82 research outputs found

    Insuficiencia cardíaca asociada a miocardiopatía infiltrativa en paciente anciano

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    An 85-year-old man was referred to our hospital because of a first episode of heart failure. An echocardiography was performed, in which severe left ventricular hypertrophy was observed, more likely due to infiltrative myocardiopathy. With this clinical suspicion, a cardiac magnetic resonance was chosen to complete the study, both with result of likely cardiac amyloidosis. After these results, a genetic test was requested, with a negative result for transthyretin gene mutation, thus our patient was diagnosed as wild cardiac amyloidosis and was referred to Heart Failure Unit, where he remains clinically stable.Varón de 85 años remitido por primer episodio de insuficiencia cardíaca. Se realiza un ecocardiograma en el que se objetiva hipertrofia concéntrica severa del ventrículo izquierdo, compatible con miocardiopatía infiltrativa. Con esta sospecha, realizamos resonancia magnética (RM) cardíaca, con resultado de probable amiloidosis cardíaca. Posteriormente, una gammagrafía con el radiotrazador 99m Tc-DPD confirmó depósito por transtirretina. Se solicitó test genético, que fue negativo para mutación del gen de la transtirretina, por lo que se diagnosticó al paciente de amiloidosis cardíaca salvaje o senil, y fue derivado a consultas en la Unidad de Insuficiencia Cardíaca, donde permanece clínicamente estable

    Study of the anticancer properties of optically active titanocene oximato compounds

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    New water soluble and optically active cyclopentadienyl titanium derivatives [(η5-C5H5)2Ti{(1R,4S)-ĸON,(R)NH}Cl] (R = Bn (Benzyl) 1a’, 2-pic (2-picolylamine) 1b’) have been synthesized. The novel compounds along with those previously described [(η5-C5H5)2Ti{(1S,4R)-ĸON,(R)NH}Cl] (R = Bn 1a, 2-pic 1b) were evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of 1b was determined by single crystal X-ray crystallography and showed a unique terminal monohapto Tisingle bondO disposition of the oximato ligand. All enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3 and DU-145, lung A-549, pancreas MiaPaca-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. In addition, 1a, 1b and 1b’ were tested against non-tumorigenic prostate RWPE-1 cell line. After 24 h of incubation, 1b and 1b’ were moderately active against Jurkat and A-549 cells. The anti-proliferative effect of titanium compounds on prostate PC-3, DU-145 and RWPE-1 cell lines was also assessed after 72 h of drug exposure. The cytotoxic profile of the enantiomers was similar, exception made for the PC-3 cells, with S,R-isomers exhibiting cytotoxicities 2 to 3 times higher than R,S-compounds. Under these conditions, derivative 1b showed calculated IC50 values better than those of Tacke's Titanocene-Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride) on both the prostate PC-3 and DU-145 cells. 1a and 1b cytotoxic behaviour shows certain selectiveness, with activities 2–4 times lower on normal prostate RWPE-1 than on cancer PC-3 cells. Furthermore, 1b produces higher cytotoxicity on prostate PC-3, DU-145 and RWPE-1 cells than the additive dose of titanocene dichloride and pro-ligand b·HCl. Additionally, compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, which suggest that these metal complexes and/or their hydrolysis products bind DNA either in the minor groove or externally.Ministerio de Economía y CompetitividadComunidad Autónoma de MadridUniversidad de Alcal

    Signature of microRNA expression during osteogenic differentiation of bone marrow MSCs reveals a putative role of miR-335-5p in osteoarthritis

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    Background: The aim of this study was to evaluate, the existence of a signature of differentially expressed microRNAs (miRNAs) during osteogenic differentiation of bone marrow MSCs from OA and healthy donors and to describe their possible implication in joint regeneration through modulation of molecular mechanisms involved in homeostatic control in OA pathophysiology. Methods: Following phenotypic assessment of BM-MSCs obtained from OA diagnosed patients (n = 10) and non-OA (n = 10), total small RNA was isolated after osteogenic induction for 1, 10 and 21 days, miRNA profiles were generated using a commercial expression array of 754 well-characterized miRNAs. MiRNAs, with consistent differential expression were selected for further validation by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. Results: A total of 246 miRNAs were differentially expressed (fold change >=+/- 2, P <= 0.05) between OA and non-OA BM-MSC samples; these miRNAs showed variable interactions depending on the cell and differentiation status. Two miRNAs, hsa-miR-210 and hsa-miR-335-5p out of 21 used for validation showed a significant downregulated expression during induced osteogenesis. In particular hsa-miR-335-5p, a critical regulator in bone homeostasis, was further studied. hsa-miR-335-5p downregulation in OA-MSCs, as well as their host coding gene, MEST, were also assessed. Conclusions: To our knowledge, this study represents the most comprehensive assessment to date of miRNA expression profiling in BM-MSCs from OA patients and their role during osteogenic differentiation. We describe the existence of a correlation between miR-335-5p expression and OA indicating the putative role of this miRNA in OA features. These findings, may contribute to our understanding of the molecular mechanisms involved in MSCs mediated homeostatic control in OA pathophysiology that could be applicable in future therapeutic approaches.This work was supported in part by institutional grants from the Instituto de Salud Carlos III CP10/00346 and PI10/00178 and the Spanish society of orthopaedics surgery and traumatology (SECOT).; J.R. Lamas is supported by the Miguel Servet program from ISCIII-Fondo Investigacion Sanitaria-Spain (CP10/00346).S

    Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

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    New water soluble, enantiopure arene ruthenium compound SRuSN-(1R,4S)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (Bn = benzyl, 1a′) has been synthesized. The novel compound along with that previously described RRuRN-(1S,4R)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a′ was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a′ induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a′ towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells.Ministerio de Economía y CompetitividadComunidad Autónoma de MadridUniversidad de Alcal

    Percebem els errors de vacunació?

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    Errors de vacunació; Immunització; Seguretat dels pacientsErrores de vacunación; Inmunización; Seguridad de los pacientesVaccination errors; Immunization; Patient safetyIntroducció. Els errors en la vacunació poden provocar, entre altres coses, efectes adversos i disminució de la resposta immunitària. L’objectiu del present estudi és conèixer el grau de percepció d’errors en la vacunació i la freqüència amb què es produeixen. Mètodes. L’any 2017 es va aplicar una enquesta transversal–basada en 20 supòsits d’errors i 5 de no errors– al personal sanitari implicat en les vacunacions a la Regió Sanitària Camp de Tarragona, la de Lleida i la d’Alt Pirineu i Aran, el qual havia de valorar la percepció i la freqüència dels supòsits. Resultats. Van respondre el 31,4% (232/740) dels enquestats. El 92,7% (215) era personal d’infermeria i el 81,1% (188) feia més de quatre anys que administrava vacunes. Van valorar 5.800 supòsits (25 x 232): 4.640 eren errors (20 x 232) i 1.160 no ho eren (5 x 232). El 5,2% (304/5.800) van tenir dubtes a l’hora de decidir sobre si era error o no ho era. Els errors eren percebuts en un 68,7% dels supòsits (3.039/4.423) i els no errors, en un 68,2% (732/1.073). La concordança entre percepció i realitat va ser dèbil (Kappa=0,2763). El 21,0% eren conscients que havien comès un error alguna vegadaIntroducción. Los errores en la vacunación pueden provocar, entre otras cosas, efectos adversos y disminución de la respuesta inmunitaria. El objetivo del presente estudio es conocer el grado de percepción de errores en la vacunación y la frecuencia con que se producen. Métodos. El año 2017 se aplicó una encuesta transversal –basada en 20 supuestos de errores y 5 de no errores– al personal sanitario implicado en las vacunaciones en la Región Sanitaria Camp de Tarragona, la de Lleida y la de Alt Pirineu y Aran, el cual debía valorar la percepción y la frecuencia de los supuestos. Resultados. Respondió el 31,4% (232/740) de los encuestados. El 92,7% (215) era personal de enfermería y el 81,1% (188) llevaba más de cuatro años administrando vacunas. Valoraron 5.800 supuestos (25 x 232): 4.640 eran errores (20 x 232) y 1.160 no lo eran (5 x 232). El 5,2% (304/5800) dudaron en el momento de decidir entre si era un error o no lo era. Los errores eran percibidos en un 68,7% de los supuestos (3.039/4.423) y los no errores, en un 68,2% (732/1.073). La concordancia entre percepción y realidad fue débil (Kappa = 0,2763). El 21,0% eran conscientes de que habían cometido un error alguna vez. Conclusiones. La percepción de los errores en la vacunación y la formación en relación con esta cuestión son mejorables y habría que incrementar la formación en este sentido.Background. Vaccination errors can give rise, among others, to adverse effects and a diminished immune response. The objective of this study was to know the degree of perceived vaccination errors and the frequency at which they occur. Methods. In 2017, a cross-sectional survey (based on 20 errors and 5 non-errors assumptions) was made to health workers involved in vaccinations in the Tarragona, Lleida and Alt Pirineu i Aran health regions. These had to assess the perception and frequency of the assumptions. Results. 31.4% (232/740) answered. 92.7% (215) were nursing staff and 81.1% (188) had been administering vaccines for more than four years. 5 800 assumptions (25×232) were rated, being 4 640 errors (20×232) and 1 160 non-errors (5×232). When perceiving them as errors or non-errors, doubt was 5.2% (304/5 800). Errors were perceived in 68.7% of the cases (3 039/4 423) and non-errors in 68.2% (732/1073). The concordance between perception and reality was weak (Kappa = 0.2763). 21.0% were aware that they had committed a vaccination error at least once. Conclusions. Error perception and related training can be improved and training should be strengthene

