Design, Synthesis, and Structure-Activity Relationship Studies of New Quinone Derivatives as Antibacterial Agents.

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae, while compound 28 demonstrated higher potency against MRSA than vancomycin.

Incidence of venous thromboembolic events in cancer patients receiving immunotherapy: a single-institution experience.

BACKGROUND: Cancer and cancer therapies have been associated with an increased incidence of venous thromboembolic events (VTE). However, the incidence of VTE in patients on immunotherapy has not been well characterized. The aim of this study was to assess the incidence of VTE in cancer patients receiving immunotherapy and ascertain its prognostic utility. MATERIALS AND METHODS: We conducted a single-institution retrospective study, including all cancer patients treated with anti-Programmed cell Death 1 (PD-1), anti-Programmed cell Death Ligand-1 (PD-L1), anti-Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4), a combination of anti-PD-1/anti-PD-L1 and anti-CTLA4 or a combination including any of these drugs with chemotherapy, antiangiogenic agents or both between June 2013 and April 2019 at La Paz University Hospital, Madrid (Spain). RESULTS: We selected 229 patients. VTE occurred in 16 of 229 patients (7%). VTE occurred more frequently in patients with lung cancer followed by melanoma. Female sex and melanoma were independently associated with an increased risk of VTE. 12 of 16 VTE (75%) were symptomatic. Progressive disease to immunotherapy [HR 31.60 (95% CI 11.44-87.22), p = 0.00], lung cancer [HR 2.55 (95% CI 1.34-4.86), p = 0.00] and melanoma [HR 2.42 (1.20-4.86), p = 0.01] were independently associated with shorter OS. VTE occurrence was not independently associated with shorter OS [HR 1.33 (95% CI 0.63-2.80), p = 0.44]. CONCLUSIONS: The incidence of VTE in cancer patients receiving immunotherapy in our study appeared to be similar to the incidence previously reported in other series of cancer patients treated with systemic therapies. VTE occurrence did not correlate with the prognosis. Further and prospective studies are needed to derive definitive conclusions.

Conjugation of NMR and SAXS for multidomain protein structure determination: from sample preparation to model refinement / Conjugación de NMR y SAXS para la determinación estructural de proteínas multidominio: de la preparación de muestras al refinamiento de modelo

Abstract Experimental information from small angle X-ray scattering (SAXS) is conjugated with nuclear magnetic resonance (NMR) spectroscopy data for the improvement of protein structure determination, particularly for flexible, multidomain or intrinsically disordered proteins. Individually, each of these techniques presents capabilities and limitations: NMR excels in local information, providing atomic resolution, but is limited by protein size, whereas SAXS yields a global envelope of the protein with lower resolution, but revealing domain positions. Different conjugation methodologies use the complementarity of both technique´s independent constraints to accomplish a comprehensive protein structure determination and dynamics understanding at a moderate computational expense.

Resumen Se conjuga información experimental proveniente de dispersión de rayos X a ángulos pequeños (SAXS) con la espectroscopía de resonancia magnética nuclear (NMR) para perfeccionar la determinación de la estructura protéica, en particular de proteínas flexibles, de multidominio o intrínsecamente desordenadas. Individualmente, cada una de estas técnicas presenta capacidades y limitaciones: NMR se destaca en la información local, proporcionando resolución atómica, pero está limitada por el tamaño de la proteína, mientras que SAXS produce una envoltura global de la proteína con una resolución menor pero revelando las posiciones de los dominios. Las diferentes metodologías de conjugación utilizan la complementariedad de las restricciones independientes de ambas técnicas para seguir estrategias adecuadas de acuerdo con la proteína, logrando una determinación integral de la estructura y una comprensión de las dinámicas del sistema proteico a un costo computacional moderado.

Vivienda social accesible: evaluación de costos / Accessible social home: cost evaluation

Introduction: Physical accessibility is considered a fundamental part in the exercise of rights and the development of independent living for people with a disability. One of the most important spaces where accessibility should be considered is the home. Accessibility is presumably associated to high construction cost therefore social homes do not incorporate this criteria. An evaluation is needed to verify this presumption. Objective: To evaluate the economic impact of incorporating physical accessibility in basic housing solutions, or type Solidarity Fund 1 (FSV1) homes. Method: Cost evaluation was performed on the basis of an academic comparison of direct construction cost of 15 built social homes (FSV1), versus 15 counterproposals with incorporated accessibility. Results: 13 of 15 cases increased costs between 1.27 percent and 6.11 percent of the basic construction cost. However, the unitary cost per constructed square meter did not increase. Conclusion: Limited cost variations was associated more to the surface increase needed to generate accessibility conditions, than to the incorporation of new elements o technical aids.

