Gene regulatory networks in disease and ageing.

The precise control of gene expression is required for the maintenance of cellular homeostasis and proper cellular function, and the declining control of gene expression with age is considered a major contributor to age-associated changes in cellular physiology and disease. The coordination of gene expression can be represented through models of the molecular interactions that govern gene expression levels, so-called gene regulatory networks. Gene regulatory networks can represent interactions that occur through signal transduction, those that involve regulatory transcription factors, or statistical models of gene-gene relationships based on the premise that certain sets of genes tend to be coexpressed across a range of conditions and cell types. Advances in experimental and computational technologies have enabled the inference of these networks on an unprecedented scale and at unprecedented precision. Here, we delineate different types of gene regulatory networks and their cell-biological interpretation. We describe methods for inferring such networks from large-scale, multi-omics datasets and present applications that have aided our understanding of cellular ageing and disease mechanisms.

Frecuentación del servicio de urgencias y reingresos no programados durante el primer año del trasplante de hígado y su repercusión en la supervivencia / Emergency department frequentation and unscheduled readmissions within the first year after liver transplantation, and their impact on survival

El objetivo de este estudio fue evaluar la frecuentación de la sala de emergencias, las causas de las visitas y los reingresos no programados dentro del primer año después del alta hospitalaria después del trasplante de hígado. También se evaluó su impacto en la supervivencia del injerto y del paciente. Se trata de un estudio retrospectivo de las historias clínicas de 98 pacientes (edad media, 55,6 ± 8,59 años, 77,6 % varones) que fueron dados de alta hospitalaria de forma consecutiva tras someterse a un primer trasplante hepático en nuestra institución durante 2012-2015. Se analizaron todas las visitas a urgencias durante los primeros años tras el trasplante y se calculó la supervivencia a los dos años tras el trasplante. Cincuenta y seis de los 98 pacientes (57,15 %) acudieron a urgencias en 117 ocasiones durante el primer año postrasplante. Fiebre (n = 34; 29,05 %) y síntomas digestivos (n = 32; 27. 35 %) fueron las causas más comunes de consulta y dieron lugar a más de la mitad de las visitas. Treinta y cinco de estos 56 pacientes (62,5 %) requirieron un reingreso urgente durante 50 de las 117 (42,7 %) visitas. Esto se debió principalmente a complicaciones infecciosas (44 %) de diversas causas (neumonía bacteriana, colangitis, colitis por Clostridium difficile) y problemas relacionados con las vías biliares. La probabilidad de reingreso aumentó del 11,22 % a los 30 días del alta al 22,4 % a los 90 días del alta. La supervivencia de los pacientes al año y 2 años después del trasplante fue menor para los pacientes que reingresaron (88,4 % y 80,7 %, respectivamente) en comparación con los que no reingresaron (95,56 % y 91,17 %, respectivamente, p = 0,002). (AU)

Emergency department frequentation and unscheduled readmissions within the first year after liver transplantation, and their impact on survival.

The aim of this study was to assess emergency room frequentation, visit causes, and unscheduled readmissions within the first year after discharge from hospital following liver transplantation. Their impact on graft and patient survival was also assessed. This was a retrospective study of the medical records of 98 patients (mean age, 55.6 ± 8.59 years, 77.6 % males) who were consecutively discharged from hospital after undergoing a first liver transplant in our institution during 2012-2015. All visits to the emergency room during the first years after transplantation were analyzed, and survival at two years after transplantation was calculated. Fifty-six of the 98 patients (57.15 %) visited the emergency room on 117 occasions within the first year post-transplantation. Fever (n = 34; 29.05 %) and digestive symptoms (n = 32; 27.35 %) were the most common causes of consultation, and resulted in over half of visits. Thirty-five of these 56 patients (62.5 %) required an urgent readmission during 50 of the 117 (42.7 %) visits. This was primarily due to infectious complications (44 %) of diverse causes (bacterial pneumonia, cholangitis, Clostridium difficile colitis) and biliary tract-related issues. The likelihood of readmission increased from 11.22 % at 30 days after discharge to 22.4 % at 90 days after discharge. Patient survival at 1 and 2 years after transplantation was lower for patients who were readmitted (88.4 % and 80.7 %, respectively) when compared to those who were not readmitted (95.56 % and 91.17 %, respectively, p = 0.002).

