Publications by authors named "Maria Alonso"

559 Publications

Additive Role of Immune System Infiltration and Angiogenesis in Uveal Melanoma Progression.

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Medical Oncology Department, Catalan Institute of Cancer (ICO), IDIBELL-OncoBell, Hospitalet de Llobregat, 08908 Barcelona, Spain.

Uveal melanoma (UM) is a malignant tumor that arises in the melanocytes of the uveal tract. It is the most frequent eye cancer, and despite new therapeutic approaches, prognosis is still poor, with up to 50% of patients developing metastasis with no efficient treatment options available. In contrast to cutaneous melanoma, UM is considered an "immune-cold" tumor due to the low mutational burden and the unique immunosuppressive microenvironment. To gain insight into the role of the UM microenvironment in regard to prognosis and metastatic progression, we have performed a pool analysis characterizing the UM microenvironment by using a bioinformatic approach. A variety of scores based on gene expression measuring stromal infiltration were calculated and used to assess association with prognosis. As a result, the highest immune and stromal scores were associated with poor prognosis. Specifically, stromal cells (fibroblasts and endothelial cells), T cells CD8+, natural killer (NK) cells, and macrophages M1 and M2 infiltration were associated with poor prognosis. Contrary to other tumors, lymphocytic infiltration is related to poor prognosis. Only B cells were associated with more favorable prognosis. UM samples scoring high in both angiogenesis (Angio) and antigen presentation (AP) pathways showed a poor prognosis suggesting an additive role of both functions. Almost all these tumors exhibited a chromosome 3 monosomy. Finally, an enrichment analysis showed that tumors classified as high Angio-high AP also activated metabolic pathways such as glycolysis or PI3K-AKT-MTOR. In summary, our pool analysis identified a cluster of samples with angiogenic and inflammatory phenotypes exhibiting poor prognosis and metabolic activation. Our analysis showed robust results replicated in a pool analysis merging different datasets from different analytic platforms.
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http://dx.doi.org/10.3390/ijms22052669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961481PMC
March 2021

Carboxymethyl-β-glucan/chitosan nanoparticles: new thermostable and efficient carriers for antigen delivery.

Drug Deliv Transl Res 2021 Apr 1. Epub 2021 Apr 1.

Center for Research in Molecular Medicine & Chronic Diseases (CIMUS), School of Pharmacy, Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, Campus Vida, Santiago de Compostela, 15706, Spain.

In the last few decades, nanotechnology has emerged as an important tool aimed at enhancing the immune response against modern antigens. Nanocarriers designed specifically for this purpose have been shown to provide protection, stability, and controlled release properties to proteins, peptides, and polynucleotide-based antigens. Polysaccharides are particularly interesting biomaterials for the construction of these nanocarriers given their wide distribution among pathogens, which facilitates their recognition by antigen-presenting cells (APCs). In this work, we focused on an immunostimulant beta-glucan derivative, carboxymethyl-β-glucan, to prepare a novel nanocarrier in combination with chitosan. The resulting carboxymethyl-β-glucan/chitosan nanoparticles exhibited adequate physicochemical properties and an important protein association efficiency, with ovalbumin as a model compound. Moreover, thermostability was achieved through the optimization of a lyophilized form of the antigen-loaded nanoparticles, which remained stable for up to 1 month at 40 ºC. Biodistribution studies in mice showed an efficient drainage of the nanoparticles to the nearest lymph node following subcutaneous injection, and a significant co-localization with dendritic cells. Additionally, subcutaneous immunization of mice with a single dose of the ovalbumin-loaded nanoparticles led to induced T cell proliferation and antibody responses, comparable to those achieved with alum-adsorbed ovalbumin. These results illustrate the potential of these novel nanocarriers in vaccination.
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http://dx.doi.org/10.1007/s13346-021-00968-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015750PMC
April 2021

Mantenimiento de tratamientos crónicos en pacientes afectados de COVID-19.

FMC 2021 Mar 23;28(3):191-201. Epub 2021 Mar 23.

Médico de familia, Unidad de Investigación Gerencia de Atención Primaria, Madrid, España.

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http://dx.doi.org/10.1016/j.fmc.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984871PMC
March 2021

Unnecessary Abdominal Surgeries in Attacks of Hereditary Angioedema with Normal C1 Inhibitor.

Clin Rev Allergy Immunol 2021 Mar 23. Epub 2021 Mar 23.

Faculdade de Medicina, Centro Universitario Saude ABC, Santo Andre, Sao Paulo, SP, Brazil.

Hereditary angioedema (HAE) is an autosomal dominant disease mostly due to the deficiency of C1 inhibitor (C1-INH). HAE with normal C1-INH was first described in 2000 and associated with mutations in the coagulation factor XII in 2006. Both diseases are associated with high bradykinin production, resulting in increased vascular permeability. Gastrointestinal edema due to HAE can be misdiagnosed as acute abdomen and unnecessary surgical procedures may be performed. The present study evaluates the prevalence of surgical procedures and/or acute abdomen in HAE patients with the coagulation factor XII mutation. It is a retrospective study where patients were diagnosed with recurrent angioedema without urticaria, normal C1-INH levels, and positive family history of angioedema. All patients were evaluated for the known mutations located at exon 9 of the F12 gene. Medical records were evaluated and questionnaires were applied to 52 patients with normal C1-INH levels (age range 13-76 years; 47/52, 90.38% women; 5/52, 9.61% men). F12 mutation was present in 32/52 patients (61.5%). Acute abdominal pain was diagnosed in 16/52 (30.76%) patients, appendicitis in 9/16 (56.2%), and undetermined diagnosis in 7/16 (43.7%). Among patients diagnosed with acute abdominal pain, 13/16 (81.2%) underwent surgery and 3/16 (18.7%) improved without surgical intervention. We conclude that many HAE patients with coagulation factor XII mutation were misdiagnosed with acute abdomen and subjected to unnecessary invasive procedures. It is critical to disseminate information about this rare mutation in patients with otherwise normal C1-INH activity, in order to speed up diagnosis and avoid misconduct.
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http://dx.doi.org/10.1007/s12016-021-08852-7DOI Listing
March 2021

Correction to: Asymmetric flow field‑flow fractionation as a multifunctional technique for the characterization of polymeric nanocarriers.

