Effects of anti-resorptive agents on trabecular bone score (TBS) in older women.

We evaluated the longitudinal effects of anti-resorptive agents (534 treated women vs. 1,150 untreated) on lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). TBS was responsive to treatment in women over age 50. The treatment-related increase in TBS was less than the increase in BMD, which is consistent with bone texture preservation. INTRODUCTION: In addition to inducing an increase in BMD, anti-resorptive agents also help to preserve bone architecture. TBS, a new gray-level texture measurement, correlates with 3D parameters of bone micro-architecture independent of BMD. Our objective was to evaluate the longitudinal effects of anti-resorptive agents on lumbar spine BMD and TBS. METHODS: Women (≥50 years), from the BMD program database for the province of Manitoba, Canada, who had not received any anti-resorptive drug prior to their initial dual X-ray absorptiometry (DXA) exam were divided into two groups: untreated, those without any anti-resorptive drug over the course of follow-up, and treated, those with a non-estrogen anti-resorptive drug (86 % bisphosphonates, 10 % raloxifene, and 4 % calcitonin). Lumbar spine TBS was calculated for each lumbar spine DXA examination. Changes in TBS and BMD between baseline and follow-up (mean follow-up 3.7 years), expressed in percentage per year, were compared between the two groups. RESULTS: A total of 1,150 untreated women and 534 treated women met the inclusion criteria. Only a weak correlation was seen between BMD and TBS in either group. Significant intergroup differences in BMD change and TBS change were observed over the course of follow-up (p < 0.001). Similar mean decreases in BMD and TBS (-0.36 %/year and -0.31 %/year, respectively) were seen for untreated subjects (both p < 0.001). Conversely, treated subjects exhibited a significant mean increase in BMD (+1.86 %/year, p < 0.002) and TBS (+0.20 %/year, p < 0.001). CONCLUSION: TBS is responsive to treatment with non-estrogen anti-resorptive drug therapy in women over age 50. The treatment-related increase in TBS is less than the increase in BMD, which is consistent with bone texture preservation.

Diabetes and immune thrombocytopenic purpura: a new association with good response to anti-CD20 therapy.

Type 1 diabetes (T1D) is rarely a component of primary immune dysregulation disorders. We report two cases in which T1D was associated with thrombocytopenia. The first patient, a 13-year-old boy, presented with immune thrombocytopenia (ITP), thyroiditis, and, 3 wk later, T1D. Because of severe thrombocytopenia resistant to immunoglobulins, high-dose steroids, and cyclosporine treatment, anti-cluster of differentiation (CD20) therapy was introduced, with consequent normalization of thrombocytes and weaning off of steroids. Three and 5 months after anti-CD20 therapy, levothyroxin and insulin therapy, respectively, were stopped. Ten months after stopping insulin treatment, normal C-peptide and hemoglobin A1c (HbA1c) levels and markedly reduced anti-glutamic acid decarboxylase (GAD) antibodies were measured. A second anti-CD20 trial for relapse of ITP was initiated 2 yr after the first trial. Anti-GAD antibody levels decreased again, but HbA1c stayed elevated and glucose monitoring showed elevated postprandial glycemia, demanding insulin therapy. To our knowledge, this is the first case in which insulin treatment could be interrupted for 28 months after anti-CD20 treatment. In patient two, thrombocytopenia followed a diagnosis of T1D 6 yr previously. Treatment with anti-CD20 led to normalization of thrombocytes, but no effect on T1D was observed. Concerning the origin of the boys' conditions, several primary immune dysregulation disorders were considered. Thrombocytopenia associated with T1D is unusual and could represent a new entity. The diabetes manifestation in patient one was probably triggered by corticosteroid treatment; regardless, anti-CD20 therapy appeared to be efficacious early in the course of T1D, but not long after the initial diagnosis of T1D, as shown for patient two.

