Major depressive disorder and oxidative stress: In silico investigation of fluoxetine activity against ROS

Major depressive disorder is a psychiatric disease having approximately a 20% lifetime prevalence in adults in the United States (U.S.), as reported by Hasin et al. in JAMA Psichiatry 2018 75, 336\u2013346. Symptoms include low mood, anhedonia, decreased energy, alteration in appetite and weight, irritability, sleep disturbances, and cognitive deficits. Comorbidity is frequent, and patients show decreased social functioning and a high mortality rate. Environmental and genetic factors favor the development of depression, but the mechanisms by which stress negatively impacts on the brain are still not fully understood. Several recent works, mainly published during the last five years, aim at investigating the correlation between treatment with fluoxetine, a non-tricyclic antidepressant drug, and the amelioration of oxidative stress. In this work, the antioxidant activity of fluoxetine was investigated using a computational protocol based on the density functional theory approach. Particularly, the scavenging of five radicals (HO\u2022, HOO\u2022, CH3OO\u2022, CH2=CHOO\u2022, and CH3O\u2022) was considered, focusing on hydrogen atom transfer (HAT) and radical adduct formation (RAF) mechanisms. Thermodynamic as well as kinetic aspects are discussed, and, for completeness, two metabolites of fluoxetine and serotonin, whose extracellular concentration is enhanced by fluoxetine, are included in our analysis. Indeed, fluoxetine may act as a radical scavenger, and exhibits selectivity for HO\u2022 and CH3O\u2022, but is inefficient toward peroxyl radicals. In contrast, the radical scavenging efficiency of serotonin, which has been demonstrated in vitro, is significant, and this supports the idea of an indirect antioxidant efficiency of fluoxetine

EAACI Task force Clinical epidemiology of anaphylaxis: experts’ perspective on the use of adrenaline autoinjectors in Europe

Background Worldwide, guidelines recommend the use of adrenaline autoinjectors (AAIs) for self-medication in patients who experience severe allergic reaction. The European Medical Agency recommends the prescription of two AAIs, which should be carried by patients at all times. The European Academy of Allergy and Clinical Immunology guidelines propose to prescribe a second AAI under some defined conditions. In the present study, we aimed to examine the adherence to these guidelines and prescription behavior of allergy experts regarding the number of AAIs prescribed for a given patient. Methods A standardized questionnaire was applied to the participants of the 5th International Conference of the Network of Online Registration for Anaphylaxis (NORA e. V.). Twenty-six experts (medical doctors with at least 2 years of experience in the field of anaphylaxis) answered the questions regarding the number of autoinjectors prescribed and the reasons influencing their decisions. Results Sixty-eight percent of the experts usually prescribed one AAI, while 32% prescribed two. The pediatricians and physicians with less experience tended to prescribe two autoinjectors more frequently. The experts were more likely to prescribe two adrenaline autoinjectors if the patient was a child, had a previous severe reaction, had mastocytosis, asthma, cardiovascular disease, or high body weight, or lived far from the emergency department. Conclusion Our data confirm the lack of consensus regarding the number of AAIs to prescribe. Despite the European Medical Agency recommendation, the majority of allergy experts prescribed one autoinjector per patient. However, under distinct circumstances (e.g. mastocytosis, asthma, excess body weight, a history of severe anaphylaxis, or restricted access to immediate emergency), experts tended to prescribe more AAIs, which is in accordance with the European Academy of Allergy and Clinical Immunology guidelines

Antimicrobial and antibiofilm activities of new synthesized Silver Ultra-NanoClusters (SUNCs) against Helicobacter pylori

Helicobacter pylori colonizes approximately 50% of the world\u2019s population and it is the cause of chronic gastritis, peptic ulcer disease and gastric cancer. The increase of antibiotic resistance is one of the biggest challenges of our century due to its constant increase. In order to identify an alternative or adjuvant strategy to the standard antibiotic therapy, the in vitro activity of newly synthesized Silver Ultra-NanoClusters (SUNCs), characterized by an average size inferior to 5 nm, against clinical strains of Helicobacter pylori, with different antibiotic susceptibilities, was evaluated in this study. MICs and MBCs were determined by the broth microdilution method, whereas the effect of drug combinations by the checkerboard assay. The Minimum Biofilm Eradication Concentration (MBEC) was measured using AlamarBlue (AB) assay and Colony Forming Unit (CFU) counts. The cytotoxicity was evaluated by performing the MTT assay on AGS cell line. The inhibitory activity was expressed in terms of bacteriostatic and bactericidal potential, with MIC50, MIC90, and MBC50 of 0.33 mg/L against planktonic Helicobacter pylori strains. Using the fractional inhibitory concentration index, SUNCs showed synergism with metronidazole in one clinical strain, and very close to synergistic effect on the reference strain; the combination with clarythromicin evidenced an effect very close to synergism on both strains considered. The biofilm eradication was obtained after treatment with 2X, 3X and 4X MIC value. Moreover, SUNCs showed low toxicity on human cells and was effective in eradicating a mature biofilm produced by H. pylori. The data presented in this study demonstrate that SUNCs could represent a novel strategy for the treatment of H. pylori infections either alone or in combination with metronidazole

