Nuevos factores genéticos asociados a la predisposición de crisis en Porfiria Aguda Intermitente.

La porfiria aguda intermitente (PAI) es una enfermedad metabólica de base genética con herencia autosómica dominante y baja penetrancia. Se origina por la deficiencia parcial de la enzima hidroximetilbilano sintasa (HMBS), que cataliza el tercer paso de la biosíntesis de hemo, resultante de la alteración del gen HMBS. La PAI se expresa clínicamente en el 10-20% de los portadores, como crisis neuroviscerales agudas que suceden de forma episódica (PAI manifiesta), a menudo asociadas a factores precipitantes como algunos fármacos, cambios endocrinos, ayuno o estrés. La PAI latente se ha asociado clásicamente a los portadores sin evidencia de crisis agudas. Estos factores externos explican parte de la variabilidad interindividual de la expresión clínica de la enfermedad, pero los factores endógenos subyacentes a la baja penetrancia son desconocidos. La dotación genética individual podría modular la penetrancia de la enfermedad. En este sentido, se ha sugerido que otros genes distintos a HMBS, podrían actuar como factores de susceptibilidad influyendo en la expresión de las crisis agudas. En situaciones de alta demanda de hemo se produce una sobrestimulación de su síntesis hepática, que en los portadores de PAI lleva a la acumulación de los precursores porfirínicos, ácido 5-aminolevulínico (ALA) y porfobilinógeno (PBG), y al desencadenamiento clínico de la enfermedad. El gen ALAS1 (isoforma ubicua de la aminolevulinato sintasa) codifica la enzima limitante de la síntesis de hemo y está sujeto a regulación por retroalimentación negativa de éste. Además, ALAS1 se induce en respuesta a fármacos paralelamente a los genes de los citocromos P450 (CYP). Las enzimas CYP constituyen las principales hemoproteínas hepáticas y son altamente polimórficas. Participan en el metabolismo de fármacos y otros xenobióticos, así como en la síntesis de compuestos endógenos de naturaleza esteroide. Objetivos: El objetivo de este trabajo fue describir la frecuencia de PAI manifiesta en nuestra región e identificar variantes genéticas en regiones reguladoras del gen ALAS1 y en los genes de los citocromos CYP2C9, CYP2C19, CYP2D6, CYP3A4 y CYP3A5 que actúen como factores de susceptibilidad para la manifestación de crisis agudas en los portadores de PAI. Material y métodos: Se realizó un estudio retrospectivo de la ocurrencia de crisis (PAI manifiesta) en 50 individuos portadores de PAI. Se obtuvieron muestras de ADN de sangre periférica para el análisis genético. Se amplificó y secuenció una extensión de 1.2 Kb del promotor proximal y dos regiones distales 5’ de respuesta a fármacos (ADRES1 y ADRES2) del gen ALAS1. Adicionalmente, se estudió el grado de metilación de una posible isla CpG localizada a -4.67 Kb del inicio de la transcripción, mediante secuenciación específica de bisulfito. Por otro lado, se genotiparon los alelos CYP2C9*2, CYP2C9*3; CYP2C19*2; CYP2D6*4, CYP2D6*5; CYP3A4*1B y CYP3A5*3, que determinan enzimas no funcionantes o con actividad reducida y se analizaron los niveles de ALA y PBG en orina en fase asintomática de la enfermedad. Resultados: El 52% de los portadores presentó PAI manifiesta, con un número medio de crisis de 2.5±2 (rango: 1-10 crisis). La penetrancia asociada a la mutación fundadora c.669_698del fue del 48.7%. No se detectaron variantes genéticas en las regiones reguladoras del gen ALAS1 analizadas. Además, todos los individuos presentaron metilación en todas las posiciones susceptibles (dinucleotidos CG) de tal modificación. En relación a los genes CYP, se observó una mayor frecuencia de alelos defectuosos en CYP2D6 (*4 y *5) en los individuos con PAI latente. La posibilidad de tener PAI manifiesta fue menor en portadores de alelos defectuosos en el gen CYP2D6. Se observó una tendencia similar en los portadores de alelos defectuosos en CYP2C9, sin suficiente evidencia estadística. Los niveles de PBG urinario fueron más bajos que en los portadores de alelos defectuosos en CYP2C9, sin embargo, este efecto estaba asociado a la ocurrencia de crisis, actuando éstas como factor explicativo intermedio. No se observó efecto del genotipo de los genes CYP2C19, CYP3A4 y CYP3A5 en la ocurrencia de crisis ni en la excreción urinaria de ALA y PBG. Discusión: En general la penetrancia descrita en la población estudiada (52%) fue muy superior a lo reportado clásicamente en PAI (10-20%) y algo más elevada a la asociada a poblaciones PAI en el norte de Europa, como es el caso Suecia (42%), donde la mutación c.593G>A (p.W198X) es predominante. La penetrancia asociada a la mutación c.669_698del (48.7%) fue comparable a la de la mutación p.W198X (44%), sugiriendo que estas mutaciones fundadoras tienen un mayor impacto en la funcionalidad de la enzima que otras mutaciones descritas con penetrancia inferior. En relación al análisis del gen ALAS1, se observó homogeneidad genética en la región 5’ reguladora (promotor proximal y regiones ADRES), de forma que ésta no interviene en la modulación de la expresión de la PAI en la población estudiada. La posible isla CpG localizada a -4.67 Kb parece que no interviene en la potenciación de la expresión de ALAS1 en el tejido analizado, puesto que se encontraba en estado metilado en todos los individuos analizados. Los resultados sugieren que CYP2D6*4 y *5, y posiblemente CYP2C9*2 y *3, son factores de protección para desarrollar crisis agudas en PAI. Estos CYP podrían constituir genes modificadores de la penetrancia. Se requieren estudios adicionales en poblaciones más extensas de PAI para validar esta asociación y obtener una visión más amplia. La confirmación de estos hallazgos permitiría predecir el perfil de riesgo de crisis para cada individuo basado en el genotipo CYP y conduciría al progreso en la medicina personalizada para los portadores de PAI.Medicin

