therefore, we assessed the efficacy of a dose-reduction schedule in anaemia prophylaxis. MATERIALS AND METHODS: The study included patients with untreated solid tumours about to receive platinum-based chemotherapy and had haemoglobin (Hb) levels ≥11 g/dL. Epoetin-&#945; was administered at a dose level of 3 × 10,000 U weekly as soon as Hb descended to < 13 g/dL. Dose reductions to 3 × 4,000 U and 3 × 2,000 U weekly were planned in 4-week intervals if Hb stabilised in the range of 11-13 g/dL. Upon ascending to ≥13 g/dL, epoetin was discontinued. Iron supplements of 100 mg intravenous doses were given weekly. Of 37 patients who enrolled, 33 could be evaluated. RESULTS AND DISCUSSION: Their median Hb level was 13.7 (10.9-16.2) g/dL at baseline and descended to 11.0 (7.4-13.8) g/dL by the end of chemotherapy. Anaemia (Hb < 10 g/dL) was prevented in 24 patients (73%). The mean dose requirement for epoetin-&#945; was 3 × 5,866 U per week per patient, representing a dose reduction of 41%. Treatment failed in nine patients (27%), in part due to epoetin-&#945; resistance in four (12%) and blood transfusion in three (9%) patients. CONCLUSION: Dose reduction was as effective as fixed doses in anaemia prophylaxis but reduced the amount of prescribed epoetin substantially.

Elevated serum f erritin is an independent predictor of severe liver fibrosis, steatosis, and treatment failure in chronic hepatitis C

Background: Infection with the hepatitis C virus (HCV) i s associatedwith hepatic iron accumulation. We performed a comprehensive analysisof serum ferritin levels and of their genetic determinants in thepathogenesis and treatment of patients with chronic hepatitis C enrolledin the Swiss Hepatitis C Cohort Study (SCCS).Methods: Serum ferritin levels at baseline o f therapy with p egylatedinterferon-&#945; ( PEG-IFN-&#945;) and ribavirin or b efore liver biopsy werecorrelated with clinical features of c hronic HCV infection, includingnecroinflammatory activity (N=970), fibrosis (N=980), steatosis (N=886)and response to treatment (N=876). The association b etween highferritin levels (> median) and the endpoints w as assessed b y logisticregression. In addition, a candidate gene analysis as well as a genomewideassociation study (GWAS) of serum ferritin levels were performed.Results: S erum ferritin > sex-specific median was one of the strongestpre-treatment predictors of failure to achieve SVR (P<0.0001, OR=0.46,95% CI=0.34-0.60). This association remained highly significant in amultivariate analysis (P=0.0001, OR=0.32, 95% CI=0.18-0.57), with anodds ratio c omparable to that of IL28B g enotype, and persisted afteradjustment for duration of infection. Additional independent predictors ofnonresponse were viral load, HCV genotype, presence of diabetes, andliver fibrosis stage. Higher serum ferritin levels were also independentlyassociated with severe liver fibrosis (P<0.0001, OR=2.67, 95% CI=1.66-4.28) a nd steatosis (P=0.0034, OR=2.34, 95% CI=1.33-4.12), but n otwith necroinflammatory a ctivity (P=0.3). No significant g eneticdeterminants of serum ferritin levels were identified.Conclusions: Elevated serum ferritin levels are associated withadvanced liver fibrosis, hepatic steatosis, and poor r esponse to IFN-&#945;-based therapy in c hronic hepatitis C, i ndependently from IL28Bgenotype.

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

BACKGROUND: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor &#945; (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. METHODS AND RESULTS: We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ER&#945; in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. CONCLUSIONS: We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

Activity of ancestral restriction factors against ancient retroviruses

Analysis of TRIM5&#945; and APOBEC3G genes suggests that these two restriction factors underwent strong positive selection throughout primate evolution. This pressure was possibly imposed by ancient exogenous retroviruses, of which endogenous retroviruses are remnants. Our study aims to assess in vitro the activity of these factors against ancient retroviruses by reconstructing their ancestral gag sequences, as well as the ancestral TRIM5&#945; and APOBEC3G for primates. Based on evolutionary genomics approach, we reconstructed ancestors of the two largest families of human endogenous retroviruses (HERV), namely HERV-K and HERV-H, as well as primate ancestral TRIM5&#945; and APOBEC3G variants. The oldest TRIM5&#945; sequence was the catarhinne TRIM5&#945;, common ancestor of Old World monkeys and hominoids, dated from 25 million years ago (mya). From the oldest, to the youngest, ancestral TRIM5&#945; variants showed less restriction of HIV-1 in vitro [1]. Likewise three ancestral APOBEC3Gs sequences common to hominoids (18 mya), Old World monkeys, and catarhinnes (25 mya) were reconstructed. All ancestral APOBEC3G variants inhibited efficiently HIV-1Δvif in vitro, compared to modern APOBEC3Gs. The ability of Vif proteins (HIV-1, HIV-2, SIVmac and SIVagm) to counteract their activity tallied with the residue 128 on ancestral APOBEC3Gs. Moreover we are attempting to reconstruct older ancestral sequences of both restriction factors by using prosimian orthologue sequences. An infectious onemillion- years-old HERV-KCON previously reconstituted was shown to be resistant to modern TRIM5&#945; and APOBEC3G [2]. Our ancestral TRIM5&#945; and APOBEC3G variants were inactive against HERV-KCON. Besides we reconstructed chimeric HERV-K bearing ancestral capsids (up to 7 mya) that resulted in infectious viruses resistant to modern and ancestral TRIM5&#945;. Likewise HERV-K viruses bearing ancestral nucleocapsids will be tested for ancestral and modern APOBEC3G restriction. In silico reconstruction and structural modeling of ancestral HERV-H capsids resulted in structures homologous to that of the gammaretrovirus MLV. Thus we are attempting to construct chimeric MLV virus bearing HERV-H ancestral capsids. These chimeric ancestral HERVs will be tested for infectivity and restriction by ancestral TRIM5&#945;. Similarly chimeric MLV viruses bearing ancestral HERV-H nucleocapsids will be reconstructed and tested for APOBEC3G restriction.

Bicc1 links the regulation of cAMP signaling in polycystic kidneys to microRNA-induced gene silencing.

Genetic defects in autosomal-dominant polycystic kidney disease (ADPKD) promote cystic growth of renal tubules, at least in part by stimulating the accumulation of cAMP. How renal cAMP levels are regulated is incompletely understood. We show that cAMP and the expression of its synthetic enzyme adenylate cyclase-6 (AC6) are up-regulated in cystic kidneys of Bicc1(-)(/-) knockout mice. Bicc1, a protein comprising three K homology (KH) domains and a sterile alpha motif (SAM), is expressed in proximal tubules. The KH domains independently bind AC6 mRNA and recruit the miR-125a from Dicer, whereas the SAM domain enables silencing by Argonaute and TNRC6A/GW182. Bicc1 similarly induces silencing of the protein kinase inhibitor PKI&#945; by miR-27a. Thus, Bicc1 is needed on these target mRNAs for silencing by specific miRNAs. The repression of AC6 by Bicc1 might explain why cysts in ADPKD patients preferentially arise from distal tubules.

Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis.

BACKGROUND: Activation of innate pattern-recognition receptors promotes CD4+ T-cell-mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms that counterregulate exaggerated heart-specific autoimmunity are poorly understood. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with &#945;-myosin heavy chain peptide and complete Freund's adjuvant. Together with interferon-γ, heat-killed Mycobacterium tuberculosis, an essential component of complete Freund's adjuvant, converted CD11b(hi)CD11c(-) monocytes into tumor necrosis factor-&#945;- and nitric oxide synthase 2-producing dendritic cells (TipDCs). Heat-killed M. tuberculosis stimulated production of nitric oxide synthase 2 via Toll-like receptor 2-mediated nuclear factor-κB activation. TipDCs limited antigen-specific T-cell expansion through nitric oxide synthase 2-dependent nitric oxide production. Moreover, they promoted nitric oxide synthase 2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, nitric oxide synthase 2 production by both radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo. CONCLUSIONS: Innate Toll-like receptor 2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T-cell responses in experimental autoimmune myocarditis via nitric oxide. Therefore, activation of innate pattern-recognition receptors is critical not only for disease induction but also for counterregulatory mechanisms, protecting the heart from exaggerated autoimmunity.

Thogoto virus infection induces sustained type I interferon responses that depend on RIG-I-like helicase signaling of conventional dendritic cells.

Type I interferon (IFN-&#945;/β) induction upon viral infection contributes to the early antiviral host defense and ensures survival until the onset of adaptive immunity. Many viral infections lead to an acute, transient IFN expression which peaks a few hours after infection and reverts to initial levels after 24 to 36 h. Robust IFN expression often is conferred by specialized plasmacytoid dendritic cells (pDC) and may depend on positive-feedback amplification via the type I IFN receptor (IFNAR). Here, we show that mice infected with Thogoto virus (THOV), which is an influenza virus-like orthomyxovirus transmitted by ticks, mounted sustained IFN responses that persisted up to 72 h after infection. For this purpose, we used a variant of THOV lacking its IFN-antagonistic protein ML, an elongated version of the matrix (M) protein [THOV(ΔML)]. Of note, large amounts of type I IFN were also found in the serum of mice lacking the IFNAR. Early IFN-&#945; expression seemed to depend on Toll-like receptor (TLR) signaling, whereas prolonged IFN-&#945; responses strictly depended on RIG-I-like helicase (RLH) signaling. Unexpectedly, THOV(ΔML)-infected bone marrow-derived pDC (BM-pDC) produced only moderate IFN levels, whereas myeloid DC (BM-mDC) showed massive IFN induction that was IPS-1-dependent, suggesting that BM-mDC are involved in the massive, sustained IFN production in THOV(ΔML)-infected animals. Thus, our data are compatible with the model that THOV(ΔML) infection is sensed in the acute phase via TLR and RLH systems, whereas at later time points only RLH signaling is responsible for the induction of sustained IFN responses.

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Adalimumab in Severe and Acute Sciatica (ASAS) : a multicentre, randomized, double-blind, placebo-controlled trial : 1240

Background Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a TNF-&#945; inhibitor, in patients with radicular pain due to lumbar disc herniation. Methods A multicentre, double-blind, randomised controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (< 12 weeks) and severe (Oswestry Disability index > 50) radicular leg pain and imaging-confirmed lumbar disc herniation were randomised to receive as adjuvant therapy either two subcutaneous injections of adalimumab (40 mg) at 7 days interval or matching placebo. The primary outcome was leg pain, which was recorded every day for 10 days and at 6-weeks and 6- months based on a visual analogue scale (0 to 100). Results Of the 265 patients screened, 61 were enrolled (adalimumab= 31) and 4 were lost to follow-up. Over time, the evolution of leg pain was more favourable in the adalimumab group than in the placebo group (p<0.001). However, the effect size was relatively small and at last follow-up the difference was 13.8 (CI95% -11.5 - 39.0). In the adalimumab group twice as many patients fulfilled the criteria for "responders" and for "low residual disease impact" ( p<0.05) and fewer surgical discectomies were performed (6 versus 13, p=0.04). Conclusion The addition of a short course of adalimumab to the treatment regimen of patients suffering from acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.

Treatment of chronic hepatitis c in 3 patients with hcv-induced severe thrombocytopenia

BACKGROUND: Thrombocytopenia has been described in HCV infection even in the absence of cirrhosis and splenomegaly. Different mechanisms have been proposed, including immunemediated platelet (plt) destruction. Here, we report on the treatment of 3 patients with HCV-HIV coinfection and HCVinduced severe thrombocytopenia. PATIENTS AND TREATMENT: All patients had an infection with HCV genotype 3, an intermediate fibrosis stage (Metavir F2 or F3), HIV infection controlled by antiretroviral combination therapy, and severe, steroid-refractory thrombocytopenia. Pegylated interferon-&#945;2a (PEG-IFN-&#945;2a) was started at 45 or 90 μg per week and doses were rapidly increased in the following, while ribavirin (RBV) was prescribed at standard doses. Treatment was pursued for 48 weeks. Two patients received intravenous immunoglobulins (IVIG) during the first weeks of PEG-IFN-&#945;2a and RBV combination therapy. RESULTS: A significant increase in plt counts (from 17, 39 and 37 G/l, respectively, to > 100 G/l) was observed in the 3 patients while they experienced a virological response. Thrombocytopenia relapsed in one patient together with a relapse of chronic hepatitis C. The other 2 patients achieved a sustained virological response (SVR), with normal plt counts at follow-up in one and persistent mild thrombocytopenia in the other. CONCLUSIONS: Carefully titrated PEG-IFN-&#945;2a and RBV combination therapy may be performed safely in this difficult-totreat patient population, with close monitoring and eventually concomitant IVIG during the first weeks. SVR can lead to normalization or significant improvement of plt counts, suggesting a causative role of HCV in this condition.

