Treatment and seroconversion in a cohort of children suffering from recent chronic Chagas infection in Yoro, Honduras

Between 1999-2002, Médécins Sans Frontières-Spain implemented a project seeking to determine the efficacy and safety of benznidazole in the treatment of recent chronic Chagas disease in a cohort of seropositive children in the Yoro Department, Honduras. A total of 24,471 children were screened for Trypanosoma cruzi IgG antibodies through conventional enzyme-linked immunosorbent assays (ELISA) on filter paper. Recombinant ELISA (0.93% seroprevalence) showed 256 initially reactive cases, including 232 confirmed positive cases. Of these, 231 individuals were treated with benznidazole (7.5 mg/kg/day) for 60 days and were followed with a strict weekly medical control and follow-up protocol. At the end of the project, 229 patients were examined by the Honduras Secretariat of Health for post-treatment serological assessments; 88.2% seroconverted after 18 months and 93.9% seroconverted after three years. No differences were found in the seroconversion rates according to age or sex. Most of the side effects of the treatment were minor. These results support the argument that in areas where T. cruzi I is predominant and in areas affected by T. cruzi II, when vector transmission has been interrupted, Chagas disease diagnosis and treatment are feasible, necessary and ethically indisputable

On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

Recent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.Fundacao para a Ciencia e Tecnologia (FCT - Portugal) [UID/Multi/04326/2013]; QREN-COMPETE-UE; CCMAR; FCT [SFRH/BD/81821/2011, RECI/BBB-BQB/0230/2012, UI0313/QUI/2013, UID/FIS/04564/2016]; FEDER/COMPETE-UE; [PTDC/QEQ-QFI/3284/2014 - POCI-01-0145-FEDER-016617]info:eu-repo/semantics/publishedVersio

The role of benralizumab in eosinophilic immune dysfunctions: a case report-based literature review

In the past years, the knowledge of eosinophils playing a primary pathophysiologic role in several associated conditions has led to the development of biologics targeting therapies aiming at normalizing the immune response, reducing chronic inflammation, and preventing tissue damage. To better illustrate the potential relationship between different eosinophilic immune dysfunctions and the effects of biological therapies in this scenario, here, we present a case of a 63-year-old male first referred to our department in 2018 with a diagnosis of asthma, polyposis, and rhinosinusitis and presenting a suspicion of nonsteroidal anti-inflammatory drugs' allergy. He also had a past medical history of eosinophilic gastroenteritis/duodenitis (eosinophilia counts >50 cells/high-power field HPF). The use of multiple courses of corticosteroid therapy failed to completely control these conditions. In October 2019, after starting benralizumab (an antibody directed against the alpha chain of the IL-5 cytokine receptor) as an add-on treatment for severe eosinophilic asthma, important clinical improvements were reported both in the respiratory (no asthma exacerbations) and gastrointestinal systems (eosinophilia count 0 cells/HPF). The patient's quality of life also increased. Since June 2020, systemic corticosteroid therapy was reduced without worsening gastrointestinal symptoms or eosinophilic inflammation. This case warns of the importance of early recognition and appropriate individualized treatment of eosinophilic immune dysfunctions and suggests the conduction of further larger studies on the use of benralizumab in gastrointestinal syndromes aiming at better understanding its relying mechanisms of action in the intestinal mucosa.info:eu-repo/semantics/publishedVersio

Preliminary evaluation of microcarrier culture for growth and monoclonal antibody production of CHO-K1 cells

Large-scale biopharmaceutical production commonly relies on suspension cell cultures that provide higher yields than adherent cultures. However, most mammalian cells grow adherently and therefore need to be adapted to suspended growth, which is not always simple or feasible. Microcarrier culture introduces new possibilities and makes achievable the practical high yield culture of anchorage-dependent cells in suspension systems. The aim of this study was to evaluate and optimize the use of microcarrier culture for the growth and antibody production of CHO-K1 cells. For this, the macroporous Cultispher microcarriers were used, and the initial cell adhesion to the microcarriers (occurring in the first 5-6 hours) and further cell proliferation were assessed. Cultures of antibody-producing CHO-K1 cells were performed in 50 ml vented conical tubes, and different conditions were tested: initial cell concentration (2x105 cells/ml and 4x105 cells/ml), microcarrier concentration (1 g/L and 2 g/L), type of rocking during the first 6 hours of adhesion (pulse or continuous) and rocking after initial adhesion (no rocking and 60 rpm). Cell concentration and viability in the microcarriers were assessed periodically (hourly for the adhesion phase, and daily after that). It was observed that an increase in the initial cell concentration does not enhance initial adhesion, possibly due to saturation of the microcarrier surface. For its turn, increasing microcarrier concentration, without further increasing initial cell concentration does not improve cell densities achieved in the culture. Concerning rocking, the most favorable type for the adhesion phase was pulse rocking and, after this, a continuous rocking provided an improved cell proliferation. In conclusion, microcarrier cultures proved to be a viable alternative to suspended cultures for the growth and antibody production of CHO-K1 cells

A full-scale timbrel cross vault subjected to vertical cyclical displacements in one of its supports

