Preconditioning of Microglia by α-Synuclein Strongly Affects the Response Induced by Toll-like Receptor (TLR) Stimulation

In recent years, it has become accepted that α-synuclein (αSyn) has a key role in the microglia-mediated neuroinflammation, which accompanies the development of Parkinson's disease and other related disorders, such as Dementia with Lewy Bodies and Alzheimer's disease. Nevertheless, the cellular and molecular mechanisms underlying its pathological actions, especially in the sporadic forms of the diseases, are not completely understood. Intriguingly, several epidemiological and animal model studies have revealed a link between certain microbial infections and the onset or progression of sporadic forms of these neurodegenerative disorders. In this work, we have characterized the effect of toll-like receptor (TLR) stimulation on primary murine microglial cultures and analysed the impact of priming cells with extracellular wild-type (Wt) αSyn on the subsequent TLR stimulation of cells with a set of TLR ligands. By assaying key interleukins and chemokines we report that specific stimuli, in particular Pam3Csk4 (Pam3) and single-stranded RNA40 (ssRNA), can differentially affect the TLR2/1- and TLR7-mediated responses of microglia when pre-conditioned with αSyn by augmenting IL-6, MCP-1/CCL2 or IP-10/CXCL10 secretion levels. Furthermore, we report a skewing of αSyn-primed microglia stimulated with ssRNA (TLR7) or Pam3 (TLR2/1) towards intermediate but at the same time differential, M1/M2 phenotypes. Finally, we show that the levels and intracellular location of activated caspase-3 protein change significantly in αSyn-primed microglia after stimulation with these particular TLR agonists. Overall, we report a remarkable impact of non-aggregated αSyn pre-sensitization of microglia on TLR-mediated immunity, a phenomenon that could contribute to triggering the onset of sporadic α-synuclein-related neuropathologies

Ablación de arritmias cardiacas empleando un sistema de mapeo electroanatómico tridimensional en el Instituto Nacional Cardiovascular - INCOR

Objective. To describe the initial experience in ablation of cardiac arrhythmias using 3D mapping at the Instituto Nacional Cardiovascular INCOR (Lima, Peru). Methods. A retrospective descriptive study was carried out. During February 2020, data was collected from the medical records of all patients in whom ablation was performed using 3D mapping from July 2017 to December 2019. This procedure was performed in patients with symptomatic arrhythmia refractory to antiarrhythmic therapy. Results. Data were collected from 123 patients (median age: 46 years, 64.2% male), who had a median time of illness of 6 years. Among the arrhythmias treated, 19% had atrial fibrillation, 17.5% atrial tachycardia, 17.5% idiopathic ventricular arrhythmias, 16.6% Wolf Parkinson White syndrome / Atrioventricular reentrant tachycardia, 11.1% ventricular arrhythmias of the His-Purkinje conduction system, 9.5% scar related ventricular tachycardia associated, 6.4% atrial flutter and 2.4% intranodal tachycardia. The median fluoroscopy time was 26 minutes. Ablation was acutely successful in 95.9% of cases, acute complications were observed in 4.8%, and recurrence-free survival during the first year of follow-up was 74%. Conclusions. Our experience in ablation of cardiac arrhythmias using 3D mapping had a high acute success rate, low frequency of complications, and one-year recurrence-free survival of 74%.Objetivo. Describir la experiencia inicial en ablación de arritmias cardiacas empleando mapeo 3D en el Instituto Nacional Cardiovascular INCOR (Lima-Perú). Materiales y métodos. Estudio descriptivo, retrospectivo, donde se recolectaron datos de historias clínicas de todos los pacientes en los cuales se realizó ablación empleando mapeo 3D, desde julio de 2017 a diciembre de 2019. Este procedimiento se realizó a pacientes sintomáticos y refractarios a terapia antiarrítmica. Resultados. Se recolectaron datos de 123 pacientes (mediana de edad: 46 años, 64,2% varones), con una mediana del tiempo de enfermedad de 6 años. Entre las arritmias tratadas 19% tuvieron fibrilación auricular; 17,5% taquicardia auricular; 17,5% arritmias ventriculares idiopáticas; 16,6% síndrome de Wolf Parkinson White/taquicardia por reentrada auriculoventricular; 11,1% arritmias ventriculares del sistema de conducción His-Purkinje; 9,5% taquicardia ventricular asociada con cicatriz; 6,4% flutter atrial y 2,4% taquicardia intranodal. La mediana del tiempo de fluoroscopía fue de 26 min. La ablación tuvo éxito agudo en el 95,9% de los casos; las complicaciones agudas se observaron en 4,8%, y la sobrevida libre de recurrencias durante el primer año de seguimiento fue de 74%. Conclusiones. Nuestra experiencia en ablación de arritmias cardiacas empleando mapeo 3D presentó una alta frecuencia de ablación exitosa aguda y baja frecuencia de complicaciones, así como una sobrevida libre de recurrencias del 74%, estimada al año de seguimiento

