How Could Antibiotics, Probiotics, and Corticoids Modify Microbiota and Its Influence in Cancer Immune Checkpoint Inhibitors: A Review.

Immunotherapy has become a new paradigm in oncology, improving outcomes for several types of cancer. However, there are some aspects about its management that remain uncertain. One of the key points that needs better understanding is the interaction between immunotherapy and gut microbiome and how modulation of the microbiome might modify the efficacy of immunotherapy. Consequently, the negative impact of systemic antibiotics and corticosteroids on the efficacy of immunotherapy needs to be clarified.

From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy.

Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRß (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.

Intratumoral Versus Circulating Lymphoid Cells as Predictive Biomarkers in Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Is the Easiest Path the Best One?

The molecular and cell determinants that modulate immune checkpoint (ICI) efficacy in lung cancer are still not well understood. However, there is a necessity to select those patients that will most benefit from these new treatments. Recent studies suggest the presence and/or the relative balance of specific lymphoid cells in the tumor microenvironment (TEM) including the T cell (activated, memory, and regulatory) and NK cell (CD56dim/bright) subsets, and correlate with a better response to ICI. The analyses of these cell subsets in peripheral blood, as a more accessible and homogeneous sample, might facilitate clinical decisions concerning fast prediction of ICI efficacy. Despite recent studies suggesting that lymphoid circulating cells might correlate with ICI efficacy and toxicity, more analyses and investigation are required to confirm if circulating lymphoid cells are a relevant picture of the lung TME and could be instrumental as ICI response biomarkers. This short review is aimed to discuss the recent advances in this fast-growing field.

Design, Synthesis, and Evaluation of Alkyl-Quinoxalin-2(1H)-One Derivatives as Anti-Quorum Sensing Molecules, Inhibiting Biofilm Formation in Aeromonas caviae Sch3.

With the increasing antibiotic resistance of bacterial strains, alternative methods for infection control are in high demand. Quorum sensing (QS) is the bacterial communication system based on small molecules. QS is enables bacterial biofilm formation and pathogenic development. The interruption of QS has become a target for drug discovery, but remains in the early experimental phase. In this study, we synthesized a set of six compounds based on a scaffold (alkyl-quinoxalin-2(1H)-one), new in the anti-QS of Gram-negative bacteria Aeromonas caviae Sch3. By quantifying biofilm formation, we were able to monitor the effect of these compounds from concentrations of 1 to 100 µM. Significant reduction in biofilm formation was achieved by 3-hexylylquinoxalin-2(1H)-one (11), 3-hexylylquinoxalin-2(1H)-one-6-carboxylic acid (12), and 3-heptylylquinoxalin-2(1H)-one-6-carboxylic acid (14), ranging from 11% to 59% inhibition of the biofilm. This pilot study contributes to the development of anti-QS compounds to overcome the clinical challenge of resistant bacteria strains.

Embarazo ectópico abdominal / Abdominal ectopic pregnancy

Se presenta un caso de embarazo ectópico abdominal del segundo trimestre, que se diagnosticó en el curso de una complicación relacionada con hemoperitoneo y que fue necesario realizarle histerectomía total con anexectomía izquierda. Se revisan aspectos de su etiología, diagnóstico y tratamiento. Es el segundo caso publicado por el autor principal(AU)

A case of abdominal ectopic pregnancy is presented in its second quarter and was diagnosed in the course of a complication related to the hemoperitoneum. It was necessary to perform a total hysterectomy with left oophorectomy. Aspects of etiology, diagnosis and treatment are reviewed. It is the second case reported by the leading author(AU)

Embarazo ectópico abdominal / Abdominal ectopic pregnancy

Se presenta un caso de embarazo ectópico abdominal del segundo trimestre, que se diagnosticó en el curso de una complicación relacionada con hemoperitoneo y que fue necesario realizarle histerectomía total con anexectomía izquierda. Se revisan aspectos de su etiología, diagnóstico y tratamiento. Es el segundo caso publicado por el autor principal.

A case of abdominal ectopic pregnancy is presented in its second quarter and was diagnosed in the course of a complication related to the hemoperitoneum. It was necessary to perform a total hysterectomy with left oophorectomy. Aspects of etiology, diagnosis and treatment are reviewed. It is the second case reported by the leading author.

Incidencia de la primera crisis no provocada y epilepsia de nuevo diagnóstico / Incidence of unprovoked first seizure newly diagnosed epilepsy

Introducción: A nivel nacional e institucional existe desconocimiento sobre la incidencia de epilepsia en la población adulta, así como las características epidemiológicas y estados comórbidos que presentan los pacientes con dicha patología. Objetivos: Por lo anterior, el objetivo principal de esta investigación fue estimar la incidencia de la primera crisis no provocada y epilepsia de nuevo diagnóstico en el Departamento de Medicina Interna del Hospital Roosevelt. Métodos: Para esto, se diseño un estudio descriptivo, prospectivo, que se realizó de enero a Diciembre del año 2011. La recolección de datos fue a través de una encuesta...

Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative typically used for recreational purposes. The participation of cytochrome P450 (CYP) 2D6 in the oxidative metabolism of MDMA may suggest an increased risk of acute toxicity in CYP2D6 poor metabolisers. This study was aimed at assessing the contribution of CYP2D6 to MDMA disposition in vivo using paroxetine as a metabolic probe inhibitor. Paroxetine, a CYP2D6 inhibitor, was repeatedly administered before MDMA administration. STUDY DESIGN: This was a randomised, double-blind, crossover, placebo-controlled trial conducted in seven healthy male volunteers who were CYP2D6 extensive metabolisers. Treatment conditions (paroxetine/MDMA and placebo/MDMA) were randomly assigned. Each volunteer participated in two 3-day sessions. On days 1, 2 and 3 subjects received a single oral dose of paroxetine or placebo 20 mg. On the third day, a single oral dose of MDMA 100 mg was administered in both paroxetine and placebo conditions. METHODS: Plasma concentration-time profiles and urinary recoveries of MDMA and its metabolites were measured, as well as plasma concentrations of paroxetine, (3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine, and (3S,4R)-4-(4-fluorophenyl)-3-(3-methoxy-4-hydroxyphenoxymethyl)-piperidine (HM-paroxetine). RESULTS: Paroxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC(27)) [23%], AUC from zero to infinity (AUC(infinity)) [27%] and maximum plasma concentration (C(max)) [17%], without significant differences in MDMA time to reach C(max) (t(max)). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (K(e)) [-14%] and plasmatic clearance (CL(P)) [-29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in C(max) with no significant differences in AUC(27), AUC(infinity), K(e) and elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC(27) (-28%), AUC(infinity) (-20%) and C(max) (-46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in C(max) (17%) and AUC(27) (16%) was found. Following paroxetine pretreatment, the urinary recovery (0-45 hours) of MDMA increased by 11%; HHMA and HMMA urinary recoveries were 27% and 16% lower, respectively compared with placebo. The ratio of C(max) values of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in t(max). DISCUSSION AND CONCLUSION: The contribution of CYP2D6 to MDMA metabolism in humans is not >30%, therefore other CYP isoenzymes may contribute to O-demethylenation of MDMA. Accordingly, the relevance of genetic polymorphism in CYP2D6 activity on MDMA effects and MDMA-induced acute toxicity should be examined as well as the interactions of other CYP2D6 substrates with MDMA, once the enzyme is inhibited. The pharmacokinetics of HM-paroxetine in humans after the administration of repeated doses is reported for the first time in this study.

Causas de evento cerebro vascular en adultos que asisten al Hospital Roosevelt años 2001-2002 / Causes of cerebrovascular accidents in adults admitted to Hospital Roosevelt. 2001-2002

Objetivo: Determinar la incidencia de pacientes adultos, que sufrieron de un evento cerebro vascular (ECV) en la población que asistió al Hospital entre junio del 2001 y junio del 2002, los grupos etarios, el sexo más afectado, los factores de riesgo y la morbimortalidad asociada. Metodología: se realizó un estudio prospectivo de todos los pacientes adultos que se presentaron a la emergencia de Medicina Interna, del Hospital Roosevelt durante el período del estudio. Resultados: Durante este período se identificaron 115 pacientes ingresados como ECV de los cuales 64 tenía criterios de inclusión, pero solo 58 llegaron a formar parte del estudio. La edad promedio fue de 75 años y un máximo de 84 años, con...

Determination of N,N-dimethyltryptamine and beta-carboline alkaloids in human plasma following oral administration of Ayahuasca.

Ayahuasca is a South American psychotropic beverage prepared from plants native to the Amazon River Basin. It combines the hallucinogenic agent and 5-HT(2A/2C) agonist N,N-dimethyltryptamine (DMT) with beta-carboline alkaloids showing monoamine oxidase-inhibiting properties. In the present paper, an analytical methodology for the plasma quantification of the four main alkaloids present in ayahuasca plus two major metabolites is described. DMT was extracted by liquid-liquid extraction with n-pentane and quantified by gas chromatography with nitrogen-phosphorus detection. Recovery was 74%, and precision and accuracy were better than 9.9%. The limit of quantification (LOQ) was 1.6 ng/ml. Harmine, harmaline, and tetrahydroharmine (THH), the three main beta-carbolines present in ayahuasca, and harmol and harmalol (O-demethylation metabolites of harmine and harmaline, respectively) were measured in plasma by means of high-performance liquid chromatography (HPLC) with fluorescence detection. Sample preparation was accomplished by solid-phase extraction, which facilitated the automation of the process. All five beta-carbolines were measured using a single detector by switching wavelengths. Separation of harmol and harmalol required only slight changes in the chromatographic conditions. Method validation demonstrated good recoveries, above 87%, and accuracy and precision better than 13.4%. The LOQ was 0.5 ng/ml for harmine, 0.3 ng/ml for harmaline, 1.0 ng/ml for THH, and 0.3 ng/ml for harmol and harmalol. Good linearity was observed in the concentration ranges evaluated for DMT (2.5-50 ng/ml) and the beta-carbolines (0.3-100 ng/ml). The gas chromatography and HPLC methods described allowed adequate characterization of the pharmacokinetics of the four main alkaloids present in ayahuasca, and also of two major beta-carboline metabolites not previously described in the literature.

La aspirina: el medicamento del siglo / Aspirin: the drug of this century

La aspirina es un fármaco muy común en nuestros días con muy buena tolerancia por el organismo, amplio margen de seguridad y de fácil manejo por el médico de asistencia. De ella se revisan sus indicaciones clásicas como analgésico, antiinflamatorio y antipirético, donde es extremadamente eficaz y en sus indicaciones recientes como son: la cardiopatía isquémica, cefalea diabetes mellitus, enfermedad cerebrovascular, demencia senil, enfermedad vascular periférica y enfermedad vascular cardiaca se ha comprobado su alta efectividad. En el embarazo se ha comprobado que es beneficiosa en la prevención de la preclampsia a bajas dosis, además de la reducción del CIUR y la prematuridad. Se han realizado nuevas indicaciones de este medicamento en el cáncer de colon y mama, obesidad, tromboembolismo pulmonar hemodiálisis y el SIDA, algunas de ellas en las cuales su efectividad, dosis, y tiempo de tratamiento están por precisar. El ácido acetil salicílico (ASA) se ha mantenido por más de 100 años casi sin modificación, por lo que podemos plantear que utilizada racionalmente, la aspirina puede ser una droga maravillosa(AU)

La detección del error y su control, un desafío para el anestesiólogo / Mistake detection and control : a challenge for the anesthesiologist

El error humano puede ocurrir en nuestra actividad cotidiana y, teniendo en cuenta que el hombre comete errores y que los mismos son inherentes a la función cognitiva humana, sería prudente tomar conciencia de ellos para evitar su reiteración. Para analizar la génesis del error es necesario considerar que en toda acción humana intervienen aspectos cognitivos y de sensopercepción. Basados en esto proponemos la clasificación de Short que divide a los errores en errores activos, errores latentes, errores humanos y errores por desatender las reglas (violation). En algunos países hay entidades que tienen como objetivo el determinar y clasificar las causas de error para crear pautas de prevención basadas en datos estadísticos, como la Australian Incidents Monitoring Study (AIMS), y otras entidades, como la Specially Workings Groups (SWG), la que ha realizado estudios y registros de incidentes para crear registros nacionales de incidentes que, basándose en resultados estadísticos, categorizan los errores y desarrollan estrategias para prevenirlos ó minimizarlos. En nuestro medio no será fácil conseguir una estrategia de prevención adecuada en tanto no se implemente un sistema de denuncias de incidentes acorde con la idiosincrasia de nuestro medio laboral, por lo que nuestra propuesta es crear un sistema de denuncias que respete anonimato, confidencialidad y seguridad legal. Los resultados serán analizados en forma conficencial por una comisión de opinión permanente, a fin de llevar a cabo la normalización de medidas preventivas y su divulgación en el ámbito nacional.

La detección del error y su control, un desafío para el anestesiólogo / Mistake detection and control : a challenge for the anesthesiologist

El error humano puede ocurrir en nuestra actividad cotidiana y, teniendo en cuenta que el hombre comete errores y que los mismos son inherentes a la función cognitiva humana, sería prudente tomar conciencia de ellos para evitar su reiteración. Para analizar la génesis del error es necesario considerar que en toda acción humana intervienen aspectos cognitivos y de sensopercepción. Basados en esto proponemos la clasificación de Short que divide a los errores en errores activos, errores latentes, errores humanos y errores por desatender las reglas (violation). En algunos países hay entidades que tienen como objetivo el determinar y clasificar las causas de error para crear pautas de prevención basadas en datos estadísticos, como la Australian Incidents Monitoring Study (AIMS), y otras entidades, como la Specially Workings Groups (SWG), la que ha realizado estudios y registros de incidentes para crear registros nacionales de incidentes que, basándose en resultados estadísticos, categorizan los errores y desarrollan estrategias para prevenirlos ó minimizarlos. En nuestro medio no será fácil conseguir una estrategia de prevención adecuada en tanto no se implemente un sistema de denuncias de incidentes acorde con la idiosincrasia de nuestro medio laboral, por lo que nuestra propuesta es crear un sistema de denuncias que respete anonimato, confidencialidad y seguridad legal. Los resultados serán analizados en forma conficencial por una comisión de opinión permanente, a fin de llevar a cabo la normalización de medidas preventivas y su divulgación en el ámbito nacional. (AU)