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Cisplatin (cis-diamminedichloroplatinum II; CDDP) is a widely used cytostatic agent; however, it tends to promote kidney and liver disease, which are a major signs of drug-induced toxicity. Platinum compounds are often presented as alternative therapeutics and subsequently easily dispersed in the environment as contaminants. Due to the major roles of the liver and kidneys in removing toxic materials from the human body, we performed a comparative study of the amino acid profiles in chicken liver and kidneys before and after the application of CDDP and platinum nanoparticles (PtNPs-10 and PtNPs-40). The treatment of the liver with the selected drugs affected different amino acids; however, Leu and Arg were decreased after all treatments. The treatment of the kidneys with CDDP mostly affected Val; PtNPs-10 decreased Val, Ile and Thr; and PtNPs-40 affected only Pro. In addition, we tested the same drugs on two healthy cell lines, HaCaT and HEK-293, and ultimately explored the amino acid profiles in relation to the tricarboxylic acid cycle (TCA) and methionine cycle, which revealed that in both cell lines, there was a general increase in amino acid concentrations associated with changes in the concentrations of the metabolites of these cycles.

ObjectiveTo determine the optimal ultrasound (US) cut-off values for cranial and extracranial arteries intima media thickness (IMT) to discriminate between patients with and without giant cell arteritis (GCA).MethodsRetrospective observational study including patients referred to an US fast-track clinic. All patients underwent bilateral US examination of the cranial and extracranial arteries including the IMT measurement. Clinical confirmation of GCA after 6 months was considered the gold standard for diagnosis. A receiver operating characteristic (ROC) analysis was performed to select the cut-off values on the basis of the best tradeoff values between sensitivity and specificity.ResultsA total of 157 patients were included, 47 (29.9%) with clinical confirmation of GCA after 6 months. 41 (87.2%) of patients with GCA had positive US findings (61.7% had cranial and 44.7% extracranial involvement). The best threshold IMT values were 0.44 mm for the common temporal artery; 0.34 mm for the frontal branch; 0.36 mm for the parietal branch; 1.1 mm for the carotid artery and 1 mm for the subclavian and axillary arteries. The areas under the ROC curves were greater for axillary arteries 0.996 (95% CI 0.991–1), for parietal branch 0.991 (95% CI 0.980–1), for subclavian 0.990 (95% CI 0.979–1), for frontal branch 0.989 (95% CI 0.976–1), for common temporal artery 0.984 (95% CI 0.959–1) and for common carotid arteries 0.977 (95% CI 0.961–0.993).ConclusionIMT cut-off values have been identified for each artery. These proposed IMT cut-off values may help to improve the diagnostic accuracy of US in clinical practice.

Cet article rend compte de la présence du motif du jardin d’Éden et de sa signification dans deux romans d’Antonio Muñoz Molina, Beatus ille (1986) et La noche de los tiempos (2009). Il propose une approche descriptive qui répertorie les occurrences de ce motif et ses ramifications – la rencontre amoureuse, la métaphore de l’île et du refuge, l’expulsion et l’exil – avant de proposer une interprétation idéologique de cette poétique qui montre que ce motif s’inscrit dans des structures narratives polarisées autour de la triade paradis/expulsion/exil qui font écho à la mémoire dominante du passé récent de l’Espagne contemporaine qui fait de la Transition un moment de réconciliation et de rédemption collective.

Abstract Metallothionein-3 has poorly characterized functions in neuroblastoma. Cisplatin-based chemotherapy is a major regimen to treat neuroblastoma, but its clinical efficacy is limited by chemoresistance. We investigated the impact of human metallothionein-3 (hMT3) up-regulation in neuroblastoma cells and the mechanisms underlying the cisplatin-resistance. We confirmed the cisplatin-metallothionein complex formation using mass spectrometry. Overexpression of hMT3 decreased the sensitivity of neuroblastoma UKF-NB-4 cells to cisplatin. We report, for the first time, cisplatin-sensitive human UKF-NB-4 cells remodelled into cisplatin-resistant cells via high and constitutive hMT3 expression in an in vivo model using chick chorioallantoic membrane assay. Comparative proteomic analysis demonstrated that several biological pathways related to apoptosis, transport, proteasome, and cellular stress were involved in cisplatin-resistance in hMT3 overexpressing UKF-NB-4 cells. Overall, our data confirmed that up-regulation of hMT3 positively correlated with increased cisplatin-chemoresistance in neuroblastoma, and a high level of hMT3 could be one of the causes of frequent tumour relapses.