Prescription profile of antiarrhythmic drugs in a group of patients in Colombia / Perfil de prescripción de fármacos antiarrítmicos en un grupo de pacientes en Colombia

Abstract Objective: To determine the prescription patterns of antiarrhythmic drugs and variables associated with their use in a population of patients affiliated with the Colombian Health System. Methods: A cross-sectional study was performed on a population database with patients who received antiarrhythmics from March to May 2016. Sociodemographic, pharmacological and comedication variables were included. SPSS-24 was used for data analysis using X2 tests and multivariate analyses. Results: In total, 2772 patients were treated with antiarrhythmics in the evaluated period. The mean age was 70.1 ± 13.1 years, and 51.2% were women. In total, 79.4% used a β-blocker, 58.5% amiodarone and 2.9% a calcium channel blocker. Moreover, 1192 (43.0%) patients were prescribed a single antiarrhythmic, and 1580 (57.0%) received two or more. There were 2603 patients (93.9%) with comedication, including lipid-lowering drugs (62.6%), inhibitors of the renin angiotensin aldosterone system (62.6%) and antiplatelet drugs (42.0%). Age older than 65 years increased the probability of comedication (odds ratio [OR]: 2.48; 95% confidence interval [95% CI]: 1.59-3.85), and the risk was proportional to age. We identified 1364 patients treated with conditional risk medications for QT prolongation (49.2%), 68 with a possible risk (2.5%) and 171 (6.2%) with a known risk. Conclusion: Antiarrhythmic drugs recommended by clinical practice guidelines are mainly used; however, risk interactions interactions of QT prolongation were identified and should be taken into account by physicians to avoid adverse events or complications.

Resumen Objetivo: determinar los patrones de prescripción de fármacos antiarrítmicos y variables asociadas a su utilización en una población de pacientes afiliados al sistema de salud de Colombia. Métodos: estudio de corte transversal sobre una base de datos poblacional con pacientes que recibieron antiarrítmicos entre marzo y mayo de 2016. Se incluyeron variables sociodemográficas, farmacológicas y de comedicación. Para el análisis de datos se utilizó SPSS-24, realizando pruebas X2 y análisis multivariado. Resultados: se encontraron 2 772 pacientes en tratamiento con antiarrítmicos en el periodo evaluado, la edad promedio fue 70,1 ± 13,1 años, 51,2 % eran mujeres. El 79,4% utilizó algún β-bloqueador, 58,5% amiodarona y 2,9 % algún bloqueante de canales de calcio. Al 43 % se les prescribió un solo antiarrítmico y 57 % recibieron dos o más. El 93,9 % tenía con alguna comedicación, especialmente hipolipemiantes (62,6 %), inhibidores del sistema renina angiotensina aldosterona (62,6 %) y antiagregantes (42 %). Ser mayor de 65 años aumentó la probabilidad de comedicación (OR:2,48; IC95 %:1,59-3,85) y el riesgo fue proporcional al incremento de la edad. El 49,2 % (n=1364) estaban tratados con medicamentos de riesgo condicional de prolongación del QT, 2,5 % (n=68) con riesgo posible y 6,2% (n=171) de riesgo conocido. Conclusión: se están utilizando los mismos fármacos recomendados por las guías de práctica clínica; sin embargo, se encontraron interacciones de riesgo de prolongación del intervalo QT que deben ser tenidas en cuenta para evitar eventos o complicaciones en los pacientes.