Determination of the temperature and humidity index (THI) for milk cows, in the Nogoyá Department, Entre Ríos

La producción láctea en la provincia de Entre Ríos tiene un lugar relevante como fuente de trabajo y por la movilidad económica en muchas localidades. Numerosos estudios dan cuenta de la importancia que tienen las condiciones ambientales, como temperatura y humedad, relacionado al confort de los rodeos y, especialmente, de los cambios en la producción cuando esas condiciones no son favorables. Una alternativa para determinar si se presentan condiciones adversas es el Índice de Temperatura Humedad (ITH) asociado directamente al estrés calórico de las vacas. Hay consenso general que cuando el índice se halla entre 72 y 78 se considera “alerta”, si está entre 78 y 83 “peligro” y si supera 83 “emergencia”. Este trabajo se enmarca en el proyecto de extensión Sistema de alerta por estrés calórico para vacas lecheras: “La vaca bacana” y está orientado a conocer las características del ITH durante la primavera y verano recientes (2014-2015) en Nogoyá. Se utilizaron 3 estaciones meteorológicas de la zona con mediciones, cada 10 minutos, de temperatura y humedad para calcular el ITH. Los resultados indican que el 65% del período analizado (7 meses) el ITH fue menor a 72 y el 35% superó ese valor. Durante los meses de enero y febrero se produjeron la mayor cantidad de casos con ITH ≥ 72. También se encontró que en la zona la persistencia de valores superiores a 72 tiene una duración media de 6 horas y en algunos casos esa situación se mantiene por más de 48 horas.Milk production in the Entre Rios province has an important place as a source of employment and economic mobility in many localities. Numerous studies realize the importance of environmental conditions such as temperature and humidity, related to the comfort of cows herds, and especially the changes in production when those conditions are not favorable. An alternative to determine if adverse conditions occur is the Temperature Humidity Index (THI) directly associated with heat stress in cows. There is general agreement that when the index is between 72 and 78 is considered "alert", “danger” if it is between 78 and 83 and “emergency” if it exceeds 83. This work is part of the extension project ‘Alert system heat stress for dairy cows: "The bacana cow" and is aimed to know the THI characteristics during the recent Spring and Summer (2014-2015) in Nogoyá. Three meteorological stations in the area were used with measurements every 10 minutes of temperature and humidity to calculate the THI. The results indicate that 65% of the analyzed period (7 months) the THI was under 72 and 35% exceeded that value. During the months of January and February most cases with ≥ 72 THI ocurred. We also found that in the persistent values above 72 have an average duration of 6 hours and in some cases it continues for more 48 hours.Fil: López, Guillermo. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: Brizuela, Armando Benito. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: Rondan, Guillermo Antonio. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lissaso, Cecilia M. A.. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: Kemerer, Alejandra Cecilia. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; ArgentinaFil: de Los Santos, Cintia Melisa. Universidad Nacional de Entre Ríos. Facultad de Ciencias Agropecuarias; Argentin

Foot thermometry with mHeath-based supplementation to prevent diabetic foot ulcers: A randomized controlled trial.

