Angels of Death: An Artistic Journey through the Great Pandemics

The History of Humanity has been marked by the suffering generated by the permanent presence of diseases. Many of these became real plagues and punishments, decimating the population of cities and towns. Science advanced slowly in the search for treatments to deal with these epidemics, which were received with real fear. This same history of the human being simultaneously assisted in the effort to offer images of its effects. In this way, a good number of painters, regardless of language or artistic period, showed in tables and canvases not only death and pain but also fear, insecurity and emotional traces. This article aims to offer an itinerary of these plastic forms that accompanied the epidemics from the Middle Ages to the present century.La Historia de la Humanidad se ha visto jalonada por el sufrimiento generado por la presencia permanente de enfermedades. Muchas de estas se convirtieron en auténticas plagas y castigos diezmando la población de ciudades y pueblos. La ciencia avanzaba de manera pausada en la búsqueda de remedios para hacer frente a estas epidemias que eran recibidas con auténtico pavor. Esa misma historia del ser humano asistía de manera simultánea al esfuerzo de ofrecer imágenes de sus efectos. De esta forma, un buen número de pintores, al margen de lenguajes o periodos artísticos, mostraban en tablas y lienzos no sólo la muerte y el dolor sino también el temor, la inseguridad y las huellas emocionales. En este artículo se pretende ofrecer un itinerario de esas formas plásticas que acompañaron a las epidemias desde la Edad Media hasta el presente siglo

Neutrophil Extracellular Trap Targeting Protects Against Ischemic Damage After Fibrin-Rich Thrombotic Stroke Despite Non-Reperfusion.

Stroke is one of the most prevalent diseases worldwide caused primarily by a thrombotic vascular occlusion that leads to cell death. To date, t-PA (tissue-type plasminogen activator) is the only thrombolytic therapy approved which targets fibrin as the main component of ischemic stroke thrombi. However, due to its highly restrictive criteria, t-PA is only administrated to less than 10% of all stroke patients. Furthermore, the research in neuroprotective agents has been extensive with no translational results from medical research to clinical practice up to now. Since we first described the key role of NETs (Neutrophil Extracellular Traps) in platelet-rich thrombosis, we asked, first, whether NETs participate in fibrin-rich thrombosis and, second, if NETs modulation could prevent neurological damage after stroke. To this goal, we have used the thromboembolic in situ stroke model which produces fibrin-rich thrombotic occlusion, and the permanent occlusion of the middle cerebral artery by ligature. Our results demonstrate that NETs do not have a predominant role in fibrin-rich thrombosis and, therefore, DNase-I lacks lytic effects on fibrin-rich thrombosis. Importantly, we have also found that NETs exert a deleterious effect in the acute phase of stroke in a platelet-TLR4 dependent manner and, subsequently, that its pharmacological modulation has a neuroprotective effect. Therefore, our data strongly support that the pharmacological modulation of NETs in the acute phase of stroke, could be a promising strategy to repair the brain damage in ischemic disease, independently of the type of thrombosis involved.This work was supported by grants from Instituto de Salud Carlos III and co-financed by the European Development Regional Fund “A Way to Achieve Europe” PI20/00535 and RETICS RD16/0019/ 0009 (IL), from Regional Madrid Government B2017/BMD- 3688 (IL), from Spanish Ministry of Science and Innovation PID2019- 106581RB-I00 (MÁM), from Leducq Foundation for Cardiovascular Research TNE-19CVD01 (MÁM), from Fundación La Caixa HR17_00527 (MM). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Desarrollo secuencial de formas de fondo en un régimen macromareal

