A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.status: publishe

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

Background:Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.Methods:PSAV was calculated using logistic regression to determine if PSA or PSAV predicted the result of prostate biopsy (PB) in men with elevated PSA values. Cox regression was used to determine whether PSA or PSAV predicted PSA elevation in men with low PSAs. Interaction terms were included in the models to determine whether BRCA status influenced the predictiveness of PSA or PSAV.Results:1634 participants had 3/43 PSA readings of whom 174 underwent PB and 45 PrCas diagnosed. In men with PSA > 3.0 ng ml -l, PSAV was not significantly associated with presence of cancer or high-grade disease. PSAV did not add to PSA for predicting time to an elevated PSA. When comparing BRCA1/2 carriers to non-carriers, we found a significant interaction between BRCA status and last PSA before biopsy (P=0.031) and BRCA2 status and PSAV (P=0.024). However, PSAV was not predictive of biopsy outcome in BRCA2 carriers.Conclusions:PSA is more strongly predictive of PrCa in BRCA carriers than non-carriers. We did not find evidence that PSAV aids decision-making for BRCA carriers over absolute PSA value alone

Kuntayhtymien talous vuonna 1968

Suomen virallinen tilasto (SVT

Concesión de viático a fray Buenaventura Malaquías, fray Guillermo Siredan y fray Bernardino Cornelio, religiosos de la orden de San Francisco, para ir a la Misión de Irlanda

Fecha del documento: 1640-11-21. 3 páginasAndrés de Rozas al secretario Juan de Otalora sobre la resolución regia de conceder a fray Buenaventura Malaquías, fray Guillermo Siredan y fray Bernardino Cornelio, religiosos de la orden de San Francisco, un viático de 100 ducados a cada uno para ir a la Misión de Irlanda. Acudan de Antonio de Campo Redondo. Orden del Antonio de Campo Redondo al secretario Juan García Dávila Muñoz para que haga la cédula para que el tesorero general Pedro Baza de Herrera libre el dinero del arca de las tres llaves y pueda entregarlo a don Alonso Pérez de Guzmán, patriarca de Indias. Hecha la cédula.Proyecto Proyección Política y Social de la Comunidad Irlandesa en la Monarquía hispánica y en la América Colonial de la Edad Moderna(siglos XVI-XVIII) (HAR2009-11339 - subprograma HIST) del Ministerio de Economía y Competitividad en colaboración con el Consejo Superior de Investigaciones Científicas (CSIC), Embajada de Irlanda en Madrid, National University of Ireland (NUI) Maynooth, University College Dublin y Trinity College DublinAndrés de Rozas, secretario del Consejo de EstadoJuan de Otalora, secretario del Consejo de HaciendaOrden de San FranciscoSí300 ducados (100x3)NoN