Prevalencia de las alteraciones biológicas causantes de trombofilia en la población española

Descripció del recurs: 8 abril 2003Títol obtingut de la portada digitalitzadaLos procesos trombóticos juegan un papel fundamental en la etiopatogenia del infarto de miocardio, del ictus isquémico y del tromboembolismo venoso. A pesar de ser causas muy comunes de morbimortalidad, la mayoría sus factores genéticos permanecen sin identificar. Los pacientes con trombofilia debutan a una edad temprana, o recurren con frecuencia, tienen antecedentes familiares, las localizaciones son inhabituales o bien la severidad es desproporcionada al estímulo causal. Los pacientes presentan episodios separados por periodos asintomáticos prolongados. Esto implica que debe existir una cierta base trombofílica y la concurrencia de factores desencadenantes: estímulo directo, deterioro de la resistencia antitrombótica o combinaciones de factores. Existen factores biológicos genéticos o adquiridos que explican en algunos casos la existencia de trombofilia. Los conocidos en la actualidad son la deficiencia de antitrombina, de proteína C, de proteína S, la resistencia a la proteína C activada, la mutación factor V Leiden, la mutación G20210A del gen de la protrombina (PTG20210A), la hiperhomocisteinemia y los anticuerpos antifosfolípidos. Con el fin de conocer las prevalencias en nuestro medio de las anomalías trombofílicas en pacientes no seleccionados con tromboembolismo venoso, el perfil clínico habitual de los pacientes según las deficiencias encontradas y las indicaciones del escrutinio de trombofilia, se plantearon diversos estudios cuyos resultados aparecen publicados en los siguientes trabajos: 1) Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism. Thromb Haemost. 1997; 77:444-51. 2) Increased risk of venous thrombosis in carriers of natural anticoagulant deficiencies. Blood Coagul Fibrinolysis. 1998 ; 9: 71-8. 3) Patients with venous thromboembolism have a lower APC response than controls. Should this be regarded as a continuous risk factor for venous thrombosis? Haematologica. 1999; 84: 470-2. 4) The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost. 1998; 80: 366-9. 5) Moderate hyper-homocysteinemia is a highly prevalent defect in Spanish patients with venous thromboembolic disease. Haematologica. 1998; 83: 1126-7. 6) Lack of association between venous thrombosis and subsequent malignancy in a retrospective cohort study in young patients. Am J Hematol. 1999; 60: 181-4. 7) Activated protein C resistance assay when applied in the general population. Am J Obstet Gynecol. 1997; 176: 358-9. 8) Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene. Haematologica 2001; 86: 965-971. De los datos obtenidos se puede concluir lo que sigue a continuación. Las prevalencias de los defectos trombofílicos en nuestro medio son: déficit de antitrombina 0,47% (0,23-0,86; IC 95%), déficit de proteína C 3,19% (2,48-4,02; IC 95%), déficit de proteína S 7,27% (6,21-8,45; IC 95%), anticuerpos antifosfolípidos 4,08% (3,28-5,01; IC 95%), resistencia a la proteína C activada 12,8% (7,9-12,7; IC 95%), mutación factor V Ledein 9,14 (5,4-14,2; IC 95%), mutación PTG20210A 17,2% (10,4-21,1; IC 95%) e hiperhomocisteinemia 23,4% (13,0-33,8; IC 95%). La probabilidad de encontrar anomalías es mayor en pacientes con menos de 45 años, en pacientes con episodios recurrentes, con antecedentes familiares, o que sus eventos trombóticos fueron espontáneos. La combinación de diversos factores clínicos se traduce en un incremento de la probabilidad de encontrar una deficiencia. De todos los hallazgos, puede concluirse que el escrutinio biológico de trombofilia está indicado en pacientes con trombosis en edad joven, o con episodios idiopáticos, recurrentes, o si existen antecedentes familiares de tromboembolismo, en especial venoso. Las determinaciones que se deben incluir son las siguientes: antitrombina, proteína C, proteína S, resistencia a la proteína C activada, las mutaciones factor V Leiden y PTG20210A, homocisteína y anticuerpos antifosfolípidos. En el estudio de las familias, se estima que la supervivencia libre de trombosis está acortada en los individuos portadores. El riesgo de trombosis en los familiares afectos es 8,1 veces superior para el déficit de proteína S tipo III, 12,6 veces más alto para el déficit de proteína C, casi 20 veces para el déficit de proteína S tipo I y 21,2 veces para el déficit de antitrombina. Debido a que estas anomalías son hereditarias, es recomendable el estudio de todos los familiares disponibles con el fin de identificar familiares afectos. Esto es útil para estos individuos ya que así es posible recomendar medidas profilácticas óptimas en situaciones de riesgo futuras. Los anticonceptivos hormonales aumentan el riesgo de trombosis en portadoras de las mutaciones factor V Leiden y PTG20210A. De manera general, no está indicado realizar estudio de trombofilia en mujeres antes de ingerir anticonceptivos hormonales, con la excepción de aquéllas que pertenezcan a familias en las que existan antecedentes de trombosis. En estos casos se recomienda la detección del estado de portadora de las mutaciones factor V Leiden y PTG20210A ya que su prevalencia es alta y se ha demostrado que ambas potencian el estado protrombótico causado por los anticonceptivos hormonales. De manera general, existe consenso en que bajo los episodios tromboembólicos venosos idiopáticos, en especial si recurren, puede subyacer una neoplasia hasta ese momento desconocida. Aunque se recomienda su búsqueda, en los pacientes jóvenes la causa más frecuente es la trombofilia, por lo que esta estrategia no está justificada. El hecho de que en los pacientes sin alteraciones biológicas exista una frecuencia superior a la esperada de la combinación de historia familiar, la primera trombosis en edad temprana y las recurrencias, hace pensar