Regulation of mass and function of pancreatic β-cells: identification of anti-apoptotic peptides and role of GLP-1

Résumé La masse de cellules β sécrétrices d'insuline est un tissu dynamique qui s'adapte aux variations de la demande métabolique pour assurer une normoglycémie. Cette adaptation se fait par un changement de sécrétion d'insuline et de la masse totale des cellules β. Une perte complète ou partielle des cellules β conduit respectivement à un diabète de type 1 et de type 2. Les mécanismes qui régulent la masse de cellules β et maintiennent leur phénotype differencié sont encore peu connus. Leur identification est nécessaire pour comprendre le développement du diabète et développer des stratégies de traitement. La greffe d'îlots est une approche thérapeutique prometteuse pour le diabète de type 1, mais est limitée par une perte précoce des cellules β due à une apoptose induite par des cytokines. Afin d'améliorer la survie des cellules β lors de la greffe d'îlots, le premier but était de trouver des peptides pouvant bloquer l'apoptose induite par FasL et TNF-α. Pour ce faire, deux librairies de phages ont été criblées pour sélectionner des peptides se liant au Fas DD ou au TNFRl DD. Nous avons identifié six peptides différents. Cependant, aucun d'entre eux n'était capable de protéger les cellules de l'apoptose induite par FasL ou TNF-α. Deuxièmement, le GLP-1 est une hormone qui stimule la sécrétion d'insuline, et est impliquée dans la prolifération des cellules β, la différentiation, et inhibe l'apoptose. Nous avons fait l'hypothèse que le GLP-1 joue un rôle crucial dans le contrôle de la masse et de la fonction des cellules β. Afin de l'évaluer, une analyse par puce à ADN a été réalisée en comparant des cellules βTC-Tet traitées avec du GLP-1 à des cellules non-traitées. 376 gènes régulés ont été identifiés, dont RGS2, CREM, ICERI et DUSP14, augmentés significativement par le GLP-1. Nous avons confirmé que le GLP-1 augmente l'expression de ces gènes, aussi bien au niveau des transcripts que des protéines. De plus, nous avons montré que le GLP-1 induit leur expression par activation de la voie cAMP/PKA, et nécessite l'entrée de calcium extracellulaire. D'après leur fonction biologique, nous avons ensuite supposé que ces gènes pourraient agir comme régulateurs négatifs de la signalisation du GLP-l, et donc freiner son effet proliférateur. Pour vérifier notre hypothèse, des siRNAs contre ces gènes ont été développés, et leurs effets sur la prolifération des cellules β seront évalués ultérieurement. Abstract The pancreatic β-cell mass is a dynamic tissue which adapts to variations in metabolic demand in order to ensure normoglycemia. This adaptation occurs through a change in both insulin secretion and the total mass of ,β-cells. An absolute or relative loss of β-cells leads to type 1 and type 2 diabetes, respectively. The mechanisms that regulate the pancreatic β-cell mass and maintain the fully differentiated phenotype of the insulin-secreting β-cells are only poorly defined. Their identification is required to understand the progression of diabetes, but also to design strategies for the treatment of diabetes. Islet transplantation is a promising therapeutic approach for type 1 diabetes, but it is still limited by an early graft loss due to cytokine-induced apoptosis. In order to improve β-cell survival during islet transplantation, our first goal was to find novel blockers of FasL- and TNF-α-mediated cell death in the form of peptides. To that end, we screened two phage display libraries to select Fas DD- or TNFR1 DD-binding peptides. We identified six different small peptides. However, none of these peptides was able to prevent cells from FasL- or TNF-α-mediated apoptosis. Secondly, GLP-1 is a hormone that has been shown to stimulate insulin secretion and to be involved in β-cell proliferation, differentiation and inhibition of apoptosis. We hypothesized that GLP-1 plays a crucial role to control mass and function of β-cells. To evaluate this hypothesis, we performed a cDNA microarray analysis with GLP-1-treated βTC-Tet cells compared to untreated cells. We found 376 regulated genes, among these, RGS2, CREM, ICERI and DUSP14, which were significantly upregulated by GLP-1. We confirmed that both their mRNA and protein levels were strongly and rapidly increased after GLP-1 treatment. Moreover, we found that GLP-1 activates their expression mainly through the activation of the cAMP/PKA signaling pathway, and requires extracellular calcium entry. According to their biological function, we then hypothesized that these genes might act as negative regulators of the GLP-1 signaling. In particular, they might brake the effects of GLP-1 on β-cell proliferation. To verify this hypothesis, siRNAs against these genes were developed. The effect of these siRNAs on GLP-1-induced β-cell proliferation will be evaluated later.

