Differential accumulation of human ß-amyloid and tau from enriched extracts in neuronal and endothelial cells.

While Aß and Tau cellular distribution has been largely studied, the comparative internalization and subcellular accumulation of Tau and Aß isolated from human brain extracts in endothelial and neuronal cells has not yet been unveiled. We have previously demonstrated that controlled enrichment of Aß from human brain extracts constitutes a valuable tool to monitor cellular internalization in vitro and in vivo. Herein, we establish an alternative method to strongly enrich Aß and Tau aggregates from human AD brains, which has allowed us to study and compare the cellular internalization, distribution and toxicity of both proteins within brain barrier endothelial (bEnd.3) and neuronal (Neuro2A) cells. Our findings demonstrate the suitability of human enriched brain extracts to monitor the intracellular distribution of human Aß and Tau, which, once internalized, show dissimilar sorting to different organelles within the cell and differential toxicity, exhibiting higher toxic effects on neuronal cells than on endothelial cells. While tau is strongly concentrated preferentially in mitochondria, Aß is distributed predominantly within the endolysosomal system in endothelial cells, whereas the endoplasmic reticulum was its preferential location in neurons. Altogether, our findings display a picture of the interactions that human Aß and Tau might establish in these cells.

Estudio retrospectivo de tasa de éxito y factores asociados de dos técnicas de dacriocistorrinostomía láser, en un hospital de tercer nivel / Retrospective study of success rate and associated factors of two laser dacryocystorhinostomy techniques, in a third-level hospital

Objetivo Comparar la tasa de éxito de dos técnicas de dacriocistorrinostomía láser (DCRL). Materiales y métodos Se realizó un estudio retrospectivo de pacientes intervenidos por obstrucción adquirida de la vía lagrimal (OAVL) entre los años 2000 y 2021 en un hospital de tercer nivel, mediante DCRL con mitomicina intraoperatoria (DCRL + MMTC) y de DCRL asociada a ampliación de ostium con endoscopio y MMTC (DCRLend-amp + MMTC). Se analizaron hallazgos intraoperatorios, complicaciones y tasa éxito anatómico y funcional de las dos técnicas. El tiempo de seguimiento fue de un año. Resultados Incluimos 92 vías lagrimales con OAVL. 71,7% mujeres, 84,8% unilaterales y edad media de 62,77 ± 13,08 años. En 61 vías lagrimales se realizó DCRL + MMTC (66,3%) y en 31 (33,6%) DCRLend-amp + MMTC. La tasa de éxito anatómica/funcional al año de la DCRLend-amp + MMTC fue de 71%/64,5%; la DCRL + MMTC obtuvo una menor tasa de éxito, 65,6%/60,7% (p = 0,391). No existen diferencias a lo largo del seguimiento entre las tasas de éxito anatómicas ni funcionales de las dos técnicas, ni en las distintas visitas (p > 0,05). La tasa de hallazgos intraoperatorios fue de 1,63% en DCRL + MMTC y 32,26% en DCRLend-amp + MMTC. La tasa de complicaciones postoperatorias fue de 3,27% en DCRL+MMTC y de 3,23% en DCRLend-amp + MMTC. Conclusiones La DCRLend-amp + MMTC obtiene una tasa de éxito ligeramente más alta que la DCRL + MMTC. Debemos tener en cuenta el tiempo-coste quirúrgico aumentado de la DCRLend-amp + MMTC, curva de aprendizaje, y destreza del cirujano, sin un beneficio claro en la tasa de éxito (AU)