[EN] Up-and-down cyclical displacement of supports-foundations, due for example to the presence of expansive soils, can affect the integrity of a structure and may even lead to its collapse. A recent study carried out at the ICITECH laboratories of the Universitat Politècnica de València analysed the effects of earth settlements on the behaviour of masonry cross vaults. One of the tests involved the construction and testing of a full-scale timbrel cross vault, one of whose supports was subjected to up-and-down vertical displacement cycles. The 4×4 m2 vault was composed of four 3.6 m diameter arches supporting a masonry web. Vertical displacements were applied to one of the supports by means of two synchronised mechanical jacks. The results of the tests provide valuable information to the scientific community, architects and engineers on the behaviour of timbrel cross vaults when one of their supports is subjected to cyclical movements.The authors wish to express their gratitude to the Spanish Ministry of Economy, Industry and Competitiveness for the funding provided through Project BIA 2014-59036-R, and also to LIC-Levantina Ingenieria y Construction and the Grupo Puma for their invaluable assistance. The second author (Elisa Bertolesi) would like to thank the Universitat Politecnica de Valencia for funding received for her postdoctoral grant (PAID-10-17).Torres Górriz, B.; Bertolesi, E.; Calderón García, PA.; Moragues, JJ.; Adam, JM. (2019). A full-scale timbrel cross vault subjected to vertical cyclical displacements in one of its supports. Engineering Structures. 183:791-804. https://doi.org/10.1016/j.engstruct.2019.01.054S79180418

Atmospheric deposition fluxes of aluminium, iron and trace metals in a coastal station on the NW-Alboran Sea, (W-Mediterranean)

El estudio se ha realizado en el marco del Proyecto del Plan Nacional con ref. CTM12-37598-C02The atmospheric deposition over the whole Mediterranean is poorly constrained and hinders a clear assessment of the extent to which atmospheric elements of various anthropogenic and natural origins affect its biogeochemistry. Available data show poor spatial representation, as most of the deposition data refer to the northwestern zone. The Alboran Sea, in particular, is a very interesting case study as regards the atmospheric input because the atmospheric chemistry is dominated by antagonistic influences of natural (mainly from the Sahara) and human activity due to the relative proximity of land-based sources and densely populated shores. The biogeochemical impact of desert dust also remains a matter of discussion regarding its contribution for different major and minor elements to terrestrial and marine systems and especially its potential fertilizing role by supplying micronutrients as iron. Atmospheric fluxes of various trace metals were measured in order to evaluate the presence of these elements in their differently bio-available forms, contents in the soluble and non-soluble fractions were determined. Sampling presented for this study was performed in Malaga (southeast of Spain, 36° 43′ 40″ N; 4° 28′ 8″ W) in an open bulk deposition collector placed 10 m above the ground. The Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model was used to calculate the backward trajectories of air masses reaching the study region.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Perturbation of spermine synthase Gene Expression and Transcript Profiling Provide New Insights on the Role of the Tetraamine Spermine in Arabidopsis Defense against Pseudomonas viridiflava1[C][W]

The role of the tetraamine spermine in plant defense against pathogens was investigated by using the Arabidopsis (Arabidopsis thaliana)-Pseudomonas viridiflava pathosystem. The effects of perturbations of plant spermine levels on susceptibility to bacterial infection were evaluated in transgenic plants (35S::spermine synthase [SPMS]) that overexpressed the SPMS gene and accumulated spermine, as well as in spms mutants with low spermine levels. The former exhibited higher resistance to P. viridiflava than wild-type plants, while the latter were more susceptible. Exogenous supply of spermine to wild-type plants also increased disease resistance. Increased resistance provided by spermine was partly counteracted by the polyamine oxidase inhibitor SL-11061, demonstrating that the protective effect of spermine partly depends on its oxidation. In addition, global changes in gene expression resulting from perturbations of spermine levels were analyzed by transcript profiling 35S::SPMS-9 and spms-2 plants. Overexpression of 602 genes was detected in 35S::SPMS-9 plants, while 312 genes were down-regulated, as compared to the wild type. In the spms-2 line, 211 and 158 genes were up- and down-regulated, respectively. Analysis of gene ontology term enrichment demonstrated that many genes overexpressed only in 35S::SPMS-9 participate in pathogen perception and defense responses. Notably, several families of disease resistance genes, transcription factors, kinases, and nucleotide- and DNA/RNA-binding proteins were overexpressed in this line. Thus, a number of spermine-responsive genes potentially involved in resistance to P. viridiflava were identified. The obtained results support the idea that spermine contributes to plant resistance to P. viridiflava

Rapid diagnosis of hereditary haemolytic anaemias using automated rheoscopy and supervised machine learning

Haemolytic anaemias arise when red blood cell (RBC) integrity is compromised, eventually resulting in premature clearance or lysis and leading to anaemia when these effects cannot be sufficiently compensated by the capacity of the bone marrow to produce new cells. Hereditary anaemia occurs as a consequence of genetic mutation (e.g. affecting membrane complex or cytoskeletal proteins, haemoglobin or metabolic enzymes), and diagnosing affected patients is a complex process since, given the wide variety of possible genetic causes, multiple examinations must be performed and an unambiguous result is usually reached only after DNA sequencing. Furthermore, phenotypic severity can vary widely not just among individuals with different mutations but also among individuals suffering from the same mutation, thereby complicating diagnosis