Studies toward new anti-cancer strategies based on alpha-mannosidase inhibition.

Changes in the glycosylation pattern of cellular glycoproteins constitute a hallmark in human cancer and influence tumor progression, suggesting that inhibitors of selected glycosidases may control cancer progression. Following the studies on swainsonine, a natural inhibitor of Golgi alpha-mannosidase II, which highlighted the inhibition of cellular mannosidases as a potential innovative approach for the treatment of cancer, several dihydroxylated pyrrolidines and analogues were developed as new potent inhibitors of alpha-mannosidases II able to induce antiproliferative effects in human cancer cells.

Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity.

The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1-expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY-ESO-1-specific T lymphocytes displayed TCRs with the highest avidity and best anti-tumor recognition activity. TCRs derived from allorestricted, NY-ESO-1-specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of NY-ESO-1-expressing hematological malignancies and solid tumors.

Development of a cross-European virtual sample repository and HIV resistance database

BACKGROUND: Several European HIV observational data bases have, over the last decade, accumulated a substantial number of resistance test results and developed large sample repositories, There is a need to link these efforts together, We here describe the development of such a novel tool that allows to bind these data bases together in a distributed fashion for which the control and data remains with the cohorts rather than classic data mergers.METHODS: As proof-of-concept we entered two basic queries into the tool: available resistance tests and available samples. We asked for patients still alive after 1998-01-01, and between 180 and 195 cm of height, and how many samples or resistance tests there would be available for these patients, The queries were uploaded with the tool to a central web server from which each participating cohort downloaded the queries with the tool and ran them against their database, The numbers gathered were then submitted back to the server and we could accumulate the number of available samples and resistance tests.RESULTS: We obtained the following results from the cohorts on available samples/resistance test: EuResist: not availableI11,194; EuroSIDA: 20,71611,992; ICONA: 3,751/500; Rega: 302/302; SHCS: 53,78311,485, In total, 78,552 samples and 15,473 resistance tests were available amongst these five cohorts. Once these data items have been identified, it is trivial to generate lists of relevant samples that would be usefuI for ultra deep sequencing in addition to the already available resistance tests, Saon the tool will include small analysis packages that allow each cohort to pull a report on their cohort profile and also survey emerging resistance trends in their own cohort,CONCLUSIONS: We plan on providing this tool to all cohorts within the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN) and will provide the tool free of charge to others for any non-commercial use, The potential of this tool is to ease collaborations, that is, in projects requiring data to speed up identification of novel resistance mutations by increasing the number of observations across multiple cohorts instead of awaiting single cohorts or studies to reach the critical number needed to address such issues.

Legal issues in promoting FOSS in R+D projects - Policy, Organisation and Management

Creating and using FLOSS in R+D projects raises several legal issues, which need to be managed as soon as possible - preferably during the project planning stage. Challenges in the areas of project structure and policy, licenses and licensing, exploitation strategies, community management, and FLOSS-friendliness in general all have their legal aspects, which are commented here. Some recommendations are made for assisting in the use of FLOSS in R+D projects, especially in multiple party consortiums.

Licensing Review in R+D Projects

FOSS packages are becoming ever more present in R&D projects carried out a variety of entities, including large corporations. I will focus on how legal risks associated with the use of FOSS licenses can be assessed and discuss measures directed to risk mitigation.

Sports practice among adolescents with chronic health conditions ; and, Are adolescents with chronic conditions particularly at risk of bullying ?

