RESUMEN
PURPOSE: To investigate the frequency of a founder mutation in NLRP7, L750V, in independent cohorts of Mexican patients with recurrent hydatidiform moles (RHMs). METHODS: Mutation analysis was performed by Sanger sequencing on DNA from 44 unrelated Mexican patients with RHMs and seven molar tissues from seven additional unrelated patients. RESULTS: L750V was present in homozygous or heterozygous state in 37 (86%) patients and was transmitted on the same haplotype to patients from different states of Mexico. We also identified a second founder mutation, c.2810+2T>G in eight (18.1%) patients, and a novel premature stop-codon mutation W653*. CONCLUSION: Our data confirm the strong founder effect for L750V, which appears to be the most common mutation in NLRP7. We also report on six healthy live births to five patients with biallelic NLRP7 mutations, two from spontaneous conceptions and four from donated ovum and discuss our recommendations for DNA testing and genetic counseling.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Efecto Fundador , Mola Hidatiforme/genética , Mutación , Femenino , Haplotipos , Heterocigoto , Humanos , Nacimiento Vivo , México , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
As reported in our previous papers, a series of quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and studied as anti-tuberculosis agents. Here, the capability of the shake-flask method was studied and the retention time (expressed as log K) of 20 compounds were determined by RP-HPLC analysis. We found that the prediction of log P by the RP-HPLC analysis can result in a high accuracy and can replace the shake-flask method avoiding the experimental problems presented by quinoxaline di-N-oxides. The studied compounds were subjected to the ALOGPS module with the aim of comparing experimental log P(o/w) values and predicted data. Moreover, a preliminary in silico screening of the QSAR relationship was made confirming the influence of reduction peak potential, lipophilicity, H-bond donor capacity and molecular dimension descriptors on anti-tuberculosis activity.
Asunto(s)
Óxidos N-Cíclicos/análisis , Óxidos N-Cíclicos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Quinolinas/análisis , Quinolinas/farmacología , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Cromatografía Líquida de Alta Presión , Óxidos N-Cíclicos/síntesis química , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad Cuantitativa , Quinolinas/síntesis química , Quinoxalinas/química , TuberculosisRESUMEN
The increase in the prevalence of drug-resistant tuberculosis cases demonstrates the need of discovering new and promising compounds with antimycobacterial activity. As a continuation of our research and with the aim of identifying new antitubercular drugs candidates, a new series of quinoxaline 1,4-di-N-oxide derivatives containing isoniazid was synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv strain. Moreover, various drug-like properties of new compounds were predicted. Taking into account the biological results and the promising drug-likeness profile of these compounds, make them valid leads for further experimental research.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Hidrazinas/síntesis química , Hidrazinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Animales , Antibacterianos/química , Células Cultivadas , Chlorocebus aethiops , Hidrazinas/química , Concentración 50 Inhibidora , Ácidos Isonicotínicos/síntesis química , Ácidos Isonicotínicos/química , Ácidos Isonicotínicos/farmacología , Estructura Molecular , Quinoxalinas/síntesis química , Quinoxalinas/química , Quinoxalinas/farmacología , Células VeroRESUMEN
For a fourth approach of quinoxaline N,N'-dioxides as anti-trypanosomatid agents against T. cruzi and Leishmania, we found extremely active derivatives. The present study allows us to state the correct requirements for obtaining optimal in vitro anti-T. cruzi activity. Derivatives possessing electron-withdrawing substituents in the 2-, 3-, 6-, and 7-positions were the most active compounds. With regard to these features and taking into account their mammal cytotoxicity, some trifluoromethylquinoxaline N,N'-dioxides have been proposed as candidates for further clinical studies. Consequently, mutagenicity and in vivo analyses were performed with the most promising derivatives. In addition, with regard to the mechanism of action studies, it was demonstrated that mitochondrial dehydrogenases are involved in the anti-T. cruzi activity of the most active derivatives.
Asunto(s)
Óxidos N-Cíclicos/química , Quinoxalinas/química , Quinoxalinas/síntesis química , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Electrones , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Pruebas de Mutagenicidad , Parasitemia/tratamiento farmacológico , Quinoxalinas/farmacología , Pruebas de Toxicidad , Tripanocidas/farmacología , Trypanosoma cruzi/metabolismoRESUMEN
We report the synthesis, anti-inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave-assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug.
Asunto(s)
Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Antioxidantes/síntesis química , Antioxidantes/farmacología , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Lipooxigenasa/metabolismo , Masculino , Estructura Molecular , Quinoxalinas/química , RatasRESUMEN
As a continuation of our research and with the aim of obtaining new anti-tuberculosis agents which can improve the current chemotherapeutic anti-tuberculosis treatments, forty-three new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis strain H(37)Rv. Active compounds were also screened to assess toxicity to a VERO cell line. Results indicate that compounds with a methyl moiety substituted in position 3 and unsubstituted benzyl substituted on the carboxamide group provide an efficient approach for further development of anti-tuberculosis agents.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Quinoxalinas/química , Quinoxalinas/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Antituberculosos/síntesis química , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Humanos , Óxidos/síntesis química , Óxidos/química , Óxidos/farmacología , Quinoxalinas/síntesis química , Tuberculosis/tratamiento farmacológico , Células VeroRESUMEN
Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents, obtaining biological values similar to the reference compound, Rifampin (RIF).