Drug Deliv Transl Res 2021 Apr;11(2):396

Center for Research in Molecular Medicine and Chronic Diseases, Singular Research Centers, 15782, Santiago de Compostela, Spain.

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http://dx.doi.org/10.1007/s13346-021-00962-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987704PMC
April 2021

Vascular and Macrophage Heme Oxygenase-1 in Hypertension: A Mini-Review.

Front Physiol 2021 26;12:643435. Epub 2021 Feb 26.

Depto. de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.

Hypertension is one predictive factor for stroke and heart ischemic disease. Nowadays, it is considered an inflammatory disease with elevated cytokine levels, oxidative stress, and infiltration of immune cells in several organs including heart, kidney, and vessels, which contribute to the hypertension-associated cardiovascular damage. Macrophages, the most abundant immune cells in tissues, have a high degree of plasticity that is manifested by polarization in different phenotypes, with the most well-known being M1 (proinflammatory) and M2 (anti-inflammatory). In hypertension, M1 phenotype predominates, producing inflammatory cytokines and oxidative stress, and mediating many mechanisms involved in the pathogenesis of this disease. The increase in the renin-angiotensin system and sympathetic activity contributes to the macrophage mobilization and to its polarization to the pro-inflammatory phenotype. Heme oxygenase-1 (HO-1), a phase II detoxification enzyme responsible for heme catabolism, is induced by oxidative stress, among others. HO-1 has been shown to protect against oxidative and inflammatory insults in hypertension, reducing end organ damage and blood pressure, not only by its expression at the vascular level, but also by shifting macrophages toward the anti-inflammatory phenotype. The regulatory role of heme availability for the synthesis of enzymes involved in hypertension development, such as cyclooxygenase or nitric oxide synthase, seems to be responsible for many of the beneficial HO-1 effects; additionally, the antioxidant, anti-inflammatory, antiapoptotic, and antiproliferative effects of the end products of its reaction, carbon monoxide, biliverdin/bilirubin, and Fe, would also contribute. In this review, we analyze the role of HO-1 in hypertensive pathology, focusing on its expression in macrophages.
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http://dx.doi.org/10.3389/fphys.2021.643435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952647PMC
February 2021

The physiology and genetics behind fruiting efficiency, a promising spike trait to improve wheat yield potential.

J Exp Bot 2021 Mar 3. Epub 2021 Mar 3.

Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires (CITNOBA, CONICET-UNNOBA-UNSADA). Monteagudo, Pergamino, Buenos Aires, Argentina.

The fruiting efficiency (FE, grains per g of spike dry weight at anthesis) was proposed as a promising spike trait to improve wheat yield potential, based on its functional relationship with grain number determination (the most important component associated with yield potential) and the evidence of trait variability in elite germplasm. During the last years, we have witnessed great advances in the understanding of the physiological and genetic bases of this trait. The present review summarises the recent heritability estimations and the genetic gains obtained when the fruiting efficiency was measured at maturity (FEm, grains per g of chaff) and used as selection criterion. In addition, by revising a detailed physiological approach based on the fertile floret efficiency (FFE, fertile florets per g of spike dry weight at anthesis) and grain set (grains per fertile floret), together with other spike fertility related traits, spike ideotypes for contrasting fruiting efficiencies are proposed. The novel genes and QTL available for using marker-assisted selection for fruiting efficiency and other spike fertility traits are also reviewed. The possible trade-off between FE and grain weight (GW) and the genes reported to alter this relation are revised. Finally, the benefits and future steps towards the use of fruiting efficiency as a selection criterion in breeding programs is discussed.
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http://dx.doi.org/10.1093/jxb/erab080DOI Listing
March 2021

Optimization and Validation of HS-GC/MS Method for the Controlled Release Study of Microencapsulated Specific Bioattractants for Target-Plaguicide Production.

Molecules 2021 Feb 13;26(4). Epub 2021 Feb 13.

Analytical Chemistry Department, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940 Leioa, Spain.

Insect plagues are a problem often hard to solve due to the harmful effects caused by the pesticides used to combat them. Consequently, the pesticide market is increasingly trying to develop new technologies to prevent the unwanted effects that common plague treatments usually bring with them. In this work, four specific bioattractants of , extracted from fungi (β-ocimene, phenol, p-cresol, and indole) were microencapsulated with β-cyclodextrin in order to produce an economically and environmentally sustainable bait containing biocides in the near future. Cyclodextrins will retain these volatile compounds until their use by the consumer when the product comes into contact with water. Then, the bioattractants will be released in the medium in a controlled manner. An analytical methodology based on headspace extraction coupled to gas chromatography and mass spectrometry (HS-GC/MS) has been developed and validated following Environmental Protection Agency (EPA) and European Commission Directorate General for Health and Food Safety guidelines for the bioattractants controlled release study from the microencapsulated product. The analytical method has been shown to be accurate and precise and has the sensitivity required for controlled release studies of the four bioattractants analyzed. The release of the bioattractants from microencapsulated products achieved the "plateau" after 3 h in all cases.
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http://dx.doi.org/10.3390/molecules26040996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917701PMC
February 2021

Comment from the editor-in-chief about the Special Issue "A perspective of drug delivery and translational research in Europe".