Design, Synthesis, and Anti-Neuroinflammatory Activity of Amide- Containing Dithiolethiones.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination of neurons and neurodegeneration. Current MS therapies ameliorate inflammatory damage but are unable to address the degenerative aspects of the disease. OBJECTIVE: In this report, we evaluate the ability of amide-based dithiolethiones (DTTs) to suppress neuroinflammation in microglia and increase anti-oxidant capacity in neuron-like cells. METHODS: A series of amide-containing DTTs were designed, synthesized, and assayed for the ability to suppress pro-neuroinflammatory cytokines IL-12p40 and IL-23p19 induced by LPS in the BV2 microglial cell line. Lead analog 2c was identified and further characterized. RESULTS: Structure-activity data revealed tolerance towards a variety of amides. Morpholine analog 2c dose-dependently reduced various other inflammatory cytokines and mediators, including TNF, IL-6, IL-1ß, NOS2, and COX2. Additionally, 2c elevated cellular levels of glutathione in SH-SH5Y neuronal cell line. Furthermore, mechanistic studies showed that 2c increased the expression of antiinflammatory Nrf2 and HMOX proteins. CONCLUSION: The combination of anti-neuroinflammatory and anti-oxidant activities of amide-based DTTs suggests that they are promising agents for the treatment of both demyelination and neurodegeneration in MS.

Geochemical, Mineralogical and Morphological Characterisation of Road Dust and Associated Health Risks.

Road dust resuspension, especially the particulate matter fraction below 10 µm (PM10), is one of the main air quality management challenges in Europe. Road dust samples were collected from representative streets (suburban and urban) of the city of Viana do Castelo, Portugal. PM10 emission factors (mg veh-1 km-1) ranging from 49 (asphalt) to 330 (cobble stone) were estimated by means of the United Stated Environmental Protection Agency method. Two road dust fractions (< 0.074 mm and from 0.0074 to 1 mm) were characterised for their geochemical, mineralogical and morphological properties. In urban streets, road dusts reveal the contribution from traffic emissions, with higher concentrations of, for example, Cu, Zn and Pb. In the suburban area, agriculture practices likely contributed to As concentrations of 180 mg kg-1 in the finest road dust fraction. Samples are primarily composed of quartz, but also of muscovite, albite, kaolinite, microcline, Fe-enstatite, graphite and amorphous content. Particle morphology clearly shows the link with natural and traffic related materials, with well-formed minerals and irregular aggregates. The hazard quotient suggests a probability to induce non-carcinogenic adverse health effects in children by ingestion of Zr. Arsenic in the suburban street represents a human health risk of 1.58 × 10-4.

Features of Vibrational and Electronic Structures of Decavanadate Revealed by Resonance Raman Spectroscopy and Density Functional Theory.

Polyoxometalates are known to be inhibitors of a diverse collection of enzymes, although the specific interactions that lead to this bioactivity are still unclear. Spectroscopic characterization may be an invaluable if indirect tool for remedying this problem, yet this requires clear, cogent assignment of polyoxometalate spectra before the complicating effect of their binding to large biomolecules can be considered. We report the use of FT-IR and resonance Raman spectroscopies alongside density functional theory to describe the vibrational and electronic structures of decavanadate, [V10O28]6-. Our computational model, which reproduced the majority of vibrational features to within 10 cm-1, was used to identify an axial oxo ligand as the most likely position of the acidic proton in the related cluster [HV10O28]5-. As resonance Raman spectroscopy can directly interrogate chromophores embedded in complex systems, this approach may be of general use in answering structural questions about polyoxometalate-enzyme systems.

Identification of N-benzyltetrahydroisoquinolines as novel anti-neuroinflammatory agents.

A series of simplified berberine analogs was designed, synthesized, and evaluated for anti-inflammatory activity. SAR studies identified N-benzyltetrahydroisoquinoline 7d as a potent berberine analog. 7d suppressed LPS-induced inflammatory cytokine levels in both BV2 cells and primary microglia. Taken together, our results suggest that simplified BB analogs have therapeutic potential as a novel class of anti-neuroinflammatory agents.

A review of exposure assessment methods for epidemiological studies of health effects related to industrially contaminated sites.

