3,995 research outputs found

    PRNP P39L variant is a rare cause of frontotemporal dementia in Iialian population

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    The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%)

    Genetics of Frontotemporal Lobar Degeneration

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    Frontotemporal lobar degeneration (FTLD), the most frequent neurodegenerative disorder with a presenile onset, presents with a spectrum of clinical manifestations, ranging from behavioral and executive impairment to language disorders and motor dysfunction. Familial aggregation is frequently reported, and about 10% of cases have an autosomal dominant transmission. Microtubule associated protein tau (MAPT) gene mutations have been the first ones identified and are associated with early onset behavioral variant frontotemporal dementia phenotype. More recently, progranulin gene (GRN) mutations were recognized in association with familial form of FTLD. In addition, other genes are linked to rare cases of familial FTLD. Lastly, a number of genetic risk factors for sporadic forms have also been identified. In this review, current knowledge about mutations at the basis of familial FTLD will be described, together with genetic risk factors influencing the susceptibility to FTLD

    Updates in the Treatment of Alzheimer\u27s Disease, Nothing to Forget About

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    A Genome-Wide Screening and SNPs-to-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia

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    Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimerā€™s disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel SNPs-to-genes approach and functional annotation analysis. We identified two novel potential loci for FTD. Suggestive SNPs reached p-values ~10-7 and OR > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation, and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-GWAS. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis

    Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study.

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    We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers. In addition, we evaluated a possible role of TMEM106B rs1990622 as a genetic modifier and correlated progranulin plasma levels and gray-matter atrophy. Plasma progranulin mean Ā± SD plasma levels in patients and asymptomatic carriers were significantly decreased compared with noncarriers (30.5 Ā± 13.0 and 27.7 Ā± 7.5 versus 99.6 Ā± 24.8Ā ng/mL, p 61.55Ā ng/mL, the test had a sensitivity of 98.8% and a specificity of 97.5% in predicting the presence of a mutation, independent of symptoms. No correlations were found between progranulin plasma levels and age, years from average age at onset in each family, or TMEM106B rs1990622 genotype (p > 0.05). Plasma progranulin levels did not correlate with brain atrophy. Plasma progranulin levels predict the presence of GRN null mutations independent of proximity to symptoms and brain atrophy

    Possible connections between the Montessori method and philosophy for children

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    This paper aims to focus on certain aspects of two education methods: one initiated in the first half of the twentieth century by Maria Montessori, and the other in the second half of that century by Matthew Lipman. The aim \u2013 neither comparative nor analytical \u2013 is to shed light on the connections and, more specifically, the elements of the Montessori Method that reflect on Lipman\u2019s proposal. The question this paper aims to answer is: can P4C find fertile ground in schools that apply the Montessori Method? The paper will focus, among other elements, on the importance of giving space for thinking experience from childhood on, and on the recognition of the value of childhood. Both Lipman and Montessori have systematically observed children of different ages \u2013 the former in the first half, the latter in the second half of the twentieth century. Both recognized, gave value, and focused their scientific contributions on children\u2019s ability to think and express their thoughts through languages (purposely in the plural form). As educational researchers and professionals know, children have the ability to think, but such ability has not always been (and still isn\u2019t) considered to exist. Even when it is evoked in words, educational choices and proposals seem\u2014even today--to express mistrust towards children\u2019s thought. The two mentioned authors have repeatedly highlighted the importance of an essential right: the right to think and to be given a space \u2013 even as children \u2013 to exercise thinking with others. In particular, both authors \u2013 though envisaging different educational paths \u2013 identified the same categories functional to exercising thinking. Their interconnection may guide the actions of teachers, educators, and learning process experts. In fact, P4C might play a role in educational contexts in which the class is already considered a community of inquiry, in which the teacher is assigned the same role as a facilitator.Este art\uedculo tiene como objetivo centrarse en ciertos aspectos de dos m\ue9todos de educaci\uf3n: uno iniciado en la primera mitad del siglo XX por Maria Montessori, y el otro en la segunda mitad del siglo XX por Matthew Lipman. El objetivo, ni comparativo ni anal\uedtico, es arrojar luz sobre las conexiones y, m\ue1s espec\uedficamente, los elementos del M\ue9todo Montessori que se reflejan en la propuesta de Lipman. La pregunta que este texto pretende responder es: \ubfpuede P4C encontrar terreno f\ue9rtil en las escuelas que aplican el M\ue9todo Montessori? El texto se centrar\ue1, entre otros elementos: en el reconocimiento de la importancia de dar espacio a la experiencia de pensamiento desde la infancia y de possible connections between the montessori method and philosophy for children reconocer el valor de la infancia. Tanto Lipman como Montessori han observado sistem\ue1ticamente a ni\uf1os de diferentes edades: el primero en la segunda mitad y la segunda en la primera mitad del siglo XX. Ambos caracterizaron, dieron valor y centraron sus contribuciones cient\uedficas en la capacidad de los ni\uf1os para pensar y expresar sus pensamientos a trav\ue9s de lenguajes (a prop\uf3sito en forma plural). Como saben los investigadores y profesionales de la educaci\uf3n, los ni\uf1os tienen la capacidad de pensar, pero esa capacidad no siempre se ha considerado (todav\ueda no es considerada). Incluso cuando se evoca con palabras, las opciones y propuestas educativas parecen, a\ufan hoy, expresar desconfianza hacia el pensamiento de los ni\uf1os. Los dos autores mencionados han subrayado en repetidas ocasiones la importancia de un derecho esencial: el derecho a pensar y a tener un espacio, incluso como ni\uf1os, para ejercitar el pensamiento con los dem\ue1s. En particular, ambos autores, aunque previeron diferentes caminos educativos, identificaron las mismas categor\uedas funcionales para ejercitar el pensamiento. Su interconexi\uf3n puede guiar las acciones de maestros, educadores y expertos en procesos de aprendizaje. De hecho, P4C podr\ueda desempe\uf1ar un papel en contextos educativos en los que la clase ya se considera una comunidad de investigaci\uf3n, en la que al profesor se le asigna el mismo papel que un facilitador