Drug Deliv Transl Res 2021 Apr;11(2):341-342

CIMUS Research Institute, University of Santiago de Compostela, Santiago de Compostela, Coruña, Spain.

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http://dx.doi.org/10.1007/s13346-021-00948-zDOI Listing
April 2021

Imaging of Endoplasmic Reticulum Ca in the Intact Pituitary Gland of Transgenic Mice Expressing a Low Affinity Ca Indicator.

Front Endocrinol (Lausanne) 2020 16;11:615777. Epub 2021 Feb 16.

Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain.

The adenohypophysis contains five secretory cell types (somatotrophs, lactotrophs, thyrotrophs, corticotrophs, and gonadotrophs), each secreting a different hormone, and controlled by different hypothalamic releasing hormones (HRHs). Exocytic secretion is regulated by cytosolic Ca signals ([Ca]), which can be generated either by Ca entry through the plasma membrane and/or by Ca release from the endoplasmic reticulum (ER). In addition, Ca entry signals can eventually be amplified by ER release calcium-induced calcium release (CICR). We have investigated the contribution of ER Ca release to the action of physiological agonists in pituitary gland. Changes of [Ca] in the ER ([Ca]) were measured with the genetically encoded low-affinity Ca sensor GAP3 targeted to the ER. We used a transgenic mouse strain that expressed erGAP3 driven by a ubiquitous promoter. Virtually all the pituitary cells were positive for the sensor. In order to mimick the physiological environment, intact pituitary glands or acute slices from the transgenic mouse were used to image [Ca]. [Ca] was measured simultaneously with Rhod-2. Luteinizing hormone-releasing hormone (LHRH) or thyrotropin releasing hormone (TRH), two agonists known to elicit intracellular Ca mobilization, provoked robust decreases of [Ca] and concomitant rises of [Ca]. A smaller fraction of cells responded to thyrotropin releasing hormone (TRH). By contrast, depolarization with high K triggered a rise of [Ca] without a decrease of [Ca], indicating that the calcium-induced calcium-release (CICR) ryanodine receptor amplification mechanism is not present in these cells. Our results show the potential of transgenic ER Ca indicators as novel tools to explore intraorganellar Ca dynamics in pituitary gland .
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http://dx.doi.org/10.3389/fendo.2020.615777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921146PMC
February 2021

Recovery of Equine Oocytes in Ambulatory Practice and Potential Complications.

J Equine Vet Sci 2021 03 26;98:103324. Epub 2020 Nov 26.

InVitro Equinos/In Vitro Clonagem Animal SA, Campinas-Mogi Mirim, SP, Brazil. Electronic address:

Field collection of oocytes in mares using transvaginal follicular aspiration (TVA) for embryo production has the potential to revolutionate the equine industry. Protocols for TVA in specialized laboratory settings have been described in the scientific literature since the early 1980s. The objective of this study was to determine the success rate of TVA oocytes recovery under ambulatory conditions. A secondary goal of this study was to determine if TVA is associated with any health complications when performed by recently trained practitioners in the field. Follicles (n = 296) from 66 adult clinically healthy mares were aspirated over a period of 6 days. TVAs were performed by 22 veterinarians with 5-20 years of experience in equine and bovine reproductive medicine, but no previous experience in TVA. Oocytes (n = 145) were recovered. No short- or long-term systemic or local complications were observed following TVA in any of the mares used in this study. Fifty-six out of 66 mares became pregnant within 3 months following TVA. This study shows that with proper training, TVA can be successfully used to obtain equine oocytes with no health complications under field conditions in nonspecialized laboratory settings.
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http://dx.doi.org/10.1016/j.jevs.2020.103324DOI Listing
March 2021

Editorial note.

Drug Deliv Transl Res 2021 Apr;11(2):331-333

CIMUS Research Institute, University of Santiago de Compostela, Santiago de Compostela, Spain.

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http://dx.doi.org/10.1007/s13346-021-00947-0DOI Listing
April 2021

A nanoemulsion/micelles mixed nanosystem for the oral administration of hydrophobically modified insulin.

Drug Deliv Transl Res 2021 Apr 11;11(2):524-545. Epub 2021 Feb 11.

Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Campus Vida, 15782, Santiago de Compostela, Spain.

The potential of nanoemulsions for the oral administration of peptides is still in its early stage. The aim of the present work was to rationally design, develop, and fully characterize a new nanoemulsion (NE) intended for the oral administration of hydrophobically modified insulin (HM-insulin). Specific components of the NE were selected based on their enhancing permeation properties as well as their ability to improve insulin association efficiency (Miglyol 812, sodium taurocholate), stability in the intestinal fluids, and mucodiffusion (PEGylated phospholipids and poloxamer 407). The results showed that the NE co-existed with a population of micelles, forming a mixed system that exhibited a 100% of HM-insulin association efficiency. The nanosystem showed good stability and miscibility in different bio-relevant media and displayed an acceptable mucodiffusive behavior in porcine mucus. In addition, it exhibited a high interaction with cell mono-cultures (Caco -2 and C2BBe1 human colon carcinoma Caco-2 clone cells) and co-cultures (C2BBe1 human colon carcinoma Caco-2 clone/HT29-MTX cells). The internalization in Caco-2 monolayers was also confirmed by confocal microscopy. Finally, the promising in vitro behavior of the nanosystem in terms of overcoming the biological barriers of the intestinal tract was translated into a moderate, although significant, hypoglycemic response (≈ 20-30%), following intestinal administration to both healthy and diabetic rat models. Overall, this information underlines the crucial steps to address when designing peptide-based nanoformulations to successfully overcome the intestinal barriers associated to the oral modality of administration.
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http://dx.doi.org/10.1007/s13346-021-00920-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987602PMC
April 2021

Asymmetric flow field-flow fractionation as a multifunctional technique for the characterization of polymeric nanocarriers.

