Management of Portal Hypertension in Children

Management of portal hypertension in children has evolved over the past several decades. Portal hypertension can result from intrahepatic or extrahepatic causes. Management should be tailored to the child based on the etiology of the portal hypertension and on the functionality of the liver. The most serious complication of portal hypertension is gastroesophageal variceal bleeding, which has a mortality of up to 30%. Initial treatment of bleeding focuses on stabilizing the patient. Further treatment measures may include endoscopic, medical, or surgical interventions as appropriate for the child, depending on the cause of the portal hypertension. β-Blockers have not been proven to effectively prevent primary or secondary variceal bleeding in children. Sclerotherapy and variceal band ligation can be used to stop active bleeding and can prevent bleeding from occurring. Transjugular intrahepatic portosystemic shunts and surgical shunts may be reserved for those who are not candidates for transplant or have refractory bleeding despite medical or endoscopic treatment

Deletion Mutants of VPg Reveal New Cytopathology Determinants in a Picornavirus

BACKGROUND: Success of a viral infection requires that each infected cell delivers a sufficient number of infectious particles to allow new rounds of infection. In picornaviruses, viral replication is initiated by the viral polymerase and a viral-coded protein, termed VPg, that primes RNA synthesis. Foot-and-mouth disease virus (FMDV) is exceptional among picornaviruses in that its genome encodes 3 copies of VPg. Why FMDV encodes three VPgs is unknown. METHODOLOGY AND PRINCIPAL FINDINGS: we have constructed four mutant FMDVS that encode only one VPG: either VPg(1), VPg(3), or two chimeric versions containing part of VPg(1) and VPg(3). All mutants, except that encoding only VPg(1), were replication-competent. Unexpectedly, despite being replication-competent, the mutants did not form plaques on BHK-21 cell monolayers. The one-VPg mutant FMDVs released lower amounts of encapsidated viral RNA to the extracellular environment than wild type FMDV, suggesting that deficient plaque formation was associated with insufficient release of infectious progeny. Mutant FMDVs subjected to serial passages in BHK-21 cells regained plaque-forming capacity without modification of the number of copies of VPg. Substitutions in non-structural proteins 2C, 3A and VPg were associated with restoration of plaque formation. Specifically, replacement R55W in 2C was repeatedly found in several mutant viruses that had regained competence in plaque development. The effect of R55W in 2C was to mediate an increase in the extracellular viral RNA release without a detectable increase of total viral RNA that correlated with an enhanced capacity to alter and detach BHK-21 cells from the monolayer, the first stage of cell killing. CONCLUSIONS: The results link the VPg copies in the FMDV genome with the cytopathology capacity of the virus, and have unveiled yet another function of 2C: modulation of picornavirus cell-to-cell transmission. Implications for picornaviruses pathogenesis are discussed

Mutagenesis-Mediated Virus Extinction: Virus-Dependent Effect of Viral Load on Sensitivity to Lethal Defection

Background: Lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. Viral load and virus fitness are known to influence virus extinction. Here we examine the effect or the multiplicity of infection (MOI) on progeny production of several RNA viruses under enhanced mutagenesis. Results: The effect of the mutagenic base analogue 5-fluorouracil (FU) on the replication of the arenavirus lymphocytic choriomeningitis virus (LCMV) can result either in inhibition of progeny production and virus extinction in infections carried out at low multiplicity of infection (MOI), or in a moderate titer decrease without extinction at high MOI. The effect of the MOI is similar for LCMV and vesicular stomatitis virus (VSV), but minimal or absent for the picornaviruses foot-and-mouth disease virus (FMDV) and encephalomyocarditis virus (EMCV). The increase in mutation frequency and Shannon entropy (mutant spectrum complexity) as a result of virus passage in the presence of FU was more accentuated at low MOI for LCMV and VSV, and at high MOI for FMDV and EMCV. We present an extension of the lethal defection model that agrees with the experimental results. Conclusions: (i) Low infecting load favoured the extinction of negative strand viruses, LCMV or VSV, with an increase of mutant spectrum complexity. (ii) This behaviour is not observed in RNA positive strand viruses, FMDV or EMCV. (iii) The accumulation of defector genomes may underlie the MOI-dependent behaviour. (iv) LCMV coinfections are allowed but superinfection is strongly restricted in BHK-21 cells. (v) The dissimilar effects of the MOI on the efficiency of mutagenic-based extinction of different RNA viruses can have implications for the design of antiviral protocols based on lethal mutagenesis, presently under development. © 2012 Moreno et al.Centro de Biología Molecular Severo Ochoa; Ministerio de Ciencia e Innovación (MICINN); Fundación Ramón ArecesPeer Reviewe