BACKGROUND: this paper is based upon work from COST Action ICSHNet. Health risks related to living close to industrially contaminated sites (ICSs) are a public concern. Toxicology-based risk assessment of single contaminants is the main approach to assess health risks, but epidemiological studies which investigate the relationships between exposure and health directly in the affected population have contributed important evidence. Limitations in exposure assessment have substantially contributed to uncertainty about associations found in epidemiological studies. OBJECTIVES: to examine exposure assessment methods that have been used in epidemiological studies on ICSs and to provide recommendations for improved exposure assessment in epidemiological studies by comparing exposure assessment methods in epidemiological studies and risk assessments. METHODS: after defining the multi-media framework of exposure related to ICSs, we discussed selected multi-media models applied in Europe. We provided an overview of exposure assessment in 54 epidemiological studies from a systematic review of hazardous waste sites; a systematic review of 41 epidemiological studies on incinerators and 52 additional studies on ICSs and health identified for this review. RESULTS: we identified 10 multi-media models used in Europe primarily for risk assessment. Recent models incorporated estimation of internal biomarker levels. Predictions of the models differ particularly for the routes 'indoor air inhalation' and 'vegetable consumption'. Virtually all of the 54 hazardous waste studies used proximity indicators of exposure, based on municipality or zip code of residence (28 studies) or distance to a contaminated site (25 studies). One study used human biomonitoring. In virtually all epidemiological studies, actual land use was ignored. In the 52 additional studies on contaminated sites, proximity indicators were applied in 39 studies, air pollution dispersion modelling in 6 studies, and human biomonitoring in 9 studies. Exposure assessment in epidemiological studies on incinerators included indicators (presence of source in municipality and distance to the incinerator) and air dispersion modelling. Environmental multi-media modelling methods were not applied in any of the three groups of studies. CONCLUSIONS: recommendations for refined exposure assessment in epidemiological studies included the use of more sophisticated exposure metrics instead of simple proximity indicators where feasible, as distance from a source results in misclassification of exposure as it ignores key determinants of environmental fate and transport, source characteristics, land use, and human consumption behaviour. More validation studies using personal exposure or human biomonitoring are needed to assess misclassification of exposure. Exposure assessment should take more advantage of the detailed multi-media exposure assessment procedures developed for risk assessment. The use of indicators can be substantially improved by linking definition of zones of exposure to existing knowledge of extent of dispersion. Studies should incorporate more often land use and individual behaviour.

Lesiones ampollosas en mujer de 81 años / Blistering lesions on a 81 year old woman

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Health risk assessment through consumption of vegetables rich in heavy metals: the case study of the surrounding villages from Panasqueira mine, Central Portugal.

Panasqueira mine is a tin-tungsten mineralization hosted by metasediments with quartz veins rich in ferberite. The mineralization also comprises wolframite, cassiterite, chalcopyrite, several sulfides, carbonates and silver sulfosalts. The mining and beneficiation processes produce arsenic-rich mine wastes laid up in huge tailings (Barroca Grande and Rio tailings). The contents of As, Cd, Cr, Cu, Pb and Zn were estimated in rhizosphere soils, irrigation waters, road dusts and in potatoes, cabbages, lettuces and beans, collected on local gardens of four neighborhood Panasqueira mine villages: S. Francisco de Assis (SFA) and Barroca suffering the influence of tailings; Unhais-o-Velho and Casegas considered as non-polluted areas. The mean concentrations of metals in rhizosphere soils and vegetables exceed the reference guidelines values and seem to be linked to the sulfides. The rhizosphere ecological risks were ranked in the order of Cd > As > Cu > Pb > Zn > Cr and SFA > Barroca > Casegas > Unhais-o-Velho. Metal concentrations, in vegetables, were found in the order of lettuce > cabbage > potatoes and SFA > Barroca > Casegas > Unhais-o-Velho. For cabbages and lettuces, the tendency of contamination is roots > leaves and for potatoes is roots > leaves > tubers. The risk for residents, due to ingesting of metals/metalloid, by consuming vegetables grown around the sampling area, was calculated and the result indicates that the inhabitants of these villages are probably exposed to some potential health risks through the intake of heavy metals and metalloids via consuming their vegetables.

