Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques

Calbindin (CB) is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH) and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA) and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv) co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%), followed by neurons located in the SNcd (34.7%). As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%), whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%). Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB) into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus (GPi). As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTPinduced degeneration, our data clearly demonstrated that these neurons are not giving rise to nigrostriatal projections and indeed CB-ir/TH-ir neurons only originate nigroextrastriatal projections

Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4–dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8–207.8, P < 0.001). The patients’ susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia

Revisiting the epidemiology of bloodstream infections and healthcare-associated episodes: results from a multicentre prospective cohort in Spain (PRO-BAC Study)

PROBAC REIPI/GEIH-SEIMC/SAEI Group.The epidemiology of bloodstream infections (BSIs) is dynamic as it depends on microbiological, host and healthcare system factors. The aim of this study was to update the information regarding the epidemiology of BSIs in Spain considering the type of acquisition. An observational, prospective cohort study in 26 Spanish hospitals from October 2016 through March 2017 including all episodes of BSI in adults was performed. Bivariate analyses stratified by type of acquisition were performed. Multivariate analyses were performed by logistic regression. Overall, 6345 BSI episodes were included; 2510 (39.8%) were community-acquired (CA), 1661 (26.3%) were healthcare-associated (HCA) and 2056 (32.6%) hospital-acquired (HA). The 30-day mortality rates were 11.6%, 19.5% and 22.0%, respectively. The median age of patients was 71 years (interquartile range 60–81 years) and 3656 (58.3%; 95% confidence interval 57.1–59.6%) occurred in males. The proportions according to patient sex varied according to age strata. Escherichia coli (43.8%), Klebsiella spp. (8.9%), Staphylococcus aureus (8.9%) and coagulase-negative staphylococci (7.4%) were the most frequent pathogens. Multivariate analyses confirmed important differences between CA and HCA episodes, but also between HCA and HA episodes, in demographics, underlying conditions and aetiology. In conclusion, we have updated the epidemiological information regarding patients’ profiles, underlying conditions, frequency of acquisition types and aetiological agents of BSI in Spain. HCA is confirmed as a distinct type of acquisition.This work was financed by grants from Plan Nacional de I+D+i 2013–2016, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades [PI16/01432] and the Spanish Network for Research in Infectious Diseases (REIPI) [RD16/0016/0001; RD16/0016/0008], co‐financed by the European Development Regional Fund ‘A way to achieve Europe’, Operative program Intelligent Growth 2014–2020

Comparative Proteomic Analysis of Aedes aegypti Larval Midgut after Intoxication with Cry11Aa Toxin from Bacillus thuringiensis

Cry toxins produced by Bacillus thuringiensis bacteria are environmentally safe alternatives to control insect pests. They are pore-forming toxins that specifically affect cell permeability and cellular integrity of insect-midgut cells. In this work we analyzed the defensive response of Aedes aegypti larva to Cry11Aa toxin intoxication by proteomic and functional genomic analyses. Two dimensional differential in-gel electrophoresis (2D-DIGE) was utilized to analyze proteomic differences among A. aegypti larvae intoxicated with different doses of Cry11Aa toxin compared to a buffer treatment. Spots with significant differential expression (p<0.05) were then identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), revealing 18 up-regulated and seven down-regulated proteins. The most abundant subcategories of differentially expressed proteins were proteins involved in protein turnover and folding, energy production, and cytoskeleton maintenance. We selected three candidate proteins based on their differential expression as representatives of the different functional categories to perform gene silencing by RNA interference and analyze their functional role. The heat shock protein HSP90 was selected from the proteins involved in protein turnover and chaperones; actin, was selected as representative of the cytoskeleton protein group, and ATP synthase subunit beta was selected from the group of proteins involved in energy production. When we affected the expression of ATP synthase subunit beta and actin by silencing with RNAi the larvae became hypersensitive to toxin action. In addition, we found that mosquito larvae displayed a resistant phenotype when the heat shock protein was silenced. These results provide insight into the molecular components influencing the defense to Cry toxin intoxication and facilitate further studies on the roles of identified genes