09 FERRY_04 LORD_c

Abstract: Interventions are crucial as they offer simple and inexpensive public health solutions that will be useful over the long term use. A Task Force on designing trials of nutritional interventions to slow cognitive decline in older adults was held in Toulouse in September 2012. The aim of the Task Force was to bring together leading experts from academia, the food industry and regulatory agencies to determine the best trial designs that would enable us to reach our goal of maintaining or improving cognitive function in apparently healthy aging people. An associated challenge for this Task Force was to determine the type of trials required by the Public Food Agencies for assessing the impact of nutritional compounds in comparison to well established requirements for drug trials. Although the required quality of the study design, rationale and statistical analysis remains the same, the studies designed to show reduction of cognitive decline require a long duration and the objectives of this task force was to determine best design for these trials. Two specific needs were identified to support trials of nutritional interventions: 1-Risk-reduction strategies are needed to tackle the growing burden of cognitive decline that may lead to dementia, 2-Innovative study designs are needed to improve the quality of these studies

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Sensitivity to hydrogen embrittlement of AISI 4140 steel: A numerical study on fracture toughness

Contamination of steel structures, working in environments where the presence of hydrogen cannot be neglected, can lead to significant degradation of mechanical properties, in particular, fracture toughness. In order to estimate the local hydrogen concentration at the crack tip and to understand the embrittlement mechanism, numerical models are important tools to support experimental tests that are quite complex to perform. This paper presents the application of a cohesive zone model, which couples diffusion and mechanical fields, to study the hydrogen embrittlement on AISI 4140 steel. The total hydrogen concentration, sum of the contents of hydrogen present in the lattice and in dislocation traps, is the quantity governing the embrittling effect. The input parameters of the model were calibrated using experimental tests performed on steel samples; then, initial lattice concentration was calibrated based on hydrogen pre-charged tests. A sensitivity analysis was proposed, discussing the effects of material, environmental and testing input parameters. The analysis confirms the capability of this numerical tool in predicting the mechanical response in presence of hydrogen, highlighting its potential to be used for practical design and assessment

Animal breeding scheme applied to the quality of pure Iberian montanera pigs

Selection programs are not frequent in the extensive Iberian porcine sector. The traditional company of Iberian pig products located in Jabugo (Sierra de Huelva), Sánchez Romero Carvajal (SRC), with the collaboration and assessment of the Animal Breeding Department of INIA, is making since the year 2012 an unusual effort to develop and implement a breeding selection scheme focused on the Iberian purebred products labelled as Bellota. The animals involved in this program belong to one herd which is placed in two different farms, Montecastilla and Tejarejo (La Granada de Riotinto). 1,205 animals of known pedigree were controlled for selection of growth, body composition, meat and fat quality traits. The main registered traits were average daily gain in montanera, slaughter and carcass weight and weight of premium cuts (ham, shoulders and loins). Besides, backfat fatty acid profile and quality traits as intramuscular fat percentage, color, thawing and cooking water loss and shear force were measured in loin as quality traits. Breeding values for these traits were estimated using an Animal model. Genetic predictions for maternal traits (number of piglets born alive and litter weight at weaning) were performed also using Animal models. Data from 5,134 litters born in 88 batches of 1456 dams and 22 sires were used. This information allowed estimating heritability and genetic correlation as well as to build a combined index for each trait weighting the breeding values by their corresponding economic values. In addition to this, molecular genetic studies on some of the traits cited above are also being implemented. These studies will allow increasing the efficiency of the conventional selection program in the future.Los programas de selección genética son inusuales en el sector porcino Ibérico de extensivo. La empresa tradicional de productos de cerdo Ibérico, Sánchez Romero Carvajal (SRC), localizada en la Sierra de Huelva, junto con el Departamento de Mejora Genética Animal del INIA, se está esforzando en desarrollar un esquema de selección basado en evaluaciones BLUP-Modelo animal y enfocado a la mejora genética de cerdos Ibéricos puros de montanera. Los animales implicados en este programa pertenecen a una piara distribuida entre las fincas Montecastila y Tejarejo (La Granada de Riotinto). Para la selección de caracteres de crecimiento, composición de canal y calidad de carne y grasa, se dispone de registros de 1.205 animales de genealogía controlada. Los caracteres principales registrados son: ganancia media diaria en montanera, peso de canal y pesos de piezas nobles (jamones, paletas y lomos). Además, como caracteres de calidad se midieron: perfil de ácidos grasos en grasa subcutánea, porcentaje de grasa intramuscular, color, pérdidas de agua después de descongelado y cocinado, así como resistencia del lomo al corte. Las valoraciones genéticas para caracteres maternos (número de lechones nacidos vivos y peso de camada al destete) se han efectuado hasta la fecha usando datos de 5.134 camadas nacidas en 88 lotes de 1.456 cerdas y 22 verracos. Las reproductoras estaban localizadas en un sistema de parideras tradicionales. Esta información permite la obtención de estimas de heredabilidad y correlaciones genéticas, así como de un índice combinado construido con los valores mejorantes ponderados por los pesos económicos respectivos para cada carácter. Las actividades del programa permiten además la realización de diversos estudios de genética molecular. Estos estudios permitirán en el futuro aumentar la eficacia del programa de selección convencional