Eretria - Nea Psara : eine klassizistische Stadtanlage über der antiken Polis

Résumé: Le présent ouvrage propose une histoire de l'Erétrie moderne, de la redécouverte du site antique au projet urbanistique de 1834 pour une ville nouvelle destinée à accueillir les réfugiés de l'île de Psara - anéantie en 1824 par les Ottomans - et au développement urbain d'Erétrie/Nea Psara au XIXe et au XXe siècles. Le nom d'Erétrie englobe trois couches historiques distinctes: la cité antique, la ville néoclassique, dessinée par l'architecte allemand Eduard Schaubert (1804-1860), et le village moderne, issu de son projet. Chacune de ces strates - vestiges antiques, tissu urbain néoclassique et constructions plus récentes - est perceptible au sein de cet ensemble urbain et se trouve en relation constante avec les autres. L'exposé des recherches archéologiques - depuis la redécouverte du site antique par Ciriaco de' Pizzicolli d'Ancona (Cyriaque d'Ancône) en 1436 déjà, puis de manière systématique par des voyageurs-archéologues dès le XIXe siècle - comble une lacune dans l'historiographie de la cité antique. Cette approche met également en lumière la relation étroite entre archéologie et urbanisme au XIXe siècle. Si l'exploration de la Grèce avait été jusqu'à son indépendance en 1827 essentiellement le fait des archéologues, des historiens et des philologues, après cette date, des géologues, des ingénieurs et des topographes travaillant pour le développement économique du jeune Etat se mirent également à parcourir le pays, le regard tourné non plus seulement vers l'Antiquité, mais aussi vers l'avenir. L'histoire de la redécouverte d'Erétrie permet ainsi d'éclairer divers aspects liés à la gestation de l'Etat grec. Le projet conçu en 1834 par Ecluard Schaubert de ville néoclassique superposée aux ruines de la cité antique d'Erétrie s'inscrit dans un réseau de créations de villes nouvelles et de modernisations de villes existantes par le nouvel Etat grec, qui cherchait à fonder sa légitimité et son identité, après la domination ottomane, sur les valeurs idéales (ou idéalisées) de l'Antiquité classique. Dans le projet de développement urbain d'Erétrie, la relation étroite entre archéologie et urbanisme et, par conséquent, la référence à l'Antiquité sont évidentes: Eduard Schaubert commença par tracer sur son plan toutes les ruines antiques, dressant ainsi l'état des connaissances archéologiques du site. Sur cette base, l'architecte conçut la ville néoclassique en y incluant les principales ruines, qui devaient servir de repères visuels et qui concrétisaient ainsi le lien idéologique de la monarchie absolue avec l'Antiquité. A Erétrie, deux perspectives principales reliaient le port à l'acropole et l'Ecole navale au théâtre antique. L'intégration de ruines antiques dans un projet urbanistique avait été réalisée par Stamatios Kleanthes et Eduard Schaubert en 1831-1832 dans le plan de l'Athènes moderne, avant que celle-ci n'ait été promue capitale de la Grèce. Les deux architectes ont ainsi anticipé le caractère idéal d'Athènes dans le processus de gestation de l'Etat grec. L'importance de ce plan et de celui qu'ifs ont établi sur le même modèle pour le Pirée a été reconnue par les historiens de l'urbanisme. En revanche, le plan d'Erétrie, qui suit pourtant les mêmes principes, n'a été que partiellement étudié. Cette monographie montre que le projet d'Erétrie était le plus abouti des trois, qui tous se caractérisent par un système de routes rayonnant depuis le siège du gouvernement (résidences royales à Athènes et au Pirée, mairie à Erétrie). Cet éventail de rues ou u patte d'oie» embrasse à Athènes l'acropole et au Pirée fa baie du port, alors qu'a Erétrie il est double, axé en raison de la topographie sur l'acropole et sur Pa baie du port. Cette double patte d'oie crée ainsi le lien idéologique avec l'Antiquité et témoigne, par son ouverture sur le port, de l'essor économique souhaité par le gouvernement. Le plan d'Erétrie représente de manière exemplaire l'urbanisme programmatique de la Grèce sous Othon ler (1832-1862). L'ouvrage s'intéresse ensuite à la réalisation du projet de Schaubert, dont la mise en oeuvre n'a pas répondu aux attentes du Gouvernement. Le faible développement d'Erétrie s'explique principalement par le surdimensionnement du projet, des finances publiques modestes, la malaria endémique et une politique économique inadaptée aux traditions commerciales des Psariotes. Les lenteurs dans la réalisation du projet et même des régressions au cours du XIXe siècle et au début du XXe siècle, puis l'urbanisation accélérée d'Erétrie à partir des années 1960, ont eu pour conséquence que les historiens de l'urbanisme et les urbanistes ont sous-estimé, voire ignoré la valeur historique de ce concept Cependant, l'exécution du projet néoclassique s'est poursuivie de manière continue et des références au plan de Schaubert peuvent être observées dans l'aménagement récent de la localité aujourd'hui encore. Ainsi, des arbres ont été plantés dans les années 1960 le long de l'enceinte urbaine antique, à l'emplacement où Schaubert avait prévu la création d'une promenade arborée. Au centre d'Erétrie, là où l'agora principale aurait dû être aménagée, une grande place publique servant au marché hebdomadaire a été créée. Dans le quartier oriental, une petite église dédiée à la Pan hagia Paravouniotissa a été construite en 2001 sur la parcelle où Schaubert en avait prévue une. D'importants éléments des projets de Schaubert, qui ne sont actuellement plus guère perceptibles à Athènes et au Pirée, le sont toujours à Erétrie. Les espaces verts, par exemple, occupent une place importante dans le domaine privé: malgré la densification du tissu urbain, des parcelles caractéristiques contiennent encore des maisons isolées d'un ou de deux niveaux côté rue, avec un grand jardin à l'arrière, séparé des parcelles voisines par un mur en pierre ou en brique crue. Erétrie mérite donc une reconnaissance plus considérable dans l'histoire de l'urbanisme, puisqu'elle contribue à faire mieux comprendre les projets de ses deux villes soeurs. L'étude du projet urbanistique