Drug Deliv Transl Res 2021 Apr 31;11(2):373-395. Epub 2021 Jan 31.

Center for Research in Molecular Medicine and Chronic Diseases, Singular Research Centers, 15782, Santiago de Compostela, Spain.

The importance of polymeric nanocarriers in the field of drug delivery is ever-increasing, and the accurate characterization of their properties is paramount to understand and predict their behavior. Asymmetric flow field-flow fractionation (AF4) is a fractionation technique that has gained considerable attention for its gentle separation conditions, broad working range, and versatility. AF4 can be hyphenated to a plurality of concentration and size detectors, thus permitting the analysis of the multifunctionality of nanomaterials. Despite this potential, the practical information that can be retrieved by AF4 and its possible applications are still rather unfamiliar to the pharmaceutical scientist. This review was conceived as a primer that clearly states the "do's and don'ts" about AF4 applied to the characterization of polymeric nanocarriers. Aside from size characterization, AF4 can be beneficial during formulation optimization, for drug loading and drug release determination and for the study of interactions among biomaterials. It will focus mainly on the advances made in the last 5 years, as well as indicating the problematics on the consensus, which have not been reached yet. Methodological recommendations for several case studies will be also included.
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http://dx.doi.org/10.1007/s13346-021-00918-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987708PMC
April 2021

The Challenges in the Follow-Up and Treatment of Brazilian Children with Hereditary Angioedema.

Int Arch Allergy Immunol 2021 Jan 28:1-7. Epub 2021 Jan 28.

Clinical Immunology, Faculdade de Medicina, Centro Universitario Saude ABC, Santo Andre, Brazil,

Introduction: Hereditary angioedema (HAE) with C1 inhibitor (C1-INH) deficiency is a rare autosomal dominant disease. Although the first symptoms can appear in childhood, the diagnosis's delay has a strong impact on the patient's quality of life. We analyzed clinical and laboratory characteristics and the drug therapy of pediatric patients with HAE in Brazil.

Methods: Medical records from 18 reference centers of HAE patients under 18 years of age were evaluated after confirmed diagnosis was performed by quantitative and/or functional C1-INH.

Results: A total of 95 participants (51 M:44 F; mean age: 7 years old) out of 17 centers were included; 15 asymptomatic cases were identified through family history and genetic screening. Angioedema attacks affected the extremities (73.5%), gastrointestinal tract (57%), face (50%), lips (42.5%), eyelids (23.7%), genitals (23.7%), upper airways (10%), and tongue (6.3%). Family history was present in 84% of patients, and the mean delay in the diagnosis was 3.9 years. Long-term prophylaxis (51/80) was performed with tranexamic acid (39/80) and androgens (13/80); and short-term prophylaxis (9/80) was performed with tranexamic acid (6/80) and danazol (3/80). On-demand therapy (35/80) was prescribed: icatibant in 7/35, fresh frozen plasma in 16/35, C1-INH plasma-derived in 11/35, and tranexamic acid in 12/35 patients.

Conclusions: This is the first study on HAE pediatric patients in Latin America. Clinical manifestations were similar to adults. Drugs such as androgens and tranexamic acid were indicated off-label, probably due to restricted access to specific drugs. Educational programs should address pediatricians to reduce late diagnosis and tailored child therapy.
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http://dx.doi.org/10.1159/000512944DOI Listing
January 2021

Sex differences in hospitalized adult patients with cellulitis: A prospective, multicenter study.

Int J Infect Dis 2021 Mar 27;104:584-591. Epub 2021 Jan 27.

Infectious Diseases Unit, Hospital Universitario Central de Asturias, Oviedo, Spain; Group of Translational Research in Infectious Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain. Electronic address:

Objectives: Sex differences in adult cellulitis, a frequent cause of hospitalization, have not been analyzed. These differences were investigated in a large cellulitis series.

Methods: This was a prospective observational study of 606 Spanish hospitalized cellulitis patients. Different comorbidities, clinical, diagnostic, and treatment data were compared between the sexes. Multiple logistic regression modeling was performed to determine the variables independently associated with sex.

Results: Overall 606 adult cellulitis patients were enrolled; 314 (51.8%) were male and 292 (48.2%) were female. Females were older (mean age 68.8 vs 58.9 years, p < 0.0001), less likely to have prior wounds (p = 0.02), and more likely to have venous insufficiency (p = 0.0002) and edema/lymphedema (p = 0.0003) than males. The location of the infection differed between the sexes (p = 0.02). Males were more likely to have positive pus cultures (p = 0.0008), the causing agent identified (p = 0.04), and higher rates of Staphylococcus aureus infection (p = 0.04) and received longer antibiotic treatment (p = 0.03). Factors independently associated with female sex in the multivariate analysis were older age (p < 0.0001), prior cellulitis (p = 0.01), presence of edema/lymphedema as the predisposing factor (p = 0.004), negative versus positive pus culture (p = 0.0002), and location of cellulitis other than in the lower extremities (p = 0.035).

