A new source of the long version of the Castigos de Sancho IV:\ud el Libro de las donas

Los Castigos de Sancho IV fueron sometidos a un intenso proceso\ud de ampliación que dio lugar a una nueva versión de la obra, que denomino\ud extensa. En este trabajo se da noticia de una de las fuentes utilizadas para\ud efectuar las adiciones, el Libro de las donas, traducción al castellano de\ud la obra homónima escrita en catalán por Francesc Eiximenis. Ello permite\ud retrasar la datación de la versión extensa de Castigos hasta el siglo xv. Pero\ud esta obra ha servido como fuente también para algunos pasajes del manuscrito\ud E de la versión breve (Z-III-4 del Escorial), lo que necesariamente hace que\ud nos cuestionemos su tradición manuscrita y, lo que es más importante, si\ud los fragmentos procedentes del Libro de las donas deben incluirse en una\ud edición crítica de la versión breve de los Castigos de Sancho IV.The Castigos of Sancho IV were put under an intense process of\ud extension that gave rise to a new version of the work, whicht I denominate\ud long version. In this article I give notice of one of the sources used to\ud carry out the additions, the Libro de las donas, Castilian translation of the\ud homonymous work written in Catalan by Francesc Eiximenis. It allows to\ud delay the dating of the long version of Castigos until century xv. But this\ud work has served like source also for some passages of the manuscript E\ud of the short version (Escorial, Z-III.4), what makes necessary to question\ud about its manuscript tradition and, which is more important, if the fragments\ud coming from Libro de las donas must be included in a critical edition of the\ud short version of the Castigos de Sancho IV

Metodologías activas y gamificación en las asignaturas de iniciación a la programación

Aprender a programar es una tarea compleja que requiere del desarrollo de diversas habilidades. Los estudiantes que se inician en la programación se encuentran con serias dificultadas en el aprendizaje de esta materia. Actualmente en los nuevos Grados se han introducido asignaturas relacionadas con las tecnologías de la información, en donde se realiza un primer contacto con la programación. En esta comunicación presentamos el trabajo realizado para el desarrollo de una metodología docente para la enseñanza de programación, basada en el uso de metodologías activas y el empleo de gamificación para incentivar la participación del alumnado y aumentar su motivación. Comentamos la implantación de esta metodología en un curso de iniciación a la programación del Grado en Ingeniería Informática y exponemos los resultados obtenidos.Learning programming is a complex task that requires the development of various skills. Students who are new to programming encounter serious difficulties in learning the subject. Nowadays degrees in the new study system have introduced subjects related to information technology, where students make their first contact with programming. In this paper we present the work done to develop a methodology for teaching programming based on the use of active methodologies and gamification, to encourage student participation and increase motivation. We discuss the implementation of this methodology in an introductory course to programming in the Degree in Computer Science and present some results

Long-term hydrological changes in northern Iberia (4.9–0.9 ky BP) from speleothem Mg/Ca ratios and cave monitoring (Ojo Guareña Karst Complex, Spain)

An absolute-dated stalagmite from Kaite Cave (Ojo Guareña Karst Complex, N Spain) provides a nearly continuous, high-resolution record of a proxy of regional precipitation patterns through the 4.9–0.9 ka BP interval. This record is based on the Mg/Ca ratio of the calcite and its variation through the stalagmite stratigraphy, which is interpreted to be primarily driven by changes in precipitation amount. The calibration of the proxy is supported by the present-day monitoring carried out in the cave for the last 10 years, which reveals a robust inverse relationship between the inter-annual/inter-decadal variability of rainfall and the Mg concentration of dripwaters and precipitating speleothems. The record of paleoprecipitation, based on 2400 Mg/Ca measurements, shows strong variability at inter-annual to inter-decadal scales, and more subtle but significant changes at secular to millennial scales. This long-term paleohydrological evolution outlines five successive intervals with consistent trends, which are bounded by abrupt shifts in the regional precipitation. These shifts took place at 4.65, 4.2, 2.6, and 1.3 ka BP. Significantly, the intervals of maximum precipitation of the whole record (around 4.9–4.65, 2.6–2.45, and 1.3–1.1 ka BP) can be related with episodes of minimum solar activity and correlated with cold climatic events elsewhere.Contribution to research projects 28 CGL2010-21499-BTE and CGL2013-43257-R of the Spanish R+D National Program 29 (MINECO) and research groups ‘‘Paleoclimatology and Global Change’’ and ‘‘Laser Induced 30 Breakdown Spectroscopy (LIBS)’’ from the UCM (Spain).Peer reviewe

Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia

This is an open access article distributed under the Creative Commons Attribution License.-- et al.The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.The study was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias 02/1041, FIS 09/01382, FIS 09/01543, and PI12/00281; RD12/0036/0069 from Red Tematica de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) “Una manera de hacer Europa”; and Caja de Burgos-Banca Cívica. A. Rodrígues was fully supported by an Ayuda Predoctoral FIS de Formación en Investigacion by the Spanish Fondo de Investigaciones Sanitarias. M. Hernandez-Sanchez was partially supported by a grant from the “Fundacion Española de Hematología y Hemoterapia.” Partially supported by grants from “Proyectos de Investigacion Biomédica del SACYL” 106/A/06.Peer Reviewe

Trombosis venosa cerebral en adultos en el Complejo Hospitalario-Universitario de A Coruña España. Revisión clínico-radiológica de 48 casos diagnosticados entre 1995 Y 2005

INTRODUCCIÓN: La trombosis venosa cerebral es una patología del sistema nervioso central cuya incidencia es aún desconocida. El diagnóstico es difícil, teniendo en cuenta que las manifestaciones neurológicas así como su etiología pueden ser extremadamente variables.  OBJETIVOS: conocer la etiología, clínica y pronóstico de las trombosis de los senos venosos cerebrales en el Complejo Hospitalario Universitario Juan Canalejo de A Coruña. Pacientes y métodos: se revisaron de forma retrospectiva los casos diagnosticados de TVC desde 1995 a 2005. Se registró la etiología, las manifestaciones clínicas, los signos radiológicos en la TAC en el momento del ingreso, el tratamiento aplicado y el pronóstico a los 6 meses empleando la escala modificada de Rankin.  RESULTADOS: se registraron 48 casos de los cuales 27 eran mujeres y 21 hombres; el rango de edad fue de 21 a 88 años, con una mediana de 43 años. La etiología infecciosa estuvo presente en cinco casos equivalente al (10,4%). En pacientes jóvenes (<43 años) los trastornos de la coagulación y/o la toma de anticonceptivos hormonales se constató en el 66,7% de los casos, mientras que en los mayores de 43 años la etiología neoplásica se encontró en el 29% y no pudo identificarse en el 45,8%. El síntoma más frecuente fue la cefalea en el 72,9%. En la tomografía axial computarizada el signo radiológico más frecuente fue la hiperdensidad de uno o varios senos venosos (62,5%), pero fue estrictamente normal en el 20% de los casos. Treinta y cuatro pacientes recibieron tratamiento anticoagulante con buena evolución, así el 75% presentó puntuación en la escala modificada de Rankin ≤1 a los seis meses. Ocho pacientes (16,7%) fallecieron, pero la mortalidad estuvo fuertemente relacionada con la patología de base de los mismos (50% cáncer).  CONCLUSIONES: en pacientes jóvenes predomina la etiología por anticonceptivos y los trastornos de la coagulación, en cambio, a partir de la sexta década dominan las neoplasias subyacentes y causas indeterminadas. El tratamiento anticoagulante es eficaz y seguro. El pronóstico es excelente en la mayoría de los casos.  Palabras clave: Trombosis venosa cerebral. Senos durales. Ictus. Anticoagulantes. Heparina. Pronóstico.     INTRODUCTION: Central venous trombosis in adults in the complejo hospitalario-universitario de A Coruña Spain. Clinic-radiology review of 48 cases between 1955 and 2005. Introduction. Cerebral venous thrombosis is a pathology of the central nervous system which incident is still unknown. The diagnosis is difficult because the neurological manifestations and its etiology may be extremely varied.  OBJECTIVES: The aim of our study was to ascertain the etiology, the clinical manifestations and the prognosis of the cases of Cerebral venous thrombosis diagnosed at our Hospital. Patients and Methods. It was reviewed retrospectively all histories of the patients who were diagnosed of cerebral venous thrombosis from 1995 to 2005. It was recorded the etiological factors, the clinical manifestations, the radiological signs in the computed tomography scan at admission, the treatment administered and the prognosis at six months was classified in accordance with the modified Rankin scale (mRS).  RESULTS:  We reviewed 48 cases (27 females; 21 males). The age range was 21 to 88 years old, with a median at 43 years. The infectious etiology was present in five patients (10,4%). In the young group (<43years), coagulation diseases and/or oral hormone contraceptives were involved in 66,7% of the cases, whereas in the age group (≥43 years), an underlying neoplasm was identified in 29% of the cases and no etiological factor in 45,8%. Headache was the most frequent symptom (72,9%). The most frequently observed radiological sign in the computed tomography scan was hyperdensity in one or more venous sinuses (62.5%), but it was normal in 20% of the cases. 34 patients received anticoagulant treatment with a good evolution, so 75% presented mRS ≤1 at six months. Death occurred in 8 patients (16,7%), although it was closely related to their basic condition (50% neoplasm).  CONCLUSIONS: In young population, the most frequently etiologies are contraceptives and coagulation disease and in people older than 60 years, the underlying neoplasm and cases of unknown etiology prevail. The anticoagulant treatment is effective and safe. The prognosis was excellent in the most of the cases.  Key words: Cerebral venous thrombosis. Venous sinuses. Stroke. Anticoagulant. Heparin. Prognosis

Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bor tezomib and dexamethasone

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.This work was in part funded by the Spanish ISCIII-FIS (PI 15/0067 and PI15/02156) and FEDER, the Spanish RTICC (RD12/0036/0058), "Asociación Española Contra el Cancer" (AECC, GCB120981SAN), the regional Council from “Castilla y León” (GRS 1175/A/15 and FIC335U14) and a research grant from Pharmamar SAU. MMS were also supported by the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León, Spain. A-A López-Iglesias was supported by a grant from the Spanish Society of Hematology and Hemotherapy.Peer Reviewe

Association of breast and gut microbiota dysbiosis and the risk of breast cancer: a case-control clinical study

We would like to thank M Luisa Puertas-Martin and Isabel Manzano-Jimenez, nurses at the Unit of Mammary Pathology, General Surgery Service, San Cecilio University Hospital (Granada), without whose enthusiasm the enrolment of participants in Granada would still be stalled. We are indebted to all the women taking part in the study.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Trial registration ClinicalTrials.gov NCT03885648, 03/25/2019. Retrospectively registered.Background Breast cancer ranks first in women, and is the second cause of death in this gender. In addition to genetics, the environment contributes to the development of the disease, although the factors involved are not well known. Among the latter is the influence of microorganisms and, therefore, attention is recently being paid to the mammary microbiota. We hypothesize that the risk of breast cancer could be associated with the composition and functionality of the mammary/gut microbiota, and that exposure to environmental contaminants (endocrine disruptors, EDCs) might contribute to alter these microbiota. Methods We describe a case-control clinical study that will be performed in women between 25 and 70 years of age. Cases will be women diagnosed and surgically intervened of breast cancer (stages I and II). Women with antecedents of cancer or advanced tumor stage (metastasis), or who have received antibiotic treatment within a period of 3 months prior to recruitment, or any neoadjuvant therapy, will be excluded. Controls will be women surgically intervened of breast augmentation or reduction. Women with oncological, gynecological or endocrine history, and those who have received antibiotic treatment within a period of 3 months prior to recruitment will also be excluded. Blood, urine, breast tissue and stool samples will be collected. Data regarding anthropometric, sociodemographic, reproductive history, tumor features and dietary habits will be gathered. Metabolomic studies will be carried out in stool and breast tissue samples. Metagenomic studies will also be performed in stool and breast tissue samples to ascertain the viral, fungal, bacterial and archaea populations of the microbiota. Quantitation of estrogens, estrogen metabolites and EDCs in samples of serum, urine and breast tissue will also be performed. Discussion: This is the first time that the contribution of bacteria, archaea, viruses and fungi together with their alteration by environmental contaminants to the risk of breast cancer will be evaluated in the same study. Results obtained could contribute to elucidate risk factors, improve the prognosis, as well as to propose novel intervention studies in this disease.This work is funded by grants PI-0538-2017 (Junta de Andalucía, Spain, to LF) and Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP) of the Institute of Health Carlos III -supported by European Regional Development Fund/FEDER (FIS-PI16/01812) (to MFF)