que existan otros factores genéticos relacionados con trombofilia. Este hallazgo garantiza la realización de estudios con el fin de localizar estos factores.The thrombotic processes play a major role in the etiology and pathogenesis of myocardial infarction, ischemic stroke and venous thromboembolism. Despite of being common causes of morbidity and mortality, most of the genetic factors remain unidentified. Patients with thrombophilia have thrombosis at a young age; they are prone to recurrences; they have a family history of thrombosis. The localization can be uncommon, or the severity can be higher than expected considering the triggering factors. Patients may have long asymptomatic periods between events. This implies that there is a thrombophilic threshold and triggering factors: such as direct stimulus; transient or permanent impairment oo the natural antithrombotic defenses, or a combination of these factors. Many biological factors, acquired or genetic, can account for thrombophilia. The currently accepted abnormalities causing thrombophilia are: antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance, the factor V Leiden mutation, the mutation G20210A of the prothrombin gene (PTG20210A), hyperhomocysteinemia, and antiphospholipid antibodies. Knowledge of the prevalence of these thrombophilic factors in Spanish patients with venous thromboembolism was incomplete. In addition, the clinical profile of these patients (i.e., the type of deficiency) was also unknown. Moreover, the indication of thrombophilia screening was not established in this population. With the aim of exploring these questions, several studies were carried out and the major results were published in the following papers: 1) Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism. Thromb Haemost. 1997; 77:444-51. 2) Increased risk of venous thrombosis in carriers of natural anticoagulant deficiencies. Blood Coagul Fibrinolysis. 1998 ; 9: 71-8. 3) Patients with venous thromboembolism have a lower APC response than controls. Should this be regarded as a continuous risk factor for venous thrombosis? Haematologica. 1999; 84: 470-2. 4) The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost. 1998; 80: 366-9. 5) Moderate hyperhomocysteinemia is a highly prevalent defect in Spanish patients with venous thromboembolic disease. Haematologica. 1998; 83: 1126-7. 6) Lack of association between venous thrombosis and subsequent malignancy in a retrospective cohort study in young patients. Am J Hematol. 1999; 60: 181-4. 7) Activated protein C resistance assay when applied in the general population. Am J Obstet Gynecol. 1997; 176: 358-9. 8) Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene. Haematologica 2001; 86: 965-971. The main conclusions from these studies are: The prevalences of the thrombophilic defects in the Spanish population are: antithrombin deficiency 0.47% (0.23-0.86; IC 95%), protein C deficiency 3.19% (2.48-4.02; IC 95%), protein S deficiency 7.27% (6.21-8.45; IC 95%), presence of antiphospholipid antibodies 4.08% (3.28-5.01; IC 95%), activated protein C resistance 12.8% (7.9-12.7; IC 95%), factor V Leiden mutation 9.14 (5.4-14.2; IC 95%), PTG20210A mutation 17.2% (10.4-21.1; IC 95%), and hyperhomocysteinemia 23.4% (13.0-33.8; IC 95%). The probability of having one of these abnormalities is higher in patients older than 45 years and in patients with recurrent events, family history, or spontaneous events. The combination of different clinical factors increases the pre-test probability of having a deficiency. Our studies indicate that the screening of thrombophilia should be performed in patients suffering from thrombosis at a young age, with recurrent episodes, family history of thrombosis or spontaneous events. The following measurements should be included: antithrombin, protein C and protein S, activated protein C resistance, antiphospholipid antibodies, homocysteine, and the factor V and PTG20210A mutations. In the family study, a shorter thrombosis-free survival was observed in carriers of thrombophilic defects. The risk of thrombosis in carriers was 8.1 times higher for type-III protein S deficiency, 12.6 times higher for protein C deficiency, 20 times higher for type-I protein S deficiency and 21.2 higher times for antithrombin deficiency. Because these abnormalities have high heritabilities and increased risks for thrombosis, the screening of all relatives in highly recommended. From such screening, asymptomatic carriers can be identified and optimal prophylaxis to prevent future risk situations can be prescribed. Oral hormonal contraceptives increase the risk of thrombosis in carries of the factor V and PTG20210A mutations. In general, the screening of thrombophilic factors in women who take hormonal contraceptives is not recommended, but it should be performed in women belonging to a family with history of thrombosis. In such a cases, the detection of the factor V Leiden and PTG20210A should be performed because of their high prevalence in the Spanish population. Moreover, both mutations increase considerably the prothrombotic state caused by hormonal contraceptives. There is general agreement that the presence of occult cancer in patients with spontaneous venous thrombotic events should be investigated. However, the more frequent cause of spontaneous thrombosis in young people is thrombophilia. For this reason, looking for an occult cancer does not seem to be justified in young patients with spontaneous events in the absence of other symptoms. Another finding was that there was an increased frequency of combination of family history, first event at a younger age, and recurrences in patients without thrombophilic abnormalities. This suggests that there are other genetic factors underlying thrombophilia. Thus, further studies looking for new genetic thrombophilic factors are recommended