Risk Factors and Predictive Score for Bacteremic Biliary Tract Infections Due to Enterococcus faecalis and Enterococcus faecium: a Multicenter Cohort Study from the PROBAC Project

Biliary-tract bloodstream infections (BT-BSI) caused by Enterococcus faecalis and E. faecium are associated with inappropriate empirical treatment and worse outcomes compared to other etiologies. The objective of this study was to investigate the risk factors for enterococcal BT-BSI. Patients with BT-BSI from the PROBAC cohort, including consecutive patients with BSI in 26 Spanish hospitals between October 2016 and March 2017, were selected; episodes caused by E. faecalis or E. faecium and other causes were compared. Independent predictors for enterococci were identified by logistic regression, and a predictive score was developed. Eight hundred fifty episodes of BT-BSI were included; 73 (8.5%) were due to target Enterococcus spp. (48 [66%] were E. faecium and 25 [34%] E. faecalis). By multivariate analysis, the variables independently associated with Enterococcus spp. were (OR; 95% confidence interval): cholangiocarcinoma (4.48;1.32 to 15.25), hospital acquisition (3.58;2.11 to 6.07), use of carbapenems in the previous month (3.35;1.45 to 7.78), biliary prosthesis (2.19;1.24 to 3.90), and moderate or severe chronic kidney disease (1.55;1.07 to 2.26). The AUC of the model was 0.74 [95% CI0.67 to 0.80]. A score was developed, with 7, 6, 5, 4, and 2 points for these variables, respectively, with a negative predictive value of 95% for a score # 6. A model, including cholangiocarcinoma, biliary prosthesis, hospital acquisition, previous carbapenems, and chronic kidney disease showed moderate prediction ability for enterococcal BT-BSI. Although the score will need to be validated, this information may be useful for deciding empirical therapy in biliary tract infections when bacteremia is suspected. IMPORTANCE Biliary tract infections are frequent, and a significant cause of morbidity and mortality. Bacteremia is common in these infections, particularly in the elderly and patients with cancer. Inappropriate empirical treatment has been associated with increased risk of mortality in bacteremic cholangitis, and the probability of receiving inactive empirical treatment is higher in episodes caused by enterococci. This is because many of the antimicrobial agents recommended in guidelines for biliary tract infections lack activity against these organisms. To the best of our knowledge, this is the first study analyzing the predictive factors for enterococcal BT-BSI and deriving a predictive score.8 página

Detección de fuentes extragalácticas en mapas de la radiación del fondo cósmico de microondas mediante técnicas multifrecuenciales

ABSTRACT: The observation and analysis of the Cosmic Microwave Background Radiation is a crucial task to understand the early Universe. When observing this radiation, we can also see other components of both Galactic and extragalactic origin, and instrumental noise. Our knowledge of the extragalactic sources is quite poor in the frequency range between 20 and 1000 GHz. The goal of this thesis is to adapt the matched multifilter (Herranz et al., 2002, MNRAS, 336, 1057) to detect extragalactic sources, because by using several frequencies in a simultaneous way, it uses more information from the data than the single-frequency methods, increasing its performance. The multifilter is applied to realistic simulations of Planck (Lanz et al., 2010, MNRAS, 403, 2120), comparing the results with the obtained by applying the single-frequency matched filter. The multifilter detects more objects and less spurious artifacts. The application of the multifilter to real data of WMAP at 61 and 94 GHz (Lanz et al., 2013, MNRAS, 428, 3048) results in an improvement of the number of detections of ~5 times with respect to other previous works with single-frequency methods, observing a steepening in the spectral behaviour of the sources above ~70 GHz.RESUMEN: La observación y análisis de la Radiación de Fondo Cósmico de Microondas es esencial para tratar de entender el universo temprano. Al observar dicha radiación se puede apreciar que junto a ella, aparecen otras de origen galáctico, extragaláctico y ruido, siendo nuestro conocimiento de las fuentes extragalácticas bastante pobre en el rango de frecuencias entre 20 y 1000 GHz. El objetivo de esta tesis es adaptar el multifiltro adaptado (Herranz et al., 2002, MNRAS, 336, 1057) para la detección de las fuentes extragalácticas, pues al filtrar varias frecuencias simultáneamente, usa mayor cantidad de información de los datos para detectar dichas fuentes que los métodos monofrecuenciales y aumentarán sus prestaciones. El multifiltro se aplicará a simulaciones realistas de la misión Planck (ver Lanz et al., 2010, MNRAS, 403, 2120), comparando los resultados con los obtenidos con el filtro adaptado, su equivalente en una sola frecuencia. El multifiltro detecta más objetos e introduce menos espurias, siendo su fiabilidad más alta. Su aplicación en datos reales de WMAP a 61 y 94 GHz (ver Lanz et al., 2013, MNRAS, 428, 3048) nos muestra que el número de detecciones es unas 5 veces superior a otros trabajos similares con métodos monofrecuenciales, apreciándose un comportamiento espectral de tipo steepening por encima de ~70 GHz

