Mapping mental health care services for children and youth population in Colombia's Pacific: potential for boundary spanning between community and formal services.

BACKGROUND: Conflict and violence can impact on the mental health of children and young people, who are in a crucial stage of their personal growth. Not much is known about the provision of mental health care to young people in conflict-affected areas. Community-based care can be essential, as state-led services are often scarce in conflict contexts, like Colombia's Pacific region where this research was conducted. According to the WHO, such care is ideally provided in the form of a network of interconnected services, offered by different actors beyond the formal health sector. This article describes the relationship between the formal and community mental health systems in Colombia's Pacific region, and identifies ways of improving their interaction. METHODS: Qualitative data were collected through 98 semi-structured interviews with community organisations, schools, international organisations and state institutions. These interviews aimed to identify the strategies used to promote young people's mental health and the interactions between the different providers. Boundary spanning theory was used to analyse how different actors and forms of mental health care provision could coordinate better. RESULTS: Community organisations and schools use a wide array of strategies to attend to the mental health of children and young people, often of a collective and psychosocial nature. State institutions offer more clinically focused strategies, which are however limited in terms of accessibility and continuity. International organisations aim to strengthen state capacity, but often struggle due to high staff turnover. Although mental health care pathways exist, their effectiveness is limited due to ineffective coordination between actors. CONCLUSIONS: To make sure that the variety of strategies to improve young people's mental health effectively reach their beneficiaries, better coordination is needed between the different actors. Mental health care pathways should therefore integrate community organisations, while community connectors can help to manage the coordination between different actors and forms of clinical and psychosocial support.

Carbapenem-Resistant Gram-Negative Bacilli Characterization in a Tertiary Care Center from El Bajio, Mexico.

Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a major public health concern. We aimed to evaluate the prevalence of CR-GNB and the frequency of carbapenemase-encoding genes in a tertiary referral center from El Bajio, Mexico. A cross-sectional study was conducted between January and October 2022; Gram-negative bacilli (GNB) were screened for in vitro resistance to at least one carbapenem. CR-GNB were further analyzed for carbapenemase-production through phenotypical methods and by real-time PCR for the following genes: blaKPC, blaGES, blaNDM, blaVIM, blaIMP, and blaOXA-48. In total, 37 out of 508 GNB were carbapenem-resistant (7.3%, 95% CI 5.2-9.9). Non-fermenters had higher rates of carbapenem resistance than Enterobacterales (32.5% vs. 2.6%; OR 18.3, 95% CI 8.5-39, p < 0.0001), and Enterobacter cloacae showed higher carbapenem resistance than other Enterobacterales (27% vs. 1.4%; OR 25.9, 95% CI 6.9-95, p < 0.0001). Only 15 (40.5%) CR-GNB had a carbapenemase-encoding gene; Enterobacterales were more likely to have a carbapenemase-encoding gene than non-fermenters (63.6% vs. 30.8%, p = 0.08); blaNDM-1 and blaNDM-5 were the main genes found in Enterobacterales; and blaIMP-75 was the most common for Pseudomonas aeruginosa. The mcr-2 gene was harbored in one polymyxin-resistant E. cloacae. In our setting, NDM was the most common carbapenemase; however, less than half of the CR-GNB showed a carbapenemase-encoding gene.

The Glycan Structure Dictionary-a dictionary describing commonly used glycan structure terms.

Recent technological advances in glycobiology have resulted in a large influx of data and the publication of many papers describing discoveries in glycoscience. However, the terms used in describing glycan structural features are not standardized, making it difficult to harmonize data across biomolecular databases, hampering the harvesting of information across studies and hindering text mining and curation efforts. To address this shortcoming, the Glycan Structure Dictionary has been developed as a reference dictionary to provide a standardized list of widely used glycan terms that can help in the curation and mapping of glycan structures described in publications. Currently, the dictionary has 190 glycan structure terms with 297 synonyms linked to 3,332 publications. For a term to be included in the dictionary, it must be present in at least 2 peer-reviewed publications. Synonyms, annotations, and cross-references to GlyTouCan, GlycoMotif, and other relevant databases and resources are also provided when available. The purpose of this effort is to facilitate biocuration, assist in the development of text mining tools, improve the harmonization of search, and browse capabilities in glycoinformatics resources and help to map glycan structures to function and disease. It is also expected that authors will use these terms to describe glycan structures in their manuscripts over time. A mechanism is also provided for researchers to submit terms for potential incorporation. The dictionary is available at https://wiki.glygen.org/Glycan_structure_dictionary.