Introducción: La accesibilidad física es considerada como parte fundamental para el ejercicio de los derechos y el desarrollo de una vida independiente de las personas en situación de discapacidad. Uno de los espacios más importantes que debiera considerar accesibilidad es la vivienda, especialmente la vivienda social, siendo uno de los principales impedimentos a la hora de incorporar este criterio, el supuesto alto costo asociado; sin embargo, no existen evaluaciones que lo puedan objetivar. Objetivo: Evaluar el impacto económico que tendría incorporar accesibilidad física en soluciones habitacionales más básicas o tipo Fondo Solidario de Vivienda I (FSV1). Materiales y Método: La evaluación de costos se realizó sobre la base de un ejercicio académico de comparación de costos directos de construcción de 15 casos de viviendas sociales construidas (FSV1) con 15 contrapropuestas con accesibilidad incorporada. Resultados: Trece de 15 casos aumentaron sus costos de construcción, entre 1,27 por ciento y 6,11 por ciento del costo base de la vivienda construida. Sin embargo, el costo unitario por metro cuadrado construido no presenta incremento. Conclusiones: Las variaciones de costo fueron bastante acotadas y estuvieron relacionadas con el aumento de superficie necesario para generar condiciones de accesibilidad, más que en la incorporación de nuevos elementos o ayudas técnicas.

Vivienda social accesible: un nuevo desafío para Chile / Accessible social homes: a new challenge for Chile

Introduction: Since 2004, Teleton´s Volunteer Corp through their Program“Abre” is working to eliminate architectural barriers in the homes of rehabilitation services users. Most of these homes are obtained by the families through State financial aid. This on site work has shown low levels of accessibility, thus a full and autonomous use of the home is restricted. Objective: To establish design criteria for social homes from the Solidary Fund 1 (FSV1), regarding unnoticed accessibility characteristics. Method: Sample gathering was obtained with the collaboration of the Housing and Town Planning Ministry (MINVU). Regions with greatest concentration of granted subsidies from FSV1 during the year 2011 were selected. Based on 15 counterproposals, the concept of unnoticed accessibility was implemented in the homes. Design criteria complied with current FSV1regulations. Results: The design process resulted in 15 cases of social homes with different degrees of accessibility. Discussion: The objective of this study allowed the accomplishment of accessibility solutions for social homes from FSV1, with marginal built surface increase. As a second gain, they allowed for the design of construction plants, which improve housing conditions for families, throughout their entire life cycle independent of health conditions. Conclusions: Accessible social home proposals were implemented with marginal increase.

Introducción: Desde el año 2004 el programa Abre del Voluntariado Teletón trabaja a través de la eliminación de barreras arquitectónicas en las viviendas de familias usuarias de Teletón, que en su mayoría acceden a viviendas sociales obtenidas mediante subsidios estatales. Esta realidad en terreno ha permitido visualizarlos bajos niveles de accesibilidad que estas viviendas poseen, dificultando el acceso, uso pleno y autónomo de los recintos. Objetivo: Establecer criterios de diseño que permitan que las viviendas sociales del fondo solidario 1 (FSV1) posean características de accesibilidad desapercibida. Material y Método: La recopilación de la muestra de tipos de vivienda social se realizó en colaboración con el Ministerio de Vivienda y Urbanismo (MINVU), trabajando con las Regiones de mayor concentración de subsidios del FSV1 asignados durante el año 2011.Se desarrollaron 15 contrapropuestas en las cuales se implementó el concepto de accesibilidad desapercibida. Los criterios de diseño se enmarcaron en el reglamento actual del FSV1. Resultados: El proceso de diseño culminó con la obtención de 15 casos de viviendas sociales con distintos grados de accesibilidad. Discusión: Desde los objetivos propuestos en este estudio, se ha podido brindar soluciones de accesibilidad para las viviendas sociales del FSV1, sin que ello implicase un aumento considerable de la superficie construida. De igual manera, se han podido diseñar plantas de edificación que permiten mejorar las condiciones de habitabilidad, independiente de la condición de salud del grupo familiar en todo su ciclo de vida. Conclusiones: Las propuestas de vivienda social accesible se lograron con un aumento marginal de superficie.

Case report on the clinical results of a combined cellular therapy for chronic spinal cord injured patients.

