Cost-Effectiveness of Magnetic Resonance Imaging with a New Contrast Agent for the Early Diagnosis of Alzheimer's Disease

Background: Used as contrast agents for brain magnetic resonance imaging (MRI), markers for beta-amyloid deposits might allow early diagnosis of Alzheimer’s disease (AD). We evaluated the cost-effectiveness of such a diagnostic test, MRI+CLP (contrastophore-linker-pharmacophore), should it become clinically available. Methodology/Principal Findings: We compared the cost-effectiveness of MRI+CLP to that of standard diagnosis using currently available cognition tests and of standard MRI, and investigated the impact of a hypothetical treatment efficient in early AD. The primary analysis was based on the current French context for 70-year-old patients with Mild Cognitive Impairment (MCI). In alternative ‘‘screen and treat’ ’ scenarios, we analyzed the consequences of systematic screenings of over-60 individuals (either population-wide or restricted to the ApoE4 genotype population). We used a Markov model of AD progression; model parameters, as well as incurred costs and quality-of-life weights in France were taken from the literature. We performed univariate and probabilistic multivariate sensitivity analyses. The base-case preferred strategy was the standard MRI diagnosis strategy. In the primary analysis however, MRI+CLP could become the preferred strategy under a wide array of scenarios involving lower cost and/or higher sensitivity or specificity. By contrast, in the ‘‘screen and treat’’ analyses, the probability of MRI+CLP becoming the preferred strategy remained lower than 5%. Conclusions/Significance: It is thought that anti-beta-amyloid compounds might halt the development of dementia i

Update on COX-2 Selective Inhibitors: Chemical Classification, Side Effects and their Use in Cancers and Neuronal Diseases

International audienc

Purification and complete sequence of a small proteolipid associated with the plasma membrane H(+)-ATPase of Saccharomyces cerevisiae.

The purified plasma membrane H(+)-ATPase of Schizosaccharomyces pombe and Saccharomyces cerevisiae display, in addition to the catalytic subunit of 100 kDa, a highly mobile component, soluble in chloroform/methanol. Chloroform/methanol extraction of S. cerevisiae plasma membranes led to isolation of a low molecular weight proteolipid identical to that present in purified H(+)-ATPase. NH2-terminal amino acid sequencing revealed a 38-residue polypeptide with a calculated molecular mass of 4250 Da. The polypeptide lacks the first two NH2-terminal amino acids as compared with the deduced sequence of the PMP1 gene (for plasma membrane proteolipid) isolated by hybridization with an oligonucleotide probe corresponding to an internal amino acid sequence of the proteolipid. The polypeptide is predicted to contain an NH2-terminal transmembrane segment followed by a very basic hydrophilic domain

Non-Destructive Examination Development for the JHR Material Testing Reactor

The Jules Horowitz Reactor (JHR) is a European material testing reactor (MTR) under construction at the CEA Cadarache centre. It will be dedicated to material and fuel irradiation tests, as well as to the production of medical isotopes. Gamma and X-Ray benches will be implemented in the reactor pool (RER), the irradiated component storage pool (EPI) and in a shielded hot cell for measuring either the whole underwater test device still containing the experimental sample or just the experimental sample before its extraction in the hot cell. The CEA/Cadarache Nuclear Measurement Laboratory (LMN) has been working in collaboration with VTT (Technical Research Centre in Finland Ltd.) since 2008 under a Finnish in-kind contribution agreement. This agreement focuses on the development of NDE systems implementing gamma-ray spectroscopy and high-energy X-ray imaging of the sample and irradiation device with the highest definition possible (resolution of 100 μm). The CEA-VTT technical specifications led to a European call for tenders launched by VTT. The contract was awarded to the Spanish company IDOM for the design, manufacturing, assembly and commissioning of: - Underwater gamma and X-ray (UGXR) mechanical benches and their associated gamma and X-ray collimation systems for the RER and EPI pools - Hot cell gamma and X-ray (HGXR) bench in the JHR NDE hot cell. The Final Design Reviews (FDR) of the UGXR and HGXR systems were completed in 2016. The design phase has been an iterative process in order to manage interfacing specifications and constraints: - Challenging experimental requirements, mainly to cover the wide diversity of sample shapes, sample activity levels and measurement processes, but also to achieve a level of mechanical accuracy to reach the ambitious geometrical resolution target in X-ray imaging, - Environmental constraints (immersion, radiation, compactness, limited accessibility for maintenance), - Nuclear safety constraints (seism, radiation protection). The whole design process has produced a number of elaborate and innovative mechatronic systems, which is rather unusual in nuclear applications since the resulting solutions have benefited from IDOM’s technological expertise in designing and commissioning large telescopes for the astronomy sector. Once the manufacturing phase and assembly finalised, the site acceptance tests for the UGXR and HGXR mechanical systems will be performed in 2019-2020 in the TOTEM facility at the CEA Cadarache center. The underwater benches will be tested in the CESARINE pool to check their requirements