Comportamiento de tejas de diferente color (rojo y paja) frente al biodeterioro

La colonización biológica es un fenómeno que afecta de forma negativa a la durabilidad de los materiales de construcción. A nivel industrial se ha observado que las tejas de color paja muestran mayor tendencia a la colonización biológica que las tejas de coloración rojiza, incluso cuando ambas presentan características similares. El objetivo de este trabajo es determinar la causa de las diferencias de biocolonización entre tejas de diferente color. Para ello, se ha determinado la composición química de la superficie de tejas de color paja y de color rojo mediante WD-FRX, la composición mineralógica por DRX, la microestructura de la superficie mediante MEB-EDX, la distribución del tamaño de poros mediante porosimetría de mercurio, y la solubilidad (Ca, Mg, Na, K, Cl and SO 2- por ICP-OES y cromatografía iónica). Se ha evaluado la biorreceptividad midiendo la intensidad de fluorescencia con un fluorómetro, utilizando la cianobacteria Oscillatoria sp. Los resultados muestran una mayor concentración de calcio y azufre, y una mayor solubilidad de éstos, en la superficie de las tejas paja, y éstas presentan una mayor tendencia a la colonización. Por lo tanto, el hecho de que presenten sales solubles en superficie favorece la biocolonización, y con ello, el deterioro estético y funcional del tejado.Biocolonization of building materials is a critical problem for the durability of constructions. Industrial experience shows that straw coloured roofing tiles are more prone to colonization than red roofing tiles, even having similar characteristics. The aim of this work is to explain the difference of biocolonization between different colour roofing tiles. The chemical composition of the surface of straw coloured and red roofing tiles, the phase composition and the microstructure of the roofing tiles were determined by WD-XRF, XRD and SEM-EDX, respectively. The pore size distribution was carried out by Hg porosimetry. The solubility was studied by determining the soluble salts (Ca, Mg, Na, K, Cl and SO 2-) by ICP-OES and ionic chromatography. Roofing tile bioreceptivity was evaluated by determining fluorescence intensity using a pulse-amplitude-modulated (PAM) fluorometer, and cyanobacteria Oscillatoria sp. The results obtained show higher concentration of calcium and sulphur in straw coloured roofing tiles surface, and higher solubility than red roofing tiles. Moreover, according to the results obtained in bioreceptivity assays, straw coloured roofing tiles are more prone to colonization than red roofing tiles, so, there is a relationship between surface properties of roofing tiles and biocolonization, as it is observed in industrial products

Inter-rater and intra-rater reliability of the extended TUG test in elderly participants