OBJECTIVES: With the intention to ameliorate the clinical condition of patients with chronic spinal cord injury (SCI), a program that combines three cell therapies and an appropriate neurorehabilitation program were used to recreate and enhance the natural conditions of SCI repair. METHODS: Vascularization recovery is approached by selective artery infusion of BMMNCs (bone marrow mononuclear cells) to the disrupted area. Eighteen days later, with the aim to restore the specific inflammatory activity, an i.v. infusion of spinal cord specific ETCs (effector T cells) is carried out. With the intention of supplying cellular components for the process of repair, an infusion of autologous neural stem cells (NSCs) through selective feeding artery infusion is carried out, followed by an appropriate neurorehabilitation program. RESULTS: A total of eight ASIA (American Spinal Injury Association) A patients (five with jeopardized brachial plexus and three without) received the treatment. No severe adverse events was observed in any of the receptor patients: five patients evolved from ASIA A to ASIA D and regained the ability to stand up and, with varying effectiveness, to walk; two patients remained in the same condition, but exhibited motor and sensitive improvements; and one patient could not be evaluated. CONCLUSIONS: These reports suggest that the biological characteristics of acute SCI may be recreated in a comprehensive, safe and effective manner.

Localisation of COX-2 protein is different in breast ductal carcinoma and adjacent non-tumour ductal epithelium.

INTRODUCTION: A number of findings suggest that cyclooxygenase-2 (COX-2) is overexpressed in breast tumours. However, there is a lack of consensus in the literature regarding the pattern of expression of this protein in invasive breast ductal carcinoma and in the adjacent non-tumour ductal epithelium. This study compares the expression of COX-2 mRNA and protein in breast ductal carcinoma relative to non-tumour breast tissue. MATERIAL AND METHODS: We analysed the expression of COX-2 mRNA by quantitative PCR, and COX-2 protein by immunohistochemistry in invasive ductal carcinoma as well as in non-tumour adjacent ductal epithelium from 34 breast biopsies diagnosed as being invasive ductal carcinoma. As control, we analysed expression of COX-2 protein by immunohistochemistry in surgically-resected benign breast lesions. RESULTS: Our results show that COX-2 mRNA and protein are overexpressed in non-tumour ductal epithelium compared with invasive ductal carcinoma. However, the pattern of the protein expression is different in tumour and non-tumour tissue: COX-2 protein is expressed predominantly in the membrane of the non-tumour ductal epithelium (including in benign breast lesions) while, in invasive ductal carcinoma cells, it is localised in the cytoplasm. CONCLUSIONS: The non-tumour ductal epithelium adjacent to invasive ductal carcinoma shows a higher COX-2 expression than does the invasive ductal carcinoma. However, the different localisation of the immunohistochemically-detected protein suggests a possible post-translational regulation of the protein.

Kinetics of Bifidobacterium longum ATCC 15707 fermentations: effect of the dilution rate and carbon source.

The effect of the dilution rate on biomass and product synthesis in fermentations of glucose, fructose and a commercial mixture of fructooligosaccharides (FOS) by Bifidobacterium longum ATCC 15707 was studied. Kinetic parameters (maximum specific growth rate, Monod constant, maintenance, and yield coefficients) in the mathematical model of the fermentation were estimated from experimental data. In the FOS mixture fermentations, approximately 12% of the total reducing sugars (mainly fructose) in the feed were not metabolized by the bacterium. In fermentations of fructose and the FOS mixture, biomass concentration increased as the dilution rate increased and, once maximum values were reached [3.90 (D=0.20 h(-1)) and 2.54 g l(-1) (D=0.15 h(-1)), respectively], decreased rapidly as the culture was washed out. Formic acid was detected at low dilution rates in glucose and fructose fermentations. The main products in fermentations of the three carbon sources were lactic and acetic acids. Average values of the molar ratio between acetic and lactic acids of 1.18, 1.21 and 0.83 mol mol(-1) were obtained in glucose, fructose and FOS mixture fermentations, respectively. In batch fermentations carried out without pH control this molar ratio was lower than 1.5 only when fructose was used as the carbon source.

Remediation of phenol, lignin and paper effluents by advanced oxidative processes.

The tremendous environmental impact of pulping and bleaching effluents and the relatively low efficiency of the current biological remediation processes represent one of the most important problems of the paper industry. In this work the efficiency of heterogeneous and homogeneous advanced oxidative processes was evaluated toward the degradation of model substrates (phenol and lignin) and the remediation of paper effluents. Best results were found by application of the UV-H2O2 system, with almost total discoloration of both pulping and bleaching effluents and typical COD removal higher than 60%, at reaction times of 120 min. In view of the reported results, and mainly on account of the simplicity of the UV-H2O2 system, shows good potential for the advanced process to remediation of recalcitrant effluents like those studied in this present work.

Semiconductor-assisted photodegradation of lignin, dye, and kraft effluent by Ag-doped ZnO.