est complétée par une approche typologique des constructions néoclassiques d'Erétrie qui souligne encore la valeur historique de cet ensemble. Comme la plupart des édifices sont, menacés de démolition, à l'exception d'un petit nombre d'entre eux qui bénéficient d'un bon entretien, un inventaire photographique des constructions d'Erétrie datant du XIXe et du début du XXe siècle a été constitué entre 1994 et 2005, complété par des photographies anciennes. Il en ressort que les formes et les techniques de construction sont représentatives de l'architecture privée à l'époque de la création de l'Etat. Enfin, le plan directeur d'Erétrie, réalisé en 1975-1976 par un séminaire du Département d'architecture de l'Ecole polytechnique fédérale de Zurich avec l'appui de l'Ecole suisse d'archéologie en Grèce, est publié ici intégralement pour la première fois. Le présent ouvrage rend ses lettres de noblesse à un ensemble urbain néoclassique, certes modeste, mais issu d'un projet urbanistique ambitieux, témoin significatif du programme politique du nouvel Etat grec. SUMMARY Translated by William Eisler This book gives an account of the history of modern Eretria. It encompasses the rediscovery of the ancient city, the 1834 urban plan for the new town designed to accommodate the refugees from the island of Psara - destroyed by the Ottomans in 1824 - and also the urban development of Eretria/Nea Psara in the 19th and 20th centuries. The name Eretria carries a rich heritage: the ancient city, the neoclassical town designed by the Germen architect Eduard Schaubert (1804-1860), and the modern village. These three distinct historical layers ancient ruins, neoclassical plan and more recent constructions - can be seen within this urban area and are interlinked with each other. The account of the archeological investigations fills a gap in the historiography of the ancient city. This started with the early rediscovery of the ancient site by Ciriaco de'Pizzicolli d'Ancona in 1436, and was followed by systematic research by travellers/ archeologists from the 19th century onward. Furthermore, this shows the close relationship between archeology and urbanism in the 19th century. The exploration of Greece prier te its independence in 1827 was mainly red by archeologists, historians and philologists. Subsequently, geologists, engineers and topographers working for the young state's economic development travelled across the country, with their attention focused not only on Antiquity but are on the future. The history of Eretria's rediscovery gives new insights on various aspects related to the development of the Greek state. In 1834, Eduard Schaubert's project, planning a neoclassical town built upon the ancient Eretria, took place alongside the development of other new cities and the modernization of existing ones du ring the Ottoman domination. By doing so, the new Greek state wanted to build its legitimacy and identity, based upon the ideal (or idealized) values of Classical Antiquity. In the urban development of Eretria, the close connection between archeology and urbanism, and the reference to Antiquity, are obvious. Eduard Schaubert began by tracing on his plan ail of the ancient ruins, thus showing the knowledge of the archeological site at that time. On this basis, the architect planned the neoclassical town, incorporating the principal ruins which were to serve as visual references embodying the ideological link between Antiquity and King Otto's absolute monarchy. In Eretria, two principal visual axes linked the port to the acropolis and the Naval School to the ancient theatre. The integration of ancient ruins in an urban project had already been achieved by Stamatios Kleanthes and Eduard Schaubert in 1831-1832 in their plan for modern Athens, before it became the capital of Greece. The two architects had therefore anticipated the ideal character of Athens at the beginning of the Greek state. The importance of this plan and that of Piraeus (designed along the same model) has long been recognized by urban historians. By contrast, the plan of Eretria based open the same principles has been only partly studied. This book explains clearly that the Eretria project was the most elaborate. The three cities are characterized by a system of roads radiating from the seat of government (the royal residences in Athens and Piraeus, the town hall in Eretria). This fan-like arrangement of streets includes the Acropolis in Athens and the harbour in Piraeus, whereas in Eretria it is twofold, orientated towards the acropolis and the harbour on account of the topography. This double fan-like arrangement shows the ideological link with Antiquity and, with its opening onto the harbour, the government's desire for economic development. The plan of Eretria is a typical ex- ample of the programmatic urbanism of Greece under Otto I (1832-1862). The book discusses the completion of Schaubert's project, which was not fully carried out as expected by the government. The poor development of Eretria can be explained primarily by the excessive scale of the project, the modest public finances, the endemic malaria and an economic policy unsuitable to the commercial traditions of the Psariotes. Delays, even regressions in the implementation of the project in the course of the 19th and the beginning of the 20th centuries, followed by the growing urbanization of Eretria starting in the 1960's, led urban historians and town planners to underestimate or even to ignore the historical value of this concept. Nevertheless, the neoclassical project was carried out steadfastly, and references to the Schaubert plan can still be seen in the modern layout of the town. Trees were planted in the 1960's all along the circumference of the ancient city, where Schaubert had planned a tree-lined promenade. A big public square serving as a weekly market place was created in the centre of Eretria, where the principal agora had been originally planned. In 2001 a small church dedicated to the Panhagia Paravouniotissa was built on a plot of land in the eastern district, where this had been