Cardiomiopatía por estrés con membrana de oxigenación extracorpórea V-A durante el puerperio. Reporte de un caso y revisión de la literatura / Stress cardiomyopathy with extracorporeal oxygenation membrane V-A during the puerperium. Case report and literature review / Cardiomiopatia de estresse com oxigenação por membrana extracorpórea V-A durante o puerpério. Relato de caso e análise literária

Resumen: Se presenta un caso de una mujer de 28 años, primera gesta, embarazo normoevolutivo, quien acudió a atención de parto, se realizó cesárea por falta de progresión. Durante el perioperatorio desarrolló atonía uterina y sangrado (2,000 mL), por lo que se le realizó histerectomía subtotal abdominal, embolización selectiva de vasos pélvicos, transfusión masiva y empaquetamiento pélvico. Evolucionó con vasoplejía y perfil hemodinámico compatible con choque cardiogénico, ecocardiograma transtorácico con disfunción sistólica severa, fracción de eyección de ventrículo izquierdo (FEVI) 18%, contractilidad normal en los tercios basales de la pared lateral. El resto de los segmentos con hipocinesia severa, NT-pro BNP 9,226 pg/mL, troponina de alta sensibilidad 490 pg/mL, electrocardiograma con taquicardia sinusal sin datos de lesión. Se estableció el diagnóstico de Takotsubo (miocardiopatía por estrés). Se colocó membrana de oxigenación extracorpórea (ECMO) V-A y balón de contrapulsación intraaórtica. Desarrolló lesión renal aguda y sobrecarga hídrica, por lo que se inició terapia de sustitución renal. La terapia ECMO se mantuvo durante nueve días, y se egresó a domicilio a los 18 días. El ECMO es una estrategia terapéutica para el soporte hemodinámico del choque cardiogénico incluyendo la cardiomiopatía por estrés; este caso ilustra su utilidad en el puerperio.

Abstract: We present a case of a 28-year-old woman currently in her first pregnancy, normal evolution, who attended delivery care, a cesarean section was performed due to lack of progression. During the perioperative period, she developed uterine atony and bleeding of 2,000 mL, for which she underwent a subtotal abdominal hysterectomy, selective embolization of the pelvic vessels, massive transfusion, and pelvic packing. She evolved with vasoplegia and hemodynamic profile compatible with cardiogenic shock, transthoracic echocardiogram exposes severe systolic dysfunction, LVEF 18%, normal contractility in the basal thirds of the lateral wall, the rest of the segments with severe hypokinesia, NT-pro BNP 9,226 pg/mL, high-sensitivity troponin 490 pg/mL, electrocardiogram whit sinus tachycardia with no evidence of injury, the diagnosis of Takotsubo (stress cardiomyopathy) was established. Extracorporeal membrane oxygenation (ECMO) V-A and intra-aortic balloon counterpulsation were placed. Acute kidney injury developed, and fluid overload, for which renal replacement therapy was started. ECMO therapy was maintained for nine days, and she was discharged home after 18 days. ECMO is an innovative therapeutic strategy for hemodynamic support of cardiogenic shock, including stress cardiomyopathy, and this case illustrates its potential utility in the postpartum period.

Resumo: Apresenta-se o caso de uma mulher de 28 anos, primigesta, gravidez evolução normal, que assistiu ao parto, tendo sido submetida a cesariana por falta de evolução. No período perioperatório, apresentou atonia uterina e sangramento (2,000 mL), sendo submetida a histerectomia abdominal subtotal, embolização seletiva de vasos pélvicos, transfusão maciça e tamponamento pélvico. Evoluiu com vasoplegia e quadro hemodinâmico compatível com choque cardiogênico, ecocardiograma transtorácico com disfunção sistólica grave, FEVE 18%, contratilidade normal nos terços basais da parede lateral, restante dos segmentos com hipocinesia grave, NT-pro BNP 9,226 pg/mL, troponina de alta sensibilidade 490 pg/mL, eletrocardiograma com taquicardia sinusal sem evidência de lesão, foi estabelecido o diagnóstico de Takotsubo (cardiomiopatia de estresse). Colocou-se uma oxigenação por membrana extracorpórea (ECMO) V-A e um balão de contrapulsação intra-aórtico. Evoluiu com lesão renal aguda e sobrecarga hídrica, sendo iniciada terapia renal substitutiva. A terapia com ECMO foi mantida por 9 dias e ele recebeu alta após 18 dias. A ECMO é uma estratégia terapêutica para suporte hemodinâmico do choque cardiogênico, incluindo a cardiomiopatia de estresse, e este caso ilustra sua utilidade no puerpério.