Conclusions: Differences between male and female patients with cellulitis were age, recurrence, presence of edema/lymphedema, positivity of pus culture, and topography of the infection.
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http://dx.doi.org/10.1016/j.ijid.2021.01.044DOI Listing
March 2021

New Approach for the Determination of Radiological Parameters on Hardened Cement Pastes with Coal Fly Ash.

Materials (Basel) 2021 Jan 21;14(3). Epub 2021 Jan 21.

Department of Materials, Eduardo Torroja Institute for Construction Sciences (IETcc-CSIC), 28033 Madrid, Spain.

Supplementary cementitious materials (SCMs) in industrial waste and by-products are routinely used to mitigate the adverse environmental effects of, and lower the energy consumption associated with, ordinary Portland cement (OPC) manufacture. Many such SCMs, such as type F coal fly ash (FA), are naturally occurring radioactive materials (NORMs). Ra, Th and K radionuclide activity concentration, information needed to determine what is known as the gamma-ray activity concentration index (ACI), is normally collected from ground cement samples. The present study aims to validate a new method for calculating the ACI from measurements made on unground 5 cm cubic specimens. Mechanical, mineralogical and radiological characterisation of 28-day OPC + FA pastes (bearing up to 30 wt % FA) were characterised to determine their mechanical, mineralogical and radiological properties. The activity concentrations found for Ra, Pb, Th and K in hardened, intact 5 cm cubic specimens were also statistically equal to the theoretically calculated values and to the same materials when ground to a powder. These findings consequently validated the new method. The possibility of determining the activity concentrations needed to establish the ACI for cement-based materials on unground samples introduces a new field of radiological research on actual cement, mortar and concrete materials.
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http://dx.doi.org/10.3390/ma14030475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864329PMC
January 2021

Chronic Low-Level Lead Exposure Increases Mesenteric Vascular Reactivity: Role of Cyclooxygenase-2-Derived Prostanoids.

Front Physiol 2020 7;11:590308. Epub 2021 Jan 7.

Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, Brazil.

Lead (Pb) exposure causes hazardous effects as hypertension and other cardiovascular diseases. We evaluated whether chronic Pb exposure alters the peripheral vascular resistance measuring the vascular reactivity of mesenteric resistance arteries in rats to identify the underlying mechanisms that are associated to the development of Pb-induced hypertension. Mesenteric resistance arteries from lead-treated and untreated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) were used. Contractile responses to phenylephrine increased, while acetylcholine and sodium nitroprusside-induced relaxation was not affected by lead treatment. Endothelium removal and inhibition of NO synthase by L-NAME similarly enhanced the response to phenylephrine in untreated and lead-treated rats. The antioxidants apocynin and superoxide dismutase (SOD) did not affect vasoconstriction in either group. The vascular expression of cyclooxygenase-2 (COX-2) protein increased after lead exposure. The respective non-specific or specific COX-2 inhibitors indomethacin and NS398 reduced more strongly the response to phenylephrine in treated rats. Antagonists of EP1 (SC19220), TP (SQ29548), IP (CAY10441) and angiotensin II type 1 (losartan) receptors reduced vasoconstriction only in treated rats. These conclusions present further evidence that lead, even in small concentration, produces cardiovascular hazards being an environmental contaminant that account for lead-induced hypertension.
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http://dx.doi.org/10.3389/fphys.2020.590308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818781PMC
January 2021

Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Cancer Signalling Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain.

(1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of DEXA on GBM cells. We tested the efficacy of tyrosine kinase inhibitors in vitro and in vivo. (3) Results: We confirm in our patient cohort that administration of DEXA correlates with worse overall survival and shorter time to relapse. In GBM cells and glioma stem-like cells (GSCs) DEXA down-regulates genes controlling G2/M and mitotic-spindle checkpoints, and it enables cells to override the spindle assembly checkpoint (SAC). Concurrently, DEXA up-regulates Platelet Derived Growth Factor Receptor (PDGFR) signalling, which stimulates expression of anti-apoptotic regulators BCL2L1 and MCL1, required for survival during extended mitosis. Importantly, the protective potential of DEXA is dependent on intact tyrosine kinase signalling and ponatinib, sunitinib and dasatinib, all effectively overcome the radio-protective and pro-proliferative activity of DEXA. Moreover, we discovered that DEXA-induced signalling creates a therapeutic vulnerability for sunitinib in GSCs and GBM cells in vitro and in vivo. (4) Conclusions: Our results reveal a novel DEXA-induced mechanism in GBM cells and provide a rationale for revisiting the use of tyrosine kinase inhibitors for the treatment of GBM.
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http://dx.doi.org/10.3390/cancers13020361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836009PMC
January 2021

First report of pathogenic Leptospira spp. in Tadarida brasiliensis bats (family Molossidae) and Eptesicus furinalis (family Vespertilionidae) of Argentina. New host species in this country?

Rev Argent Microbiol 2021 Jan 16. Epub 2021 Jan 16.

Laboratory of Leptospirosis, Institute of Pathobiology, National Institute of Agricultural Technology (INTA), Nicolás Repetto and Reseros w/n, Hurlingham, Buenos Aires, Argentina.