Background: Novel approaches to reduce diabetic foot ulcers (DFU) in low- and middle-income countries are needed. Our objective was to compare incidence of DFUs in the thermometry plus mobile health (mHealth) reminders (intervention) vs. thermometry-only (control). Methods: We conducted a randomized trial enrolling adults with type 2 diabetes mellitus at risk of foot ulcers (risk groups 2 or 3) but without foot ulcers at the time of recruitment, and allocating them to control (instruction to use a liquid crystal-based foot thermometer daily) or intervention (same instruction supplemented with text and voice messages with reminders to use the device and messages to promote foot care) groups, and followed for 18 months. The primary outcome was time to occurrence of DFU. A process evaluation was also conducted. Results: A total of 172 patients (63% women, mean age 61 years) were enrolled; 86 to each study group. More patients enrolled in the intervention arm had a history of previous DFU (66% vs. 48%). Follow-up for the primary endpoint was complete for 158 of 172 participants (92%). Adherence to ?80% of daily temperature measurements was 87% (103 of 118) among the study participants who returned the logbook. DFU cumulative incidence was 24% (19 of 79) in the intervention arm and 11% (9 of 79) in the control arm. After adjusting for history of foot ulceration and study site, the hazard ratio (HR) for DFU was 1.44 (95% CI 0.65, 3.22). Conclusions: In our study, conducted in a low-income setting, the addition of mHealth to foot thermometry was not effective in reducing foot ulceration. Importantly, there was a higher rate of previous DFU in the intervention group, the adherence to thermometry was high, and the expected rates of DFU used in our sample size calculations were not met. Trial registration: ClinicalTrials.gov NCT02373592 (27/02/2015)

Could increased axial wall stress be responsible for the development of atheroma in the proximal segment of myocardial bridges?

<p>Abstract</p> <p>Background</p> <p>A recent model describing the mechanical interaction between a stenosis and the vessel wall has shown that axial wall stress can considerably increase in the region immediately proximal to the stenosis during the (forward) flow phases, so that abnormal biological processes and wall damages are likely to be induced in that region. Our objective was to examine what this model predicts when applied to myocardial bridges.</p> <p>Method</p> <p>The model was adapted to the hemodynamic particularities of myocardial bridges and used to estimate by means of a numerical example the cyclic increase in axial wall stress in the vessel segment proximal to the bridge. The consistence of the results with reported observations on the presence of atheroma in the proximal, tunneled, and distal vessel segments of bridged coronary arteries was also examined.</p> <p>Results</p> <p>1) Axial wall stress can markedly increase in the entrance region of the bridge during the cardiac cycle. 2) This is consistent with reported observations showing that this region is particularly prone to atherosclerosis.</p> <p>Conclusion</p> <p>The proposed mechanical explanation of atherosclerosis in bridged coronary arteries indicates that angioplasty and other similar interventions will not stop the development of atherosclerosis at the bridge entrance and in the proximal epicardial segment if the decrease of the lumen of the tunneled segment during systole is not considerably reduced.</p

Peptide Bond Distortions from Planarity: New Insights from Quantum Mechanical Calculations and Peptide/Protein Crystal Structures

By combining quantum-mechanical analysis and statistical survey of peptide/protein structure databases we here report a thorough investigation of the conformational dependence of the geometry of peptide bond, the basic element of protein structures. Different peptide model systems have been studied by an integrated quantum mechanical approach, employing DFT, MP2 and CCSD(T) calculations, both in aqueous solution and in the gas phase. Also in absence of inter-residue interactions, small distortions from the planarity are more a rule than an exception, and they are mainly determined by the backbone ψ dihedral angle. These indications are fully corroborated by a statistical survey of accurate protein/peptide structures. Orbital analysis shows that orbital interactions between the σ system of Cα substituents and the π system of the amide bond are crucial for the modulation of peptide bond distortions. Our study thus indicates that, although long-range inter-molecular interactions can obviously affect the peptide planarity, their influence is statistically averaged. Therefore, the variability of peptide bond geometry in proteins is remarkably reproduced by extremely simplified systems since local factors are the main driving force of these observed trends. The implications of the present findings for protein structure determination, validation and prediction are also discussed