intended by Schaubert. Important elements of Schaubert's projects, which are barely perceptible in modern-day Athens and Piraeus, remain visible in Eretria. Green areas, for example, occupy a significant place within the private properties. In spite of the urban densification, characteristic plots still include isolated houses of one or two stories facing the street, with large gardens in the rear, separated from neighbours by stone or mudbrick walls. Eretria therefore deserves a more prominent position in the history of urbanism, as it contributes to a better understanding of ifs two sister cities. The study of the urban project is enriched by a typological approach to the neoclassical constructions of Eretria, underlining once again the historical value of this heritage. Since only a small number of the buildings have benefited from good maintenance and the greater part is threatened with demolition, a photographic inventory of the constructions of Eretria dating from the 19tIt and early 20th centuries was produced between 1994 and 2005, supplemented by old photographs. This documentation clearly shows that the forms and techniques of construction are characteristic of private architecture at the beginning of modern Greece. Finally, the master plan of Eretria drafted in 1975-1976 by a seminar of the Department of Architecture of the Swiss Federal Institute of Technology, Zurich, with the support of the Swiss School of Archeology in Greece, is published here in full for the first time. This book gives credit to a neoclassical urban heritage which, although modest in scale, derives from an ambitious project that embodies the political programme of the new Greek state. ΠΕΡΙΛΗΨΗ Μετάβρ&#945;ση Ελενή Δημητρ&#945;κοπούλου Η π&#945;ρούσ&#945; εργ&#945;σί&#945; προτείνει μι&#945;. ιστορί&#945; της σύγχρονης πόλης της Ερέτρι&#945;ς, ξεκινώντ&#945;ς &#945;πό την &#945;ποκάλύψη του &#945;ρχ&#945;ιολογικού χώρου, περνώντ&#945;ς &#945;πό την σύντ&#945;ξη, το 1834, του ρυμοτομικού σχεδίου γι&#945; μι&#945; νέ&#945;. πόλη που σκοπό είχε ν&#945; υποδεχθεί τούς πρόσφυγες &#945;πό τ&#945; Ψ&#945;ρά. - που κ&#945;τ&#945;στράφηκ&#945;ν ολοσχερώς το 1824 &#945;πό τούς Οθωμ&#945;νούς - κ&#945;ι εξετάζοντ&#945;ς τέλος την πολεοδομική εξέλιξη της Ερέτρι&#945;ς/Νέων Ψ&#945;ρών κ&#945;τά τον 19° κ&#945;ι τον 20° &#945;ι. Πίσω &#945;πό το όνομ&#945; της Ερέτρι&#945;ς κρύβοντ&#945;ι τρί&#945; δι&#945;φορετικά. ιστορικά στρώμ&#945;τ&#945;,: η &#945;ρχ&#945;ί&#945; πόλη, η νεοκλ&#945;σική πόλη πού σχεδιάστηκε &#945;πό τον γερμ&#945;νό &#945;ρχιτε κτον&#945; "Εντον&#945;ρντ Σάουμπερτ (1804-1860) κ&#945;ι η σύγχρονη πόλη που κτίστηκε πάνω στά. σχέδι&#945; του τελευτ&#945;ίού. Κάθε έν&#945; &#945;πό &#945;υτά τ&#945; στρώμ&#945;τ&#945; - &#945;ρχ&#945;ί&#945; κ&#945;τάλοιπ&#945;. νεοκλ&#945;σικός πολεοδομικός ιστός κ&#945;ι νεώτερ&#945; κτίσμ&#945;τ&#945; - γίνετ&#945;ι &#945;ντιληπτό στο πλ&#945;ίσιο &#945;υτού του πολεοδομικού συνόλου κ&#945;ι βρίσκετ&#945;ι σε άμεση σχέση με τ&#945; άλλ&#945; δύο. Ηπ&#945;ρονσί&#945;ση των &#945;ρχ&#945;ιολογικών ερευνών, που ξεκινούν το 1436 με την &#945;ποκάλυψη τον &#945;ρχ&#945;ιολογικού χώρού &#945;πό τον Ciriaco de' Pizzicolli d'Ancona (Κυριάκος ο Αγκωνίτης) κ&#945;ι συνεχίζοντ&#945;ι συστημ&#945;τικά. &#945;πό περιηγητές_&#945;ρχ&#945;ιολόγούς κ&#945;τά το 19° &#945;ι., κ&#945;λύπτει έν&#945; κενό στην ιστοριογρ&#945;φί&#945; της έρεύν&#945;ς της &#945;ρχ&#945;ί&#945;ς πύλης. Η προσέγγιση &#945;υτή φωτίζει επίσης τη στενή σχέσημετ&#945;ξύ&#945;ρχ&#945;ιολογί&#945;ς κ&#945;ι πολεοδομί&#945;ς κ&#945;τά τον 190 &#945;ι. Αν η εξερεύνηση της Ελλάδος, ως την &#945;νεξ&#945;ρτησί&#945; της το 1827, ήτ&#945;ν έργο κνρϊως &#945;ρχ&#945;ιολόγων, ιστορικών κ&#945;ι φιλολόγων, μετά &#945;πό &#945;υτήν την χρονολογί&#945;., γεωλόγοι, μηχ&#945;νικοί κ&#945;ι τοπογράφοι που εργάζοντ&#945;ν γι&#945; την οικονομική &#945;νάπτυξη τον νεοσύστ&#945;του Ελληνικού Κράτούς, άρχισ&#945;ν επίσης ν&#945; περιτρέχονν όλη την χώρ&#945;., με το βλέμμ&#945;. στρ&#945;μμένο όχι μόνο προς την Αρχ&#945;ιότητ&#945;, &#945;λλά κ&#945;ι προς το μέλλον. Η ιστορί&#945; της &#945;ποκάλυψης της Ερέτρι&#945;ς φωτίζει έτσι κ&#945;ι διάφορες όψεις που συνδέοντ&#945;ι με την γένεση του Ελληνικού Κράτους. Το 1834, υ 'Εντον&#945;ρντ Σάουμπερτ εκπόνησε το σχέδιο μι&#945;ς νεοκλ&#945;σικής πόλης που Θ&#945; επικ&#945;θότ&#945;ν στ&#945;; ερείπι&#945;. της &#945;ρχ&#945;ί&#945;ς Ερέτρι&#945;ς?το έργο εντάσσετ&#945;ι στο δίκτυο δημιουργί&#945;ς νέων πόλεων κ&#945;ι εκσυγχρονισμού των υπ&#945;ρχυυσών &#945;πό το νεοσύστ&#945;το Ελληνικό Κράτος. το οποίο, μετά την Οθωμ&#945;νική κυρι&#945;ρχί&#945;, επεδίωκε ν&#945; Θεμελιώσει την νομιμότητ&#945; κ&#945;ι την τ&#945;υτότητά του πάνω στις ιδ&#945;νικές ή εξιδ&#945;νικευμένες &#945;ξίες της κλ&#945;σικής &#945;ρχ&#945;ιότητ&#945;ς. Στο σχέδιο της πολεοδομικής &#945;νάπτυξης της Ερέτρι&#945;ς, η στενή σχέση μετ&#945;ξύ &#945;ρχ&#945;ιολογί&#945;ς κ&#945;ι πολεοδομί&#945;ς κ&#945;ι, κ&#945;τ επέκτ&#945;ση. οι σ&#945;φείς &#945;ν&#945;φορές στην Αρχ&#945;ιότητ&#945;. είν&#945;ι εμφ&#945;νείς: ο Εντον&#945;ρντ Σάουμπερτ άρχισε σχεδιάζοντ&#945;ς στο τοπογρ&#945;φικό τον όλ&#945; τ&#945; &#945;ρχ&#945;ί&#945;. ερείπι&#945;, κ&#945;τ&#945;γράφοντ&#945;ς έτσι τις τότε &#945;ρχ&#945;ιολογικές γνώσεις γι&#945;, το χώρο. Σε &#945;υτή τη βάση, ο &#945;ρχιτέκτον&#945;ς συνέλ&#945;βε την νεοκλ&#945;σική πόλη εντάσσοντ&#945;ς σε &#945;υτήν τ&#945; κυριότερ&#945; &#945;ρχ&#945;ί&#945; μνημεί&#945;, τ&#945; οποί&#945; χρησίμευ&#945;ν ως οπτικά σημεί&#945; &#945;ν&#945;φοράς, ενώ συγχρόνως υλοποιούσ&#945;ν την ιδεολογική σχέση της &#945;πόλύτης μον&#945;ρχί&#945;ς με την Αρχ&#945;ιότητ&#945;. Στην Ερέτρι&#945;, δυο β&#945;σικοί άξονες συνέδε&#945;ν το λιμάνι με την Ακρόπολη κ&#945;ι τη Ν&#945;υτική Σχολή με το Αρχ&#945;ίο Θέ&#945;τρο. Η έντ&#945;ξη &#945;ρχ&#945;ίων ερειπίων σε έν&#945; πολεοδομικό σχέδιο είχε ήδη πρ&#945;γμ&#945;τοποιηθεί &#945;πό τούς Στ&#945;μάτιο Κλεάνθη κ&#945;ι'Εντου&#945;ρντ Σάουμπερτ στ&#945; 1831-1832, στον σχεδι&#945;σμό της νέ&#945;ς Αθήν&#945;ς, πριν &#945;υτή &#945;ν&#945;κηρυχθεί σε πρωτεύουσ&#945;. της