Leptospirosis is an endemic disease caused by Leptospira spp., a bacterium that affects animals and humans. In recent years, the number of reports of leptospirosis in wild animals has increased, which highlights the need to study the infectious agents in these animals. In this study, a duplex PCR for the detection of leptospiral DNA was performed on 50 kidney samples from bats, and a MAT (Microscopic Agglutination Test) for serological detection of anti-leptospiral antibodies was applied to 47 serum samples from bats from different regions of Buenos Aires Province, Argentina. DNA was extracted using Chelex-100 and duplex PCR was performed by targeting the detection of genes secY and flaB, of pathogenic Leptospira spp. Of the 50 kidney samples, 3 were positive for Eumops sp. and Tadarida brasiliensis by duplex PCR. Of the 47 serum samples, 12 were positive for different serovars: Leptospira interrogans serovars Icterohaemorrhagiae, Cynopteri and Bataviae, and Leptospira borgpetersenii serovar Ballum. This is the first report of the detection of pathogenic leptospires by serology in bats belonging to the T. brasiliensis and Eptesicus furinalis species in Argentina. In addition, this is the first report of the detection of pathogenic leptospiral DNA by PCR in T. brasiliensis species. The detection of Leptospira spp. in these wild animals shows that they may play an important role as wildlife reservoirs of leptospires.
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http://dx.doi.org/10.1016/j.ram.2020.09.007DOI Listing
January 2021

Androglobin gene expression patterns and FOXJ1-dependent regulation indicate its functional association with ciliogenesis.

J Biol Chem 2021 Jan 13:100291. Epub 2021 Jan 13.

Section of Medicine, Department of Endocrinology, Metabolism and Cardiovascular System, University of Fribourg, Switzerland. Electronic address:

Androglobin (ADGB) represents the latest addition to the globin superfamily in metazoans. The chimeric protein comprises a calpain domain and a unique circularly permutated globin domain. ADGB expression levels are most abundant in mammalian testis, but its cell type-specific expression, regulation and function have remained unexplored. Analyzing bulk and single-cell mRNA-Seq data from mammalian tissues, we found that -in addition to testes- ADGB is prominently expressed in the female reproductive tract, lungs and brain, specifically being associated with cell types forming motile cilia. Correlation analysis suggested co-regulation of ADGB with FOXJ1, a crucial transcription factor of ciliogenesis. Investigating the transcriptional regulation of the ADGB gene, we characterized its promoter using epigenomic datasets, exogenous promoter-dependent luciferase assays and CRISPR/dCas9-VPR-mediated activation approaches. Reporter gene assays revealed that FOXJ1 indeed substantially enhanced luciferase activity driven by the ADGB promoter. ChIP assays confirmed binding of FOXJ1 to the endogenous ADGB promoter region. We dissected the minimal sequence required for FOXJ1-dependent regulation and fine mapped the FOXJ1 binding site to two evolutionarily conserved regions within the ADGB promoter. FOXJ1 overexpression significantly increased endogenous ADGB mRNA levels in HEK293 and MCF-7 cells. Similar results were observed upon RFX2 overexpression, another key transcription factor in ciliogenesis. The complex transcriptional regulation of the ADGB locus was illustrated by identifying a distal enhancer, responsible for synergistic regulation by RFX2 and FOXJ1. Finally, cell culture studies indicated an ADGB-dependent increase in the number of ciliated cells upon overexpression of the full-length protein, confirming a ciliogenesis-associated role of ADGB in mammals.
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http://dx.doi.org/10.1016/j.jbc.2021.100291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949040PMC
January 2021

Sticholysins, pore-forming proteins from a marine anemone can induce maturation of dendritic cells through a TLR4 dependent-pathway.

Mol Immunol 2021 03 6;131:144-154. Epub 2021 Jan 6.

Laboratory of Toxins and Liposomes, Center for Protein Studies, Faculty of Biology, University of Havana (UH), Lab UH-CIM, Havana, 10400, Cuba. Electronic address:

Sticholysins (Sts) I and II (StI and StII) are pore-forming proteins (PFPs), purified from the Caribbean Sea anemone Stichodactyla helianthus. StII encapsulated into liposomes induces a robust antigen-specific cytotoxic CD8 T lymphocytes (CTL) response and in its free form the maturation of bone marrow-derived dendritic cells (BM-DCs). It is probable that the latter is partially supporting in part the immunomodulatory effect on the CTL response induced by StII-containing liposomes. In the present work, we demonstrate that the StII's ability of inducing maturation of BM-DCs is also shared by StI, an isoform of StII. Using heat-denatured Sts we observed a significant reduction in the up-regulation of maturation markers indicating that both PFP's ability to promote maturation of BM-DCs is dependent on their conformational characteristics. StII-mediated DC maturation was abrogated in BM-DCs from toll-like receptor (TLR) 4 and myeloid differentiation primary response gene 88 (MyD88)-knockout mice but not in cells from TLR2-knockout mice. Furthermore, the antigen-specific CTL response induced by StII-containing liposomes was reduced in TLR4-knockout mice. These results indicate that StII, and probably by extension StI, has the ability to induce maturation of DCs through a TLR4/MyD88-dependent pathway, and that this activation contributes to the CTL response generated by StII-containing liposomes.
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http://dx.doi.org/10.1016/j.molimm.2020.12.032DOI Listing
March 2021

Incidence, Characteristics, Laboratory Findings and Outcomes in Acro-Ischemia in COVID-19 Patients.

Vasc Health Risk Manag 2020 24;16:467-478. Epub 2020 Nov 24.

Vascular Surgery Department, Asturias University Central Hospital (HUCA), Oviedo, Spain.

Aim: In addition to its respiratory impact of SARS-CoV2, skin lesions of probable vascular origin have been described. This study intends to quantify the incidence of acro-ischemic lesions in COVID-19 infected adult subjects in our population, describing clinical patterns and associated findings.

Methods: All adult confirmed cases of COVID-19 infection who presented with acro-ischemic lesions and received care in our institution were prospectively enrolled up to May 15th, 2020. The variables included demographics, comorbidities, analytical parameters, clinical presentations and COVID-19 treatment.

