Temperature measurement of sub-micrometric ICs by scanning thermal microscopy

Surface temperature measurements were performed with a Scanning Thermal Microscope mounted with a thermoresistive wire probe of micrometrSurface temperature measurements were performed with a Scanning Thermal Microscope mounted with a thermoresistive wire probe of micrometric size. A CMOS device was designed with arrays of resistive lines 0.35µm in width. The array periods are 0.8 µm and 10µm to study the spatial resolution of the SThM. Integrated Circuits with passivation layers of micrometric and nanometric thicknesses were tested. To enhance signal-to-noise ratio, the resistive lines were heated with an AC current. The passivation layer of nanometric thickness allows us to distinguish the lines when the array period is 10μm. The results raise the difficulties of the SThM measurement due to the design and the topography of ICs on one hand and the size of the thermal probe on the other hand.ic size. A CMOS device was designed with arrays of resistive lines 0.35µm in width. The array periods are 0.8 µm and 10µm to study the spatial resolution of the SThM. Integrated Circuits with passivation layers of micrometric and nanometric thicknesses were tested. To enhance signal-to-noise ratio, the resistive lines were heated with an AC current. The passivation layer of nanometric thickness allows us to distinguish the lines when the array period is 10μm. The results raise the difficulties of the SThM measurement due to the design and the topography of ICs on one hand and the size of the thermal probe on the other hand

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Haematopoietic stem cells and mesenchymal stem cells as tools for present and future cellular therapies

Postnatal stem cells are present in many adult tissues, and are thought to ensure homoeostasis by replacing functionally declining cells by newly differentiated ones. Postnatal stem cells used as such or after in vitro manipulation hold out strong hopes for reconstructive therapies. For instance, the grafting of native haematopoietic stem cells (HSC) restores haematopoiesis in genetically deficient individuals or in lethally conditioned leukaemic patients, and systemic injection of in vitro amplified mesenchymal stem cells (MSC) induces recovery of bone growth in patients with osteogenesis imperfecta. Moreover, cells differentiated in vitro from postnatal stem cells exhibiting a specific function can also be used for cell therapy. Myeloid dendritic cells (DC) derived from cultures of HSC may induce tumour-specific cytotoxic T lymphocytes to eradicate the tumour via antigen recognition. In addition, long-lived MSC has been engineered to secrete specific proteins coded by a transgene and used as a source of therapeutic molecules in vivo. All these approaches require large quantities of cells that cannot be obtained (with the exception of HSC) directly from the donor. In vitro procedures allowing the production of therapeutic cells from postnatal stem cells are needed and are at present under development. Below we discuss the rationale and methods currently available for generation of therapeutic cells derived from haematopoietic and mesenchymal stem cells

Non-hematopoietic human bone marrow contains long-lasting, pluripotential mesenchymal stem cells

Mesenchymal stem cells (MSC) are considered as potential agents for reconstructive and gene-targeting therapies since they differentiate into various cell-lineages, exhibit an extended survival once injected into a host, and can easily be transfected with engineered DNA. MSC are essentially isolated from hematopoietic bone marrow (BM), a process that is rather invasive and may raise ethical concerns. In an attempt to find an alternative source, we evaluated whether non-hematopoietic (nh)BM recovered from femoral heads of patients undergoing hip arthroplasty contained MSC. Ex vivo, 99% of nhBM cells were CD45(+) leukocytes. After culture, leukocytes were replaced by a homogeneous layer of adherent CD45(-) CD14(-) CD34(-) CD11b(-) CD90(+) HLA-ABC(+) cells. Culture doubling time (mean = 4 days, range 1.6-6.7 days) was not correlated with patient age (27-81 years, n = 16). Amplified cultures supported long-term hematopoiesis, and could be differentiated in vitro into adipocytes and chondrocytes. Moreover, a small fraction of nhBM cells spontaneously expressed MyoD1 and formed myotubes, suggesting that myogenic differentiation also occurred. nhBM contained clonogenic cells whose frequency (1/13,000), doubling time (2.1 days), and maximal amplification (up to 10(6)-fold) were not age-related. All 14 clones analyzed (from five patients, ages 27-78 years) differentiated into at least one mesenchymal lineage, and 66% were bipotential (n = 8/12), or tripotential (n = 2/3). In conclusion, nhBM contains pluripotential mesenchymal progenitors which are similar to hematopoietic BM-derived MSC, and whose biological functions are not altered by aging. Furthermore, if MSC-based therapies hold their promises, nhBM may become the source of choice for responding to the increasing demand for MSC