This work reports a preliminary study of semiconductor-assisted photochemical degradation of lignin, Remazol Brilliant Blue R and Kraft E1 paper effluent by using ZnO and Ag-doped ZnO photocatalysts. The doped semiconductor was prepared in the reaction media by photoreduction of silver nitrate. With the use of 100 mg of ZnO and 15 mg of Ag-ZnO, almost total decolorization of the dye and lignin samples in reaction times lower than 60 min were observed. Extending the photochemical reaction up to 120 min, the total organic carbon content (TOC) was reduced in 90%. For the paper effluent, a fast decolorization was obtained for relatively short reaction times. However, de TOC reduction was negligible (near of 10%) up to high reaction times (300 min). By using the Ag-ZnO photocatalyst, the toxicity of lignin and Kraft E1 effluent toward E. Coli was completely removed. For the dye, the formation of transient toxic species was observed.

Semiconductor-assisted photocatalytic degradation of reactive dyes in aqueous solution.

This work reports the semiconductor-assisted photochemical degradation of reactive dyes. In an oxygenated-UV-ZnO system almost total decolorization of Remazol Brilliant Blue R, Remazol Black B, Reactive Blue 221 and Reactive Blue 222 was observed in reaction times of about 60 min. Extending the photochemical treatment up to 120 min, mineralization higher than 80% for all the dyes was observed. During the same period, the residual acute toxicity was significantly reduced only for Remazol Black B. A systematic optimization study carried out by factorial design showed that for the reactive dyes tested, the ZnO semiconductor exhibits a better efficiency than that observed with anatase TiO2. A synergistic effect in the coupled TiO2-ZnO system was not observed.

Preparation and Characterization of a Kaolinite-1-methyl-2-Pyrrolidone Intercalation Compound.

Well-crystallized kaolinite was initially reacted at 60 degreesC with a water-dimethyl sulfoxide mixture. After washing and characterization, the resulting material (Al2Si2O5(OH)4(DMSO)0,4) was reacted with 1-methyl-2-pyrrolidone (NMP) at room temperature. The product was a light yellow powder with a stoichiometry that attests to the quantitative substitution of the DMSO by the NMP molecules. (Al2Si2O5(OH)4(NMP)0,39+/-0,02) was characterized by X-ray diffractometry, thermal analysis (simultaneous TG and DSC), and FTIR. The fact that the NMP molecules are located in the interlamellar space of the kaolinite permits a notable enhancement of the thermal stability of the complex. While the DMSO-derived system decomposes at 175 degreesC under air, the NMP complex remains stable up to 431 degreesC. Copyright 1999 Academic Press.

Anomalies in the spectrophotometric and extractive behaviour of zirconium and hafnium: evidence of a synergistic effect.

In this work, some observations that confirm non-specific interactions between zirconium and hafnium are presented. This phenomenon, which induces significant differences between the spectrophotometric and extractive behaviour of the isolated elements related to their mixtures, indicates the existence of an important synergistic effect on the depolymerisation reactions involved in the aqueous chemistry of the elements. All experimental evidences suggest that the presence of zirconium can minimise the polymerisation of hafnium, favouring its reaction with the studied complexing agent.

Degradation of reactive dyes I. A comparative study of ozonation, enzymatic and photochemical processes

The environmental problems associated with textile activities are represented mainly by the extensive use of organic dyes. A great number of these compounds are recalcitrant and shown carcinogenic or mutagenic character. In this work three processes were studied for degradation of an anthraquinone dye (C.I. reactive blue-19). The ozonation process leads to complete decolorization with a very short reaction time; however, effective mineralization of the dye was not observed. The enzymatic process promotes quick decolorization of the dye; nevertheless, maximum decolorization degrees of about 30% are insignificant in relation to the decolorization degree achieved by the other processes. The best results were found for the photocatalytical process. The use of ZnO or TiO2 as photocatalysts, permits total decolorization and mineralization of the dye with reaction times of about 60 min.

Covalent Grafting of Phenylphosphonate Groups onto the Interlamellar Aluminol Surface of Kaolinite.

Kaolinite (K) was reacted with phenylphosphonic acid (PPA) in a water:acetone (1:1 V/V) solution (molar ratio 1 K:3 PPA), at 95 +/- 5 degreesC for different periods of time. Two different compounds (white powders) were identified but only one was isolated as a single phase and characterized by X-ray diffraction (powder method), thermal analysis (TG-DSC), Fourier-transformed infrared spectroscopy, and chemical analysis. The first compound showed a layer expansion of 7.86 Å and the second, a layer expansion of 9.29 Å, obtained as a decomposition product. Both compounds are consistent with the grafting of the phenylphosphonate group to the layers of kaolinite. The compounds have a formula of Al2Si2O5(OH)(HO3PPh)3.0 . 2H2O, as determined by thermal (water and total organic matter loss) and chemical (C content) analysis, respectively. Copyright 1998 Academic Press.

