VZV retinal vasculitis without systemic infection: diagnosis and monitoring with quantitative polymerase chain reaction

To report a case of unilateral varicella zoster virus (VZV) retinal vasculitis aspect in an immunocompetent child without systemic infection. Clinically, no signs of retinal necrosis or frosted branch vasculitis were present. This is an observational case report. Quantitative PCR was performed on the aqueous humor (AH) using primers specific for herpes virus (cytomegalovirus, Epstein-Barr virus, herpes simplex virus 1-2, and VZV). The patient was treated with intravenous acyclovir, intravitreous ganciclovir, and oral valacyclovir. A positive quantitative PCR result was found for VZV DNA (1.72×106 viral copies/ml) in the AH. After 6months, PCR of the AH was negative. Herpes viruses are involved in the pathogenesis of isolated retinal vasculitis. This case demonstrates that quantitative PCR is useful to detect viral DNA in AH and to monitor the viral activity and the therapeutic respons

Afatinib in the first-line treatment of patients with non-small cell lung cancer: clinical evidence and experience

Epidermal growth factor receptor (EGFR) gene mutations identify a molecularly defined subset of non-small cell lung cancer (NSCLC) patients who display an excellent sensitivity to EGFR tyrosine kinase inhibitors (TKIs). First-generation reversible EGFR TKIs, gefitinib and erlotinib have been proven to improve the objective response rate and to prolong the progression-free survival compared with standard chemotherapy in large phase III trials. Unfortunately, virtually all patients develop resistance to treatment, usually within 9–12 months. Afatinib is an irreversible ErbB family inhibitor initially designed to overcome the development of resistance. Compared with gefitinib in a first-line setting, afatinib prolonged progression-free survival and time to treatment failure, without impacting on overall survival in the general population of EGFR-mutant patients. However, afatinib has been shown to prolong overall survival in the subset of patients with an EGFR exon 19 deletion compared with chemotherapy. The aim of this review is to summarize the clinical evidence available to date and to critically discuss the place in therapy of afatinib in the rapidly expanding landscape of EGFR-mutant NSCLC first-line therapy

An Integer Linear Programming approach to minimize the cost of the refurbishment of a façade to improve the energy efficiency of a building

[EN] Buildings account 40% of the EU's total energy consumption. Therefore, they represent a key potential source of energy savings to fight, among others, against climate change. Furthermore, around 54% of the buildings in Spain date back before 1980, when no thermal regulation was available. The refurbishment of a façade of an old building is usually the most effective way to improve its energy efficiency, by adding layers to the external envelope in order to reduce its thermal transmittance. This paper deals with the problem of minimizing costs for the thermal refurbishment of a façade with thickness and thermal ransmittance bounds and with an intervention both on the opaque part (wall) and the transparent part (windows). Among thousands, even millions of combinations of materials and thicknesses for the different layers to be added to the opaque part, types of frame, and combinations of glasses and air chambers for the transparent part, the aim is to choose the one that minimizes the cost without violating any restriction imposed to the thermal refurbishment, in particular the current energy efficiency regulations in the zone. To optimally solve this problem, it will be modelled as an Integer Linear Programming problem with binary variables. The case study will be Building 1B of the School for Building Engineering of the Polytechnic University of Valencia, Spain. It was built in the late 1960s and has had a very inefficient energy consumption record. The optimal solution will be found among more than 6 million feasible solutions.Salandin, A.; Soler Fernández, D.; Bevivino, M. (2020). 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A., Olofsson, T., & Ödlund (former Trygg), L. (2018). Environmental impact of energy refurbishment of buildings within different district heating systems. Applied Energy, 227, 231-238. doi:10.1016/j.apenergy.2017.07.022Mickaitytė, A., Zavadskas, E. K., Kaklauskas, A., & Tupėnaitė, L. (2008). THE CONCEPT MODEL OF SUSTAINABLE BUILDINGS REFURBISHMENT. International Journal of Strategic Property Management, 12(1), 53-68. doi:10.3846/1648-715x.2008.12.53-68Passer, A., Ouellet-Plamondon, C., Kenneally, P., John, V., & Habert, G. (2016). The impact of future scenarios on building refurbishment strategies towards plus energy buildings. Energy and Buildings, 124, 153-163. doi:10.1016/j.enbuild.2016.04.008Energy efficiency in buildings.https://www.buildingtechnologies.siemens.com/bt/global/en/building‐knowledge/pages/energy‐efficiency.aspx(accessed 27.12.2018).Baglivo, C., & Congedo, P. M. (2015). 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Version of 2013 with comments of 2016.http://www.codigotecnico.org/images/stories/pdf/ahorroEnergia/DccHE.pdf(accessed 27.12.2018).Sherali, H. D., & Driscoll, P. J. (2000). Evolution and state-of-the-art in integer programming. Journal of Computational and Applied Mathematics, 124(1-2), 319-340. doi:10.1016/s0377-0427(00)00431-3Kurnitski, J., Saari, A., Kalamees, T., Vuolle, M., Niemelä, J., & Tark, T. (2013). Cost optimal and nearly zero energy performance requirements for buildings in Estonia. Estonian Journal of Engineering, 19(3), 183. doi:10.3176/eng.2013.3.02Congedo, P. M., Baglivo, C., D’Agostino, D., & Zacà, I. (2015). Cost-optimal design for nearly zero energy office buildings located in warm climates. Energy, 91, 967-982. doi:10.1016/j.energy.2015.08.078Sambou, V., Lartigue, B., Monchoux, F., & Adj, M. (2009). Thermal optimization of multilayered walls using genetic algorithms. 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Thermal Modeling of a Historical Building Wall: Using Long-Term Monitoring Data to Understand the Reliability and the Robustness of Numerical Simulations

