Don't forget primary progressive aphasia for anti-amyloid drugs: An estimation of eligible patients from the Lausanne Memory Center registry.

The study recently published on the clinical effect of lecanemab in early Alzheimer's disease (AD) only includes patients with amnestic presentation. However, a significant portion of AD patients presents a non-amnestic phenotype of AD, such as primary progressive aphasia (PPA) and could benefit of rather than on lecanemab. Therefore, we conducted a 10-year retrospective study at the Leenaards Memory Center in Lausanne (Switzerland) to identify how many PPA patients would be eligible for lecanemab. Among 54 patients with PPA, we identified 11 (20%) eligible patients. Furthermore, almost half of the 18 patients with logopenic variant would be eligible for lecanemab treatment

Evaluation des sources de polluants susceptibles d'impacter les ouvrages de gestion des eaux pluviales – Diagnostic exhaustif à l'échelle du territoire nantais

International audienceTo offset the effects of soil sealing and to deal with stormwater management issue s , cities have adopted BMPs (Best Management Practices) for twenty years . Many facilities exist on urban areas and h ave proved to be efficient on a hydrological point of view, but questions remain about pollutants. Under the Matriochkas project, w h ich focuses on performances of stormwater management facilities in terms of retention of pollutants, an inventory on retention and infiltration basins and swales is conducted throughout the Nantes metropole territory. An exhaustive diagnosis of sources of pollutants is carried out on the facilities identifi ed in this inventory, using a methodology based on spatial analysis of geographic data. More specifically, contributive area of facilities is identified by an automatic method based on drainage networks. The description of these contributive areas in terms of geographic data (land use, human activities such as road traffic , and practices ), and literature data on emissions of pollutants in urban areas, makes it possible to estimate potential pollutant loads which discharge into these facilities.Afin de compenser les effets de l'imperméabilisation des sols et pour répondre à la problématique de gestion des eaux pluviales, les collectivités se tournent depuis une vingtaine d'années vers les techniques alternatives. De nombreux ouvrages existent sur les territoires urbains, et si leurs performances hydrologiques sont connues, leur rôle vis-à-vis de la rétention des polluants l'est moins. Dans le cadre du projet Matriochkas, qui s'intéresse aux performances des ouvrages de gestion à la source vis-à-vis de la rétention des polluants, un recensement des bassins de rétention et d'infiltration ainsi que des noues est mené sur l'ensemble de l'agglomération nantaise. Un diagnostic exhaustif des sources de pollution est réalisé sur les ouvrages identifiés dans ce recensement, en utilisant une méthodologie basée sur l'exploitation de données géographiques. Cette méthodologie consiste à déterminer la zone contributive des ouvrages en développant une méthode automatique qui s'appuie sur les réseaux de drainage. La description de ces zones contributives à partir de données géographiques (occupation du sol, activités anthropiques dont le trafic routier, et usages) et de données de la littérature relatives aux émissions de polluants sur les surfaces urbaines, permet d'estimer a priori les flux de polluants déversés dans ces ouvrages

Contribution of the d-Serine-Dependent Pathway to the Cellular Mechanisms Underlying Cognitive Aging

An association between age-related memory impairments and changes in functional plasticity in the aging brain has been under intense study within the last decade. In this article, we show that an impaired activation of the strychnine-insensitive glycine site of N-methyl-d-aspartate receptors (NMDA-R) by its agonist d-serine contributes to deficits of synaptic plasticity in the hippocampus of memory-impaired aged rats. Supplementation with exogenous d-serine prevents the age-related deficits of isolated NMDA-R-dependent synaptic potentials as well as those of theta-burst-induced long-term potentiation and synaptic depotentiation. Endogenous levels of d-serine are reduced in the hippocampus with aging, that correlates with a weaker expression of serine racemase synthesizing the amino acid. On the contrary, the affinity of d-serine binding to NMDA-R is not affected by aging. These results point to a critical role for the d-serine-dependent pathway in the functional alterations of the brain underlying memory impairment and provide key information in the search for new therapeutic strategies for the treatment of memory deficits in the elderly

Design and development of apparatus to provide repeatable surface temperature-time treatments on inoculated food samples