Early high-titer plasma therapy to prevent severe Covid-19 in older adults

BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. METHODS We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. RESULTS A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. CONCLUSIONS Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.).Fil: Libster, Romina Paula. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Pérez Marc, Gonzalo. Hospital Militar Central, Buenos Aires; ArgentinaFil: Wappner, Diego. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Coviello, Silvina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Bianchi, Alejandra. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Braem, Virginia. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Esteban, Ignacio. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Caballero, Mauricio Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wood, Cristian. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Berrueta, Mabel. Hospital Militar Central; ArgentinaFil: Rondan, Aníbal. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Lescano, Gabriela Mariel. Hospital Dr. Carlos Bocalandro; ArgentinaFil: Cruz, Pablo. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Ritou, Yvonne. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Fernández Viña, Valeria Silvina. Hospital Simplemente Evita; ArgentinaFil: Álvarez Paggi, Damián Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Esperante, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ferreti, Adrián. Hospital Dr. Carlos Bocalandro; ArgentinaFil: Ofman, Gaston. University of Oklahoma; Estados UnidosFil: Ciganda, Álvaro. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal Especializado de Agudos y Cronicos San Juan de Dios.; ArgentinaFil: Rodriguez, Rocío. Hospital Simplemente Evita; ArgentinaFil: Lantos, Jorge. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Valentini, Ricardo. No especifíca;Fil: Itcovici, Nicolás. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Hintze, Alejandra. No especifíca;Fil: Oyarvide, M. Laura. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Etchegaray, Candela. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Neira, Alejandra. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Name, Ivonne. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Alfonso, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Swiss Medical Group; ArgentinaFil: López Castelo, Rocío. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Caruso, Gisela. Hospital Militar Central; ArgentinaFil: Rapelius, Sofía. Hospital Militar Central; ArgentinaFil: Alvez, Fernando. Hospital Militar Central; ArgentinaFil: Etchenique, Federico. Hospital Militar Central; ArgentinaFil: Dimase, Federico. Hospital Militar Central; ArgentinaFil: Alvarez, Darío. Hospital Militar Central; ArgentinaFil: Aranda, Sofía S.. Hospital Militar Central; ArgentinaFil: Sánchez Yanotti, Clara Inés. Hospital Militar Central; ArgentinaFil: De Luca, Julián. Hospital Militar Central; ArgentinaFil: Jares Baglivo, Sofía. Hospital Militar Central; ArgentinaFil: Laudanno, Sofía. Fundación Hematológica Sarmiento; ArgentinaFil: Nowogrodzki, Florencia. Swiss Medical Group; ArgentinaFil: Larrea, Ramiro. Hospital Municipal San Isidro; ArgentinaFil: Silveyra, María. Hospital Militar Central; ArgentinaFil: Leberzstein, Gabriel. No especifíca;Fil: Debonis, Alejandra. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Molinos, Juan. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: González, Miguel. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Perez, Eduardo. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Kreplak, Nicolás. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Pastor Argüello, Susana. Fundación para la Investigación en Infectología Infantil; ArgentinaFil: Gibbons, Luz. Hospital Municipal de San Isidro; ArgentinaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bergel, Eduardo. Sanatorio Sagrado Corazón; ArgentinaFil: Polack, Fernando Pedro. Provincia de Buenos Aires. Ministerio de Salud; Argentin

Computational Thermochemistry and Benchmarking of Reliable Methods

During the first and second years of the Computational Thermochemistry and Benchmarking of Reliable Methods project, we completed several studies using the parallel computing capabilities of the NWChem software and Molecular Science Computing Facility (MSCF), including large-scale density functional theory (DFT), second-order Moeller-Plesset (MP2) perturbation theory, and CCSD(T) calculations. During the third year, we continued to pursue the computational thermodynamic and benchmarking studies outlined in our proposal. With the issues affecting the robustness of the coupled cluster part of NWChem resolved, we pursued studies of the heats-of-formation of compounds containing 5 to 7 first- and/or second-row elements and approximately 10 to 14 hydrogens. The size of these systems, when combined with the large basis sets (cc-pVQZ and aug-cc-pVQZ) that are necessary for extrapolating to the complete basis set limit, creates a formidable computational challenge, for which NWChem on NWMPP1 is well suited