Literatura, vida cotidiana y educación

Pensar, Vivir y Hacer la educación: visiones compartidas, nos introduce en los ámbitos de la reflexión del fenómeno educativo, de la vivencia en el aula de clases y de la aplicación de los diferentes métodos y técnicas orientadas al aprendizaje. El texto recoge un conjunto de ensayos e investigaciones articulados por tres ejes: Pensar, Vivir y Hacer. En ellos se transmiten reflexiones, prácticas y vivencias, que desean trascender la pura intencionalidad del “enseñar”, correlato del “aprender a conocer”. Los tres editores de este estudio son docentes de la Facultad de Ciencias de la Educación de la Pontificia Universidad católica del Ecuador.125-14

La praxis educativa como acontecimiento ético: una aproximación a las propuestas de Mélich y Savater

En este trabajo pretendemos indagar la propuesta ético-educativa de Joan Carles Mélich (1994) y sus posibles vínculos con las ideas de Fernando Savater (1999, 2004). Creemos que el ámbito de la educación y la ética son dos planos que en Mélich y Savater permanecen inextricables, de modo que esta, como filosofía moral que hurga los valores de un nuevo modo de vivir en sociedad, implica la irrupción de un acontecimiento educativo que marca de forma indeleble al educando. Así, el individuo o “yo” debe construirse a partir de la relación mutua con un “tú” reconocido como ontológicamente igual, al punto de que la comunidad resultante, es decir la sociedad, se deriva de la interacción permanente entre sujetos que imponen mutuamente responsabilidades, respetos, dignidades (Kant, 2002), que desembocan en una concepción de la educación en tanto revelación de la condición humana. Los discursos educativos sobre los que se asienta este trabajo corresponden a las propuestas de Joan Carles Mélich (1994) y Fernando Savater (1999, 2004), reportadas en las respectivas referencias bibliográficas. Se trata de una investigación de tipo descriptivo-explicativo cuyo enfoque epistemológico es intuitivo-introspectivo

Risk of neurally mediated syncope in hypothyroidism and obesity

Introduction and rationale: Thyroid hormones participate in several known mechanisms of cardiac&nbsp;function, being compromised in hypothyroidism (HPT), when uncontrolled, is associated with weight gain. HPT and Obesity participate in autonomic dysfunction.&nbsp

No depression for my old heart, before and after the event

Background: Depression and cardiovascular diseases (CVD) are highly prevalent in the elderly. Depression could be a CVD risk factor as well as an ailment sequela. Objective: To review diagnostical, pathophysiological, and therapeutic factors involved in depression-cardiovascular diseases. Methods: The research was carried out using the keywords of a 10-years range of published studies in Portuguese, English, and Spanish from Scielo and PubMed databases. Inclusion criteria: In vitro studies, cohort studies, case-control, and clinical trials. Studies out of time range, mean age &lt;60 years, other psychiatric diseases were excluded