Survival of Moss Reproductive Structures under Simulated Martian Environmental Conditions and Extreme Thermal Stress: Vibrational Spectroscopic Study and Astrobiological Implications

The principal goal of astrobiology is the search for extraterrestrial life forms. A key aspect is the study of the ability of different kinds of terrestrial organisms to support simulated extraterrestrial environmental conditions. Mosses are multicellular green plants, poorly studied from an astrobiological perspective. In this paper, we report experimental results obtained using two species of moss, which demonstrate that both the spores of the moss Funaria hygrometrica as well as the desiccated vegetative gametophyte shoots of the moss Tortella squarrosa (=Pleurochaete squarrosa) were capable of resisting Simulated Martian Environmental Conditions (SMEC): Mars simulated atmospheric composition 99.9% CO2, and 0.6% H2O with a pressure of 7 mbars, -73 ºC and UV irradiation of 30 mW cm-2 in a wavelength range of 200-400 nm under a limited short time of exposition of 2 hours. After being exposed to SMEC and then transferred to an appropriate growth medium, the F. hygrometrica spores germinated, producing typical gametophyte protonemal cells and leafy shoots. Likewise, detached leaves from SMEC-exposed gametophyte shoots of T. squarrosa retained the ability to produce new protonemata and shoots under suitable growth conditions. Furthermore, we studied the tolerance of these moss structures to a thermal stress of 100 °C for 1 h; in both cases the spores and shoots were capable of resisting this heat treatment. Our study using FT-Raman and FT-IR vibrational spectroscopy demonstrated that neither spores nor shoots apparently suffered significant damage in their biomolecular makeup after being subject to these stress treatments. The implications of these findings for the search of life on Mars are discussed

Relationships between growth-related traits with carcass and meat quality traits in Spanish Assaf suckling lambs

[EN] Suckling lamb meat is a relevant product in Mediterranean European dairy sheep farms, and the dairy breed Spanish Assaf is widely extended through the Iberian Peninsula. Knowledge of the influence of birth body weight (bBW) and growth rate on suckling lamb carcass and meat quality is scarce, but useful for breeding optimisation and product homogeneity. In turn, these growth-related traits of lambs might be affected by dietary restrictions of their dams. In this study, 34 male Assaf suckling lambs born from two groups of ewes that had been fed diets with different protein levels when they were prepubertal female lambs (17 lambs per group) were analysed. After birth, the suckling lambs were fed ad libitum on milk replacer until their sacrifice (10–12.5 kg live body weight). The quality traits evaluated in carcasses and meat were carcass compactness, fatness and jointing, meat composition, colour, texture and oxidative stability, and fatty acid profile. The dam group did not show significant effects on lamb growth characteristics or carcass and meat quality traits. The bBW factor showed a negative effect on leg subcutaneous fatness and a positive effect on the forequarter and shoulder percentages of the carcass. The bBW also resulted in increased moisture, lipid oxidation stability, and n-3 FA content (lowering the n-6/n-3 ratio) in the meat. Suckling lambs showing very low average daily gain (ADG) tended to present low carcass quality, i.e., higher bone percentage in the loin and low percentages of muscle or fat compared to those showing high ADG. Further studies are needed to confirm and explain the mechanisms of the significant effects reported here for bBW and ADG on the affected quality traits.S