Lesión pulmonar autoinfligida por el paciente / Patient self inflicted lung injury / Lesão pulmonar autoinfligida pelo paciente

Resumen: La optimización del esfuerzo espontáneo en la ventilación mecánica tiene un lugar central en la Unidad de Cuidados Intensivos; aporta beneficios a los pacientes como la mejoría en el intercambio de gases, ayuda a recuperar la función del diafragma y el mantenimiento de los músculos periféricos. Por otro lado, también puede estar asociado al deterioro de la oxigenación y la lesión pulmonar. El incremento del impulso respiratorio neural aumenta el esfuerzo muscular inspiratorio, lo que condiciona presiones de distensión pulmonar lesivas, que en el contexto del síndrome de insuficiencia respiratoria aguda es de vital relevancia, ya que puede provocar el colapso y la sobredistensión regional alveolar de forma cíclica, con distribución heterogénea del estrés y tensión pulmonar. Existen tres mecanismos de lesión pulmonar por esfuerzo espontáneo: sobredistensión, aumento de la perfusión pulmonar y asincronía paciente-ventilador. La lesión pulmonar causa fuga capilar, edema pulmonar y alteración del intercambio de gases. Esto conduce a un aumento del impulso respiratorio y mayores volúmenes corrientes de las propias respiraciones espontáneas del paciente, que provocan fuga capilar y mayor daño pulmonar de forma similar a la lesión pulmonar inducida por ventilador.

Abstract: The optimization of spontaneous effort in mechanical ventilation has a central place in the intensive care unit; provides benefits to patients such as improved gas exchange, helps to regain function of the diaphragm and maintenance of peripheral muscles. On the other hand, it can also be associated with impaired oxygenation and lung injury. The increase in the neural respiratory drive increases the inspiratory muscular effort, conditioning damaging pulmonary distension pressures, which in the context of acute respiratory distress syndrome is of vital importance, since it can cause collapse and regional alveolar overdistention in a cyclical way. with heterogeneous distribution of pulmonary stress and strain. There are three mechanisms of lung injury due to spontaneous effort: overdistention, increased pulmonary perfusion, and patient-ventilator asynchrony. Lung injury causes capillary leakage, pulmonary edema, and impaired gas exchange. This leads to increased respiratory drive and higher tidal volumes of the patient's own spontaneous breaths, causing capillary leakage and increased lung damage like ventilator-induced lung injury.

Resumo: A otimização do esforço espontâneo na ventilação mecânica tem lugar central na unidade de terapia intensiva; Proporciona benefícios aos pacientes como melhora nas trocas gasosas, auxilia na recuperação da função do diafragma e na manutenção da musculatura periférica. Por outro lado, também pode estar associada ao deterioro da oxigenação e lesão pulmonar. O incremento do impulso respiratório neural aumenta o esforço muscular inspiratório, condicionando pressões de distensão pulmonar prejudiciais, o que no contexto da síndrome de insuficiência respiratória aguda é de vital relevância, pois pode causar colapso e hiperdistensão alveolar regional de forma cíclica, com distribuição heterogênea do estresse e tensão pulmonar. Existem três mecanismos de lesão pulmonar espontânea por esforço: hiperdistensão, aumento da perfusão pulmonar e assincronia paciente-ventilador. A lesão pulmonar causa vazamento capilar, edema pulmonar e troca gasosa prejudicada. Isso leva ao aumento do impulso respiratório e aos volumes correntes mais altos das próprias respirações espontâneas do paciente, causando vazamento capilar e danos pulmonares adicionais semelhantes aos danos pulmonares induzidos pelo ventilador.

Carbohydrate-Derived Polytriazole Nanoparticles Enhance the Anti-Inflammatory Activity of Cilostazol.