Background: To analyse the reliability, variance and execution time of the Extended Timed Up and Go (Extended TUG) test in three age groups of elderly participants (G1: 55–64 years; G2: 65–74 years; G3: 75–85 years). Methods: An analytical cross-sectional study of 114 recruited participants (63 women) of average age 70.17 (± 7.3) years was undertaken. Each participant performed the Extended TUG three consecutive times, with a rest break between tests of 120 s. Both the intragroup and intergroup reliability of the measurements in the Extended TUG were analysed. Results: The reliability of the Extended TUG test is excellent for the first and second decades but drops down to good for the third decade. Specifically, intragroup reliability ranged from 0.784 for G3 to 0.977 for G1 (G2 = 0.858). Intergroup reliability, compared with intragroup reliability, was slightly lower, ranging between 0.779 for G3 and 0.972 for G1 (G2 = 0.853). Conclusion: The reliability of the Extended TUG test progressively decreases with increasing age, being excellent for the younger age groups and good for the oldest age group

Retinal Vascularization Abnormalities Studied by Optical Coherence Tomography Angiography (OCTA) in Type 2 Diabetic Patients with Moderate Diabetic Retinopathy

Diabetic retinopathy (DR) is the most severe and frequent retinal vascular disease that causes significant visual loss on a global scale. The purpose of our study was to evaluate retinal vascularization in the superficial capillary plexus (SCP), the deep capillary plexus (DCP) and the choriocapillaris (CC) and changes in the foveal avascular zone (FAZ) by optical tomography angiography (OCTA) in patients with type 2 diabetes mellitus (DM2) with moderate DR but without diabetic macular oedema (DME). Fifty-four eyes of DM2 with moderate DR (level 43 in the ETDRS scale) and without DME and 73 age-matched healthy eyes were evaluated using OCTA with swept-source (SS)-OCT to measure microvascularization changes in SCP, DCP, CC and the FAZ. The mean ages were 64.06 ± 11.98 and 60.79 ± 8.62 years in the DM2 and control groups, respectively. Visual acuity (VA) was lower in the DM2 patients (p = 0.001), OCTA showed changes in the SCP with a significant diminution in the vascular density and the FAZ area was significantly higher compared to healthy controls, with p < 0.001 at the SCP level. The most prevalent anatomical alterations were peripheral disruption in the SCP (83.3%), microaneurysms (MA) in the SCP and in the DCP (79.6% and 79.6%, respectively) and flow changes in the DCP (81.5%). A significant positive correlation was observed between the DM2 duration and the FAZ area in the SCP (0.304 with p = 0.025). A significant negative correlation was also found between age and CC central perfusion (p < 0.001). In summary, a decrease in the vascular density in DM2 patients with moderate DR without DME was observed, especially at the retinal SPC level. Furthermore, it was found that the FAZ was increased in the DM2 group in both retinal plexuses and was greater in the SCP group

Summer truffle in the Iberian Peninsula: current status and crop potential

La trufa de verano (Tuber aestivum, incluyendo Tuber uncinatum) es una especie de un gran valor económico y social, que se produce de modo silvestre en toda Europa, norte de África y parte de Oriente medio. Los esfuerzos de cultivo de esta especie en la península ibérica han permanecido en un segundo plano debido a las condiciones adecuadas de ciertos terrenos para cultivar especies de mayor valor económico, como la trufa negra (Tuber melanosporum). Sin embargo, la trufa de verano es una alternativa viable y muy productiva para zonas de dudosa aptitud para T. melanosporum. En este trabajo, mediante revisión bibliográfica, se ponen de manifiesto los siguientes aspectos: la distribución y ecología de T. aestivum, la situación actual del cultivo, así como las perspectivas de futuro propias de esta especie en la península ibérica. En rasgos generales, se ha constatado su mayor amplitud ecológica y geográfica en relación a la trufa negra y se ha observado que es un cultivo incipiente pero en crecimiento. Sin embargo, se ha deducido que aún es necesario realizar un gran esfuerzo para dar a conocer este producto tanto a cultivadores como a consumidores potenciales en España así como divulgar aspectos técnicos sobre la gestión de su cultivo.Summer truffle (Tuber aestivum, including Tuber uncinatum) is a species of great economic and social value. Wild summer truffles are produced all over Europe, North Africa and part of the Middle East. This species has been underutilized in the Iberian Peninsula due to ability of certain areas to cultivate species of greater economic value, such as the black truffle (Tuber melanosporum). However, the summer truffle is an alternative species for areas where the black truffle is not well adapted. In this paper, the distribution and ecology of T. aestivum, the current situation and the future prospects of this crop in the Iberian Peninsula is reviewed. Summer truffle is a growing crop, well adapted in greater ecological and geographical areas than black truffle. However, it is still necessary to carry out further efforts to publicize it to both growers and consumers in Spain and to spread technical aspects of its managementPublishe

La truficultura en Teruel y el somontano de Huesca

Publishe

Age-dependent association of clonal hematopoiesis with COVID-19 mortality in patients over 60 years.

Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four studies have attempted to associate CHIP with COVID-19 severity without conclusive findings. In the present work, we explore the association between CHIP and COVID-19 mortality. Genomic DNA extracted from peripheral blood of COVID-19 patients (n = 241 deceased, n = 239 survivors) was sequenced with the Myeloid Solutions™ panel of SOPHiA Genetics. The association between clonality and age and clonality and mortality was studied using logistic regression models adjusted for sex, ethnicity, and comorbidities. The association with mortality was performed with patients stratified into four groups of age according to the quartiles of the distribution: 60–74 years, 75–84 years, 85–91 years, and 92–101 years. Clonality was found in 38% of the cohort. The presence of CHIP variants, but not the number, significantly increased with age in the entire cohort of COVID-19 patients, as well as in the group of survivors (p < 0.001). When patients were stratified by age and the analysis adjusted, CHIP classified as pathogenic/likely pathogenic was significantly more represented in deceased patients compared with survivors in the group of 75–84 years (34.6% vs 13.7%, p = 0.020). We confirmed the well-established linear relationship between age and clonality in the cohort of COVID-19 patients and found a significant association between pathogenic/likely pathogenic CHIP and mortality in patients from 75 to 84 years that needs to be further validated.post-print1034 K

Characterization of the Antitumor Potential of Extracts of Cannabis sativa Strains with High CBD Content in Human Neuroblastoma

Cannabis has been used for decades as a palliative therapy in the treatment of cancer. This is because of its beneficial effects on the pain and nausea that patients can experience as a result of chemo/radiotherapy. Tetrahydrocannabinol and cannabidiol are the main compounds present in Cannabis sativa, and both exert their actions through a receptor-mediated mechanism and through a non-receptor-mediated mechanism, which modulates the formation of reactive oxygen species. These oxidative stress conditions might trigger lipidic changes, which would compromise cell membrane stability and viability. In this sense, numerous pieces of evidence describe a potential antitumor effect of cannabinoid compounds in different types of cancer, although controversial results limit their implementation. In order to further investigate the possible mechanism involved in the antitumoral effects of cannabinoids, three extracts isolated from Cannabis sativa strains with high cannabidiol content were analyzed. Cell mortality, cytochrome c oxidase activity and the lipid composition of SH-SY5Y cells were determined in the absence and presence of specific cannabinoid ligands, with and without antioxidant pre-treatment. The cell mortality induced by the extracts in this study appeared to be related to the inhibition of the cytochrome c oxidase activity and to the THC concentration. This effect on cell viability was similar to that observed with the cannabinoid agonist WIN55,212-2. The effect was partially blocked by the selective CB1 antagonist AM281, and the antioxidant α-tocopherol. Moreover, certain membrane lipids were affected by the extracts, which demonstrated the importance of oxidative stress in the potential antitumoral effects of cannabinoids.This work has been partially supported by a grant from the Ministry of Economy and Competitiveness (DIN2019-010902 and DIN2020-011349) and the Basque Government Department of Economic Development, Sustainability and Environment (Bikaintek program: 005-B2/2021)

Presence of rare potential pathogenic variants in subjects under 65 years old with very severe or fatal COVID-19

Rare variants affecting host defense against pathogens could be involved in COVID-19 severity and may help explain fatal outcomes in young and middle-aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID-19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization-based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic and were located in genes mainly involved in immune response. A network analysis, including the 42 genes with candidate variants, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA metabolism and repair processes. In conclusion, we have detected candidate variants that may potentially influence COVID-19 outcome in our cohort of patients. Further studies are needed to confirm the ultimate role of the genetic variants described in the present study on COVID-19 severityTis work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID19 Research Call, COV20/00181) co-fnanced by European Development Regional Fund (FEDER, A way to achieve Europe) and contributions from Estrella de Levante S.A. and Colabora Mujer Association. CIBERer (Centro de Investigación en Red de Enfermedades Raras) is funded by Instituto de Salud Carlos III.R.L-R.and M.dP.V. are sponsored by the project COV20/00181. M.C., P.M. and B.A. are supported by the Miguel Servet (CP17/00006, CP16/00116) and Juan Rodes (JR17/00020) programs, respectively, of the Instituto de Salud Carlos III, co-fnanced by the European Regional Development Fund (FEDER). R.R. is supported by a postdoctoral fellowship of the Comunidad de Madrid (2019-T2/BMD-13714) and G.N.-M. by a contract of the Comunidad de Madrid (PEJ-2020-AI/BMD-18610