Results: We enrolled 24 patients. The overall rate of acro-ischemic findings in COVID-19 patients was 1.2% [0.6% for outpatients and 2.9% for hospitalized (ICU and non-ICU patients)], but the observed incidence for acro-ischemia in ICU patients was remarkably higher (23.0%, p<0.001). We have described four different clinical patterns of acroischemia: atypical Raynaud´s phenomenon (ARP), (4); pseudo-pernio (PP), (5); severe microcirculatory ischemia with preserved pulse (SMI), (6); and dry gangrene with arteriosclerosis obliterans (AO), (9). Kendall´s τ correlation with lung disease severity was 0.877 (95% CI, 0.756 to 0.968); p<0.01). ARP individuals were predominantly female, while SMI appeared lately in elderly hospitalized subjects with better prognosis. AO occurred in patients with more comorbidity and younger than those with SMI. We observed other associated lesions of suggestive ischemic nature in other organs in all groups (15 patients of total sample). Plasma procalcitonin was significantly higher in patients who developed SMI (median and interquartile range: 9.99 (4.2, 12.3) mg/mL vs 0.26 (0.11, 0.89) mg/mL; p<0.001), and D-dimer level at hospital admission was significantly higher in AO patients (median and interquartile range: 1166 (1050, 2111) mg/L vs 502 (448, 777) mg/L; p<0.001).

Conclusion: The observed risk for acroischemia in COVID-19 is high in ICU patients (23%). We have described four different clinical patterns of acroischemia (ARP, PP, SMI and AO) associated with lung disease severity. Authors have communicated various lesions of suggestive ischemic nature in other organs. Raynaud-like pattern is reported as a "novelty".
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http://dx.doi.org/10.2147/VHRM.S276530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699992PMC
December 2020

Galileo Broadcast Ephemeris and Clock Errors Analysis: 1 January 2017 to 31 July 2020.

Sensors (Basel) 2020 Nov 29;20(23). Epub 2020 Nov 29.

Research Group of Astronomy and Geomatics (gAGE), Universitat Politècnica de Catalunya (UPC), 08034 Barcelona, Spain.

A preliminary analysis of Galileo F/NAV broadcast Clock and Ephemeris is performed in this paper with 43 months of data. Using consolidated Galileo Receiver Independent Exchange (RINEX) navigation files, automated navigation data monitoring is applied from 1 January 2017 to 31 July 2020 to detect and verify potential faults in the satellite broadcast navigation data. Based on these observation results, the Galileo Signal-in-Space is assessed, and the probability of satellite failure is estimated. The Galileo nominal ranging accuracy is also characterized. Results for GPS satellites are included in the paper to compare Galileo performances with a consolidated constellation. Although this study is limited by the short observation period available, the analysis over the last three-year window shows promising results with Psat = 3.2 × 10/sat, which is below the value of 1 × 10 stated by the Galileo commitments.
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http://dx.doi.org/10.3390/s20236832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731340PMC
November 2020

Effect of hCG application at different moments of the estrous cycle on corpus luteum and uterine vascularization and serum progesterone concentration in mares.

Anim Reprod 2019 Oct 24;16(2):317-327. Epub 2019 Oct 24.

Laboratory of Semen Biotechnology and Andrology, Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of Sao Paulo (USP), Pirassununga, São Paulo, Brazil.

Establishment of pregnancy after embryo transfer is the ultimate goal of an embryo transfer program and increasing pregnancy rates and reducing pregnancy loss are mandatory. The utilization of treatments to improve conception rates in recipient mares has been the focus of several research groups over the last years and the results are controversial. Some studies using human chorionic gonadotrophin (hCG) found promising results. Our hypothesis was that hCG administration would cause an additional stimulation on luteal function, uterine and luteal vascularization and progesterone concentration, and the mares would have increased uterine and cervix tone. Therefore, in the present study the effects of hCG administration to induce ovulation, on day 0 (day of ovulation) or day 5 postovulation were evaluated on corpus luteum characteristics, reproductive tract vascularization, and serum progesterone concentration from ovulation until day 15 postovulation. Groups were: G1: (control) - no hCG; G2: 2500 IU of hCG to induce ovulation when a follicle greater than 35mm and uterine edema were detected; G3: 2500 IU hCG on day 0; G4: 2500 IU hCG on day 5 postovulation. Twelve mares were randomly assigned to each group, during consecutive cycles, in a Latin Square experimental design, in a total of 48 cycles. Doppler ultrasound evaluations were performed daily from day 0 until day 15 postovulation, including mesometrial vascularity, endometrial vascularity and corpus luteum vascularity. Blood samples were collected for serum progesterone concentration. Data was analyzed using the Proc Glimmix SAS Procedure for nonparametric variables and Proc Mixed for parametric parameters. There was no treatment effect for all variables studied (P > 0.05). Characteristics were only affected by day (P < 0.05). It can be concluded that hCG administration at the time points suggested in the current study did not alter the characteristics evaluated.
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http://dx.doi.org/10.21451/1984-3143-AR2018-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673598PMC
October 2019

Clones of enterotoxigenic and Shiga toxin-producing Escherichia coli implicated in swine enteric colibacillosis in Spain and rates of antibiotic resistance.

Vet Microbiol 2021 Jan 9;252:108924. Epub 2020 Nov 9.