Poly(amide-triazole) and poly(ester-triazole) synthesized from d-galactose as a renewable resource were applied for the synthesis of nanoparticles (NPs) by the emulsification/solvent evaporation method. The NPs were characterized as stable, spherical particles, and none of their components, including the stabilizer poly(vinyl alcohol), were cytotoxic for normal rat kidney cells. These NPs proved to be useful for the efficient encapsulation of cilostazol (CLZ), an antiplatelet and vasodilator drug currently used for the treatment of intermittent claudication, which is associated with undesired side-effects. In this context, the nanoencapsulation of CLZ was expected to improve its therapeutic administration. The carbohydrate-derived polymeric NPs were designed taking into account that the triazole rings of the polymer backbone could have attractive interactions with the tetrazole ring of CLZ. The activity of the nanoencapsulated CLZ was measured using a matrix metalloproteinase model in a lipopolysaccharide-induced inflammation system. Interestingly, the encapsulated drug exhibited enhanced anti-inflammatory activity in comparison with the free drug. The results are very promising since the stable, noncytotoxic NP systems efficiently reduced the inflammation response at low CLZ doses. In summary, the NPs were obtained through an innovative methodology that combines a carbohydrate-derived synthetic polymer, designed to interact with the drug, ease of preparation, adequate biological performance, and environmentally friendly production.

Hypertensive Stimuli Indirectly Stimulate Lymphangiogenesis through Immune Cell Secreted Factors.

(1) Background: Renal immune cells and lymphatic vessel (LV) density have been reported previously to be increased in multiple mouse models of hypertension (HTN). However, whether interstitial levels of HTN stimuli such as angiotensin II, salt, or asymmetric dimethylarginine have a direct or indirect effect on lymphangiogenesis is unknown. We hypothesized that these 3 HTN stimuli directly increase lymphatic endothelial cell (LEC) proliferation, LEC 3-D matrix invasion and vessel formation, and sprouting of mouse mesometrial LVs. (2) Methods: Human LECs (hLECs) and mouse LECs (mLECs) were treated with HTN stimuli while explanted mouse mesometrial LVs were treated with either the same HTN stimuli or with HTN stimuli-conditioned media. Conditioned media was prepared by treating murine splenocytes with HTN stimuli. (3) Results: HTN stimuli had no direct effect on hLEC or mLEC proliferation. Treatment of hLECs with HTN stimuli increased the number of lumen-forming structures and invasion distance (both p < 0.05) in the 3-D matrix but decreased the average lumen diameter and the number of cells per invading structure (both p < 0.05). Conditioned media from HTN-stimuli-treated splenocytes significantly attenuated the decrease in sprout number (aside from salt) and sprout length of mouse mesometrial LVs that is found in the HTN stimuli alone. (4) Conclusions: These data indicate that HTN stimuli indirectly prevent a decrease in lymphangiogenesis through secreted factors from HTN-stimuli-treated immune cells.

Impacto de la nutrición enteral temprana en la mortalidad y días de estancia en la unidad de cuidados intensivos / Impact of early enteral nutrition over mortality and days of stay in the intensive care unit / Impacto da nutrição enteral precoce na mortalidade e dias de permanência na unidade de terapia intensiva

Resumen: Introducción: el retraso en el inicio de la nutrición enteral (NE), a diferencia de la NE precoz, está asociado a resultados adversos en los pacientes críticos. Objetivos: correlacionar el tiempo de inicio de la nutrición con la mortalidad, días de ventilación mecánica, estancia en la unidad de cuidados intensivos (UCI) y estancia hospitalaria. Material y métodos: se realizó un estudio tipo cohorte, retrospectivo, comparativo de los pacientes hospitalizados durante un periodo de enero a julio de 2022 en la Unidad de Cuidados Intensivos del Hospital Centro Médico ABC Campus Observatorio. Se incluyeron todos los pacientes ingresados que recibieron nutrición enteral. Resultados: de 242 pacientes, 62.8% son masculinos, con una mediana de edad de 65 (62.8-67.7) años, de los cuales 22% de la población requirió ventilación mecánica, encontrando una mortalidad global de 6.3%. Se observó diferencia significativa con p = 0.001, con un OR 0.210 (0.087-0.509) en la mortalidad de los pacientes con nutrición temprana 5.5 versus 13.2% nutrición tardía, sin diferencia en días de ventilación, estancia en la unidad de cuidados intensivos adultos (UCIA) ni hospitalización. Conclusiones: el retraso en la NE se asoció significativamente con menos días libres de UCI, estancia más prolongada en la UCI, hospitalizaciones más largas y mortalidad en comparación con la NE temprana.

Abstract: Introduction: the delay in the start of enteral nutrition (EN) or late EN, unlike early EN, is associated with adverse outcomes in critically ill patients. Objectives: to correlate the start time of nutrition with mortality, days of mechanical ventilation, Intensive Care Unit (ICU) and hospital length of stay. Material and methods: a retrospective, comparative, cohort study of hospitalized patients during the period from January to July 2022 in the ICU of the ABC Medical Center Observatory Campus was carried out. All hospitalized patients who received enteral nutrition were included. Results: of 242 patients, 62.8% were male, with a median age of 65 (62.8-67.7) years, 22% of the population required mechanical ventilation, finding an overall mortality of 6.3%. A significant difference was found with p = 0.001, with an OR 0.210 (0.087-0.509) in the mortality of patients with early nutrition 5.5 vs 13.2% late nutrition, without difference in days of mechanical ventilation, ICU or hospitalization length of stay. Conclusions: delayed EN was significantly associated with less ICU-free days, longer intrahospital length of stay and mortality, compared with early EN.

Resumo: Introdução: o atraso no início da nutrição enteral (NE) ou NE tardia, ao contrário da NE precoce, está associado a desfechos adversos em pacientes críticos. Objetivos: correlacionar o tempo de início da nutrição com mortalidade, dias de ventilação mecânica, internação na UTI e internação. Material e métodos: realizou-se um estudo de coorte, retrospectivo e comparativo de pacientes internados no período de janeiro a julho de 2022 na UTI do Hospital Centro Médico ABC Campus Observatorio. Todos os pacientes admitidos que receberam nutrição enteral foram incluídos. Resultados: dos 242 pacientes, 62.8% são do sexo masculino, com idade média de 65 (62.8-67.7) anos, dos quais 22% da população necessitou de ventilação mecânica, encontrando-se uma mortalidade geral de 6.3%. Uma diferença significativa foi encontrada com p = 0.001, com OR 0.210 (0.087-0.509) na mortalidade de pacientes com nutrição precoce 5.5 vs 13.2% nutrição tardia, sem diferença em dias de ventilação, permanência na UTI ou hospitalização. Conclusões: o atraso da NE foi significativamente associada a menos dias livres de UTI, estadias mais longas na UTI, internações mais longas e mortalidade, em comparação com NE precoce.

Concentration trend study on foaming properties for native soy protein isolate treated by ultrasound and heating.

Given the non-linearity of many protein properties with a short range of concentration which cannot be predicted a priori, and due to the lack of references in the food industry, we proceeded to analyze the foaming ones. The existing bibliography belongs to other fields of research but it is scarcely found for this area. For the food industry, ultrasound is considered one of the most environment-friendly processing. In addition, heating combination would alter their results considerably by synergistic or additive phenomena. Native soy protein isolate was obtained in our laboratory to use it as starting material; ultrasound with temperature was applied at 2, 4 and 6%w/w protein concentrations. Therefore, the objective of this paper was to determine the effect of ultrasound+temperature (50 or 90 °C) simultaneously applied, on the foamability by relating with the relative viscoelasticity, aggregates particle size distribution and their surface charge by zeta potential. The results indicated that treatments promoted changes on the functional parameters depending on the protein concentration. The analysis showed that at 4%wt/wt was adequate to improve foam formation and stability at same time. Dynamic rheology of continuous phase was relation with foamability showing the higher relative viscoelasticity at 4% of concentration after the combined treatment. Light scattering studies could partially explain this observation, taking into account both, the bulk viscosity and the low number of large particles formed after treating. Surface charge was increased for all concentrations equally leading to the aggregates formation of greater colloidal stability for all concentration and treatment conditions investigated. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s13197-020-04954-w).

Exploring the conformational dynamics of PD1 in complex with different ligands: What we can learn for designing novel PD1 signaling blockers?

Activation of T cells triggers the expression of regulatory molecules like the programmed cell death 1 (PD1) protein. The association of PD1 with the natural ligands PDL1 and PDL2 induces an inhibitory signal that prevents T cells from proliferating and exerting effector functions. However, little is known about how the binding of the ligands induce the PD1 inhibitory signal over T cells effector functions. Here, we explore the dynamics of PD1 free, and in complex with different PDL1 variants as well as the therapeutic antibodies nivolumab and pembrolizumab in order to assess the conformational changes in PD1 related to the signaling process. Our simulations suggest a pre-conformational selection mechanism for the binding of the different PDL1 variants, while an induced-fit model fits better for the molecular recognition process of the therapeutic antibodies. A deep analysis of the changes on PD1 movement upon the binding to different ligands revealed that as larger is the difference in the conformation adopted by loop C'D with respect to the complex with PDL1 is higher the ligand ability to reduce the PD1 inhibitory signaling. This behavior suggests that targeting specific conformations of this loop can be useful for designing therapies able to recover T cells effector functions.