En el extremo NO del golfo San Matías (sector exterior de la bahía de San Antonio) grandes bancos arenosos forman, hasta una profundidad de 14 m, un gran delta de marea, el cual constituye la característica morfológica general. La circulación del área es gobernada por un régimen semidiurno macromareal con amplitudes de sicigias de hasta 9 m. Por medio de métodos sísmico-acústicos (sonar de barrido lateral y ecosonda) y muestreo de sedimentos del fondo se analizaron rasgos morfológicos subácueos (ondas de arena y megaóndulas, lineaciones sedimentarias, marcas de cometa), conducentes a inferir las condiciones físicas ambientales referidas a su generación y a completar el conocimiento de la dinámica sedimentaria regional. Ondas de arena de hasta 4 m de altura se presentan agrupadas en campos bien definidos o en cubetas sedimentarias delimitadas por material rocoso con una configuración tipo "barján". En general, el talud de las mismas se orienta hacia el sur-sureste. Sobre las rampas de las ondas de arena y en sectores de menor profundidad es común el desarrollo de megaóndulas. La composición de todas estas geoformas varía desde arena gruesa a fina (0,28 phi-2,31 phi). Las lineaciones sedimentarias se encuentran a partir de los 8 m de profundidad sobre la plataforma adyacente al delta de marea. Se agrupan en dos tipos: 1) franjas con espaciamiento del orden de los 10 m; 2) franjas con espaciamiento de 30-40 m. Estas acumulaciones arenosas, cuyo relieve no supera el metro, alcanzan los 200 m de longitud. Asociadas a las mismas se producen marcas de cometa ("comet marks"). La generación de ambas geoformas se relaciona a un sedimento arenoso movilizado sobre un sustrato gravoso. La estrecha relación entre la dinámica sedimentaria y formas de fondo es evidente y refleja un transporte neto como carga de fondo hacia el exterior de la bahía de San Antonio. El análisis morfológico determina la coexistencia de las diferentes formas mencionadas, las que se ordenan en sucesión lateral según el siguiente patrón: 1) ondas de arena y megaóndulas, 2) lineaciones sedimentarias de pequeño espaciamiento y marcas de cometa, 3) lineaciones de gran espaciamiento. La disponibilidad de sedimento es el factor preponderante que define la generación secuencial de las diversas formas de fondo. Así, los sectores que reciben mayor aporte del interior de la bahía de San Antonio se caracterizan por el desarrollo de ondas de arena. En cambio en aquellas zonas intermedias con menor disponibilidad de sedimento, las lineaciones arenosas y marcas de cometa resultan el rasgo característico.Facultad de Ciencias Naturales y Muse

The role of gut microbiota in cerebrovascular disease and related dementia.

In recent years, increasing evidence suggests that commensal microbiota may play an important role not only in health but also in disease including cerebrovascular disease. Gut microbes impact physiology, at least in part, by metabolizing dietary factors and host-derived substrates and then generating active compounds including toxins. The purpose of this current review is to highlight the complex interplay between microbiota, their metabolites. and essential functions for human health, ranging from regulation of the metabolism and the immune system to modulation of brain development and function. We discuss the role of gut dysbiosis in cerebrovascular disease, specifically in acute and chronic stroke phases, and the possible implication of intestinal microbiota in post-stroke cognitive impairment and dementia, and we identify potential therapeutic opportunities of targeting microbiota in this context.Instituto de Salud Carlos III (ISCIII), Grant/Award Number: PI20/00535; Leducq Foundation for Cardiovascular Research Grant/Award Numbers: TNE-21CVD04 (MAM, IL), TNE19CVD01 (MAM, MIC), TNE21CVD04, TNE19CVD01; Ministerio de Ciencia e Innovacion (MCIN), Grant/Award Numbers: PID2020-117765RB-I00, PID2019-106581RB-I00; RICORS-ICTUS, Grant/Award Number: RD21/0006/0001.N

Addressing the issue of trust in elementary teachers' Maths-specific education: ANFoMAM project

Trabajo presentado al International Symposium Elementary Mathematics Teaching. Praga, 2019To improve primary school teachers' maths-specific education at university, our project will develop a series of workshops, as ready-to-use instruments, which closely consider children's way of learning and their relationship with mathematics. Thus, the interest of participants in children is exploited in sessions which take into account both their professional work as teachers and their own childhood experiences. The aim is to help participants to evolve in the key aspect of trust. The paper describes the objectives and first results of the ANFoMAM project, supported by the Erasmus Plus Programme in the area of strategic partnerships for innovation in higher education in Europe.The paper was supported by the Erasmus+ project 2018-1-ES01-KA203-050986 entitled 'Learning from children to improve primary school teachers' maths-specific education'

Validation of housekeeping genes for quantitative real-time PCR in in-vivo and in-vitro models of cerebral ischaemia