Ελλάδος. Οι δυο &#945;ρχιτέκτονες προεξόφλησ&#945;ν έτσι τον συμβολικό χ&#945;ρ&#945;κτήρ&#945; της Αθήν&#945;ς στην δι&#945;δικ&#945;σί&#945;. γένεσης του Ελληνικού Κράτούς, Η σημ&#945;σί&#945; &#945;υτού τον σχεδίου κ&#945;θώς κ&#945;ι εκείνου που συνέτ&#945;ξ&#945;ν, πάνω στο ίδιο πνεύμ&#945;, γι&#945; τον Πειρ&#945;ιά έχει &#945;ν&#945;γνωριστεί &#945;πό τους σύγχρονούς πολεοδόμους. Αντίθετ&#945;, το σχέδιο της Ερέτρι&#945;ς, π&#945;ρ όλο που &#945;κολούθεί τις ίδιες &#945;ρχές, μελετήθηκε πολύ λίγο. Η π&#945;ρούσ&#945; μονογρ&#945;φί&#945; δείχνει ότι το σχέδιο της Ερέτρι&#945;ς ήτ&#945;ν το πιο ολοκληρωμένο &#945;πό τ&#945; τρί&#945;. Β&#945;σικό χ&#945;ρ&#945;κτηριστικό των σχεδίων &#945;υτών είν&#945;ι έν&#945; σύστημ&#945; οδών που &#945;ν&#945;πτύσσοντ&#945;ι &#945;κτινωτά &#945;πό το κέντρο εξουσί&#945;ς (β&#945;σιλική κ&#945;τοικί&#945; στην Αθήν&#945; κ&#945;ι τον Πειρ&#945;ιά, δημ&#945;ρχείο στην Ερέτρι&#945;). Αυτή η &#945;κτινωτή διάτ&#945;ξη των οδών συμπεριλ&#945;μβάνει στην Αθήν&#945; την Ακρόπολη κ&#945;ι στον Πειρ&#945;ιά το λιμάνι, ενώ στην Ερέτρι&#945; είν&#945;ι &#945;μφίροπη, προσ&#945;ν&#945;τολισμένη, λόγω της τοπογρ&#945;φί&#945;ς, προς την &#945;κρόπολη &#945;λλά κ&#945;ι προς τον όρμο του λιμ&#945;νιού. Αυτή η διπλή &#945;κτινωτή διάτ&#945;ξη &#945;πό τη μι&#945; δημιούργεί τον ιδεολογικό δεσμό ιιε την Αρχ&#945;ιότητ&#945;, ενώ &#945;πό την άλλη τονίζει, με το άνοιγμά της προς το λιμάνι, την οικονομική άνθηση της πόλης που επιθυμούσε η κεντρική εξουσί&#945;. Τ&#945; σχέδιο της Ερέτρι&#945;ς &#945;ποτελεί &#945;ντιπροσωπευτικό δείγμ&#945; της προγρ&#945;μμ&#945;τικής πολεοδομί&#945;ς της Ελλάδος κ&#945;τά τ&#945;, χρόνι&#945; της Β&#945;σιλεί&#945;ς του "Οθωνος (1832-1862). Η υλοποίηση του σχεδίου του Σάουμπερτ δεν &#945;ντ&#945;ποκρίθηκε στις προσδοκίες της κυβέρνησης. Η μικρή &#945;νάπτύξη της Ερέτρι&#945;ς οφείλετ&#945;ι κυρίως στούς &#945;νεδ&#945;φικούς, μεγ&#945;λεπί βολονς στόχους του σχεδίού, στ&#945; μέτρι&#945; δημόσι&#945; οικονομικά, στην ενδημική ελονοσί&#945; λόγω των υφιστ&#945;μένων ελών κ&#945;θώς κ&#945;ι σε μι&#945;, οικονομική πολιτική που ήτ&#945;ν ξένη στις εμπορικές π&#945;ρ&#945;δόσεις των Ψ&#945;ρι&#945;νών. Οι &#945;ργοί ρυθμοί της πρ&#945;γμ&#945;τοποίησης του σχεδίού κ&#945;ι μάλιστ&#945; κάποιες περικοπές τον κ&#945;τά τη διάρκει&#945; τον 19°ν κ&#945;ι στις &#945;ρχές του 2θ &#945;ι., κ&#945;ι στη συνέχει&#945; η τ&#945;χεί&#945; πολεοδομική εξέλιξη της Ερέτρι&#945;ς &#945;πό τη δεκ&#945;ετί&#945; του 1960, είχ&#945;ν σ&#945;ν συνέπει&#945; ν&#945; υποτιμηθεί ή κ&#945;τ ν&#945; &#945;γνοηθεί η ιστορική &#945;ξί&#945; του πολεοδομικού σχεδίου &#945;πό τους ιστορικούς της πολεοδομί&#945;ς. Ωστόσο, η εκτέλεση τον νεοκλ&#945;σικού σχεδίου &#945;κολουθήθηκε με συνέπει&#945;, ενώ &#945;ν&#945;φορές στο σχέδιο του Σάουμπερτ μπορούν ν&#945; π&#945;ρ&#945;τηρηθούν, &#945;κόμ&#945;. κ&#945;ι σήμερ&#945;. στις νεώτερες διευθετήσεις τον χώρου. Ετσι, στη δεκ&#945;ετί&#945; του 1960, κ&#945;τά μήκος του &#945;ρχ&#945;ίού τείχούς της πόλης φυτεύθηκ&#945;ν δέντρ&#945;, στη Θέση όπού ο Σάουμπερτ είχε προβλέψει τη δημιουργί&#945; ενός δεντροφυτεμένου περιπάτου. Στο κέντρο της Ερέτρι&#945;ς, εκεί όπου Θ&#945; έπρεπε ν&#945; δι&#945;μορφωθεί η κύρι&#945; &#945;γορά της πόλης, δημιουργήθηκε μι&#945; μεγάλη δημόσι&#945; πλ&#945;τεί&#945; όπου γίνετ&#945;ι η εβδομ&#945;δι&#945;ί&#945; λ&#945;ϊκή &#945;γορά. Στην &#945;ν&#945;τολική συνοικί&#945;, χτίστηκε, το 2001, μι&#945; μικρή εκκλησί&#945; &#945;φιερωμένη στην Π&#945;ν&#945;γί&#945;, την Π&#945;ρ&#945;βοννιώτισσ&#945;, στο οικόπεδο όπου ο Σάουμπερτ είχε προβλέψει μι&#945; εκκλησί&#945;. Σημ&#945;ντικά στοιχεί&#945; των σχεδίων του Σάουμπερτ, που δεν γίνοντ&#945;ι πι&#945; κ&#945;θόλου &#945;ντιληπτά στην ΑΘήν&#945; κ&#945;ι στον Πειρ&#945;ιά, μπορούν ν&#945; π&#945;ρ&#945;τηρηθούν στην Ερέτρι&#945;. Το πράσινο, γι&#945; π&#945;ράδειγμ&#945;, κ&#945;τ&#945;λ&#945;μβάνει σημ&#945;ντική Θέση τον ιδιωτικού χώρου: π&#945;ρά την πύκνωση τον πολεοδομικού ιστού, χ&#945;ρ&#945;κτηριστικά είν&#945;ι τ&#945; οικόπεδ&#945; που περιέχούν &#945;κόμ&#945; μεμονωμέν&#945; σπίτι&#945;, μονώροφ&#945; ή διώροφ&#945;, επί προσώπου οδού, με έν&#945; μεγάλο κήπο στο πίσω μέρος, που χωρίζοντ&#945;ι &#945;πό τ&#945;, γειτονικά οικόπεδ&#945; με έν&#945; μ&#945;ντρότοιχο πέτρινο ή &#945;πό ωμές πλίνθους. Η Ερέτρι&#945; οφείλει λοιπόν ν&#945; λάβει τη Θέση που της &#945;ξίζει στην ιστορί&#945; της Νεοελληνικής πολεοδομί&#945;ς, εφόσον συμβάλλει στην κ&#945;λύτερη κ&#945;τ&#945;νόηση των σχεδίων των δυο &#945;υτών &#945;δελφών πόλεων. Η μελέτη τον πολεοδομικού σχεδίού συμπληρώνετ&#945;ι &#945;πό μι&#945; τυπολογική προσέγγιση των νεοκλ&#945;σικών κτηρίων της Ερέτρι&#945;ς, η οποί&#945; υπογρ&#945;μμίζει &#945;κόμ&#945; περισσότερο την ιστορική &#945;ξί&#945; του συνόλου &#945;υτού. Κ&#945;θώς τ&#945; περισσότερ&#945; κτήρι&#945; &#945;πειλούντ&#945;ι με κ&#945;τεδάφιση, με εξ&#945;ίρεση λίγ&#945; &#945;πό &#945;υτά που είχ&#945;ν την τύχη ν&#945; συντηρούντ&#945;ι σωστά, μετ&#945;ξύ 1994 κ&#945;ι 2005, κ&#945;τ&#945;ρτίστηκε έν&#945; φωτογρ&#945;φικό &#945;ρχείο των κτιρίων της Ερέτρι&#945;ς που χρονολογούντ&#945;ι στο 19° κ&#945;ι στις &#945;ρχές τον 200υ &#945;ι., συμπληρωμένο κ&#945;ι &#945;πό π&#945;λιές φωτογρ&#945;φίες. Από &#945;υτό προκύπτει ότι οι μορφές κ&#945;τ οι τεχνικές δομήσεως είν&#945;ι &#945;ντιπροσωπευτικές της ιδιωτικής &#945;ρχιτεκτονικής κ&#945;τά την εποχή της σύστ&#945;σης τον Ελληνικού Κράτους. Τέλος, το γενικό ρυθμιστικό σχέδιο της Ερέτρι&#945;ς, που εκπονήθηκε στ&#945; 1975-1976 &#945;πό μελετητική ομάδ&#945;της σχολής Αρχιτεκτόνων του Ομοσπονδι&#945;κού Πολυτεχνείου της Ζυρίχης, με την υποστήριξη της Ελβετικής Αρχ&#945;ιολογικής Σχολής στην Ελλάδ&#945;., δημοσιεύετ&#945;ι εδώ γι&#945; πρώτη φορά στην πλήρη μορφή του. Η π&#945;ρούσ&#945; εργ&#945;σί&#945;, &#945;φορά έν&#945; νεοκλ&#945;σικό πολεοδομικό σύνολο, τ&#945;πεινό ίσως, &#945;λλά &#945;ποτέλεσμ&#945; ενός φιλόδοξου πολεοδομικού σχεδι&#945;σμού, ο οποίος &#945;ποτελεί σημ&#945;ντικό μάρτυρ&#945; του πολιτικού προγράμμ&#945;τος τον νεοσύστ&#945;τού Ελληνικού Κράτους.