    Management of deep caries lesions with or without pulp involvement in primary teeth: a systematic review and network meta-analysis

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    There is a lack of evidence about the best approach for cavitated caries lesions with the possibility of pulpal involvement in primary teeth. Thus, the present authors aimed to verify the best treatment for deep caries lesions with or without pulp involvement in primary teeth. The search was conducted in MEDLINE/Pubmed and Web of Science databases until May 2020. Studies that compared techniques to manage deep caries lesions with at least 12 months of follow-up were included. The risk of bias was evaluated using the RoB tool. Network meta-analysis and pairwise meta-analyses were conducted considering the treatment clinical success as an outcome, according to the pulp health condition. From 491 potentially eligible studies, 9 were included. For deep caries lesions with pulp vitality, the Hall Technique presented the highest probability of success (78%). In the event of accidental pulp exposure, pulpectomy presented a 76% chance of providing the best clinical results. For pulp necrosis, no difference was observed between a pulpectomy and non-instrumented endodontic treatment (RR = 0.69; 95%CI: 0.21ā€“2.33) Thus, it was concluded that the Hall Technique may be a better option for deep caries lesions with pulp vitality. In cases of accidental pulp exposure of vital teeth during caries removal, a pulpectomy may be considered the best option. However, there are insuficient studies to build up evidence about the best treatment option when irreversible pulpitis or pulp necrosis is present.info:eu-repo/semantics/publishedVersio

    Virus transcript levels and cell growth rates after naturally occurring HPV16 integration events in basal cervical keratinocytes.

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    Cervical carcinogenesis is characterized by a clonal selection process in which the high-risk human papillomavirus (HRHPV) genome usually changes from the extra-chromosomal (episomal) state seen in productive infections to DNA that is integrated into host chromosomes. However, it is not clear whether all HRHPV integration events provide cells with a selective growth advantage compared with the episome-containing cells from which they originate. It is also unclear whether selection of cells containing a particular integrant from a mixed population simply reflects the highest levels of virus oncogene expression or has additional determinants. These early events in cervical carcinogenesis cannot readily be addressed by cross-sectional studies of clinical samples. We used the W12 model system to generate a panel of cervical squamous cell clones that were derived from an identical background under non-competitive conditions and differed only by the genomic site of HPV16 integration. Compared with the 'baseline' episome-containing cells from which they were isolated, only 9/17 clones (53%) showed significantly greater growth rates and only 7/17 (41%) showed significantly greater expression of the major virus oncogenes E7/E6. There were significant variations in levels of HPV16 transcription per DNA template, changes that were associated with histone modifications in the integrated virus chromatin. Cell growth rates showed only weak and non-significant associations with protein and mRNA levels for E7, E6, and the mean E7/E6 values. We conclude that HPV16 integration in basal cervical cells does not necessarily lead to increased levels of virus oncogenes, or to a competitive growth advantage, when compared with the initiating episome-containing cells

    Disease-related cortical thinning in presymptomatic granulin mutation carriers

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    Ā© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by FundaciĆ³ MaratĆ³ de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimerā€™s Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimerā€™s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schƶrling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme ā€“ Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 ā€œSolve-RDā€ from the Horizon 2020 research and innovation programme.info:eu-repo/semantics/publishedVersio
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