Resveratrol encapsulation in high molecular weight chitosan-based nanogels for applications in ocular treatments: Impact on human ARPE-19 culture cells.

Oxidative stress and inflammation play a pivotal role in ocular diseases. Resveratrol (RSV) is a natural bioactive that has recently attracted attention due to it potent antioxidant and anti-inflammatory properties. However, RSV presents poor aqueous solubility and chemical instability. Besides, effective drug delivery to the posterior segment of the eye is challenge. Nanotechnology emerges as a possible solution to improve both limitations. Here, we developed and characterized nanogels (NG) based on high molecular weight chitosan (HCS) crosslinked with sodium tripolyphosphate. The distribution size of NG presented a major population around 140 nm with a ζ-potential value of 32 ± 2 mV. TEM and AFM images showed that NG exhibited a rounded morphology. RSV encapsulation efficiency was 59 ± 1%. Photodegradation experiments showed that HCS by its own protects RSV from UV light-induced degradation. Biocompatibility assays revealed that NG were not cytotoxic neither inflammatory in human retinal pigment epithelial cells (ARPE-19), which constitutes the outer blood-retinal barrier. After cellular internalization, we report an endo-lysosomal escape of NG, which is crucial for efficient nanocarriers delivery systems. In conclusion, we envision that HCS based NG could constitute novel carriers for RSV, opening the possibility of its application in ocular diseases.

Serum Kynurenines Correlate With Depressive Symptoms and Disability in Poststroke Patients: A Cross-sectional Study.

BACKGROUND: Poststroke depression (PSD) is related to adverse functional and cognitive prognosis in stroke patients. The participation of kynurenine pathway metabolites in depression has been previously proposed; however, there are few studies on its role in PSD and disability in stroke. OBJECTIVE: To investigate if there is a correlation between serum kynurenines levels with poststroke anxiety and depression symptoms and disability scales. METHODS: A cross-sectional case-control study was conducted in patients with first stroke, of >1 month and <1 year of evolution, with no history of previous psychiatric or neurological disorders; the Hospital Anxiety and Depression Scale (HADS), Montreal Cognitive Assessment (MoCA), functional evaluations (Barthel index, Functional Independence Measure [FIM]) were applied and serum kynurenines (Kyns) were determined. RESULTS: Sixty patients were included; significant depressive symptoms were found in 63% of the cases; a significant and positive correlation was obtained between levels of 3-hydroxykynurenine (3-HK) with HADS-T (r = 0.30, P = .025) and HADS-D (r = 0.28, P = .039). Depressed patients showed significantly higher levels of 3HK (P = .048) and KYNA (P = .0271) than nondepressed patients; the 3HK levels were inversely correlated with functional scales: Barthel index (r = -0.31, P = .02), FIM (r = -0.40, P = .01); in addition, serum 3HK levels were significantly higher in patients with poor sleep quality (P = .0190). CONCLUSIONS: Serum Kyns show correlation with the presence and severity of depressive symptoms and with the disability and sleep quality. Kyns may be a potential marker of depression risk and disability in stroke in future.

Structural characterization of nanoemulsions stabilized with sodium caseinate and of the hydrogels prepared from them by acid-induced gelation.

Hydrogels obtained by acidification with glucono-δ-lactone (GDL), starting from nanoemulsions formulated with different concentrations of sodium caseinate (1-4 wt%) or 4 wt% sodium caseinate and sucrose (2-8 wt%), were prepared with the aim of quantifying structural parameters of both, initial nanoemulsions and hydrogels after 2.5 h of GDL addition, using the Guinier-Porod (GP) or the generalized GP models. Gelation process was followed by performing in situ temperature-controlled X-ray small angle scattering experiments (SAXS) using synchrotron radiation. In nanoemulsions, the calculated radius of gyration for oil nanodroplets (Rg oil ) decreased with increasing protein concentration and for the 4 wt% protein nanoemulsion, with increasing sucrose content. Calculated values of Rg oil were validated correlating them with experimental Z-average values as measured by dynamic light scattering (DLS). For hydrogels, radii of gyration for the sphere equivalent to the hydrogel scattering object (R gsph ) were close to 3 nm while correlation distances among building blocks (R g2 ) were dependent on formulation. They increased with increasing contents of sodium caseinate and sucrose. R g2 parameter linearly correlated with hydrogel strength (G' ∞ ): a more connected nanostructure led to a stronger hydrogel.