Endoglycan mediates malignant leukocyte rolling on e-selectin and signals through SYK and the MAPK pathway

Selectins play a key role regulating leukocyte migration into tissues by mediating leukocyte tethering (capture) and rolling on inflamed endothelium and/or on adherent leukocytes or platelets. During leukocyte rolling, endothelial E- or P-selectin bind to glycoprotein ligands carrying sialyl Lewis χ (sLex) determinant. P-selectin glycoprotein ligand-1 (PSGL-1) is a common ligand for L-, P- and E-selectin, which sequentially cooperates with CD44 and E- selectin ligand-1 (ESL-1) to roll on E-selectin. During rolling on endothelial selectins, PSGL-1 and CD44 signal through Src family kinases and Syk, leading to &#945;ι_β2 integrin partial activation and slow rolling on intercellular adhesion molecule-1 (ICAM-1). Leukocyte exposure to chemokines then leads to firm adhesion. Little information is available on ligands that mediate malignant leukocyte rolling on E- selectin. We defined these ligands on U937 monoblasts by immunoadsorbtion and immunoblotting using mAb raised against CD43, CD44, PSGL-1, sLex/CLA determinants and E-selectin/IgM chimera. Immunoblotting and blot rolling assays demonstrated that PSGL-1, CD43, CD44 and a -125 kDa sLex/CLA positive ligand contribute to support E-seiectin- dependent rolling. This -125 kDa ligand is endoglycan, a member of the CD34 family of sialomucins. Endoglycan was frequently detected by flow cytometry on primary leukemia, lymphoma and multiple myeloma ceils (in -50% of cases). Endoglycan, immunopurified from U937 cells, as well as endoglycan/IgG chimera efficiently supported E-selectin dependent rolling. Membrane fractionation on sucrose gradient demonstrated that endoglycan is expressed in lipid rafts. We tested the hypothesis that it signals, like PSGL-1 and CD44, through Src kinases and the MAPK pathway. Indeed, endoglycan engagement induced Syk and ERK phosphorylation in a iipid raft-dependent manner. Syk activation was dependent on Src kinase activity. Downstream of Syk, endoglycan activated PI3K and Akt as well as Bruton's tyrosine kinase and p38 MAPK. Thus, endoglycan is a ligand for endothelial selectins which may contribute to regulate leukemia, lymphoma and multiple myeloma cell trafficking and interactions with bone marrow microenvironment. - Les sélectines contrôlent la migration tissulaire des leucocytes en assurant leur capture et leur roulement sur l'endothélium vasculaire enflammé et/ou sur des plaquettes ou des leucocytes adhérant à la paroi vasculaire. Lors du roulement leucocytaire, les sélectines endothéliales (E- et P-sélectine) se lient à des ligands porteurs du saccharide sialyl Lewis χ (sLex). PSGL-1 est un ligand commun des sélectines qui coopère avec CD44 et ESL-1 pour permettre la capture et le roulement des neutrophiles. Lorsque PSGL-1 et CD44 se lient aux sélectines endothéliales, elles induisent la phosphorylation des kinases Src et de Syk conduisant à l'activation partielle de l'intégrine aLp2 et au ralentissement des leucocytes sur les sélectines et ICAM-1. Les chimiokines induisent ensuite l'adhésion ferme des leucocytes. Les ligands des sélectines qui assurent le roulement, sur la E-sélectine, des cellules issues d'hémopathies malignes sont peu connus. Nous avons caractérisé ces ligands en les purifiant avec des anticorps dirigés contre CD43, CD44, PSGL-1, sLex/CLA et en utilisant la chimère E-sélectine/IgM. Des tests d'adhésion ont montré que PSGL-1, CD43, CD44 et une glycoprotéine de ~125 kDa soutiennent les interactions cellulaires dépendant de la E- sélectine. Le ligand de -125 kDa a été identifié comme étant l'endoglycan. Il a été détecté, par cytométrie de flux, sur les cellules leucémiques, les cellules de lymphomes ou de myélome multiple, dans ~50% des cas analysés. Sa forme membranaire, immunopurifiée, ou recombinante (endoglycan/lgG) soutient les interactions cellulaires dépendant de la E- sélectine. Nous avons montré qu'il réside dans les rafts lipidiques membranaires puis avons testé l'hypothèse que l'endoglycan, comme PSGL-1 et CD44, induit une signalisation via les kinases de type Src et la voie des MAPK. Nous avons pu observer que son engagement induit la phosphorylation de Syk et de ERK pour autant que la structure des rafts soit préservée. En aval de Syk, l'endoglycan active la PI3K, Akt, Btk et la MAPK p38. Ces résultats montrent que l'endoglycan est un ligand des sélectines endothéliales qui pourrait participer au contrôle du trafic et des interactions des cellules leucémiques, de lymphomes ou de myélomes multiples avec leur microenvironnement. - Le sang est un élément clé du fonctionnement de notre corps. La circulation sanguine permet la communication et le transfert de molécules et cellules entre divers organes. Lors d'une inflammation aiguë due à une réaction allergique, une infection ou une blessure, on observe un oedème local accompagné de rougeur, de chaleur et souvent de douleurs. Au sein des tissus enflammés, on observe des globules blancs (leucocytes) et diverses molécules inflammatoires qui attirent les leucocytes dans les tissus lésés (chimiokines). Le sang est composé de globules rouges, de plaquettes et de leucocytes spécialisés dans les défenses immunes. Pour atteindre le site d'inflammation, les leucocytes doivent quitter la circulation sanguine. Ils utilisent pour cela des molécules d'adhésion présentes à leur surface qui se lient à d'autres molécules d'adhésion de la paroi sanguine. Leurs interactions permettent aux leucocytes de rouler à la surface du vaisseau sanguin. Lorsqu'ils roulent au voisinage d'un site d'inflammation, les leucocytes sont exposés à des chimiokines qui induisent leur arrêt et les dirigent dans les tissus enflammés. Ce processus physiologique est aussi impliqué dans des pathologies telles que l'infarctus, l'artériosclérose ou la thrombose. Il peut être détourné à des fins moins louables par des cellules cancéreuses pour permettre leur dissémination (métastatisation). Dans ce travail de thèse, nous avons caractérisé une molécule d'adhésion qui soutient l'adhésion des leucocytes aux sélectines endothéliales: l'endoglycan. Nous avons observé que cette molécule d'adhésion est fréquemment exprimée par les cellules malignes de nombreuses maladies du sang comme les leucémies, les lymphomes et le myélome multiple. Nous avons également pu montrer que l'endoglycan envoie des signaux à l'intérieur des cellules malignes lorsqu'elles se lient aux sélectines endothéliales. Ces signaux pourraient jouer un rôle déterminant dans la régulation des interactions des cellules malignes avec leur microenvironnement. Elles pourraient peut-être aussi favoriser leur survie et leur prolifération.

