Introduction

This issue contains ten papers presented at the 2008 EAAE/ARCC International Conferenceheld in Denmark. The Royal Danish Academy of Fine Arts, School of Architecture, inCopenhagen graciously and superbly hosted the EAAE/ARCC 2008 conference entitled"Changes of Paradigms in the Basic Understanding of Architectural Research. ArchitecturalResearch and the Digital World.” The papers that follow were selected from over fifty presentedat the conference. The moderators of each paper session and members of the conferenceorganizing committee selected these papers for special recognition. These papers werethen blind peer-reviewed and two papers were selected to receive the designation as ‘BestPaper', one represents the ARCC and one represents the EAAE.Excerpts from the 2008 Conference Introductio

Immunosuppressive Activity of Size-Controlled PEG-PLGA Nanoparticles Containing Encapsulated Cyclosporine A

We encapsulated cyclosporine A (CsA) in poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) (PEG-PLGA) nanoparticles (NPs) by nanoprecipitation of CsA and PEG-PLGA. The resulting CsA/PEG-PLGA-NPs were <100 nm in diameter with a narrow particle size distribution. The NP size could be controlled by tuning the polymer concentration, solvent, or water/solvent ratio during formulation. The PEGylated NPs maintained non-aggregated in salt solution. Solid NPs lyoprotected with bovine serum albumin were prepared for the convenience of storage and transportation. The release kinetics of CsA (55.6% released on Day 1) showed potential for maintaining therapeutic CsA concentrations in vivo. In T-cell assays, both free CsA and CsA/PEG-PLGA-NPs suppressed T-cell proliferation and production of inflammatory cytokines dose dependently. In a mixed lymphocyte reaction assay, the IC50 values for free CsA and CsA/PEG-PLGA-NPs were found to be 30 and 35 ng/mL, respectively. This nanoparticulate CsA delivery technology constitutes a strong basis for future targeted delivery of immunosuppressive drugs with improved efficiency and potentially reduced toxicity

The Novel Therapeutic Effect of Phosphoinositide 3-Kinase-γ Inhibitor AS605240 in Autoimmune Diabetes

Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes

Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Sensibilité orale au gras chez l'homme : liens avec la composition salivaire

La perception du gras chez l’homme est un phénomène complexe du fait de sa nature multi-sensorielle impliquant la perception de la texture, la perception aromatique mais également la perception gustative. Cette dernière a été suggérée après l’identification de récepteurs aux acides gras au niveau des bourgeons gustatifs. Par ailleurs, des études récentes ont montré que la sensibilité au gras est variable entre individus. Des facteurs génétiques ou environnementaux pourraient expliquer en partie cette variation interindividuelle. Cependant, la salive pourrait aussi jouer un rôle dans cette perception. En effet, elle contient des molécules capables d’interagir avec le gras comme la lipase et les lipocalines. C’est aussi un fluide complexe qui contient une large diversité de protéines et de métabolites. De plus, sa régulation est complexe et peut varier à la suite d’une stimulation. En effet, des études récentes ont montré que le protéome salivaire est modifié à la suite d’une stimulation par des molécules correspondant aux saveurs primaires. Dans ce contexte, l’objectif de ce travail était de déterminer dans un premier temps s’il existe des liens entre la composition salivaire et la sensibilité gustative à un acide gras libre: l’acide oléique. Le deuxième objectif était d’étudier les modifications de la composition salivaire à la suite d’une stimulation gustative par l’acide oléique. Pour ceci deux approches ont été utilisées: des approches ciblées (activité enzymatique, capacité antioxydante etc) et des approches non-ciblées (protéomique et métabolomique). Deux groupes de treize sujets (hyper et hyposensible au goût de l’acide oléique) ont été sélectionnés à partir d’un panel de 73 participants. Leur salive a été collectée au repos et après stimulation par l’acide oléique. Les résultats montrent que la composition de la salive au repos est liée à la sensibilité à l’acide oléique. En effet, des marqueurs liés à la perception du goût ont été identifiés au sein du groupe des hypersensibles (anhydrase carbonique, cystatines et zinc alpha 2 glycoprotéine), alors que des marqueurs pouvant indiquer une activité bactérienne élevée (acides organiques) ont été identifiés au sein du groupe des hyposensibles. Par ailleurs, la composition de la salive collectée après stimulation par l’acide oléique est également modifiée et ces modifications sont différentes pour les sujets hyper et hyposensibles à cette stimulation.Human fat perception has recently triggered particular interest as it was shown that it does not only involve aroma and texture perception but also taste perception. The latter was supported by the presence of free fatty acids (FFA) taste receptors on the tongue. Recent studies have shown that fat taste sensitivity is variable among individuals. This inter-individual variation could be linked to genetic or environmental factors. However, saliva could also play a role in this perception. The role of saliva in taste perception is increasingly recognized. Saliva contains molecules able of interacting with fat such as lipase and lipocalin. It is also a complex fluid which contains a large diversity of proteins and metabolites. Its regulation is also complex and its composition may vary after a sensory stimulation. Indeed, studies have shown that when giving primary taste stimulations, the whole salivary proteome is modified. Thus, the first aim of the present work was to use both targeted (enzymatic activity, antioxidant capacity etc) and untargeted approaches (proteomics and metabolomics) to identify links between taste sensitivity to a fatty acid, oleic acid, and the salivary composition. The second aim was to investigate whether the salivary composition is modified after an oral stimulation by oleic acid.Two groups of thirteen male subjects (highly and weakly sensitive to the taste of oleic acid) were selected from an initial panel of 73 healthy participants. Their whole saliva was collected in two ways; the first without stimulation in order to study the links between oral sensitivity to oleic acid and saliva composition and the second using a stimulation by the same fatty acid in order to study potential modifications of saliva composition depending on sensitivity. Results show that salivary composition is linked to oral fatty acid perception. Markers previously reported as associated to taste perception were determined in the highly sensitive group (carbonic anhydrase, Zinc Alpha 2 glycoprotein and cystatins) while markers (organic acids) indicating a higher bacterial load were identified in weakly sensitive group. Furthermore, results obtained after stimulation by oleic acid suggest that saliva composition is modified, which confirms its dynamic nature. As different modifications were observed for the highly and weakly sensitive group, our results suggest that saliva is not only modified after a stimulation but also depending on the sensitivity to that particular stimulation

Community-based grassroot communication strategies, process and product: The drawings that saved our hospital

A case-study analysis of an urban design communication strategy employed by our university-based design team entrusted with re-envisioning the uncertain future of a local small-town community hospital in Indiana. The design process is carefully constructed from structured public input, and community participation, whereby students, faculty, physicians, nurses, as well as ordinary citizens combine their efforts to strategically develop their ‘plan for planning’. Finding a strategy to define the scope of their future needs and the definition of important priorities to organize the project scope prior to engaging professional consultants. In this scenario, the design team is only the guide and translator, working closely with stakeholders to help them visualize and clarify the aspirations of their town. This paper will present our community-based design methods and most importantly our graphic communication techniques, specifically formulated to envision and facilitate consensus for a new unified public health system in a small Midwestern American city

Registres d'interpretation des eleves et des professeurs de college dans le domaine de la mecanique

CNRS T 56767 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc