Insights into the coordination chemistry of antineoplastic doxorubicin with 3d-transition metal ions Zn2+, Cu2+, and VO2+: a study using well-calibrated thermodynamic cycles and chemical interaction quantum chemistry models.

We present a computational strategy based on thermodynamic cycles to predict and describe the chemical equilibrium between the 3d-transition metal ions Zn2+, Cu2+, and VO2+ and the widely used antineoplastic drug doxorubicin. Our method involves benchmarking a theoretical protocol to compute gas-phase quantities using DLPNO Coupled-Cluster calculations as reference, followed by estimating solvation contributions to the reaction Gibbs free energies using both explicit partial (micro)solvation steps for charged solutes and neutral coordination complexes, as well as a continuum solvation procedure for all solutes involved in the complexation process. We rationalized the stability of these doxorubicin-metal complexes by inspecting quantities obtained from the topology of their electron densities, particularly the bond critical points and non-covalent interaction index. Our approach allowed us to identify representative species in solution phase, infer the most likely complexation process for each case, and identify key intramolecular interactions involved in the stability of these compounds. To the best of our knowledge, this is the first study reporting thermodynamic constants for the complexation of doxorubicin with transition metal ions. Unlike other methods, our procedure is computationally affordable for medium-sized systems and provides valuable insights even with limited experimental data. Furthermore, it can be extended to describe the complexation process between 3d-transition metal ions and other bioactive ligands.

Variaciones fenotípicas relacionadas a respuestas hipóxicas entre andinos a distintas altitudes / Phenotypic variations related to hypoxic responses among Andeans at different altitudes

Introducción. La adaptación a grandes altitudes implica cambios evolutivos que conllevan respuestas adaptativas, como a la hipoxia. Los andinos desarrollaron fenotipos eritroides diferentes en relación con otras poblaciones a gran altitud que pueden variar dependiendo la altitud. Objetivo. Determinar las variaciones fenotípicas de hemoglobina (Hb), saturación de oxígeno (SpO2), P50 y lactato en andinos bolivianos con radicatorias entre 400, 4000 y 5000 msnm. Material y métodos. Estudio descriptivo transversal de tipo prospectivo. Se recolectó sangre venosa periférica de andinos bolivianos (n=124) nacidos a 4000 m, pero con radicatoria en altitudes diferentes (400 m, 4000 m, 5000 m), así como de aquellos con eritrocitosis patológicas. Adicionalmente, se recolectó muestras de europeos residentes a 4000 m (n=11). Se realizó estudios de hemograma, oximetría y gasometría. La P50 fue calculada con fórmula de Lichtman. Resultados. Los andinos sanos, comparados entre distintas altitudes, reflejaron aumento de Hb al ser mayor la altitud (p: 0,001), empero disminución de SpO2 (p: 0,001) y P50 (p: 0,001); sin variaciones en lactato. Los europeos a 4000 m, en relación con andinos a la misma altitud, presentaron Hb incrementada (p: 0,01), SpO2 y P50 sin variaciones, pero lactato significativamente aumentado (p: 0,001). Los pacientes con eritrocitosis comparados con sujetos sanos, a 4000 m y 5000 m respectivamente, presentaron Hb aumentada (p: 0,001); SpO2 disminuida (p: 0,001); P50 sin variaciones, pero lactato incrementado (p: 0,01). El lactato elevado en sujetos a 5000 m con eritrocitosis fue llamativo (1,7 mmol/L). Conclusiones. Las variaciones fenotípicas observadas entre andinos en diferentes altitudes constituyen una expresión de una adaptación parcial a la altura.

Introduction. Human adaptation to high altitude involves evolutionary changes leading adaptive responses, such as to hypoxia. Andeans developed different erythroid phenotypes in relation to other populations at high altitude, which can vary depending on the altitude. Objective. To determine the phenotypic variations of hemoglobin (Hb), oxygen saturation (SpO2), P50 and lactate in Bolivian Andeans residing between 400, 4000 or 5000 masl. Material and methods. Prospective cross-sectional descriptive study. Peripheral venous blood from Bolivian Andeans (n=124) born at 4000 m, but residing at different altitudes (400 m, 4000 m, 5000 m), likewise from those with pathological erythrocytosis were collected. Additionally, samples from Europeans residing at 4000 m (n=11) were collected. CBC, oximetry and blood gas studies were performed. P50 was calculated using the Lichtman formula. Results. Healthy Andeans, compared between different altitudes, reflected an increased Hb (p: 0.001), but a decreased SpO2 (p: 0.001) and P50 (p: 0.001) as the altitude was higher; without variations in lactate. Europeans at 4000 m, related to Andeans at the same altitude, presented increased Hb (p: 0.01), SpO2 and P50 without variations, but significantly increased lactate (p: 0.001). Patients with erythrocytosis compared to healthy subjects, at 4000 m and 5000 m respectively, depicted increased Hb (p: 0.001); decreased SpO2 (p: 0.001); P50 without changes, but increased lactate (p: 0.01). Increased lactate in subjects with erythrocytosis at 5000 m was remarkable (1.7 mmol/L). Conclusion. The phenotypic variations observed among Andeans residing at different altitudes constitute an expression of partial adaptation to altitude.

Eritrocitosis patológicas con niveles de eritropoyetina baja e incrementada: características clínicas y laboratoriales / Pathological erythrocytosis with low and increased erythropoietin levels: clinical and laboratory characteristics

RESUMEN: Introducción: Los pacientes con eritrocitosis patológicas en la altura, Eritrocitosis Secundaria o Eritrocitosis Patológica de Altura, ocasionalmente suelen presentar niveles de eritropoyetina (EPO) con variaciones notables respecto de los parámetros normales, reflejando ya sea concentraciones muy bajas o muy altas de EPO. Objetivo: Analizar la prevalencia de las eritrocitosis con EPO disminuida y de las eritrocitosis con EPO incrementada, así como, las características laboratoriales y clínicas inmiscuidas entre ellas. Material y Métodos: Se realizó un estudio descriptivo transversal de tipo retrospectivo. Se analizó historias clínicas de 44 pacientes eritrocíticos; de estos, 22 pacientes (5 mujeres, 17 varones) con registros de EPO sérica disminuida (100 mUI/ml) que constituyeron el Grupo 2. Todos ellos residentes a una altura >3650 m s. n. m. Se recolectó datos demográficos, clínicos y laboratoriales; asimismo, datos referentes a los tratamientos administrados, seguimiento y respectivas respuestas en ambos grupos. Resultados: La frecuencia de las eritrocitosis patológicas con EPO disminuida representó 5 % y de aquellas con EPO elevada 5 %.: Se debe considerar estudios específicos en pacientes eritrocíticos con EPO baja para descartar Policitemia Vera, asimismo, los pacientes con EPO incrementada implican mayor complejidad en el manejo médico.

ABSTRACT: Introduction: Patients with pathological erythrocytosis at high altitude, Secondary Erythrocytosis or High Altitude Pathological Erythrocytosis, occasionally present notable variations of erythropoietin (EPO) levels regarding normal parameters, reflecting either very low or very high EPO concentrations. Objective: To analyze the prevalence of erythrocytosis with decreased EPO and erythrocytosis with increased EPO, as well as the laboratory and clinical characteristics involved between them. Material and methods: A retrospective cross-sectional descriptive study was conducted. Clinical records of 44 patients with erythrocytosis were analyzed; of these, 22 (5 women, 17 men) with records of decreased serum EPO (100 mIU/ml) ml) specified as Group 2. All of them were high altitude dwellers (>3650 m a. s. l). Demographic, clinical and laboratory data were collected, including data about administered treatments, follow-up and responses in both groups. Results: Frequency of pathological erythrocytosis with decreased EPO was 5% and with elevated EPO 5%. There were no representative differences between both groups concerning the CBC variables. Patients with increased EPO showed more complications of erythrocytosis (27%) compared to those with decreased EPO (0%). Two types of treatment regimen were evidenced in each group: a) ATV+ASA, and b) ATV+ASA+HU. Erythrocytosis patients with decreased EPO receiving ATV+ASA had higher favorable responses 90% versus those with elevated EPO (80%). The ATV+ASA+HU regimen reflected better applicability in the increased EPO group. Conclusion: Specific studies should be considered in erythrocytosis patients with decreased EPO to rule out Polycythemia Vera, similarly, patients with increased EPO imply more complexity at medical management.

Altas dosis de cobalamina y ácido fólico en el tratamiento de leucopenias post covid-19 / High doses of cobalamin and folic acid in post-covid-19 leukopenia treatment

Introducción: La leucopenia es una de las manifestaciones observadas en pacientes que padecieron COVID-19 y sus características son similares a las observadas en deficiencia de vitamina B12 y ácido fólico. Objetivo: Mostrar la utilidad de altas dosis de vitamina B12 y ácido fólico en el tratamiento de leucopenias post COVID-19. Métodos: Estudio descriptivo transversal de tipo retrospectivo. Se recolectó datos demográficos, clínicos y laboratoriales de pacientes (n=22) con leucopenia post COVID-19 que fueron tratados con dosis de vitamina B12 y ácido fólico. Se valoró seguimiento de datos clínicos y laboratoriales correspondientes tanto al diagnóstico como a las 4 y 8 semanas del tratamiento. Resultados: El cuadro de leucopenia se revirtió totalmente, los leucocitos incrementaron hasta alcanzar valores normales. Los niveles de hemoglobina incrementaron, aunque sin alcanzar valores normales. Si bien los linfocitos no presentaron disminución al diagnóstico, estos incrementaron manteniéndose dentro de parámetros normales. El VCM se mantuvo con leves modificaciones y las plaquetas no presentaron modificaciones. La sintomatología remitió a los 2 meses. Conclusiones: Los datos obtenidos pueden servir como parte de los fundamentos para el tratamiento del síndrome post COVID-19.

Introduction: Leukopenia is one of the persistent manifestations in patients who have suffered from COVID-19 and its characteristics are similar to those patients with vitamin B12 and folic acid deficiency. Objective: To show the usefulness high doses of vitamin B12 and folic acid in post COVID-19 leukopenia treatment. Material and methods: Retrospective descriptive cross-sectional study. Demographic, clinical and laboratory data were collected from patients (n = 22) with post COVID-19 leukopenia who were treated with doses of vitamin B12 and folic acid. Follow-up of clinical and laboratory data corresponding to diagnosis as well as 4 and 8 weeks after treatment was assessed. Results: Leukopenia was totally reversed, leukocytes increased and reached normal values. Hemoglobin levels increased, although without reaching normal values. Lymphocytes increased within normal parameters though they were not decreased at diagnosis. MCV levels remained with slight modifications, and platelets without modifications. Patients symptoms subsided after 2 months treatment. Conclusion: Data obtained can serve as part of treatment rationale in post-COVID-19 syndrome.

Chemical Equilibrium of Zinc Acetate Complexes in Ethanol Solution. A Theoretical Description through Thermodynamic Cycles.

The Gibbs free energy of complexation between the Zn(II) species and acetate ligands, forming the [Zn(OAc)n]2-n complexes with n = 1, 2 in an ethanol solution, was assessed by two different theoretical protocols based on thermodynamic cycles. In both approaches, the solution phase Gibbs free energy of each reaction is computed by summing up contributions from gas phase thermochemistry calculations to solvation Gibbs free energies obtained in a hybrid fashion, i.e., each (neutral or electrically charged) solute was first solvated by explicit solvent molecules in order to capture relevant (micro) solute-solvent and/or solvent-solvent interactions and then, a continuum model calculation is performed in order to get the corresponding bulky solute-solvent contributions. For our first thermodynamic protocol, here denominated as variant 1, a set of x independent solvent molecules are used to screen each of the involved solutes, while the variant 2 strategy uses the fact that a set of solvent molecules may exist as aggregates (or molecular clusters) in the solvent macroscopic media, before the solvation process of solutes. Our selected quantum theoretical protocol was the M05-2X/6-31+G(d)/SMD level. We made a systematic exploration about the influence of several sources of errors, such as the solvent conformation, the number of solvent molecules used to screen each of the involved solutes, the coordination geometry of the metallic center before and after the complexation process, and the pertinence of using molecular geometries optimized in gas phase and in ethanol solution, for the computation of the Gibbs free energy variation regarding the two chemical reactions under study. We set an accuracy threshold equal or less than 4.0 kcal·mol-1, with respect to the corresponding experimental records. The robustness of our thermodynamic strategies was then tested by computing the gas phase free energy contributions to the (solution phase) reaction free energies here assessed, using different density functional approximations, namely the M05-2X, BH&HLYP, PBE0, ωb97X-D and M06-2X functionals in conjunction with the larger 6-311+G(d,p) basis set.

Valores de hemoglobina en la población de chorolque a 5000 msnm / Hemoglobin levels in chorolque highlanders at 5000 masl

Introducción. Los valores de hemoglobina (Hb) en una población dependen de diversas variables entre ellas la altura y tiempo de radicatoria. Poblaciones que consiguieron adaptarse a grandes alturas albergan peculiares concentraciones de hemoglobina, los tibetanos tienen concentraciones similares a las del nivel del mar; mientras que, en los aymaras están incrementadas. Chorolque es una localidad minera situada a 5000 msnm que fue poblada desde hace 100 años aproximadamente y sus datos hematológicos requieren dilucidación. Objetivo. Describir concentraciones de hemoglobina y prevalencia de eritrocitosis patológica en habitantes de Chorolque. Material y métodos. Estudio descriptivo transversal realizado mediante revisión retrolectiva de 1328 (varones=1176, mujeres=142) resultados de hemograma y datos epidemiológicos. Se estableció parámetros normales preliminares de hemoglobina (varones 17 - 20 g/dl, mujeres 16 - 19 g/dl) considerando la altura y hemoglobina de otras poblaciones residentes de altura. Se consideró eritrocitosis cuando la Hb fue >18 g/dl en mujeres y >19 g/dl en varones. Resultados. La edad promedio fue de 39 años en varones y 45 años en mujeres. Se evidenció Hb media de 18.5 g/dl en mujeres y 20.8 g/dl en varones. Referente a los parámetros normales preliminares, la Hb media fue 17.5 g/dl en mujeres (n=83) y 18.0 g/dl en varones (n=282). Adicionalmente, 8 % de mujeres reflejaron Hb <16 g/dl y 2 % de varones Hb <17 g/dl. Se consideró eritrocitosis en 34 % de mujeres y 74 % de varones, Hb media de 20,7 g/dl y 21,8 g/dl respectivamente. Conclusión. Las concentraciones promedio de hemoglobina en los habitantes de Chorolque reflejan valores hematológicos no reportados en el territorio boliviano. Estudios biomoleculares permitirán caracterizar valores normales de hemoglobina y eritrocitosis patológicas en esta población.

Introduction. Hemoglobin values in a population depend on several variables, including altitude and time of residence. Populations living at high altitudes have peculiar hemoglobin levels, Tibetan hemoglobin levels are similar to those of sea level; while in Aymaras those are increased. Chorolque is a mining district located at 5000 masl and inhabited for 100 years approximately, in this sense, its hematological values require to be elucidated. Objective. To describe hemoglobin levels and prevalence of pathological erythrocytosis in Chorolque high altitude dwellers. Material and methods. Cross-sectional descriptive study carried out through a retrolective review of 1328 (men=1176, women=142) blood cell counts and epidemiological data. Preliminary normal hemoglobin parameters (males 17-20 g/ dl, females 16-19 g/dl) were established considering the altitude and hemoglobin levels in other high altitude populations. Erythrocytosis was considered when Hb was >18 g/dl in women and >19 g/dl in men. Results. The average age was 39 years for men and 45 years for women. A mean Hb of 18.5 g/dl in women and 20.8 g/dl in men were observed. Regarding the preliminary normal parameters, the mean Hb was 17.5 g/dl in women (n=83) and 18.0 g/dl in men (n=282). Additionally, 8 % of women reflected Hb <16 g/dl and 2 % of men Hb <17 g/dl. Erythrocytosis was considered in 34% of women and 74% ofmen, mean Hb of 20.7 g/dl and 21.8 g/dl respectively. Conclusion. The average hemoglobin levels in Chorolque highlanders evidences unreported hematological values in Bolivia. Biomolecular studies will allow to characterize normal hemoglobin values and pathological erythrocytoses in this population

Diagnostic accuracy of immunological methods in patients with tuberculous pleural effusion from Venezuela.

In recent years, better diagnostics for tuberculosis (TB) has received increasing attention, especially the diagnosis of tuberculous pleural effusion, which is difficult and at present the main tool in TPE diagnostic is pleural effusion smear and culture, but unfortunately, sensitivities are low, therefore better TPE diagnostic tools are needed. The aim of this study was to find a diagnostic algorithm to assess the progress in TPE diagnostic at the Hospital Vargas de Caracas, that permits identification of the majority of patients, at a satisfactory cost-benefit ratio, evaluating the levels of IFN-gamma and IL-12p40 in pleural effusion and serum, as well as the antibody reactivity in order to compare it with microbiological tests. A total of 60 individuals with pleural effusion were studied; 20 patients with tuberculous pleural effusion (TPE) formed the patient group and 40 patients with non-tuberculous pleural effusion (NTPE) formed the control group. The levels of IFN-gamma and IL-12p40 in effusion and serum and class and subclasses of IgG reactivity to Mycobacterium tuberculosis antigens were measured by ELISA. The utility of these methods for diagnosis of TPE was evaluated using receiver operating characteristic (ROC) curve analysis. The results of the 11 immunological methods evaluated showed that the anti-PPD IgG2 method was able to reach the highest specificity of 95% (CI: 88.3-101.8), positive predictive value (PPV) = 75 (at 30% sensitivity); while that the overall sensitivity of methods was between 95% and 30%, of these, two methods reached higher sensitivities; increased levels of pleural IFN-gamma, with a sensitivity of 95% (CI: 85.5-104.5) with the highest negative predictive value (NPV) = 97, (at 82.5% specificity), followed by decreased levels of serum IL-12p40 with a sensitivity of 95% (CI: 85.5-104.5), NPV = 95.2 (at 50% specificity). In contrast, microbiological methods showed that smear had a sensitivity of only 20%, while smear plus culture had, a sensitivity of 70%. Considering that TPE represents approximately 15 percent of all the TB clinically diagnosed at the Hospital Vargas de Caracas, in those patients with preliminary microbiology negativity in the effusion, the combined analysis of pleural IFN-gamma and anti-PPD IgG2 could represent a fast and effective diagnostic algorithm for improving the diagnosis previous to obtain culture results. In this way treatment against TB could be initiated or the need to cytological and pleural biopsy could be considered.

Diagnostic accuracy of immunological methods in patients with tuberculous pleural effusion from Venezuela / Precisión diagnóstica de métodos inmunológicos en pacientes con tuberculosis pleural de Venezuela

In recent years, better diagnostics for tuberculosis (TB) has received increasing attention, especially the diagnosis of tuberculous pleural effusion, which is difficult and at present the main tool in TPE diagnostic is pleural effusion smear and culture, but unfortunately, sensitivities are low, therefore better TPE diagnostic tools are needed. The aim of this study was to find a diagnostic algorithm to assess the progress in TPE diagnostic at the Hospital Vargas de Caracas, that permits identification of the majority of patients, at a satisfactory cost-benefit ratio, evaluating the levels of IFN-g and IL-12p40 in pleural effusion and serum, as well as the antibody reactivity in order to compare it with microbiological tests. A total of 60 individuals with pleural effusion were studied; 20 patients with tuberculous pleural effusion (TPE) formed the patient group and 40 patients with non-tuberculous pleural effusion (NTPE) formed the control group. The levels of IFN-g and IL-12p40 in effusion and serum and class and subclasses of IgG reactivity to Mycobacterium tuberculosis antigens were measured by ELISA. The utility of these methods for diagnosis of TPE was evaluated using receiver operating characteristic (ROC) curve analysis. The results of the 11 immunological methods evaluated showed that the anti-PPD IgG2 method was able to reach the highest specificity of 95% (CI: 88.3-101.8), positive predictive value (PPV)=75 (at 30% sensitivity); while that the overall sensitivity of methods was between 95% and 30%, of these, two methods reached higher sensitivities; increased levels of pleural IFN-g, with a sensitivity of 95% (CI: 85.5-104.5) with the highest negative predictive value (NPV)=97, (at 82.5% specificity), followed by decreased levels of serum IL-12p40 with a sensitivity of 95% (CI: 85.5-104.5), NPV=95.2 (at 50% specificity). In contrast, microbiological methods showed that smear had a sensitivity of only 20%, while smear plus ...

Recientemente existe un gran interés hacia un mejor y más rápido diagnóstico de tuberculosis (TB), especialmente de tuberculosis pleural, el cual es difícil. Al presente las principales herramientas diagnósticas son la baciloscopia y el cultivo de líquido pleural; desafortunadamente, las sensibilidades de estos métodos son bajas, por lo que el desarrollo de nuevas herramientas diagnósticas es necesario. El objetivo del presente estudio consistió en encontrar un algoritmo que permita la rápida identificación de la mayoría de los pacientes con TB pleural que ingresan en el Hospital Vargas de Caracas a un buen costo-beneficio. Para esto se evaluaron los niveles de las citocinas Interferón-gamma (IFN-g) y la Interleucina 12p40 (IL-12p40) en líquido pleural y suero, así como la reactividad de anticuerpos contra antígenos de Mycobacterium tuberculosis. Se estudiaron 60 individuos con derrame pleural; 20 individuos con líquido pleural tuberculoso (LPT) conformaron el grupo de pacientes y 40 individuos con líquido pleural no tuberculoso (LPNT) el grupo de controles. La técnica de inmunoensayo de ELISA fue utilizada para medir los niveles de IFN-g y IL-12p40; así como las reactividades de los diversos isotipos y subclases de inmunoglobulina G (IgG) frente a antígenos del bacilo. La utilidad de los métodos fue evaluada utilizando el análisis de las curvas ROC (receiver operating characteristic). Los resultados de los 11 métodos inmunológicos evaluados mostraron que el método IgG2 anti-PPD alcanzó la mayor especificidad de 95%, (CI: 88,3-101,8) con un valor predictivo positivo (VPP) de 75. La sensibilidad de los métodos estuvo entre 30% y 95%; dos métodos alcanzaron altas sensibilidades: los altos niveles de IFN-g en líquido pleural, con sensibilidad de 95% (CI: 85,5-104,5), con un valor predictivo negativo (VPN) de 97, seguido de los bajos niveles de IL-12p40 en suero, con una sensibilidad de 95% (CI: 85,5-104,5) con un VPN de 95,2. En contraste, ...

A high-throughput colorimetric and fluorometric microassay for the evaluation of nitroimidazole derivatives anti-trichomonas activity.

Several nitroimidazole derivatives were synthesized and tested as possible trichomonicidal agents. A fast, simple, practical and reliable in vitro colorimetric method was applied to the screening of the nitroimidazole derivatives anti-trichomonas activity. The colorimetric technique was based on the use of Alamar blue as a redox-indicator. The test was carried out both qualitatively (minimal inhibitory concentration determined by naked eye observation) and quantitatively (fluorometric determination of 50% and 90% inhibitory concentrations), the latter took advantage of the dye fluorometric properties. The performance of the method was excellent affording an exactitude 97.86% and a reproducibility of 95% and no interference of the trichomonas-culture medium was observed during the test. Some of the nitroimidazole compounds tested showed a fair trichomonicidal activity, however none of them was as active as the model compound, metronidazole.