Background and objective To compare the success rate of two laser dacryocystorhinostomy (L-DCR) techniques. Materials and methods A retrospective study of patients who underwent surgery for acquired nasolacrimal duct obstruction (NLDO) between 2000 and 2021, carried out in a third level hospital, using L-DCR and modifications of this technique. Intraoperative findings, complications, and anatomical and functional success rate of the 2 techniques were analyzed. The follow-up time was 1 year. Result We included 92 lacrimal ducts with NLDO. 66 (71.7%) were women. 78 (84.8%) underwent unilateral surgery. The mean age was 62.77 ± 13.08 years. 61 (66.3%) underwent intraoperative laser dacryocystorhinostomy with MMTC (L-DCR + MMTC) and 31 (33.6%) L-DCR associated with endoscopic ostium enlargement (L-DCRend-amp). The one-year anatomical/functional success rate of the L-DCRend-amp + MMTC was 71%/64,5%. L-DCR + MMTC obtained a lower success rate, 65.6/60,7% (P = .391). There were no differences throughout the follow-up between the anatomical or functional success rates of the 2 techniques, nor between the different visits (P > .05). Intraoperative findings rate was 3.63% in L-DCR + MMTC, and 32.26% in L-DCRend-amp + MMTC. Postoperative complication rate was 3.27% in L-DCR + MMTC, and 3.23% in L-DCRend-amp + MMTC. Conclusions The L-DCRend-amp + MMTC gets a higher success rate than the L-DCR + MMTC. We must consider the surgical time-cost of the L-DCRend-amp + MMTC, as well as the learning curve of endoscopy techniques, and the skill of the surgeon, without a clear benefit in the success rate (AU)

Retrospective study of success rate and associated factors of two laser dacryocystorhinostomy techniques, in a third-level hospital.

BACKGROUND AND OBJECTIVE: To compare the success rate of two laser dacryocystorhinostomy (L-DCR) techniques. MATERIALS AND METHODS: A retrospective study of patients who underwent surgery for acquired nasolacrimal duct obstruction (NLDO) between 2000 and 2021, carried out in a third level hospital, using L-DCR and modifications of this technique. Intraoperative findings, complications, and anatomical and functional success rate of the 2 techniques were analyzed. The follow-up time was 1 year. RESULTS: We included 92 lacrimal ducts with NLDO. 66 (71.7%) were women. 78 (84.8%) underwent unilateral surgery. The mean age was 62.77 ±â€¯13.08 years. 61 (66.3%) underwent intraoperative laser dacryocystorhinostomy with MMTC (L-DCR + MMTC) and 31 (33.6%) L-DCR associated with endoscopic ostium enlargement (L-DCRend-amp). The one-year anatomical/functional success rate of the L-DCRend-amp + MMTC was 71%/64,5%. L-DCR + MMTC obtained a lower success rate, 65.6/60,7% (P = .391). There were no differences throughout the follow-up between the anatomical or functional success rates of the 2 techniques, nor between the different visits (P > ,05). Intraoperative findings rate was 3.63% in L-DCR + MMTC, and 32.26% in L-DCRend-amp + MMTC. Postoperative complication rate was 3.27% in L-DCR + MMTC, and 3.23% in L-DCRend-amp + MMTC. CONCLUSIONS: The L-DCRend-amp + MMTC gets a higher success rate than the L-DCR + MMTC. We must consider the surgical time-cost of the L-DCRend-amp + MMTC, as well as the learning curve of endoscopy techniques, and the skill of the surgeon, without a clear benefit in the success rate.

Effective index model as a reliable tool for the design of nanostructured thin-film solar cells.

Nanostructured anti-reflection coatings (ARC) are used to reduce the reflectivity of the front surface of solar cells. Computational electromagnetism helps to evaluate the spectral reflectivity of of this type of ARC using several approaches. They typically require large computational resources both in time and hardware elements (memory allocation, speed of processors, etc.). Long computational times may jeopardize optimization processes based on the iterative evaluation of a given merit function that depends on several parameters. Then, simplified analytic methods can speed up this evaluation with moderate computational resources. In this contribution we adapt an Effective Index Model (EIM) to the case of the design of an ARC made with nanoparticles (NP) embedded in a medium at the front surface of a thin-film silicon solar cell. Our approach modifies the discrete dipole approximation method to adapt it to the geometric and material properties of the NPs. The results obtained from the analytic method are compared with those evaluated through a Finite Element Method (FEM) for several cases involving variations in the size and geometry of the NP arrangement, obtaining reflectances that differ less than 10[Formula: see text] for the worst case analyzed but bieng about 100 times faster than the FEM.