Thermal modeling of building components plays a crucial role in designing energy efficiency measures, assessing living comfort, and preventing building damages. The accuracy of the modeling process strongly depends on the reliability of the physical models and the correct selection of input parameters, especially for historic buildings where uncertainties on wall composition and material properties are higher. This work evaluates the reliability of building thermal modeling and identifies the input parameters that most affect the simulation results. A monitoring system is applied to a historic building wall to measure the temperature profile. The long-term dataset is compared with the result of a simulation model. A sensitivity analysis is applied for the determination of the influential input parameters. A two-step optimization is performed to calibrate the numerical model: the first optimization step is based on an optimized selection of the database materials, while the second optimization step uses a particle swarm algorithm. The results indicate that the output of the simulation model is largely influenced by the coefficients describing the coupling with the boundary conditions and by the thermal conductivities of the materials. Very good results are obtained already after the first optimization step ((Formula presented.) while the second optimization step improves further the agreement ((Formula presented.). The parameter values reported in the datasheets do not match those found through optimization. Even with extensive optimization using an algorithm, starting with monitoring data is insufficient to identify material parameter values

Antimicrobial Activity in the Pallial Cavity Fluids of the Oyster Crassostrea virginica (Gmelin) from a Highly Impacted Harbor in Western Long Island Sound

Fluid and its associatedmucus from the pallial (mantle) cavity of eastern oysters Crassostrea virginica (Gmelin) from Black RockHarbor, Bridgeport, Connecticut, inhibited growth of both Gram-positive (Bacillus subtilis, Staphylococcus aureus) and Gram-negative (Escherichia coli, Serratia marcescens, and Vibrio parahaemolyticus) bacteria in antimicrobial assays. In the presence of oyster fluid, E. coli resulted in significant reduction in growth after 26 h. Soluble lysozyme activity in pallial cavity fluid of oysters collected in the fall was 3 times greater than that measured in combined winter—spring—summer samples (P = 0.0008). During the course of the study, copper concentrations in pallial cavity fluid ranged from 0.60–2.49 ppm and zinc concentrations ranged from 9.7–61.0 ppm. Copper concentrations remained relatively constant throughout the study; the highest zinc concentrations were recorded in the fall. Fall antimicrobial assays showed heightened antimicrobial activity compared with the spring, which may be the result of increased lysozyme activity and higher zinc concentrations present in the pallial cavity fluid at that time of year. Results of this study suggest that pallial cavity fluid and its associated mucus likely serve an important role in defense-related functions as the first line of defense against infections from environmental pathogens in Crassostrea virginica

Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: Rationale, evidence and place in therapy

The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9-14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC

Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins

Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml153-149 and zinc-lacking Ml452-151. The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml153-149 appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml452-151 folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml452-151 and Ml153-149 to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml153-149 has formed only amorphous aggregates and Ml452-151 is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases

Ml proteins from Mesorhizobium loti and MucR from Brucella abortus: an AT-rich core DNA-target site and oligomerization ability

Mesorhizobium loti contains ten genes coding for proteins sharing high amino acid sequence identity with members of the Ros/MucR transcription factor family. Five of these Ros/MucR family members from Mesorhizobium loti (Ml proteins) have been recently structurally and functionally characterized demonstrating that Ml proteins are DNA-binding proteins. However, the DNA-binding studies were performed using the Ros DNA-binding site with the Ml proteins. Currently, there is no evidence as to when the Ml proteins are expressed during the Mesorhizobium loti life cycle as well as no information concerning their natural DNA-binding site. In this study, we examine the ml genes expression profile in Mesorhizobium loti and show that ml1, ml2, ml3 and ml5 are expressed during planktonic growth and in biofilms. DNA-binding experiments show that the Ml proteins studied bind a conserved AT-rich site in the promoter region of the exoY gene from Mesorhizobium loti and that the proteins make important contacts with the minor groove of DNA. Moreover, we demonstrate that the Ml proteins studied form higher-order oligomers through their N-terminal region and that the same AT-rich site is recognized by MucR from Brucella abortus using a similar mechanism involving contacts with the minor groove of DNA and oligomerization