Asunto(s)
Antituberculosos/síntesis química , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Animales , Chlorocebus aethiops , Cromatografía en Capa Delgada , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/crecimiento & desarrollo , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Relación Estructura-Actividad , Tuberculosis/epidemiología , Células VeroRESUMEN
Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis (TB). Besides TB, Chagas disease, affects approximately 20 million people. Quinoxalines display great activities against TB and Chagas. Forty new quinoxaline 1,4-di-N-oxide derivatives have been prepared and tested against M. tuberculosis and T. cruzi. Carboxylic acid quinoxaline 1,4-di-N-oxides (CAQDOs) 5 and 17 showed MIC values on the same order as the reference antituberculosis drug, rifampicin. Meanwhile, CAQDOs 12 and 22 presented IC(50) values in the same order as the anti-chagasic drug, nifurtimox.
Asunto(s)
Antituberculosos/química , Antituberculosos/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Animales , Espectroscopía de Resonancia Magnética , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Rifampin , Trypanosoma/efectos de los fármacosRESUMEN
Spindle epithelial tumor with thymus-like elements is a rare thyroid lesion of children and young adults thought to be derived from branchial pouch remnants or foci of ectopic thymus. The lesion is poorly understood, and although it was originally believed to follow an indolent clinical course, its potential for late metastasis is becoming generally acknowledged. We have recently seen a unique case of this rare tumor in an 11-year-old boy, in which an unexpected and salient feature is the presence of a micrometastasis in a single lymph node at presentation. With the exception of 1 case with extensively infiltrative tumor and metastatic disease at the time of onset, in all other cases dissemination occurred years after surgical resection of the primary lesion. We review all previously reported cases and provide a detailed study of the histologic and ultrastructural appearances of this lesion.
Asunto(s)
Neoplasias Glandulares y Epiteliales/secundario , Timo , Neoplasias de la Tiroides/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biopsia con Aguja Fina , Quimioterapia Adyuvante , Niño , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Humanos , Inmunohistoquímica , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Neoplasias Glandulares y Epiteliales/diagnóstico por imagen , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/terapia , Tiroidectomía , Tomografía Computarizada por Rayos XAsunto(s)
Humanos , Recién Nacido , Servicios Básicos de Salud , Trastornos de la Nutrición del Niño , Desnutrición , Argentina , Accesibilidad a los Servicios de Salud/tendencias , Atención Primaria de Salud/tendencias , Equidad en el Acceso a los Servicios de Salud , Pobreza , Factores Socioeconómicos , Sistemas de Salud/organización & administración , Sistemas de Salud/tendenciasRESUMEN
La sociedad asigna a madres y niños alta prioridad, derivada de la vulnerabilidad y de los procesos de crecimiento y desarrollo que los caracteriza, así como por ser el niño sujeto de derecho, con rango constitucional. La salud materno infantil está fuertemente sujeta a los cambios socioeconómicos y culturales y especialmente por la situación de pobreza. En nuestro país, los altos porcentajes de niños bajo la línea de pobreza, se han manifestado con un aumento de la mortalidad infantil en diez jurisdicciones con cifras extremas. Los programas delicados a este grupo se han caracterizado por su discontinuidad y no representar políticas de estado, de manera que para superar esta situación se proponen dos líneas de trabajo: abogar por políticas sociales que disminuyan la pobreza y estimulen el trabajo intersectorial y actuar desde el sector salud mejorando la cobertura y calidad de la atención del grupo. Se señalan las actividades que se han demostrado más efectivas en el ámbito nacional e internacional y se destacan entre las estrategias el desarrollo del primer nivel y la participación comunitaria.
Asunto(s)
Humanos , Planes y Programas de Salud , Salud Materno-Infantil , Pobreza , Atención Primaria de Salud , Factores Socioeconómicos , Argentina , Trastornos de la Nutrición del Niño , Mortalidad Infantil , Mortalidad Materna , Atención Perinatal , Salud Pública , Política Pública , Calidad de la Atención de Salud , Servicios de Salud ReproductivaAsunto(s)
Humanos , Masculino , Femenino , Preescolar , Salud , Estrategias de Salud , Salud Infantil/tendencias , Argentina , Mortalidad Infantil , América LatinaAsunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Mortalidad Infantil/tendencias , Morbilidad/tendencias , Argentina/epidemiologíaRESUMEN
Se describe el proceso del cambio curricular de la Facultad de Medicina de la Universidad Nacional de Tucumán para el que se contó con la cooperación técnica de la Organización Panamericana de la Salud. El presente trabajo relata esta larga historia que ha dejado un cúmulo de experiencia y satisfacciones en quienes son aun protagonistas de este proceso que ya ha comenzado a evaluarse y que en un futuro muy próximo podrá ser evaluado en términos de sus ambiciosos resultados