Laboratorio de Referencia de Escherichia coli (LREC), Departamento de Microbioloxía e Parasitoloxía, Facultade de Veterinaria, Universidade de Santiago de Compostela (USC), Lugo, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain. Electronic address:

Shiga toxin-producing E. coli (STEC) and enterotoxigenic E. coli (ETEC) are the main agents of swine colibacillosis, an infectious disease which implies important economic losses. We characterized here 186 diarrheagenic E. coli from Spanish industrial pig farms (2005-2017) to know which clones were involved in this syndrome, and the rates of antibiotic resistance. The PCR based on pathotype-associated virulence genes determined that 161 of 186 isolates (86.5 %) exhibited the ETEC pathotype, 10 (5.4 %) the STEC pathotype, and 15 (8.1 %) the hybrid ETEC/STEC pathotype. The majority of the isolates showed phylogroup A (85.5 %), clonotype CH11-24 (72 %) and belonged to the clonal complex (CC) 10, including two ETEC clones accounting for around 50 % of the 186 isolates: O157:HNM-A-ST10 (CH11-24), which exhibited mostly the fimbrial antigen F4ac; and O108:HNM-A-ST10 (CH11-24), which exhibited mainly F18. Other associations were O139:H1-E-ST1 (CH2-54) with the STEC pathotype, and both O141:H4-A-CC10 (CH11-24) and O138:HNM-E-ST42 (CH28-41) with ETEC/STEC. We found that 87.1 % of the isolates were multidrug-resistant, including 9% ESBL-producers, with the highest rates to nalidixic acid (82 %), colistin (77 %), ticarcillin (76 %) and ampicillin (76 %). Besides, more than 50 % of isolates showed non-susceptibility to gentamicin, tobramycin, doxycycline, ciprofloxacin, trimethoprim-sufamethoxazole and chloramphenicol. Additionally, 11 out of 17 ESBL-producing isolates were mcr-carriers. Results suggest that O108:HNM-A-ST10 (CH11-24) F18 is an emerging clone taking space left by other classical serogroups. Further follow-up studies on predominant clones in pig colibacillosis are essential for the update of vaccines, as alternative to the use of antibiotics.
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http://dx.doi.org/10.1016/j.vetmic.2020.108924DOI Listing
January 2021

Molecular Characteristics of Extraintestinal Pathogenic (ExPEC), Uropathogenic (UPEC), and Multidrug Resistant Isolated from Healthy Dogs in Spain. Whole Genome Sequencing of Canine ST372 Isolates and Comparison with Human Isolates Causing Extraintestinal Infections.

Microorganisms 2020 Oct 31;8(11). Epub 2020 Oct 31.

Laboratorio de Referencia de E. coli (LREC), Departamento de Microbioloxía e Parasitoloxía, Facultade de Veterinaria, Universidade de Santiago de Compostela (USC), 27002 Lugo, Spain.

Under a one health perspective and the worldwide antimicrobial resistance concern, we investigated extraintestinal pathogenic (ExPEC), uropathogenic (UPEC), and multidrug resistant (MDR) from 197 isolates recovered from healthy dogs in Spain between 2013 and 2017. A total of 91 (46.2%) isolates were molecularly classified as ExPEC and/or UPEC, including 50 clones, among which (i) four clones were dominant (B2-CH14-180-ST127, B2-CH52-14-ST141, B2-CH103-9-ST372 and F-CH4-58-ST648) and (ii) 15 had been identified among isolates causing extraintestinal infections in Spanish and French humans in 2015 and 2016. A total of 28 (14.2%) isolates were classified as MDR, associated with B1, D, and E phylogroups, and included 24 clones, of which eight had also been identified among the human clinical isolates. We selected 23 ST372 strains, 21 from healthy dogs, and two from human clinical isolates for whole genome sequencing and built an SNP-tree with these 23 genomes and 174 genomes (128 from canine strains and 46 from human strains) obtained from public databases. These 197 genomes were segregated into six clusters. Cluster 1 comprised 74.6% of the strain genomes, mostly composed of canine strain genomes ( < 0.00001). Clusters 4 and 6 also included canine strain genomes, while clusters 2, 3, and 5 were significantly associated with human strain genomes. Finding several common clones and clone-related serotypes in dogs and humans suggests a potentially bidirectional clone transfer that argues for the one health perspective.
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http://dx.doi.org/10.3390/microorganisms8111712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716232PMC
October 2020

Streptococcus suis spondylodiscitis: 2 new cases and a literature review.

Enferm Infecc Microbiol Clin 2020 Oct 14. Epub 2020 Oct 14.

Unidad de Enfermedades Infecciosas, Hospital Universitario Lucus Augusti, Lugo, España.

Introduction: Streptococcus suis (S. suis) infection is poorly described zoonosis in our country, which is related with exposure to pigs or their meat. The most common clinical presentation is meningitis, while spinés involvement is rare.

Methods: We report 2 cases of S. suis infection and perform a systematic review of the articles published on S. suis spondylodiscitis between January 1994 and May 2020 with the aim of defining the clinical characteristics, predisposing factors and evolution.

Results: 17 cases are described, 76.5% males with a mean age of 57.6 years, generally without associated underlying disease. Enolism was a factor present in 17.6%. 70.6% had exposure to pigs or their meat and 20% hand injuries. The mean duration of symptoms was 10.2 days and the most affected segment was the lumbar level. 70.6% had meningitis. All were treated with beta-lactams with an average duration of 53.2 days. There was a recurrence and none died.

Conclusion: There are few cases of S. suis spondylodiscitis in the literature. When occurs, it is associated with another type of infection in most cases. They present a good response to medical treatment and a good prognosis.
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http://dx.doi.org/10.1016/j.eimc.2020.08.005DOI Listing
October 2020