RAPPORT DE SYNTHESE : Les deux articles présentés dans ce mémoire de thèse sont le résultat de recherches effectuées au sein du Groupe de Recherche sur la Santé des Adolescents, affilié à l'Unité Multidisciplinaire de Santé des Adolescents du Centre Hospitalier Universitaire Vaudois. Les études qui constituent les présents articles ont pour thème commun la santé des adolescents atteints d'affections chroniques, à savoir d'une maladie chronique et/ou d'un handicap physique. Les données qui ont servi à ces deux études sant issues de l'enquête SMASH02 (Swiss Multicenter Adolescent Survey on Health 2002), une étude transversale multicentrique, menée en 2002 dans les écoles post-obligatoires de la majorité des cantons suisses par l'intermédiaire de questionnaires anonymes. 7548 adolescents de 16 à 20 ans ont été recrutés dans cette enquête, qui porte sur de nombreux aspects de la santé et des modes de vie des adolescents. Les analyses des données ont été effectuées à l'aide du logiciel de statistiques STATA 9 et avec l'aide d'un statisticien de l'université de Lausanne. Le premier article, intitulé "Sport Practice Among Adolescents Witte Chrome Health Conditions", est publié en juin 2009 dans la revue Archives of Pediatrics and Adolescent Medicine. Cette étude compare le niveau d'activité sportive entre les adolescents atteints d'affections chroniques et leurs pairs. L'hypothèse de recherche postule que les adolescents malades chroniques et/ou en situation de handicap pratiquent significativement moins de sport que les autres. Il ressort des analyses statistiques que cette hypothèse n'est vérifiée que si l'on considère les adolescents de sexe masculin. En effet, l'étude montre également que les filles de 16 à 20 ans en général pratiquent significativement moins de sport que leurs pairs masculins. Et le fait d'être atteint d'une affection chronique semble ne pas représenter chez elles un facteur,de risque supplémentaire de diminution de la pratique sportive. Dans ce même article, nous traitons également des éléments perçus par les adolescents comme des barrières à la pratique sportive. Il s'avère que les adolescents atteints d'affections chroniques ne perçoivent pas leur maladie ou leur situation de handicap comme la principale raison de leur faible activité sportive. Ils évoquent plus fréquemment un manque de temps libre ou une préférence pour d'autres activités, soit les mêmes barrières que celles évoquées par leurs pairs. Les conclusions de cette étude doivent rappeler aux professionnels de la santé l'importance d'encourager la pratique sportive chez leurs jeunes patients, particulièrement ceux atteints d'affections chroniques ainsi que les adolescentes en général. Dans le second article, intitulé "Are Adolescents With Chronic Conditions Particularly at Risk of Bullying?", il est question de violence entre adolescents. Plus précisément, nous étudions la prévalence de bullying chez les adolescents atteints d'affections chroniques et leurs pairs. Le terme de bullying, volontairement emprunté à l'Anglais, représente un phénomène complexe, que l'on peut approximer en Français comme une victimisation par les pairs en milieu scolaire. Il résulte de cette étude que le fait d'être atteint d'une affection chronique semble être un facteur de risque significatif de bullying chez les adolescents de 16 à 20 ans. Cette conclusion amène à considérer le problème du bullying dans l'intégration des élèves malades chroniques et en situation de handicap dans le système scolaire principal, notamment par la mise en place de mesures de prévention. Cet article est publié en ligne par la revue Archives of Disease in Childhood en mars 2009.

Compendium of projects in the European nanosafety cluster

This is the fourth edition of the Nanosafety Cluster compendium. It documents the status of important projects on nanomaterial toxicity and exposure monitoring, integrated risk management, research infrastructure and coordination and support activities. The compendium is not intended to be a guidance document for human health and environmental safety management of nanotechnologies, as such guidance documents already exist and are widely available. Neither is the compendium intended to be a medium for the publication of scientific papers and research results, as this task is covered by scientific conferences and the peer reviewed press. The compendium aims to bring researchers closer together and show them the potential for synergy in their work. It is a means to establish links and communication between them during the actual research phase and well before the publication of their results. It thus focuses on the communication of projects' strategic aims, extensively covers specific work objectives and the methods used in research, and documents human capacities and available laboratory infrastructure. As such, the compendium supports collaboration on common goals and the joint elaboration of future plans, whilst compromising neither the potential for scientific publication, nor intellectual property rights.