High chromosomal mobility of rDNA clusters in holocentric chromosomes of Triatominae, vectors of Chagas disease (Hemiptera-Reduviidae).

The subfamily Triatominae (Hemiptera-Reduviidae) includes more than 150 blood-sucking species, potential vectors of the protozoan Trypanosoma cruzi, causative agent of Chagas disease. A distinctive cytogenetic characteristic of this group is the presence of extremely stable chromosome numbers. Unexpectedly, the analyses of the chromosomal location of ribosomal gene clusters and other repetitive sequences place Triatominae as a significantly diverse hemipteran subfamily. Here, we advance the understanding of Triatominae chromosomal evolution through the analysis of the 45S rDNA cluster chromosomal location in 92 Triatominae species. We found the 45S rDNA clusters in one to four loci per haploid genome with different chromosomal patterns: On one or two autosomes, on one, two or three sex chromosomes, on the X chromosome plus one to three autosomes. The movement of 45S rDNA clusters is discussed in an evolutionary context. Our results illustrate that rDNA mobility has been relatively common in the past and in recent evolutionary history of the group. The high frequency of rDNA patterns involving autosomes and sex chromosomes among closely related species could affect genetic recombination and the viability of hybrid populations, which suggests that the mobility of rDNA clusters could be a driver of species diversification.

NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS.

Amyotrophic Lateral Sclerosis (ALS) is a devastating heterogeneous disease with still no convincing therapy. To identify the most strategically significant hallmarks for therapeutic intervention, we have performed a comprehensive transcriptomics analysis of dysregulated pathways, comparing datasets from ALS patients and healthy donors. We have identified crucial alterations in RNA metabolism, intracellular transport, vascular system, redox homeostasis, proteostasis and inflammatory responses. Interestingly, the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) has significant effects in modulating these pathways. NRF2 has been classically considered as the master regulator of the antioxidant cellular response, although it is currently considered as a key component of the transduction machinery to maintain coordinated control of protein quality, inflammation, and redox homeostasis. Herein, we will summarize the data from NRF2 activators in ALS pre-clinical models as well as those that are being studied in clinical trials. As we will discuss, NRF2 is a promising target to build a coordinated transcriptional response to motor neuron injury, highlighting its therapeutic potential to combat ALS.

Queratoplastia penetrante temprana después de queratitis fúngica de la interface en la queratoplastia endotelial de la membrana de Descemet / Early Penetrating Keratoplasty after interface fungal keratitis in Descemet Membrane Endothelial Keratoplasty

Este caso clínico describe el primer caso publicado de queratitis fúngica de la interfaz (QI) de inicio temprano después de una queratoplastia endotelial de la membrana de Descemet (DMEK) tratada satisfactoriamente con queratoplastia penetrante (QP) durante la etapa activa de la infección. Un paciente con fracaso de injerto después de una queratoplastia endotelial automatizada con pelado de Descemet (DSAEK) fue intervenido con DMEK. El cultivo y el medio de cultivo del donante dieron positivo para Candida albicans. Se confirmaron y localizaron varios infiltrados de la interface utilizando tomografía de coherencia óptica de segmento anterior. Tres días después del diagnóstico, observándose signos claros de infección intraocular, se retiró el injerto con lavado simultáneo de cámara anterior con fluconazol al 1% seguido de una QP e inyecciones corneales intraestromales de fluconazol. Se consiguió una mejor agudeza visual corregida de 20/20. Este caso resalta la importancia de analizar cada pieza y medio de cultivo de donantes a pesar de que el paciente no exhiba síntomas o signos durante el periodo posoperatorio. La QP es una opción de tratamiento viable para la queratitis de interface de inicio temprano