Abstract Background Patients with Hailey-Hailey and Darier diseases present with disabling inflammatory lesions located in large skin folds, which are often exacerbated or induced by sweating. Quality of life is highly impaired because of pain and recurrent skin infections. An improvement in skin lesions after botulinum toxin A injections has previously been reported in some patients but no prospective interventional studies are available. The aim of this open-label, 6-month, interventional pilot study (NCT02782702) was to evaluate the effectiveness and safety of botulinum toxin A for patients with moderate to very severe skin lesions located in folds. Results Thirty patients (26 Hailey-Hailey/4 Darier) were included. Botulinum toxin A proved effective within the first month in two-thirds of patients, taking all study parameters (itchiness, cutaneous pain, sweating and odour, infections, psychosocial impairment and quality of life) into account and persisted during the 6-month follow-up period. No patient was classed as a BtxA non-responder, but 11 (37%) Hailey-Hailey patients (the most severe ones), experienced a relapse during the study. No serious side effects were reported. Mild transient clear fluid discharge at the site of the injections was reported for 27% of patients. Conclusions Botulinic toxin seems to be an effective and safe treatment for Hailey-Hailey and Darier diseases. Nevertheless, it may prove insufficient for the severest of Hailey-Hailey cases and could be considered as supplementary to other conventional treatments. Further studies are required to confirm our results on larger Darier cohorts.

Abstract The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR), and also facilitates the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. In contrast to σ1R deficient mice, σ2R knockout mice developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R−/− mice and diminished in σ2R−/− mice. The analgesic effect of morphine was increased in σ2R−/− mice by treatment with S1RA. However, σ2R−/− mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55,212-2 and the α2-adrenergic receptor agonist clonidine. Therefore, while σR1 inhibits and σ2R facilitates MOR-mediated analgesia these receptors exchange their roles when regulating neuropathic pain perception. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.

Neuronal differentiation is a complex process through which newborn neurons acquire the morphology of mature neurons and become excitable. We employed a combination of functional and transcriptomic approaches to deconvolute and identify key regulators of the differentiation process of a DRG neuron-derived cell line, and we focused our study on the NaV1.5 ion channel (encoded by Scn5a) as a channel involved in the acquisition of DRG neuronal features. Overexpression of Scn5a enhances the acquisition of neuronal phenotypic features and increases the KCl-elicited hyperexcitability response in a DRG-derived cell line. Moreover, pharmacologic inhibition of the NaV1.5 channel during differentiation hinders the acquisition of phenotypic features of neuronal cells and the hyperexcitability increase in response to changes in the extracellular medium ionic composition. Taken together, these data highlight the relevance of sodium transients in regulating the neuronal differentiation process in a DRG neuron-derived cell line.

Abstract Background Currently, the diagnosis and treatment of neuroblastomas—the most frequent solid tumors in children—exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides. Results The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (

[This corrects the article DOI: 10.1371/journal.pone.0163983.].