Cuerpo extraño intraocular tras un viaje a Camerún / Intraocular foreign body after a trip to Cameroon

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Integrated approach to assess the environmental impact of mining activities: estimation of the spatial distribution of soil contamination (Panasqueira mining area, Central Portugal).

Through the years, mining and beneficiation processes in Panasqueira Sn-W mine (Central Portugal) produced large amounts of As-rich mine wastes laid up in huge tailings and open-air impoundments (Barroca Grande and Rio tailings) that are the main source of pollution in the surrounding area once they are exposed to the weathering conditions leading to the formation of acid mine drainage (AMD) and consequently to the contamination of the surrounding environments, particularly soils. The active mine started the exploration during the nineteenth century. This study aims to look at the extension of the soil pollution due to mining activities and tailing erosion by combining data on the degree of soil contamination that allows a better understanding of the dynamics inherent to leaching, transport, and accumulation of some potential toxic elements in soil and their environmental relevance. Soil samples were collected in the surrounding soils of the mine, were digested in aqua regia, and were analyzed for 36 elements by inductively coupled plasma mass spectrometry (ICP-MS). Selected results are that (a) an association of elements like Ag, As, Bi, Cd, Cu, W, and Zn strongly correlated and controlled by the local sulfide mineralization geochemical signature was revealed; (b) the global area discloses significant concentrations of As, Bi, Cd, and W linked to the exchangeable and acid-soluble bearing phases; and (c) wind promotes the mechanical dispersion of the rejected materials, from the milled waste rocks and the mineral processing plant, with subsequent deposition on soils and waters. Arsenic- and sulfide-related heavy metals (such as Cu and Cd) are associated to the fine materials that are transported in suspension by surface waters or associated to the acidic waters, draining these sites and contaminating the local soils. Part of this fraction, especially for As, Cd, and Cu, is temporally retained in solid phases by precipitation of soluble secondary minerals (through the precipitation of hydrated metal sulfates) in warm, dry periods, but such minerals are easily dissolved during rainy periods. Climate is an important instability factor, and the hot and dry summers and cold, rainy, and windy winters in this region are physical phenomena that enhance the good receptivity of these soils to retain some of the metals present in the primary and also the secondary mineralogy. Considering the obtained results from both the sequential chemical extraction and the environmental risk assessment according to the risk assessment code, Ag, Cd, Cu, and Zn are classified with very high risk while As is classified with medium risk.

Quantitative-spatial assessment of soil contamination in S. Francisco de Assis due to mining activity of the Panasqueira mine (Portugal).

Through the years, mining and beneficiation processes produces large amounts of As-rich mine wastes laid up in huge tailings and open-air impoundments (Barroca Grande and Rio tailings) that are the main source of pollution in the surrounding area once they are exposed to the weathering conditions leading to the formation of AMD and consequently to the contamination of the surrounding environments, in particularly soils. In order to investigate the environmental contamination impact on S. Francisco de Assis (village located between the two major impoundments and tailings) agricultural soils, a geochemical survey was undertaken to assess toxic metals associations, related levels and their spatial distribution, and to identify the possible contamination sources. According to the calculated contamination factor, As and Zn have a very high contamination factor giving rise to 65.4% of samples with a moderate to high pollution degree; 34.6% have been classified as nil to very low pollution degree. The contamination factor spatial distribution put in evidence the fact that As, Cd, Cu, Pb, and Zn soils contents, downstream Barroca Grande tailing, are increased when compared with the local Bk soils. The mechanical dispersion, due to erosion, is the main contamination source. The chemical extraction demonstrates that the trace metals distribution and accumulation in S. Francisco de Assis soils is related to sulfides, but also to amorphous or poorly crystalline iron oxide phases. The partitioning study allowed understanding the local chemical elements mobility and precipitation processes, giving rise to the contamination dispersion model of the study area. The wind and hydrological factors are responsible for the chemical elements transport mechanisms, the water being the main transporter medium and soils as one of the possible retention media.