In this case-report we describe the first reported case of early-onset fungal interface keratitis (IK) after Descemet Membrane Endothelial Keratoplasty (DMEK) successfully treated with penetrating keratoplasty (PK) during the active stage of infection. A patient with graft failure after Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) was operated on with DMEK. Donor rim culture and broth were positive for Candida albicans. Several interface infiltrates were confirmed and localized using anterior segment optical coherence tomography. Three days after diagnosis, observing clear signs of intraocular infection, the graft was removed with simultaneous washed-up of anterior chamber with fluconazole 1% followed by a PK and intrastromal corneal injections of fluconazole. A best-corrected visual acuity of 20/20 was achieved. This case highlights the importance of analysing every donor rim and broth, despite the patient doesn't show any symptoms or signs during the post-operative period. PK is a viable treatment option in early-onset interface keratitis

Early Penetrating Keratoplasty after interface fungal keratitis in Descemet Membrane Endothelial Keratoplasty. / Queratoplastia penetrante temprana después de queratitis fúngica de la interface en la queratoplastia endotelial de la membrana de Descemet.

In this case-report we describe the first reported case of early-onset fungal interface keratitis (IK) after Descemet Membrane Endothelial Keratoplasty (DMEK) successfully treated with penetrating keratoplasty (PK) during the active stage of infection. A patient with graft failure after Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) was operated on with DMEK. Donor rim culture and broth were positive for Candida albicans. Several interface infiltrates were confirmed and localized using anterior segment optical coherence tomography. Three days after diagnosis, observing clear signs of intraocular infection, the graft was removed with simultaneous washed-up of anterior chamber with fluconazole 1% followed by a PK and intrastromal corneal injections of fluconazole. A best-corrected visual acuity of 20/20 was achieved. This case highlights the importance of analysing every donor rim and broth, despite the patient doesn't show any symptoms or signs during the post-operative period. PK is a viable treatment option in early-onset interface keratitis.

Epidemiología y curso clínico de la hepatitis A en Cantabria antes y después del brote epidémico de junio 2016 / Epidemiology and clinical course of hepatitis A in Cantabria before and after the epidemic outbreak of June 2016

ANTECEDENTES Y OBJETIVOS: Desde junio de 2016 se han producido brotes de hepatitis A en diversos países europeos, afectando principalmente a hombres que tienen sexo con hombres (HSH). El objetivo del presente trabajo fue valorar su impacto clínico y epidemiológico en Cantabria. MATERIAL Y MÉTODOS: Se recogieron retrospectivamente todos los casos de hepatitis A diagnosticados en Cantabria entre enero de 2013 y septiembre de 2018. Se compararon dos periodos (enero 2013-mayo 2016 y junio 2016-septiembre 2018). RESULTADOS: Se diagnosticaron un total de 156 casos, objetivándose un aumento de la incidencia a partir de octubre de 2016. Con respecto al periodo 2013-2016, se observó una mayor proporción de varones (50,0 vs. 84,5%; p = 0,012) con una predominancia de la orientación sexual homosexual (80,6%) y una mayor frecuencia de transmisión sexual (0 vs. 48,3%; p = 0,061) en los pacientes del periodo 2016-2018. Desde el punto de vista clínico destacó que todos los casos de hepatitis grave ocurrieron en este último periodo. CONCLUSIONES: Nuestros resultados reafirman el elevado impacto clínico y epidemiológico del brote epidémico en Cantabria y ponen de relieve la necesaria optimización de las actuales medidas de prevención contra la hepatitis A