Introducción: La intubación traqueal, además de formar parte de la atención a pacientes críticos, puede conllevar diferentes complicaciones. Una presión inadecuada dentro del manguito del tubo endotraqueal es el principal factor de riesgo. Objetivo: Evaluar la presión del neumotaponamiento del tubo en los pacientes adultos en el servicio de urgencias. Métodos: Diseño observacional, analítico. Se analizaron 60 procedimientos de intubación endotraqueal por personal médico de urgencias. La presión del neumotaponamiento fue calculada de forma empírica, posteriormente registrada con un manómetro en cmH2O. Se compararon las diferentes categorías con la presión de insuflado. Se utilizó análisis descriptivo, chi cuadrada de Pearson y ANOVA de un factor. Se consideró significativo un grado de significación (p) menor a 0.05. Resultados: Se incluyeron 60 pacientes. El 77% fueron neumotaponamientos suprainsuflados y el 23% normoinsuflados. El 64% de las intubaciones las realizaron residentes de 3.er año de urgencias. El volumen administrado al neumotaponamiento fue entre 4 y 10 ml. La presión de insuflado fue de 22 a 45 cmH2O, sin diferencia significativa entre el personal que manipuló el globo. Conclusiones: La presión del neumotaponamiento del tubo endotraqueal insuflado de manera empírica en los pacientes adultos en el servicio de urgencias es mayor al límite normal.

A series of novel 1-N-α-d-glucopyranosyl-1H-1,2,3-triazole xanthines was synthesized from azido sugars (glucose, galactose, and lactose) and propargyl xanthines (theophylline and theobromine) using a typical copper (I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition. The corrosion inhibition activities of these new carbohydrate-xanthine compounds were evaluated by studying the corrosion of API 5 L X70 steel in a 1 M HCl medium. The results showed that, at 10 ppm, a 90% inhibition efficiency was reached by electrochemical impedance spectroscopy. The inhibitory efficiency of these molecules is explained by means of quantum chemical calculations of the protonated species with the solvent effect, which seems to better represent the actual situation of the experimental conditions. Some quantum chemical parameters were analyzed to characterize the inhibition performance of the tested molecules.

PurposeThe chick chorioallantoic membrane (CAM) assay can provide an alternative versatile, cost-effective, and ethically less controversial in vivo model for reliable screening of drugs. In the presented work, we demonstrate that CAM assay (in ovo and ex ovo) can be simply employed to delineate the effects of cisplatin (CDDP) and ellipticine (Elli) on neuroblastoma (Nbl) cells in terms of their growth and metastatic potential.MethodsThe Nbl UKF-NB-4 cell line was established from recurrent bone marrow metastases of high-risk Nbl (stage IV, MYCN amplification, 7q21 gain). Ex ovo and in ovo CAM assays were optimized to evaluate the antimetastatic activity of CDDP and Elli. Immunohistochemistry, qRT-PCR, and DNA isolation were performed.ResultsEx ovo CAM assay was employed to study whether CDDP and Elli exhibit any inhibitory effects on growth of Nbl xenograft in ex ovo CAM assay. Under the optimal conditions, Elli and CDDP exhibited significant inhibition of the size of the primary tumor. To study the efficiency of CDDP and Elli to inhibit primary Nbl tumor growth, intravasation, and extravasation in the organs, we adapted the in ovo CAM assay protocol. In in ovo CAM assay, both studied compounds (CDDP and Elli) exhibited significant (p < 0.001) inhibitory activity against extravasation to all investigated organs including distal CAM.ConclusionsTaken together, CAM assay could be a helpful and highly efficient in vivo approach for high-throughput screening of libraries of compounds with expected anticancer activities.

The super-cationic peptide dendrimers (SCPD) family is a valuable class of antimicrobial peptide candidates for the future development of antibacterial agents against multidrug-resistant gram-negative bacteria. The deep knowledge of their mechanism of action is a major challenge in research, since it may be the basis for future modifications/optimizations. In this work we have explored the interaction between SCPD and membranes through biophysical and microbiological approaches in the case of the G1OLO-L2OL2 peptide. Results support the idea that the peptide is not only adsorbed or close to the surface of the membrane but associated/absorbed to some extent to the hydrophobic-hydrophilic region of the phospholipids. The presence of low concentrations of the peptide at the surface level is concomitant with destabilization of the cell integrity and this may contribute to osmotic stress, although other mechanisms of action cannot be ruled out.