<p>Abstract</p> <p>Background</p> <p>Studies of gene expression in experimental cerebral ischaemia models can contribute to understanding the pathophysiology of brain ischaemia and to identifying prognostic markers and potential therapeutic targets. The normalization of relative qRT-PCR data using a suitable reference gene is a crucial prerequisite for obtaining reliable conclusions. No validated housekeeping genes have been reported for the relative quantification of the mRNA expression profile activated in in-vitro ischaemic conditions, whereas for the in-vivo model different reference genes have been used.</p> <p>The present study aims to determine the expression stability of ten housekeeping genes (Gapdh, β2m, Hprt, Ppia, Rpl13a, Oaz1, 18S rRNA, Gusb, Ywhaz and Sdha) to establish their suitability as control genes for in-vitro and in-vivo cerebral ischaemia models.</p> <p>Results</p> <p>The expression stability of the candidate reference genes was evaluated using the 2^-ΔC'Tmethod and ANOVA followed by Dunnett's test. For the in-vitro model using primary cultures of rat astrocytes, all genes analysed except for Rpl13a and Sdha were found to have significantly different levels of mRNA expression. These different levels were also found in the case of the in-vivo model of pMCAO in rats except for Hprt, Sdha and Ywhaz mRNA, where the expression did not vary. Sdha and Ywhaz were identified by geNorm and NormFinder as the two most stable genes.</p> <p>Conclusion</p> <p>We have validated endogenous control genes for qRT-PCR analysis of gene expression in in-vitro and in-vivo cerebral ischaemia models. For normalization purposes, Rpl13a and Sdha are found to be the most suitable genes for the in-vitro model and Sdha and Ywhaz for the in-vivo model. Genes previously used as housekeeping genes for the in-vivo model in the literature were not validated as good control genes in the present study, showing the need for careful evaluation for each new experimental setup.</p

Dimethylformamide Reduces Cerebral Ischaemia in Diabetic Rats Hours after Its Occurrence; A New Horizon

The antioxidant properties of dimethylformamide (DMF) depend on its interference with the hydroxyl-radical-transduction pathway. Diabetes is a risk factor of cerebral ischaemia (CI), and both entities are associated with oxidative stress (OS). We evaluated DMF’s effects on CI in non-diabetic rats (NDRs) and in diabetic rats (DRs). One hour after CI, the animals were divided into two treatment groups (300 μl subcutaneous): either DMF or isotonic saline solution. Treatment effects were analysed in NDRs or DRs without CI. Eight hours after CI, a neurophysiologic score (NS) was determined; CI and OS biomarkers were measured in the ischaemic cerebral hemisphere. Infarct/oedema volumes were measured on dyed brain slices. DMF reduced infarct volume in NDRs and DRs but only improved the NS in DRs. Basal concentrations of all the biomarkers were similar in the NDRs and DRs. Metalloproteinase 9 (MMP9) did not change with DMF. Malondialdehyde (MDA) increased with CI, and DMF only reduced it in DRs. RAGE, nitrite/nitrate and nitrotyrosine increased with CI only in DRs (all prevented by DMF). We conclude that DMF’s benefits on CI were greater in the DRs due to a higher susceptibility of diabetic animals to the OS produced by CI. The results open a new horizon in CI treatment since DMF has not been investigated before

Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury

<p>Abstract</p> <p>Background</p> <p>An increase in intracellular calcium concentration [Ca²⁺]_iis one of the first events to take place after brain ischemia. A key [Ca²⁺]_i-regulated signaling molecule is the phosphatase calcineurin (CN), which plays important roles in the modulation of inflammatory cascades. Here, we have analyzed the role of endogenous regulator of CN 1 (Rcan1) in response to experimental ischemic stroke induced by middle cerebral artery occlusion.</p> <p>Methods</p> <p>Animals were subjected to focal cerebral ischemia with reperfusion. To assess the role of Rcan1 after stroke, we measured infarct volume after 48 h of reperfusion in <it>Rcan1 </it>knockout (KO) and wild-type (WT) mice. <it>In vitro </it>studies were performed in astrocyte-enriched cortical primary cultures subjected to 3% oxygen (hypoxia) and glucose deprivation (HGD). Adenoviral vectors were used to analyze the effect of overexpression of Rcan1-4 protein. Protein expression was examined by immunohistochemistry and immunoblotting and expression of mRNA by quantitative real-time Reverse-Transcription Polymerase Chain Reaction (real time qRT-PCR).</p> <p>Results</p> <p>Brain ischemia/reperfusion (I/R) injury <it>in vivo </it>increased mRNA and protein expression of the calcium-inducible Rcan1 isoform (Rcan1-4). I/R-inducible expression of Rcan1 protein occurred mainly in astroglial cells, and in an <it>in vitro </it>model of ischemia, HGD treatment of primary murine astrocyte cultures induced Rcan1-4 mRNA and protein expression. Exogenous Rcan1-4 overexpression inhibited production of the inflammatory marker cyclo-oxygenase 2. Mice lacking Rcan1 had higher expression of inflammation associated genes, resulting in larger infarct volumes.</p> <p>Conclusions</p> <p>Our results support a protective role for Rcan1 during the inflammatory response to stroke, and underline the importance of the glial compartment in the inflammatory reaction that takes place after ischemia. Improved understanding of non-neuronal mechanisms in ischemic injury promises novel approaches to the treatment of acute ischemic stroke.</p

Cav-1 Protein Levels in Serum and Infarcted Brain Correlate with Hemorrhagic Volume in a Mouse Model of Thromboembolic Stroke, Independently of rt-PA Administration.

Thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is currently the only FDA-approved drug for acute ischemic stroke. However, its administration is still limited due to the associated increased risk of hemorrhagic transformation (HT). rt-PA may exacerbate blood-brain barrier (BBB) injury by several mechanisms that have not been fully elucidated. Caveolin-1 (Cav-1), a major structural protein of caveolae, has been linked to the endothelial barrier function. The effects of rt-PA on Cav-1 expression remain largely unknown. Here, Cav-1 protein expression after ischemic conditions, with or without rt-PA administration, was analyzed in a murine thromboembolic middle cerebral artery occlusion (MCAO) and in brain microvascular endothelial bEnd.3 cells subjected to oxygen/glucose deprivation (OGD). Our results show that Cav-1 is overexpressed in endothelial cells of infarcted area and in bEnd.3 cell line after ischemia but there is disagreement regarding rt-PA effects on Cav-1 expression between both experimental models. Delayed rt-PA administration significantly reduced Cav-1 total levels from 24 to 72 h after reoxygenation and increased pCav-1/Cav-1 at 72 h in the bEnd.3 cells while it did not modify Cav-1 immunoreactivity in the infarcted area at 24 h post-MCAO. Importantly, tissue Cav-1 positively correlated with Cav-1 serum levels at 24 h post-MCAO and negatively correlated with the volume of hemorrhage after infarction, the latter supporting a protective role of Cav-1 in cerebral ischemia. In addition, the negative association between baseline serum Cav-1 levels and hemorrhagic volume points to a potential usefulness of baseline serum Cav-1 levels to predict hemorrhagic volume, independently of rt-PA administration.This work was supported by grants from Instituto de Salud Carlos III and co-fnanced by the European Development Regional Fund “A Way to Achieve Europe” Health Strategic Action Program PI13/02258 and PI17/02123 (MC), PI20/00535 (IL), and Spanish Stroke Research Network RETICS RD12/0014/0010 (MC), and RD16/0019/0003 (JS), RD16/0019/0004 (MC), and RD16/0019/0009 (IL); from Regional Madrid Government B2017/BMD- 3688 (IL); from Spanish Ministry of Science and Innovation PID2019-106581RBI00 (MAM); from Leducq Foundation for Cardiovascular Research TNE-19CVD01 (MAM); and from Fundación La Caixa HR17_00527 (MAM). P. Comajoan was a recipient of a predoctoral fellowship from the University of Girona (IF-UdG 2015).S

Myeloid cells in vascular dementia and Alzheimer's disease: Possible therapeutic targets?

Growing evidence supports the suggestion that the peripheral immune system plays a role in different pathologies associated with cognitive impairment, such as vascular dementia (VD) or Alzheimer's disease (AD). The aim of this review is to summarize, within the peripheral immune system, the implications of different types of myeloid cells in AD and VD, with a special focus on post-stroke cognitive impairment and dementia (PSCID). We will review the contributions of the myeloid lineage, from peripheral cells (neutrophils, platelets, monocytes and monocyte-derived macrophages) to central nervous system (CNS)-associated cells (perivascular macrophages and microglia). Finally, we will evaluate different potential strategies for pharmacological modulation of pathological processes mediated by myeloid cell subsets, with an emphasis on neutrophils, their interaction with platelets and the process of immunothrombosis that triggers neutrophil-dependent capillary stall and hypoperfusion, as possible effector mechanisms that may pave the way to novel therapeutic avenues to stop dementia, the epidemic of our time.Spanish Ministry of Science and Innovation (MCIN), Grant/Award Number: PID2019-106581RB-I00; Leducq Foundation for Cardiovascular Research, Grant/Award Numbers: TNE19CVD01, TNE-21CVD04; Instituto de Salud Carlos III (ISCIII) and cofinanced by the European Development Regional Fund “A Way to Achieve Europe”, Grant/Award Numbers: PI20/00535, RICORSICTUSRD21/0006/0001; Severo Ochoa Center of Excellence, Grant/Award Number: CEX2020-001041-S.S