Variation at the ADAM10 gene locus is not associated with Creutzfeldt-Jakob disease

Prion diseases are characterized by the accumulation in the brain of a misfolded and protease-resistant form of the prion protein (PrP(c)). PrP(c) contains an amyloidogenic, neurotoxic sequence that is essential for conversion into PrP(Sc), the pathological isoform. During normal processing, PrP(c) is cleaved at a site within this sequence, and this cleavage is thought to destroy the amyloidogenic potential of the protein. ADAM10, a disintegrin and metalloprotease that plays a key role in the pathogenesis of Alzheimer's disease, was recently shown to use PrP(c) as a substrate. We investigated whether variability in the ADAM10 gene could contribute to the pathogenesis of Creutzfeldt-Jakob disease (CJD), by analyzing a single nucleotide polymorphism (SNP) within ADAM10, as a genetic marker potentially in linkage disequilibrium with a functional polymorphism, in patients with sporadic or variant CJD. We observed no significant differences in ADAM10 genotype or allele frequencies between CJD patients and healthy individuals. Moreover, the distribution of ADAM10 SNP genotypes and alleles did not differ between groups of patients based on genotype at the polymorphic codon 129 of the prion protein gene--the sole major genetic risk factor for CJD identified to date. Our data indicate that ADAM10 is unlikely to confer genetic susceptibility to CJD.     

V180I mutation of the prion protein gene associated with atypical PrP glycosylation

A valine to isoleucine mutation at residue 180 was identified in a French patient with Creutzfeldt-Jakob disease (CJD). The mutation is located in the close vicinity of one of the two N-glycosylation sites of the cellular prion protein (PrP^C). Western blot analysis revealed accumulation in the brain of the pathogenic proteinase K-resistant PrP (PrP^Sc) isoform with the notable absence of the diglycosylated band. The mutant protein expressed in CHO cells was correctly glycosylated, suggesting that the atypical glycosylation pattern of PrP^Sc was not due to the mutation at position 180. These results suggest that the diglycosylated form of the mutant PrP^180I prevents its conversion into the pathogenic mutant form PrP^Sc180I, supporting a central role of N-linked glycan chains in the PrP conversion process.     

Highly Pathogenic Avian Influenza A(H5N8) Virus Spread by Short- and Long-Range Transmission,France, 2016–17

We detected 3 genotypes of highly pathogenic avian influenza A(H5N8) virus in France during winter 2016–17. Genotype A viruses caused dramatic economic losses in the domestic duck farm industry in southwestern France. Our phylogenetic analysis suggests that genotype A viruses formed 5 distinct geographic clusters in southwestern France. In some clusters, local secondary transmission might have been started by a single introduction. The intensity of the viral spread seems to correspond to the density of duck holdings in each production area. To avoid the introduction of disease into an unaffected area, it is crucial that authorities limit the movements of potentially infected birds.     

Human vascular endothelial cells with extended life spans: in vitro cell response,protein expression,and angiogenesis

An in vitro angiogenesis system was designed for screening angiogenic agonists and antagonists. In order to obtain large quantities of cells and reproducibility, human endothelial cells with extended life spans were developed by retroviral transfection. The resulting cells grown in a serum-free medium containing endothelial cell growth supplement (ECGS) have a telomerase activity, extended life spans of at least 21 passages, and an endothelial cell phenotype (diI-acetylated-LDL upake, factor VIII-related antigen, VEGFR-1 and R-2, and tissue-type plasminogen activator (tPA)) that resembled that of unaltered primary endothelial cells. Exceptions were (i) a higher expression of tPA, and (ii) a non-significant growth response to FGF-2 or VEGF stimulation. Within three-dimensional fibrin gels, specific cell clones rapidly formed tubular structures in a more reproducible manner than those observed with low-passage primary cells. Tube formation by primary endothelial cells and those with extended life spans was dependent upon FGF-2 and ECGS, respectively. Both cell types produced FGF-2 and VEGF cytokines. Increasing doses of suramin significantly decreased the size of microvessels formed by both cell lines. These functional results indicate that a vascular matrix system containing human cells with extended life spans can be successfully utilized as an in vitro assay for antiangiogenic compounds.     

Polyspecificity of antimicrosomal thyroid antibodies in hepatitis C virus–related infection

OBJECTIVES: The outcome of dysthyroidism and the presence of antithyroid antibodies in patients with chronic hepatitis C virus (HCV) infection receiving interferon-alpha therapy is clearly established. However, the prevalence and the specificity of antithyroid antibodies in HCV patients before interferon-alpha therapy remain controversial. The aim of the present study is to clarify within a large population of HCV patients the prevalence of antithyroid antibodies before interferon-alpha therapy and to determine whether their immunodominant antigen is the same as described in autoimmune thyroiditis. METHODS: Sera from 99 patients with chronic hepatitis C before (n = 99) and after (n = 37) interferon-alpha treatment were investigated for the presence of antimicrosomal and antithyroperoxidase antibodies assessed by indirect immunofluorescence and ELISA, respectively. Dot blotting on human thyroid lysate was designed to further characterize these autoantibodies. Data were compared to those obtained with sera of patients with autoimmune thyroiditis (n = 75) and healthy subjects (n = 96). RESULTS: In HCV patients, antimicrosomal antibodies were found with a higher proportion before interferon-alpha therapy (12.1%) than after therapy (8%). Thyroperoxidase constitutes the main antigen in only 4% before treatment, a prevalence similar to that observed in healthy controls. CONCLUSIONS: The prevalence of antithyroid antibodies is low in patients with chronic hepatitis C before interferon-alpha therapy. Thyroperoxidase may not be their main target. Further studies are required to determine whether HCV infection leads to a breakdown of tolerance to a thyroid self-protein other than thyroperoxidase.     

The screening of Alzheimer’s patients with CSF biomarkers,modulates the distribution of APOE genotype: impact on clinical trials

Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer’s disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1–42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1–42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1–42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies.     

Detecting hippocampal hypometabolism in Mild Cognitive Impairment using automatic voxel-based approaches

While the hippocampus is constantly reported as the site of earliest and highest structural alteration in Alzheimer's disease (AD), findings regarding the metabolic status of this region are rather heterogeneous. It has been proposed that only a time-consuming individual region-of-interest (ROI) approach would allow the detection of hypometabolism in this complex and small area. Our main goal with this study is to assess whether more automatic and clinically useful methods would be sensitive enough when considering other methodological confounds. From a single PET data set collected in 28 patients with amnestic Mild Cognitive Impairment (aMCI) and 19 controls, we assessed the effects of partial volume effect (PVE) correction, scaling (using vermis or global means), and analysis method (individual ROI versus more automatic template-based ROI or voxel-based approaches) on hippocampal hypometabolism detection in aMCI. PVE correction and scaling both showed a significant effect on group comparison, while the analysis method (individual versus template-based ROI) surprisingly did not. Hippocampal metabolic decrease was significant in all vermis-scaled conditions, and more so after PVE correction. Our findings highlight the crucial relevance of using reference-region-based (instead of global) scaling, and the higher sensitivity of PVE-corrected PET measures, to detect hippocampal hypometabolism in aMCI. They also show that hippocampal metabolic decline can be detected using template-based ROI as well as voxel-based methods. These findings have clinical relevance since they support the validity of more automatic and time-saving approaches to assess hippocampal metabolism changes in aMCI and early AD.