Sigma-1 receptor (σ1R) ligands have been shown to be effective at relieving neuropathic and inflammatory pain, but have not yet been tested in experimental models of fibromyalgia. The objective of this study was to evaluate the effect of a σ1R antagonist (BD1063) compared to pregabalin. ICR-CD1 female mice were subjected to either six repeated injections of reserpine, to cause reserpine-induced myalgia (RIM6), or acidified saline intramuscular injections (ASI). In these two models, we evaluated the effect of BD1063 and pregabalin on thermal hypersensitivity, anxiety-like and depression-like behaviors, and on spinal cord gliosis. BD1063 exerted an antinociceptive effect on both reflexive (thermal hyperalgesia) and nonreflexive (anxiety- and depression-like) pain behaviors, and reduced spinal astroglial and microglial reactivity, following repeated treatment for 2 weeks. Interestingly, the effects of BD1063 were long-term, lasting several weeks after treatment discontinuation in both fibromyalgia-like models. Similar results were obtained with pregabalin, but the effects on pain behaviors lasted for a shorter length of time, and pregabalin did not significantly modulate spinal glial reactivity. The inhibitory and long-lasting effect of pharmacological blockade of σ1Rs on both sensory and affective dimensions of nociplastic-like pain and spinal cord gliosis in two experimental models of fibromyalgia support the application of this therapeutic strategy to treat fibromyalgia.

Singularizando el lugar del arte en el contexto escolar argentino, particularmente en la provincia de Buenos Aires, nos proponemos indagar perspectivas curriculares de finales del siglo XX. Específicamente nos interesa identificar y analizar las consideraciones de su enseñanza en los documentos producidos entre 1984 y 1999. Interpelar la consideración de Educación Estética que proponen los documentos del período 1984-1987, y las fundamentaciones de Educación Artística que presentan las publicaciones producidas entre 1995-1999. Partimos de la hipótesis de que entre una y otra denominación encontramos superposiciones de sentidos en los discursos pedagógicos sobre la presencia y las funciones del arte en la escolaridad bonaerense. A la luz de nuestro objetivo principal, elaboramos un mapeo de los diferentes lineamientos oficiales, esto es presentación, descripción y ordenamiento de los mismos, desde una mirada etnográfica sobre los documentos, que implica reconocer aquello que se produce en el campo de lo estatal como un campo de investigación en sí (Muzzopapa E., Villalta C., 2011).

En Guatemala en el 2015, el Ministerio de Salud Pública y Asistencia Social (MSPAS) reportó nuevos casos de la enfermedad de Chagas en la región suroriental del país, siendo Santa Rosa uno de los departamentos endémicos en donde Triatoma dimidiata es el principal transmisor. Se estimó la infestación de T. dimidiata en la aldea Chuchuapa, municipio de Santa María Ixhuatán, de abril a junio de 2019, se calcularon los índices entomológicos y se caracterizaron intra y peridomiciliar 149 viviendas (79.67% de las viviendas habitadas). Los datos se obtuvieron mediante un cuestionario mixto, en entrevista cara a cara y evaluación de las viviendas, por un equipo profesional experimentado, mediante el método y protocolo estándar hombre-hora. Se capturaron 20 triatominos en 10 viviendas, con un índice de infestación de 6.71% (10/149), un índice de densidad de 13.42% (20/149), 19 triatominos intradomiciliares y uno peridomiciliar, con un índice de infección natural por Trypanosoma cruzi intradomiciliar de 26.3% (5/19), índice de infección natural por T. cruzi peridomiciliar de 100.0% (1/1) e índice de infección natural por T. cruzi en los triatominos capturados de 30.0 % (6/20). Las viviendas infestadas presentaron techo de lámina, pared de bajareque con grietas y sin repello, piso de tierra y afiches en la pared, acumulación de leña u otros materiales tanto intra como peridomiciliar, convivencia con animales domésticos y tenencia de animales de corral. Los resultados representan un alto riesgo para la transmisión de la enfermedad de Chagas entre los habitantes de la aldea.

Human-adapted bacterial pathogens have evolved specific mechanisms to colonize their host niche. Phase variation is a contingency strategy to allow adaptation to changing conditions, as phase-variable bacterial loci rapidly and reversibly switch their expression.

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