Final architecture diploma projects in the analysis of the UPC buildings energy performance

A partir de maig de 2003, per iniciativa del Vicerectorat adjunt d’Edificacions de la UPC, el Centre Interdisciplinari de Tecnologia, Innovació i Educació per a la Sostenibilitat (CITIES) treballa en l’elaboració i la implantació del Pla d’Eficiència en el Consum de Recursos (PECR), amb l’objectiu d’establir polítiques i definir línees d’actuació per a l’estalvi i l’eficiència en el consum dels recursos energètics i d’ aigua en els edificis de la UPC.El PECR contempla, en una de les primeres fases, la realització d’avaluacions energètiques en les edificacions de la UPC per valorar l’estat actual dels edificis i poder establir uns indicadors del seu comportament energètic a partir dels quals establir els objectius d’estalvi i d’eficiència. Per fer aquestes avaluacions, es va crear una línea de projectes finals de carrera (PFC) per a estudiants de l’Escola Politècnica Superior de l’Edificació de Barcelona (EPSEB), sota la coordinació de professors tutors de diferents departaments y amb la col•laboració indispensable de totes les unitats de recolzament de la UPC.Aquesta publicació és la ponència presentada al IV Congrès "Sustainable City", a Tallinn, en el que es va presentar aquest projecte com a una eina de treball amb l'objectiu de reduir l'impacte ambiental dels edificis universitaris en les ciutats.

Business Development Efforts and Performance Improvements in SMEs Case Study of Business Development Projects Implemented in SME

Under the circumstances of the increasing market pressure, enterprises try to improve their competitive position by development efforts, and a business development project is one tool for that. There are not many answers to the question of how the development projects launched to improve the business performance in SMEs have succeeded. Theacademic interest in the business development project success has mainly focused on projects implemented in larger organisations rather than in SMEs. The previous studies on the business success of SMEs have mainly focused on new business ventures rather than on existing SMEs. However, nowadays a large number of business development projects are undertaken in existing SMEs, where they can pose a great challenge. This study focuses on business development success in SMEs thathave already established their business. The objective of the present study is to gain a deep understanding on business development project success in the SME-context and to identify the dimensions and factors affecting the project success. Further, the aim is to clarify how the business development projects implemented in SMEs have affected their performance. The empirical evidence is based on multiple case study. This study builds a framework for a generic theory of business development success in the SME-context, based on literature from the areas ofproject and change management, entrepreneurship and small business management, as well as performance measurement, and on empirical evidence from SMES. The framework consists of five success dimensions: entrepreneurial, project preparation, change management, project management and project success. The framework provides a systematic way for analysing the business development project and its impact on the performance and on the performing company. This case evidence indicates that successful business development projects have a balanced, high performance concerning all the dimensions. Good performance in one dimension is not enoughfor the project success, but it gives a good ground for the other dimensions. The other way round, poor performance in one success dimension affects the others, leading to poor performance of the project. In the SME-context the business development project success seems to be dependent on several interrelated dimensions and factors. Success in one area leads to success in other areas, and so creates an upward success spiral. Failure in one area seems to lead to failure in other areas, creating a downward failure spiral. The study indicates that the internal business development projects have affected the SMEs' performance widely also on areas and functions not initially targeted. The implications cover all thesuccess categories: the project efficiency, the impact on the customer, the business success and the future potentiality. With successful cases, the success tends to spread out to areas and functions not mentioned as the project goals, andwith unsuccessful cases the failure seems to spread out widely to the SMEs' other functions. This study also indicates that the most important key factors for successful business development project implementation are the strength of intention, business ability, knowledge, motivation and participation of the employees, as well as adequate and well-timed training provided to the employees.