Non-Destructive Examination Development for the JHR Material Testing Reactor

The Jules Horowitz Reactor (JHR) is a European material testing reactor (MTR) under construction at the CEA Cadarache centre. It will be dedicated to material and fuel irradiation tests, as well as to the production of medical isotopes. Gamma and X-Ray benches will be implemented in the reactor pool (RER), the irradiated component storage pool (EPI) and in a shielded hot cell for measuring either the whole underwater test device still containing the experimental sample or just the experimental sample before its extraction in the hot cell. The CEA/Cadarache Nuclear Measurement Laboratory (LMN) has been working in collaboration with VTT (Technical Research Centre in Finland Ltd.) since 2008 under a Finnish in-kind contribution agreement. This agreement focuses on the development of NDE systems implementing gamma-ray spectroscopy and high-energy X-ray imaging of the sample and irradiation device with the highest definition possible (resolution of 100 μm). The CEA-VTT technical specifications led to a European call for tenders launched by VTT. The contract was awarded to the Spanish company IDOM for the design, manufacturing, assembly and commissioning of: - Underwater gamma and X-ray (UGXR) mechanical benches and their associated gamma and X-ray collimation systems for the RER and EPI pools - Hot cell gamma and X-ray (HGXR) bench in the JHR NDE hot cell. The Final Design Reviews (FDR) of the UGXR and HGXR systems were completed in 2016. The design phase has been an iterative process in order to manage interfacing specifications and constraints: - Challenging experimental requirements, mainly to cover the wide diversity of sample shapes, sample activity levels and measurement processes, but also to achieve a level of mechanical accuracy to reach the ambitious geometrical resolution target in X-ray imaging, - Environmental constraints (immersion, radiation, compactness, limited accessibility for maintenance), - Nuclear safety constraints (seism, radiation protection). The whole design process has produced a number of elaborate and innovative mechatronic systems, which is rather unusual in nuclear applications since the resulting solutions have benefited from IDOM’s technological expertise in designing and commissioning large telescopes for the astronomy sector. Once the manufacturing phase and assembly finalised, the site acceptance tests for the UGXR and HGXR mechanical systems will be performed in 2019-2020 in the TOTEM facility at the CEA Cadarache center. The underwater benches will be tested in the CESARINE pool to check their requirements

Mass spectrometric characterization of a three-enzyme tandem reaction for assembly and modification of the novobiocin skeleton

The tripartite scaffold of the natural product antibiotic novobiocin is assembled by the tandem action of novobiocin ligase (NovL) and novobiocic acid noviosyl transferase (NovM). The noviosyl ring of the tripartite scaffold is further decorated by a methyltransferase (NovP) and a carbamoyltransferase (NovN), resulting in the formation of novobiocin. To facilitate kinetic evaluation of alternate substrate usage by NovL and NovM toward the creation of variant antibiotic scaffolds, an electrospray ionization/MS assay for obtaining kinetic measurements is presented for NovL and NovM separately, in each case with natural substrate and the 3-methyl-4-hydroxybenzoic acid analog. Additionally, assays of tandem two-enzyme (NovL/NovM) and three-enzyme (NovL/NovM/NovP) incubations were developed. The development of these assays allows for the direct detection of each intermediate followed by its utilization as substrate for the next enzyme, as well as the subsequent formation of final product as a function of time. This MS tandem assay is useful for optimization of conditions for chemoenzymatic generation of novobiocin and is also suitable for evaluation of competitive usage of variant substrate analogs by multiple enzymes. The studies presented here serve as a platform for the subsequent expansion of the repertoire of coumarin-based antibiotics

Fishing anti-inflammatories from known drugs: In silico repurposing, design, synthesis and biological evaluation of bisacodyl analogues

Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several biological in vitro and in vivo assays were performed in order to understand its mechanism of action. A set of analogues of BSL was prepared using low-cost synthetic procedures and further biologically investigated in zebrafish models. Compound 5c and 7e exhibited the best antiinflammatory activities and represent new promising anti-inflammatory agents for further preclinical development.Dany Siverio-Mota acknowledges the Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven (Belgium) for kind hospitality and VLIR (Vlaamse InterUniversitaire Raad, Flemish Interuniversity Council, Belgium) under the IUC Program VLIR-UCLV for in part financial support of this work. Yovani Marrero Ponce thanks the program ‘Estades Temporals per a Investigadors Convidats’ for a fellowship to work at Universitat de València, Spain. The spanish Ministry of Science and Innovation (project SAF2009- 10399) and LabEx LERMIT (ANR-10-LABX-33) are also acknowlwdged for the financial supportPeer Reviewe