Efficacy of direct current generated by multiple-electrode arrays on F3II mammary carcinoma: experiment and mathematical modeling.

BACKGROUND: The modified Gompertz equation has been proposed to fit experimental data for direct current treated tumors when multiple-straight needle electrodes are individually inserted into the base perpendicular to the tumor long axis. The aim of this work is to evaluate the efficacy of direct current generated by multiple-electrode arrays on F3II mammary carcinoma that grow in the male and female BALB/c/Cenp mice, when multiple-straight needle electrodes and multiple-pairs of electrodes are inserted in the tumor. METHODS: A longitudinal and retrospective preclinical study was carried out. Male and female BALB/c/Cenp mice, the modified Gompertz equation, intensities (2, 6 and 10 mA) and exposure times (10 and 20 min) of direct current, and three geometries of multiple-electrodes (one formed by collinear electrodes and two by pair-electrodes) were used. Tumor volume and mice weight were measured. In addition, the mean tumor doubling time, tumor regression percentage, tumor growth delay, direct current overall effectiveness and mice survival were calculated. RESULTS: The greatest growth retardation, mean doubling time, regression percentage and growth delay of the primary F3II mammary carcinoma in male and female mice were observed when the geometry of multiple-pairs of electrodes was arranged in the tumor at 45, 135, 225 and 325o and the longest exposure time. In addition, highest direct current overall effectiveness (above 66%) was observed for this EChT scheme. CONCLUSIONS: It is concluded that electrochemical therapy may be potentially addressed to highly aggressive and metastic primary F3II murine mammary carcinoma and the modified Gompertz equation may be used to fit data of this direct current treated carcinoma. Additionally, electrochemical therapy effectiveness depends on the exposure time, geometry of multiple-electrodes and ratio between the direct current intensity applied and the polarization current induced in the tumor.

Combined Experimental and Molecular Simulation Study of Insulin-Chitosan Complexation Driven by Electrostatic Interactions.

Protein-polysaccharide complexes constructed via self-assembly methods are often used to develop novel biomaterials for a wide range of applications in biomedicine, food, and biotechnology. The objective of this work was to investigate theoretically and to demonstrate via constant-pH Monte Carlo simulations that the complexation phenomenon between insulin (INS) and the cationic polyelectrolyte chitosan (CS) is mainly driven by an electrostatic mechanism. Experimental results obtained from FTIR spectra and ζ-potential determinations allowed us to complement the conclusions. The characteristic absorption bands for the complexes could be assigned to a combination of signals from CS amide I and INS amide II. The second peak corresponds to the interaction between the polymer and the protein at the level of amide II. INS-CS complexation processes not expected when INS is in its monomeric form, but for both tetrameric and hexameric forms, incipient complexation due to charge regulation mechanism took place at pH 5. The complexation range was observed to be 5.5 < pH < 6.5. In general, when the number of INS units increases in the simulation process, the solution pH at which the complexation can occur shifts toward acidic conditions. CS's chain interacts more efficiently, i.e. in a wider pH range, with INS aggregates formed by the highest monomer number. The charge regulation mechanism can be considered as a previous phase toward complexation (incipient complexation) caused by weak interactions of a Coulombic nature.

Quantitative assessment of extracellular IL-1 regulation.

IL-1 system is involved in the induction and maintenance of chronic inflammation associated with several autoimmune diseases and cancer, mainly due to its capacity to promote the secretion of inflammatory mediators. For this reason, several intracellular and extracellular mechanisms for this system have been fixed during the evolution. In spite of the large description of molecular interactions between IL-1 ligands and receptors, little is known about the relevance and limits of the extracellular regulatory mechanims in different scenarios. To tackle this problem, we developed and calibrated a mathematical model including all the known interactions between IL-1 ligands and IL-1Rs and calibrate it with experimental data of IL-1 binding to different cells. The model predicts that, independently on the IL-1Rs expression, IL-1α has more ability than IL-1ß to induce IL-1 signaling, which suggests that both ligands can be equally relevant for the IL-1 related inflammation. On the other hand, at the cell level, IL-1 signaling is mainly controlled by IL-1R1 and IL-1R3 and not by IL-1R2. Moreover, the soluble form of IL-1R1 and IL-1RA have the highest capacity to prevent IL-1α while IL-1R2 and IL-1R1 and IL-1RA have a similar capacity to prevent IL-1ß signaling. The soluble IL-1R3 has the lowest capacity to prevent IL-1 signaling and preferentially inhibits cells with low number of IL-1R3. In general, model predictions suggest several ways in which IL-1 controlling system may fail, developing IL-1 related inflammation.