BACKGROUND AND OBJECTIVES: Since June 2016, there have been outbreaks of hepatitis A in various European countries, mainly affecting men who have sex with men (MSM). The aim of this study was to assess their clinical and epidemiological impact in Cantabria, Spain. MATERIAL AND METHODS: We retrospectively collected all cases of hepatitis A diagnosed in Cantabria between January 2013 and September 2018. We compared 2 periods: January 2013-May 2016 and June 2016-September 2018. RESULTS: A total of 156 cases were diagnosed, observing an increase in the incidence starting in October 2016. With regard to 2013-2016, we observed a higher proportion of men (50.0% vs. 84.5%; p=.012) with a predominance of the homosexual orientation (80.6%) and a higher rate of sexual transmission (0% vs. 48.3%; p=.061) for the patients in the 2016-2018 period. From the clinical standpoint, all cases of severe hepatitis occurred during this latter period. CONCLUSIONS: Our results reaffirm the high clinical and epidemiological impact of the epidemic outbreak in Cantabria and emphasizes the need for optimising the current prevention measures against hepatitis A

Vitamin D, preeclampsia and prematurity: A systematic review and meta-analysis of observational and interventional studies.

BACKGROUND: Vitamin D has important functions outside of bone metabolism. Deficiency has been associated with several adverse outcomes during pregnancy such as preeclampsia and prematurity. There is an increasing body of literature on this topic with studies performed to date having produced contradictory results. OBJECTIVE: To synthesize the literature about vitamin D deficiency and its association with preeclampsia and prematurity in order to determine if maternal vitamin D insufficiency and/or deficiency during pregnancy is associated with the prevalence of preeclampsia and prematurity. DESIGN: A systematic review and meta-analysis of observational and interventional studies. METHODS: Two independent researchers reviewed the included studies according to PRISMA reporting guidelines. A protocol for this review was registered in PROSPERO with the registration number: "CRD42019136318". Three electronic databases (PubMed, ScienceDirect and Web of Science); were searched in order to identify eligible studies. Observational and interventional studies were selected which had been published in the last 6 years, and analysed the association between maternal vitamin D concentrations during pregnancy and the development of preeclampsia and/or preterm birth. Data were extracted and presented in tables and figures. Fixed and random-effects meta-analyses were performed on the studies which provided enough sample data to calculate odds ratios. Results from both statistical methods were compared. Meta-analysis cut-off points for vitamin D insufficiency and deficiency were defined as <75nmol/L and <50nmol/L, respectively. RESULTS: Fifty-five studies met the inclusion criteria. Fixed-effects meta-analysis of the interventional studies indicated that vitamin D supplementation acts as a prevention factor for preeclampsia and prematurity. Fixed-effects meta-analysis of observational studies concluded that vitamin D insufficiency and deficiency are associated with a higher risk of developing preeclampsia. However, prematurity and vitamin D were only associated when maternal vitamin D concentrations was <75 nmol/L. Random-effects meta-analysis found no significant association between vitamin D, preeclampsia and prematurity in either observational or interventional studies. CONCLUSION: Higher vitamin D concentrations during pregnancy could be associated with a decreased risk of preeclampsia and prematurity but statistical significance of associations depends on the study design used. Well-designed clinical trials with vitamin D supplementation are needed in order to better define associations.

Pathway towards an ideal and sustainable framework agreement for the public procurement of vaccines in Spain: a multi-criteria decision analysis.

Objective: To advance the development of an ideal and sustainable framework agreement for the public procurement of vaccines in Spain, and to agree on the desirable award criteria and their relative weight. Methods: A multidisciplinary committee of seven health-care professionals and managers developed a partial multi-criteria decision analysis to determine the award criteria that should be considered and their specific weights for the public procurement of routine vaccines and seasonal influenza vaccines, considering their legal viability. A re-test of the results was carried out. The current situation was analyzed through 118 tender specifications and compared to the ideal framework. Results: Price is the prevailing award criterion for the public procurement of both routine (weighting of 60% versus 40% for all other criteria) and influenza (36% versus 64%) vaccines. Ideally, 22 criteria should be considered for routine vaccines, grouped and weighted into five domains: efficacy (weighting of 29%), economic aspects (27%), vaccine characteristics (22%), presentation form and packaging (13%), and others (9%). Per criteria set, price was the most important criterion (22%), followed by effectiveness (9%), and composition/formulation (7%). Regarding influenza vaccines, 20 criteria were selected, grouped, and weighted: efficacy (29%), economic aspects (25%), vaccine characteristics (20%), presentation form and packaging (16%), and others (11%). Per criteria set, price was also the most relevant criterion (19%), followed by composition/formulation (8%), and effectiveness (8%). Conclusions: Contrary to the current approach, technical award criteria should prevail over economic criteria in an ideal and sustainable framework agreement for the public procurement of vaccines.