Allele and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DQB1 and -DQA1 in Castile and Leon region from North West of Spain

HLA studies have been used to determine the admixture of different populations within the Iberian Peninsula including neighbouring regions with shared origins, such as Portugal and Castile and Leon. These studies certainly can be used to study human migration that could establish populations currently settled according to genetic distant analysis based on the HLA diversity and language variety.This work was supported by the “Gerencia Regional de Salud de Castilla y Leon” (GRS 2080/A/19, 2019) and (GRS COVID 70/A/20, 2020)

Characterization of the platelet phenotype caused by a germline RUNX1 Variant in a CRISPR/Cas9-generated murine model

RUNX1-related disorder (RUNX1-RD) is caused by germline variants affecting the RUNX1 gene. This rare, heterogeneous disorder has no specific clinical or laboratory phenotype, making genetic diagnosis necessary. Although international recommendations have been established to classify the pathogenicity of variants, identifying the causative alteration remains a challenge in RUNX1-RD. Murine models may be useful not only for definitively settling the controversy about the pathogenicity of certain RUNX1 variants, but also for elucidating the mechanisms of molecular pathogenesis. Therefore, we developed a knock-in murine model, using the CRISPR/Cas9 system, carrying the RUNX1 p.Leu43Ser variant (mimicking human p.Leu56Ser) to study its pathogenic potential and mechanisms of platelet dysfunction. A total number of 75 mice were generated; 25 per genotype (RUNX1WT/WT, RUNX1WT/L43S, and RUNX1L43S/L43S). Platelet phenotype was assessed by flow cytometry and confocal microscopy. On average, RUNX1L43S/L43S and RUNX1WT/L43S mice had a significantly longer tail-bleeding time than RUNX1WT/WT mice, indicating the variant's involvement in hemostasis. However, only homozygous mice displayed mild thrombocytopenia. RUNX1L43S/L43S and RUNX1WT/L43S displayed impaired agonist-induced spreading and α-granule release, with no differences in δ-granule secretion. Levels of integrin αIIbβ3 activation, fibrinogen binding, and aggregation were significantly lower in platelets from RUNX1L43S/L43S and RUNX1WT/L43S using phorbol 12-myristate 13-acetate (PMA), adenosine diphosphate (ADP), and high thrombin doses. Lower levels of PKC phosphorylation in RUNX1L43S/L43S and RUNX1WT/L43S suggested that the PKC-signaling pathway was impaired. Overall, we demonstrated the deleterious effect of the RUNX1 p.Leu56Ser variant in mice via the impairment of integrin αIIbβ3 activation, aggregation, α-granule secretion, and platelet spreading, mimicking the phenotype associated with RUNX1 variants in the clinical setting.This work was partially supported by grants from Instituto de Salud Carlos III (ISCIII) and Feder (PI17/01311, PI17/01966, and CB15/00055), Fundación Séneca (19873/GERM/15), Gerencia Regional de Salud (GRS 2061A/19 and 1647/A/17), Fundación Mutua Madrileña (FMM, AP172142019), and Sociedad Española de Trombosis y Hemostasia (SETH-FETH; Premio López Borrasca 2019 and Ayuda a Grupos de Trabajo en Patología Hemorrágica 2019). The authors' research on IPDs is conducted in accordance with the aims of the Functional and Molecular Characterization of Patients with Inherited Platelet Disorders Project, which is supported by the Hemorrhagic Diathesis Working Group of the Spanish Society of Thrombosis and Haemostasis. A.M.-Q., C.F.-I., and L.H.-C. were supported by predoctoral grants from the Junta de Castilla y León, Spain. E.V. was supported by the predoctoral grant from the University of Salamanca, Spain. IG-T and RB were supported by "Contratos postdoctorales Programa II) from the University of Salamanca, Spain