Pre-concentration of rare earths using silica gel loaded with 1-(2-pyridylazo)-2-naphthol (PAN) and determination by energy dispersive X-ray fluorescence.

The determination of a single rare earth element in a mixture with other species of this family is a very challenging problem in analytical chemistry due to the close similarity of their chemical properties. In this work, a liquid-solid extraction procedure for praseodymium, neodymium, samarium and yttrium mixtures and subsequent determination by energy dispersive X-ray fluorescence spectrometry is described. The pre-concentration procedure, which involves the use of silica modified with 1-(2-pyridylazo)-2-naphthol, permits complete recovery of the rare earths and significant sensitivity enhancement in comparison with direct determination in the aqueous phase. Determinations in quaternary mixtures show typical precisions and accuracies of 3% and 5%, respectively.

Spectrophotometric determination of organic dye mixtures by using multivariate calibration.

The simultaneous determination of organic dye mixtures by using spectrophotometric methods is a difficult problem in analytical chemistry, due to spectral interferences. By using multivariate calibration methods such as partial least-squares regression (PLSR), it is possible to obtain a model adjusted to the concentration values of the mixtures used in the calibration stage. In this study, the calibration model is based on absorption spectra in the 350-650-nm range for a set of 16 different mixtures of reactive red 195, reactive yellow 145 and reactive orange 122 dyes, and made the determination of the dye concentrations possible in a validation set with significantly greater accuracy than the conventional univariate calibration method. By using the developed model it was possible to monitor the decolorization kinetic of one dye (reactive orange 122), when the mixture of the three dyes was previously submitted to an ozonation process.

Zirconium and hafnium determination by energy dispersive X-ray fluorescence with solid phase preconcentration.

Two preconcentration methods has been developed for simultaneous determination of zirconium and hafnium by energy dispersive X-ray fluorescence (EDXRF). The first method is a liquid-solid extraction procedure with the use of an anionic exchange resin modified with xylenol orange. The second is a precipitation procedure carried out in the presence of lanthanum. Both methods permit significant enhancement of sensitivity in comparison with direct measurement in the aqueous phase. The applicability of both procedures for the preconcentration of Zr and Hf prior to their determination by EDXRF was demonstrated by analyzing synthetic mixtures and a sample of zirconium ore. The results obtained with the use of the modified resin show relative standard deviation of about 4% and good agreement with those obtained by spectrographic analysis.

Chemometric alternatives for resolution of classical analytical problems Spectrophotometric determination of lanthanide mixtures.

The simultaneous determination of lanthanide family elements is one of the greatest problems in analytical chemistry, due to the close similarity of their chemical properties. Spectrophotometric methods are generally of limited use, due to the various mutual spectral interferences involved. By using multivariate calibration methods (partial least-squares regression, PLSR), it was possible to obtain a model that adjusts itself perfectly to the values of the mixture concentrations used in the calibration. The model used absorption spectra in the 290-800 nm range for a set of 20 different mixtures of Ce, Pr, Nd and Sm, and made possible the determination of Ce, Pr and Nd concentrations of a commercial rare-earth product, with significantly greater precision than the conventional univariate calibration method. Determination of the Sm concentrations was not possible, since its concentration was below the concentrations used in the model definition.

Chagas'infection in university students of Santa Cruz de la Sierra, Bolivia: a serologic electrocardiographic study

Desde una poblacion de 4600 nuevos estudientes de la Universidad Estatal de la ciudad de Santa Cruz de la Sierra, se tomo una muestra aleatoria de 372 estudiantes a los que se realizo um test de hemaglutinacion indirecta(HAI) para enfermedad de Chagas y un electocardiograma(ECG) convencional. El 17.2 por cento (63/373) tenian el test HAI positivo y de estos el 16.5 por cento(10/64) tenian algun trantorno electocardiografico. En el grupo con HAI negativa el 10 por cento (31/308) presento alguna anormalidad electocardiografica. No se observo asociacion entre serologia positiva para la enfermedad de Chagas y alteracion del ECG en general (x2=1.67 p=0.2). Se observo una asociacion positiva entre serologia para Chagas y trastornos de conduccion intraventricular (TCIV) y esta parece intensificarse entre los menores de 19 anos con un odds ratio de 10.4 (p<0.05)>