Transcriptome analysis of perirenal fat from Spanish Assaf suckling lamb carcasses showing different levels of kidney knob and channel fat

[EN] Introduction: Suckling lamb meat is highly appreciated in European Mediterranean countries because of its mild flavor and soft texture. In suckling lamb carcasses, perirenal and pelvic fat depots account for a large fraction of carcass fat accumulation, and their proportions are used as an indicator of carcass quality. Material and Methods: This study aimed to characterize the genetic mechanisms that regulate fat deposition in suckling lambs by evaluating the transcriptomic differences between Spanish Assaf lambs with significantly different proportions of kidney knob and channel fat (KKCF) depots in their carcasses (4 High-KKCF lambs vs. 4 Low-KKCF lambs). Results: The analyzed fat tissue showed overall dominant expression of white adipose tissue gene markers, although due to the young age of the animals (17–36 days), the expression of some brown adipose tissue gene markers (e.g., UCP1, CIDEA) was still identified. The transcriptomic comparison between the High-KKCF and Low-KKCF groups revealed a total of 80 differentially expressed genes (DEGs). The enrichment analysis of the 49 DEGs with increased expression levels in the Low-KKCF lambs identified significant terms linked to the biosynthesis of lipids and thermogenesis, which may be related to the higher expression of the UCP1 gene in this group. In contrast, the enrichment analysis of the 31 DEGs with increased expression in the High-KKCF lambs highlighted angiogenesis as a key biological process supported by the higher expression of some genes, such as VEGF-A and THBS1, which encode a major angiogenic factor and a large adhesive extracellular matrix glycoprotein, respectively. Discussion: The increased expression of sestrins, which are negative regulators of the mTOR complex, suggests that the preadipocyte differentiation stage is being inhibited in the High-KKCF group in favor of adipose tissue expansion, in which vasculogenesis is an essential process. All of these results suggest that the fat depots of the High-KKCF animals are in a later stage of development than those of the Low-KKCF lambs. Further genomic studies based on larger sample sizes and complementary analyses, such as the identification of polymorphisms in the DEGs, should be designed to confirm these results and achieve a deeper understanding of the genetic mechanisms underlying fat deposition in suckling lambsSIThe research described here has been funded by the project EpiMilksheep (RTI2018-093535-B-100) funded by the Spanish Ministry of Science and Innovation. MA-G is funded by a predoctoral fellowship from the Junta de Castilla and León Government and the European Social Fun

Integrated analyses of the methylome and transcriptome to unravel sex differences in the perirenal fat from suckling lambs

[EN] In sheep, differences were observed regarding fat accumulation and fatty acid (FA) composition between males and females, which may impact the quality and organoleptic characteristics of the meat. The integration of different omics technologies is a relevant approach for investigating biological and genetic mechanisms associated with complex traits. Here, the perirenal tissue of six male and six female Assaf suckling lambs was evaluated using RNA sequencing and whole-genome bisulfite sequencing (WGBS). A multiomic discriminant analysis using multiblock (s)PLS-DA allowed the identification of 314 genes and 627 differentially methylated regions (within these genes), which perfectly discriminate between males and females. These candidate genes overlapped with previously reported QTLs for carcass fat volume and percentage of different FAs in milk and meat from sheep. Additionally, differentially coexpressed (DcoExp) modules of genes between males (nine) and females (three) were identified that harbour 22 of these selected genes. Interestingly, these DcoExp were significantly correlated with fat percentage in different deposits (renal, pelvic, subcutaneous and intramuscular) and were associated with relevant biological processes for adipogenesis, adipocyte differentiation, fat volume and FA composition. Consequently, these genes may potentially impact adiposity and meat quality traits in a sex-specific manner, such as juiciness, tenderness and flavourSIThis research work was financially supported by the RTI2018-093535-B-I00 project funded by the “Agencia Estatal de Investigación” of the Spanish Ministry of Science and Innovation (Madrid, Spain). MA-G is funded by the Junta de Castilla y Leon fellowship. This research has used the high- performance computing resources of the Castilla y León Supercomputing Center (SCAYLE, www.scayle.es; León, Spain). PF is the beneficiary of a Maria Zambrano Grant of the University of Leon funding by the Ministry of Universities (Madrid, Spain) and financed by the European Union-Next Generation E