A Self-Assembled 2D Thermofunctional Material for Radiative Cooling

[EN] The regulation of temperature is a major energy-consuming process of humankind. Today, around 15% of the global-energy consumption is dedicated to refrigeration and this figure is predicted to triple by 2050, thus linking global warming and cooling needs in a worrying negative feedback-loop. Here, an inexpensive solution is proposed to this challenge based on a single layer of silica microspheres self-assembled on a soda-lime glass. This 2D crystal acts as a visibly translucent thermal-blackbody for above-ambient radiative cooling and can be used to improve the thermal performance of devices that undergo critical heating during operation. The temperature of a silicon wafer is found to be 14 K lower during daytime when covered with the thermal emitter, reaching an average temperature difference of 19 K when the structure is backed with a silver layer. In comparison, the soda-lime glass reference used in the measurements lowers the temperature of the silicon by just 5 K. The cooling power of this simple radiative cooler under direct sunlight is found to be 350 W m when applied to hot surfaces with relative temperatures of 50 K above the ambient. This is crucial to radiatively cool down devices, i.e., solar cells, where an increase in temperature has drastic effects on performance.The European Union’s Horizon 2020 research and innovation program under the Marie Sklodoswa-Curie grant agreement N 665919 supported J.J.-F. and funded this project. Moreover, the research received funds from the Spanish Minister of Science, Innovation and Universities via the Severo Ochoa Program (Grant No. SEV-2017-0706), RTI2018-093921-B-C41 and RTI2018-093921-A-C44 (SMOOTH), as well as by the CERCA Program/Generalitat de Catalunya. P.D.G. was supported by a Ramon y Cajal fellowship nr. RyC-2015-18124. J.

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

The continuous emergence of drug-resistant viruses is a major obstacle for the successful treatment of viral infections, thus representing a persistent spur to the search for new therapeutic strategies. Among them, multidrug treatments are currently at the forefront of pharmaceutical, clinical, and computational investigation. Still, there are many unknowns in the way that different drugs interact among themselves and with the pathogen that they aim to control. Inspired by experimental studies with picornavirus, here, we discuss the performance of sequential vs. combination therapies involving two dissimilar drugs: the mutagen ribavirin and an inhibitor of viral replication, guanidine. Because a systematic analysis of viral response to drug doses demands a precious amount of time and resources, we present and analyze an in silico model describing the dynamics of the viral population under the action of the two drugs. The model predicts the response of the viral population to any dose combination, the optimal therapy to be used in each case, and the way to minimize the probability of appearance of resistant mutants. In agreement with the theoretical predictions, in vitro experiments with foot-and-mouth disease virus confirm that the suitability of simultaneous or sequential administration depends on the drug doses. In addition, intrinsic replicative characteristics of the virus (e.g., replication through RNA only or a DNA intermediate) play a key role to determine the appropriateness of a sequential or combination therapy. Knowledge of several model parameters can be derived by means of few, simple experiments, such that the model and its predictions can be extended to other viral systems