    Functional and Structural Analysis of C-Terminal BRCA1 Missense Variants

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    Germline inactivating mutations in BRCA1 and BRCA2 genes are responsible for Hereditary Breast and Ovarian Cancer Syndrome (HBOCS). Genetic testing of these genes is available, although approximately 15% of tests identify variants of uncertain significance (VUS). Classification of these variants into pathogenic or non-pathogenic type is an important challenge in genetic diagnosis and counseling. The aim of the present study is to functionally assess a set of 7 missense VUS (Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V) located in the C-terminal region of BRCA1 by combining in silico prediction tools and structural analysis with a transcription activation (TA) assay. The in silico prediction programs gave discrepant results making its interpretation difficult. Structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L and G1770V) reveals significant alterations of BRCT structure. The TA assay shows that variants Y1703S, W1718L and G1770V dramatically compromise the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G and R1589H behave like wild-type BRCA1. In conclusion, our results suggest that variants Y1703S, W1718L and G1770V can be classified as likely pathogenic BRCA1 mutations

    No radiographic sacroiliitis progression was observed in patients with early spondyloarthritis at 6 years: results of the Esperanza multicentric prospective cohort

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    Objective: To estimate the 6-year radiographic progression of sacroiliitis in patients with early spondyloarthritis (SpA). Patients and methods: Sacroiliac joint (SIJ) radiographs (baseline and 6 years) of 94 patients with recent-onset SpA from the Esperanza cohort were scored, blindly and in a random order, by nine readers. The modified New York criteria were used to define the presence of sacroiliitis. As the gold standard for radiographic (r) sacroiliitis, the categorical opinion of at least five readers was used. Progression was defined as the shift from non-radiographic (nr) to r-sacroiliitis. Results: In the 94 SIJ radiographs (baseline and 6 years), 78/94 (83%) pairs of radiographs had not changed from baseline to 6 years. Sacroiliitis was present in 20 patients at baseline (21.3%) and in 18 (19.2%) patients at 6 years; 11 patients had sacroiliitis at both the baseline and final visits; 9 patients changed from baseline r-sacroiliitis to nr-sacroiliitis at 6 years, and 7 changed from baseline nr-sacroiliitis to r-sacroiliitis at 6 years. The mean continuous change score (range: -8 to +8) was 2.80 at baseline and 2.55 at 6 years (mean net progression of -0.25). The reliability of the readers was fair (mean inter-reader kappa of 0.375 (0.146-0.652) and mean agreement of 73.7% (58.7-90%)). Conclusion: In the early SpA Esperanza cohort, progression from nr-axSpA to r-axSpA over 6 years was not observed, although the SIJ radiographs scoring has limitations to detect low levels of radiographic progression

    A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape

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    We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk

    The dynamic assembly of distinct RNA polymerase I complexes modulates rDNA transcription

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    Cell growth requires synthesis of ribosomal RNA by RNA polymerase I (Pol I). Binding of initiation factor Rrn3 activates Pol I, fostering recruitment to ribosomal DNA promoters. This fundamental process must be precisely regulated to satisfy cell needs at any time. We present in vivo evidence that, when growth is arrested by nutrient deprivation, cells induce rapid clearance of Pol I-Rrn3 complexes, followed by the assembly of inactive Pol I homodimers. This dual repressive mechanism reverts upon nutrient addition, thus restoring cell growth. Moreover, Pol I dimers also form after inhibition of either ribosome biogenesis or protein synthesis. Our mutational analysis, based on the electron cryomicroscopy structures of monomeric Pol I alone and in complex with Rrn3, underscores the central role of subunits A43 and A14 in the regulation of differential Pol I complexes assembly and subsequent promoter association.The project was supported by grant BFU2013-48374-P of the Spanish MINECO and by the Ramón Areces Foundation. O.G. held a research contract under the Ramón y Cajal program of the Spanish MINECO (RYC-2011-07967). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from the Spanish MINECO.Peer reviewe
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