Hepatocellular Carcinoma of Fibrolamellar Type in an Adolescent: Case Report and Literature Review.

We present a female patient, 13 years old, with diagnosis of hepatocellular carcinoma of fibrolamellar type, which was rapidly evolving. The fibrolamellar hepatocellular carcinoma invaded more than 80% of the hepatic parenchyma without surgical possibility or liver transplantation. Measures applied corresponded to chemotherapy of 1 cycle of cisplatin 40 mg/s/5 days + vincristine 1.5 mg/m2/day, 5-fluorouracil, doxorubicin, and dexrazoxane. The case presented aggressive evolution of hepatocellular carcinoma, which led to acute liver failure, with hyperammonemia, sepsis, pulmonary focus plus septic shock, grade III-IV encephalopathy, portal hypertension, and ascites with intra-abdominal hypertension. Death occurred due to multiple organ failure, which involved respiratory failure type KDIGO 1 and 2, acute liver failure, severe pneumonia, pericardial effusion, AKIN 2 acute kidney injury, carcinoma, and pulmonary metastasis. This type of ailment is infrequent in children and adolescents, and the first symptoms are crucial to achieve treatment possibilities.

Combining computational and experimental biology to develop therapeutically valuable IL2 muteins.

High-dose IL2, first approved in 1992, has been used in the treatment of advanced renal cell carcinoma and melanoma. In these indications, IL2 induces long lasting objective responses in 5% to 20% of patients. However, toxicity and the unexpected expansion of regulatory T cells (Tregs) have limited its practical use and therapeutic impact, respectively. At the Center of Molecular Immunology in Havana, Cuba, a project was launched in 2005 to rationally design IL2 muteins that could be deployed in the therapy of cancer. The basic goal was to uncouple the pleiotropic effect of IL2 on different immune T cells, to obtain a mutein with a therapeutic index that was better than that achieved with wild type (wt) IL2. Using a combination of computational and experimental biology approaches, we predicted and developed two novel IL2 muteins with therapeutic potential. The first, designated no-alpha mutein, is an agonist of IL2R signaling with a reduced ability to expand Treg in vivo. In mice, the no-alpha mutein IL2 has higher antitumor activity and lower toxicity than wt IL2. It represents a potential best-in-class drug that has begun phase I/II clinical trials in solid tumors. The second, designated no-gamma mutein, is an antagonist of IL2R signaling, with some preferential affinity for Tregs. This mutein has antitumor activity in mice that likely derives from its ability to reduce Treg accumulation in vivo. It represents a first-in-class drug that offers a novel strategy to inhibit Treg activity in vivo.

Neuropharmacological Profile of Gamma-Decanolactone on Chemically-induced Seizure in Mice.

BACKGROUND: Gamma-Decanolactone (GD) is a monoterpene compound that presents anticonvulsant effect in acute and chronic models of epilepsy and it acts as a noncompetitive glutamate antagonist. OBJECTIVE: This study evaluated the anticonvulsant profile and the possible mechanism of action of GD in seizures induced by isoniazid (INH; 250 mg/kg), picrotoxin (PCT; 5 mg/kg) and 4- aminopyridine (4-AP; 13 mg/kg) in male mice. METHOD: Thirty minutes before the convulsants administration, animals received a single administration of saline, GD (100 or 300 mg/kg) or the positive control diazepam (DZP; 2 mg/kg). The parameters evaluated were the latency to the first seizure and the occurrence of clonic forelimb seizures. The rotarod performance test was used to evaluate the neurotoxicity of GD (300 mg/kg). Also, the DZPinduced sleep test was used. RESULTS: DZP increased the latency to the first seizure on all used models and decreased the percentage of seizures in two of the three behavioral models. GD was able to prolong the latency to the first seizure and decreased the percentage of seizures induced by INH and 4-AP, but not by PCT. It reduced the latency to fall off the rotarod test only at the time of 30 min. In the DZP-induced sleep test, GD shortened the onset and prolonged the time of sleep. CONCLUSION: Our findings suggested that GD reduced the convulsive behavior in the seizure models used here and it could modulate GABA pathways and affect potassium channels directly or indirectly, involving more than one cellular target in the central nervous system.