Dietary lipids reduce the expression of carotenoid-based coloration in Lacerta vivipara

1. The importance of dietary lipids for carotenoid-based ornaments has rarely been investigated, although theory predicts that dietary lipids may control the development of these widespread animal signals. Dietary lipids have been suggested to enhance the expression of male carotenoid-based ornaments because they provide carotenoids with a hydrophobic domain that facilitates their absorption and transport. Dietary lipids may also enhance the uptake of tocopherols (vitamin E), which share common absorption and transport routes with carotenoids. Here, we test whether dietary lipids enhance carotenoid availability and male carotenoid-based colorations. We also explore the effects of dietary lipids on plasma tocopherol concentration, which allow disentangling between different pathways that may explain how dietary lipids affect ornamental expression. 2. Following a two-factorial design, we manipulated dietary access of naturally occurring fatty acids (oleic acid) and carotenoids (lutein and zeaxanthin) and measured its effects on the circulating concentrations of carotenoids (lutein and zeaxanthin) and vitamin E (&#945;- and γ-(β-) tocopherols) and on the ventral, carotenoid-based coloration of male common lizards (Lacerta vivipara). 3. Lutein but not zeaxanthin plasma concentrations increased with carotenoid supplementation, which, however, did not affect coloration. Lipid intake negatively affected circulating concentrations of lutein and γ-(β-) tocopherol and led to significantly less orange colorations. The path analysis suggests that a relationship between the observed colour change and the change in plasma concentrations of γ-(β-) tocopherol may exist. 4. Our study shows for the first time that dietary lipids do not enhance but reduce the intensity of male carotenoid-based ornaments. Although dietary lipids affected plasma carotenoid concentration, its negative effect on coloration appeared to be linked to lower vitamin E plasma concentrations. These findings suggest that a conflict between dietary lipids and carotenoid and tocopherol uptake may arise if these nutrients are independently obtained from natural diets and that such conflict may reinforce signal honesty in carotenoid-based ornaments. They also suggest that, at least in the common lizard, sexual selection with respect to carotenoid-based coloration may select for males with low antioxidant capacity and thus for males of superior health.

Psychometric evaluation of the French version of the questionnaire attitudes towards morphine use; a cross-sectional study in Valais, Switzerland.

BACKGROUND: In Switzerland, nurses are allowed to prescribe and administer morphine in emergency situations without a doctor. Still, nurses and other health professionals are often reluctant to prescribe and administer morphine for pain management in patients. No valid French-speaking instrument is available in Switzerland to assess the attitudes of nurses and other health professionals towards the prescription and administration of morphine. In this study, we evaluated the psychometric properties of the French version of the questionnaire "Attitudes towards morphine use". METHODS: The instrument was derived from an Italian version. Forward and back translations of the questionnaire were performed. Item analysis and construct validity were assessed between April and December 2010 in a cross sectional study including five Swiss hospitals in a sample of 588 health professionals (533 nurses, mean age 38.3 ± 10.2 years). Thirty subjects participated in test-retest reliability. RESULTS: The time to complete the instrument ranged between 12 and 15 minutes and neither floor nor ceiling effect were found. The initial 24-item instrument showed an intraclass correlation (ICC) of 0.69 (95% CI: 0.64 to 0.73, P < 0.001), and a Cronbach's &#945; of 0.700. Factor analysis led to a six-component solution explaining 52.4% of the total variance. After excluding five items, the shortened version showed an ICC of 0.74 (95% CI, 0.70 to 0.77, P < 0.001) and a Cronbach's &#945; of 0.741. Factor analysis led to a five-component solution explaining 54.3% of the total variance. The five components were named "risk of addiction/dependence"; "operational reasons for not using morphine"; "risk of escalation"; "other (non-dependence) risks" and "external (non-operational) reasons". In test-retest, the shortened instrument showed an ICC of 0.797 (95% CI, 0.630 to 0.911, P < 0.001) and a Cronbach's &#945; of 0.797. CONCLUSIONS: The 19-item shortened instrument assessing attitudes towards the prescription and administration of morphine showed adequate content and construct validity.

Genotyping of the MTL loci and susceptibility to two antifungal agents of Candida glabrata clinical isolates

The opportunistic fungal pathogen Candida glabrata is the second most common isolate from bloodstream infections worldwide and is naturally less susceptible to the antifungal drug fluconazole than other Candida species. C. glabrata is a haploid yeast that contains three mating-type like loci (MTL), although no sexual cycle has been described. Strains containing both types of mating information at the MTL1 locus are found in clinical isolates, but it is thought that strains containing type a information are more common. Here we investigated if a particular combination of mating type information at each MTLlocus is more prevalent in clinical isolates from hospitalized patients in Mexico and if there is a correlation between mating information and resistance to fluconazole and 5-fluorocytosine. We found that while both types of information at MTL1 are equally represented in a collection of 64 clinical isolates, the vast majority of isolates contain a-type information at MTL2 and &#945;-type at MTL3. We also found no correlation of the particular combination of mating type information at the three MTL loci and resistance to fluconazole.