Compact S-band linear accelerator system for ultrafast, ultrahigh dose-rate radiotherapy

Radiation therapy is currently the most utilized technique for the treatment of tumors by means ofionizing radiation, such as electrons, protons and x/gamma rays, depending on the type, size and depth ofthe cancer mass. Radiation therapy has in general fulfilled the main requirement of targeting thus damagingthe malignant cells and sparing the healthy tissues as best as possible. In this scenario, electron linearaccelerators have been operated as viable tools for the delivery of both high-energetic electrons and x-raybeams, which are obtained via the bremsstrahlung process of the electrons hitting on a high-Z material.Recently, it has been experimentally demonstrated that ultrahigh dose-rate bursts of electrons and x-raybeams increase the differential response between healthy and tumor tissues. This beneficial response isreferred to as the FLASH effect. For this purpose, we have developed the first dedicated compactS-bandlinear accelerator for FLASH radiotherapy. This linac is optimized for a nominal energy of 7 MeV and apulsed electron beam current of 100 mA and above. The accelerator is mounted on a remote-controlledsystem for preclinical research studies in the FLASH regime. We will show the rf and beam dynamicsdesign of theS-band linac as well as the commissioning and high-power rf tests. Furthermore, the results ofthe dosimetric measurements will be illustrate

Measurement of secondary particle production induced by particle therapy ion beams impinging on a PMMA target

Particle therapy is a technique that uses accelerated charged ions for cancer treatment and combines a high irradiation precision with a high biological effectiveness in killing tumor cells [1]. Informations about the secondary particles emitted in the interaction of an ion beam with the patient during a treatment can be of great interest in order to monitor the dose deposition. For this purpose an experiment at the HIT (Heidelberg Ion-Beam Therapy Center) beam facility has been performed in order to measure fluxes and emission profiles of secondary particles produced in the interaction of therapeutic beams with a PMMA target. In this contribution some preliminary results about the emission profiles and the energy spectra of the detected secondaries will be presente

Developing a global operational seasonal hydro-meteorological forecasting system: GloFAS-Seasonal v1.0

Global overviews of upcoming flood and drought events are key for many applications, including disaster risk reduction initiatives. Seasonal forecasts are designed to provide early indications of such events weeks, or even months, in advance, but seasonal forecasts for hydrological variables at large or global scales are few and far between. Here, we present the first operational global scale seasonal hydro-meteorological forecasting system: GloFAS-Seasonal. Developed as an extension of the Global Flood Awareness System (GloFAS), GloFAS-Seasonal couples seasonal meteorological forecasts from ECMWF with a hydrological model, to provide openly available probabilistic forecasts of river flow out to 4 months ahead for the global river network. This system has potential benefits not only for disaster risk reduction through early awareness of floods and droughts, but also for water-related sectors such as agriculture and water resources management, in particular for regions where no other forecasting system exists. We describe the key hydro-meteorological components and computational framework of GloFAS-Seasonal, alongside the forecast products available, before discussing initial evaluation results and next steps

Gene-specific inhibition of breast carcinoma in BALB-neuT mice by active immunization with rat Neu or human ErbB receptors

Employing the transgenic BALB-neuT mouse tumor model, we explored the in vivo biologic relevance of immunocompetent epitopes shared among the four ErbB receptors. The outcome of neu-mediated tumorigenesis was compared following vaccination with isogeneic normal rat ErbB2/Neu (LTR-Neu) or xenogeneic human ErbB receptors (LTR-EGFR, LTR-ErbB2, LTR-ErbB3 and LTR-ErbB4), each recombinantly expressed in an NIH3T3 murine cell background. Vaccination using rat LTR-Neu at the stage of atypical hyperplasia potently inhibited neu-mediated mammary tumorigenesis. Moreover, all human ErbB receptors specifically interfered with tumor development in BALB-neuT mice. Relative increase in tumor-free survival and reduction in tumor incidence corresponded to structural similarity shared with the etiologic neu oncogene, as rat orthologue LTR-Neu proved most effective followed by the human homologue LTR-ErbB2 and the other three human ErbB receptors. Vaccination resulted in high titer specific serum antibodies, whose tumor-inhibitory effect correlated with cross-reactivity to purified rat Neu extracellular domain in vitro. Furthermore, a T cell response specific for peptide epitopes of rat Neu was elicited in spleen cells of mice immunized with LTR-Neu and was remotely detectable for discrete peptides upon vaccination with LTR-ErbB2 and LTR-EGFR. The most pronounced tumor inhibition by LTR-Neu vaccination was associated with leukocyte infiltrate and tumor necrosis in vivo, while immune sera specifically induced cytotoxicity and apoptosis of BALB-neuT tumor cells in vitro. Our findings indicated that targeted inhibition of neu oncogene-mediated mammary carcinogenesis is conditional upon the immunization schedule and discrete immunogenic epitopes shared to a variable extent by different ErbB receptors