Epidemiology and clinical course of hepatitis A in Cantabria before and after the epidemic outbreak of June 2016. / Epidemiología y curso clínico de la hepatitis A en Cantabria antes y después del brote epidémico de junio 2016.

BACKGROUND AND OBJECTIVES: Since June 2016, there have been outbreaks of hepatitis A in various European countries, mainly affecting men who have sex with men (MSM). The aim of this study was to assess their clinical and epidemiological impact in Cantabria, Spain. MATERIAL AND METHODS: We retrospectively collected all cases of hepatitis A diagnosed in Cantabria between January 2013 and September 2018. We compared 2 periods: January 2013-May 2016 and June 2016-September 2018. RESULTS: A total of 156 cases were diagnosed, observing an increase in the incidence starting in October 2016. With regard to 2013-2016, we observed a higher proportion of men (50.0% vs. 84.5%; p=.012) with a predominance of the homosexual orientation (80.6%) and a higher rate of sexual transmission (0% vs. 48.3%; p=.061) for the patients in the 2016-2018 period. From the clinical standpoint, all cases of severe hepatitis occurred during this latter period. CONCLUSIONS: Our results reaffirm the high clinical and epidemiological impact of the epidemic outbreak in Cantabria and emphasizes the need for optimising the current prevention measures against hepatitis A.

The Role of Free Radicals in Autophagy Regulation: Implications for Ageing.

Reactive oxygen and nitrogen species (ROS and RNS, resp.) have been traditionally perceived solely as detrimental, leading to oxidative damage of biological macromolecules and organelles, cellular demise, and ageing. However, recent data suggest that ROS/RNS also plays an integral role in intracellular signalling and redox homeostasis (redoxtasis), which are necessary for the maintenance of cellular functions. There is a complex relationship between cellular ROS/RNS content and autophagy, which represents one of the major quality control systems in the cell. In this review, we focus on redox signalling and autophagy regulation with a special interest on ageing-associated changes. In the last section, we describe the role of autophagy and redox signalling in the context of Alzheimer's disease as an example of a prevalent age-related disorder.

Rapid Response Teams: a great opportunity / Equipos de Respuesta Rápida: Una gran oportunidad

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Utilidad del cribado toxicológico en pediatría. Respuesta / Toxicology screening in paediatrics. Authors reply

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Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ.

Wild-type p53 (wtp53) is described as a tumour suppressor gene; mutations in this gene occur in many human cancers and promote oncogenic capacity. Here, we establish that the oncogenic activity of mutant p53 (mtp53) is driven by the WASP-interacting protein (WIP). WIP knockdown from mtp53-expressing glioblastoma and breast cancer cells (BCC) greatly reduced proliferation and growth capacity of cancer stem cell (CSC)-like cells and decreased CSC-like markers (CD133, CD44 or YAP/TAZ). mtp53 overexpression in human astrocytes enhanced their proliferative capacity in suspension culture and increased expression of CSC markers and WIP. WIP knockdown compromised tumour glioblastoma and BCC growth capacity in vivo. We show that WIP is phosphorylated by AKT2 and is regulated by mtp53/p63 through enhancement of PI3K/AKT2-mediated integrin/receptor recycling pathways. WIP regulates this oncogenic pathway by controlling YAP/TAZ stability. We thus establish a new CSC signalling pathway downstream of mtp53 in which AKT2 regulates WIP and controls YAP/TAZ stability.