The majority of data relating heat treatments to thermal death kinetics has previously been obtained by carrying out in vitro tests on small samples of microorganisms in growth medium or food slurries. However, strong evidence exists that suggests microbial death on heat-treated food surfaces cannot be predicted accurately from such systems. An apparatus was therefore designed to enable microbial death on food surfaces to be quantified. The apparatus uses hot air to provide a ‘dry’ heat treatment to raise the surface of a food sample to a given temperature, up to 100 °C, hold and then cool it. The surface temperature was measured using an infra-red (IR) thermometer and the air heater was controlled to give a specified surface temperature history. Steam was also used to provide a ‘wet’, but less controlled heating cycle

Cingulin Binds to the ZU5 Domain of Scaffolding Protein ZO-1 to Promote Its Extended Conformation, Stabilization, and Tight Junction Accumulation

Zonula occludens-1 (ZO-1), the major scaffolding protein of tight junctions (TJs), recruits the cytoskeleton-associated proteins cingulin (CGN) and paracingulin (CGNL1) to TJs by binding to their N-terminal ZO-1 interaction motif. The conformation of ZO-1 can be either folded or extended, depending on cytoskeletal tension and intramolecular and intermolecular interactions, and only ZO-1 in the extended conformation recruits the transcription factor DbpA to TJs. However, the sequences of ZO-1 that interact with CGN and CGNL1 and the role of TJ proteins in ZO-1 TJ assembly are not known. Here, we used glutathione-S-transferase pulldowns and immunofluorescence microscopy to show that CGN and CGNL1 bind to the C-terminal ZU5 domain of ZO-1 and that this domain is required for CGN and CGNL1 recruitment to TJs and to phase-separated ZO-1 condensates in cells. We show that KO of CGN, but not CGNL1, results in decreased accumulation of ZO-1 at TJs. Furthermore, ZO-1 lacking the ZU5 domain showed decreased accumulation at TJs, was detectable along lateral contacts, had a higher mobile fraction than full-length ZO-1 by fluorescence recovery after photobleaching analysis, and had a folded conformation, as determined by structured illumination microscopy of its N-terminal and C-terminal ends. The CGN-ZU5 interaction promotes the extended conformation of ZO-1, since binding of the CGN-ZO-1 interaction motif region to ZO-1 resulted in its interaction with DbpA in cells and in vitro. Together, these results show that binding of CGN to the ZU5 domain of ZO-1 promotes ZO-1 stabilization and accumulation at TJs by promoting its extended conformation

Novel gene mutation in an atypical late-onset mitochondrial form of multifocal dystonia

Mitochondrial complex I, the largest component of the mitochondrial respiratory chain, comprises 44 subunits of which 7 are encoded by the mitochondrial genome and the remainder by the nuclear genome. Isolated complex I deficiencies represent a major contribution within the group of respiratory chain defects. We report an atypical case carrying a homozygous NDUFS4 missense mutation, with late-onset multifocal dystonia, in contrast to expected clinical phenotypes due to other NDUFS4 mutations, which have been constantly reported to be responsible for Leigh syndrome of early onset and death

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Background Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. Methods A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. Results VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Conclusion Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication

The elusive meningococcal meningitis serogroup: a systematic review of serogroup B epidemiology

<p>Abstract</p> <p>Background</p> <p>Invasive meningococcal disease (IMD), is a widely distributed, complex human disease affecting all age categories. The causative agent, <it>Neisseria meningitidis</it>, is spread through aerosol respiratory droplets. 13 different serogroups have been identified, each with varying epidemiological features including prevalence, virulence, immunogenicity, geographical and temporal distribution. Although preventative measures are available for several of the serogroups, meningococcal disease caused by serogroup B is of particular interest due to the challenge it presents concerning vaccine development.</p> <p>Methods</p> <p>A systematic review of peer reviewed studies and reports, the collection of data from national and international health resources, along with the analysis of the Multi Locus Sequence Typing database was carried out aimed at collecting information concerning serogroup B IMD and the epidemiology attached to it.</p> <p>Results</p> <p>A continuous output of related and novel STs occurring worldwide in terms of the hypervirulent clonal complexes was observed both in published studies and the MLST database in this case using the eburst software, which highlights the genetically diverse nature of serogroup B strains.</p> <p>Conclusions</p> <p>With the recent dominance of serogroup B IMD seen in many countries, along with the presence of antibiotic resistance, vaccine development needs to target areas of the bacterium which tackle this widespread and heterogeneous aspect of meningococcal meningitis disease.</p