L’architecture de la mobilité comme fabrique de la ville, du paysage et du territoire : une stratégie intégrative de projet

La recherche se situe dans le cadre du programme “architecture de la grande échelle“ proposé par le BRAUP et le PUCA.Elle s’intéresse à la mobilité dans la fabrique de la ville du paysage et du territoire. Partant du constat que les infrastructuresentretiennent un rapport difficile avec le territoire qu’elles traversent, elle pose la question de savoir si l’architecture peutproposer une alternative à l’ingénierie classique dans cette fabrique dans la conception des infrastructures. Elle part d’unesituation concrète, celle d’un groupement d’architecte-paysagiste-urbaniste-ingénieur qui, à l’issue de sept années deprojets d’infrastructures urbaines pour la communauté urbaine Marseille Provence Métropole dans le cadre d’un marché àbons de commande, s’est questionné sur sa propre pratique et s’est interrogé sur le caractère original et la consistance desa stratégie de projet.En termes méthodologiques, ce travail croise la “Recherche Réflexive“ de D.Schön – qui se traduit par la posture depraticiens réflexifs certains membres du groupement - et “l’anatomie de projet urbain“ de Tsiomis et Ziegler qui procède dela confrontation des points de vue des acteurs des projets anbalysés par des observateurs extérieurs : sociologue,d’historien et de philosophe.L’analyse d’un corpus de trois projets a permis de définir en quoi la stratégie de projet du groupement peut être considéréecomme “intégrative“. Mais il a aussi été montré en quoi l’intégration n’était pas forcément accomplie pour chacun d’eux.Cela a permis de dégager de nouvelles modalités de mise en œuvre de cette stratégie. Cela a permis aussi d’initier uneproposition pédagogique pour les enseignements de Master à l’ENSA-Marseille

L’architecture de la mobilité comme fabrique de la ville, du paysage et du territoire : une stratégie intégrative de projet

La recherche se situe dans le cadre du programme “architecture de la grande échelle“ proposé par le BRAUP et le PUCA.Elle s’intéresse à la mobilité dans la fabrique de la ville du paysage et du territoire. Partant du constat que les infrastructuresentretiennent un rapport difficile avec le territoire qu’elles traversent, elle pose la question de savoir si l’architecture peutproposer une alternative à l’ingénierie classique dans cette fabrique dans la conception des infrastructures. Elle part d’unesituation concrète, celle d’un groupement d’architecte-paysagiste-urbaniste-ingénieur qui, à l’issue de sept années deprojets d’infrastructures urbaines pour la communauté urbaine Marseille Provence Métropole dans le cadre d’un marché àbons de commande, s’est questionné sur sa propre pratique et s’est interrogé sur le caractère original et la consistance desa stratégie de projet.En termes méthodologiques, ce travail croise la “Recherche Réflexive“ de D.Schön – qui se traduit par la posture depraticiens réflexifs certains membres du groupement - et “l’anatomie de projet urbain“ de Tsiomis et Ziegler qui procède dela confrontation des points de vue des acteurs des projets anbalysés par des observateurs extérieurs : sociologue,d’historien et de philosophe.L’analyse d’un corpus de trois projets a permis de définir en quoi la stratégie de projet du groupement peut être considéréecomme “intégrative“. Mais il a aussi été montré en quoi l’intégration n’était pas forcément accomplie pour chacun d’eux.Cela a permis de dégager de nouvelles modalités de mise en œuvre de cette stratégie. Cela a permis aussi d’initier uneproposition pédagogique pour les enseignements de Master à l’ENSA-Marseille