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019

Altres ajuts: Spanish AIDS Research Network; European Funding for Regional Development (FEDER).Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population

SuperCam Calibration Targets: Design and Development

SuperCam is a highly integrated remote-sensing instrumental suite for NASA’s Mars 2020 mission. It consists of a co-aligned combination of Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), Visible and Infrared Spectroscopy (VISIR), together with sound recording (MIC) and high-magnification imaging techniques (RMI). They provide information on the mineralogy, geochemistry and mineral context around the Perseverance Rover. The calibration of this complex suite is a major challenge. Not only does each technique require its own standards or references, their combination also introduces new requirements to obtain optimal scientific output. Elemental composition, molecular vibrational features, fluorescence, morphology and texture provide a full picture of the sample with spectral information that needs to be co-aligned, correlated, and individually calibrated. The resulting hardware includes different kinds of targets, each one covering different needs of the instrument. Standards for imaging calibration, geological samples for mineral identification and chemometric calculations or spectral references to calibrate and evaluate the health of the instrument, are all included in the SuperCam Calibration Target (SCCT). The system also includes a specifically designed assembly in which the samples are mounted. This hardware allows the targets to survive the harsh environmental conditions of the launch, cruise, landing and operation on Mars during the whole mission. Here we summarize the design, development, integration, verification and functional testing of the SCCT. This work includes some key results obtained to verify the scientific outcome of the SuperCam system

Early adipose deposits in sheep: comparative analysis of the perirenal fat ranscriptome of Assaf and Churra suckling lambs

13 páginas, 3 figuras, 2 tablas.Adipose deposits influence the quality of ruminant carcasses, and in suckling lambs, internal types of adipose deposits represent a notable proportion of total fat. The aim of this study was to perform a comparative analysis of the perirenal fat transcriptomes of suckling lambs from two breeds with different growth and carcass characteristics. The perirenal fat tissue from 14 suckling lambs (Assaf, n = 8; Churra, n = 6) was used for the RNA-seq analysis. The functional enrichment analysis of the 670 highly expressed genes (>150 fragments per kilobase of exon per million fragments mapped) in the perirenal fat transcriptome of both breeds revealed that the majority of these genes were involved in energy processes. The expression of the UCP1 gene, a classical biomarker of brown fat, and the presence of multilocular adipocytes in the two breeds supported the presence of brown fat at the transition stage towards white fat tissue. The differential expression analysis performed identified 373 differentially expressed genes (DEGs) between the two compared breeds. Brown/white fat gene biomarkers were not included in the list of DEGs. In Assaf lambs, DEGs were enriched in Gene Ontology (GO) biological processes related to fatty-acid oxidation, whereas in Churra lambs, the majority of the significantly enriched GO terms were related to cholesterol synthesis, which suggests that upregulated DEGs in Assaf lambs are implicated in fat burning, whereas the Churra upregulated DEGs are linked to fat accumulation. These results can help to increase knowledge of the genes controlling early fat deposition in ruminants and shed light on fundamental aspects of adipose tissue growth.This work was supported by the associated funding of aRamon y Cajal contract (RYC-2012-10230) from the Spanish Ministry of Economy, Industry and Competitiveness(MINECO). BGG is funded by the Ramon y Cajal Programme(RYC-2012-10230) from MINECO. We sincerely thank thestaff from the farm of the Faculty of Veterinary Sciences ofthe University of Leon for the management of lambs and the collaborating slaughterhousePeer reviewe

Unidades didácticas de Matemáticas. Secundaria Obligatoria

Este libro consta de tres unidades didácticas: A) Nuestro entorno geométrico. B) Azar y probabilidad. C) Procedimientos de estimación. La primera de ellas aborda aspectos de la Geometría tridimensional, basándose en los cuerpos geométricos, en la superficie de los poliedros y en el volúmen. Fue programada por el CEP I de Valladolid para el área de Matemáticas durante el curso 1990/91. La segunda unidad didáctica abarca los fenómenos aleatorios, la terminología utilizada y la asignación de probabilidades a un suceso (espacio muestral, sucesos probables, frecuencias, etc.). Fue realizada en el CEP de Móstoles (Madrid) durante el curso 1992/93. La tercera unidad didáctica propone comprender el significado de la estimación estadística, conocer algunas técnicas de muestreo, identificar las medias de las distintas muestras y calcular estimaciones y muestras.Ministerio Educación CIDEBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín 5 -3 Planta; 28014 Madrid; Tel. +34917748000; [email protected]