Efecto citotóxico de los compuestos de inclusión de paladio (II) en la beta-ciclodextrina

Introduction: Thiosemicarbazones and palladium (II) complexes have antineoplastic activities with mild side effects, for which they are considered new alternative antineoplastic drugs. However, the IC50 ranges of these complexes vary due to differences in their structure and solubility and their sensitivities for various cellular targets. Beta-cyclodextrin is an additive used to improve the solubility and stability of various drugs for therapeutic use, but the combination of beta-cyclodextrin with palladium (II) complexes and thiosemicarbazones has not been tested yet.Objective: To study the cytotoxic effect of palladium (II) inclusion complexes in beta-cyclodextrin.Materials and methods: We tested the cytotoxic activity of palladium complexes combined with beta-cyclodextrin in the breast cancer cell line MCF-7 using a sulforhodamine B assay.Results: We tested the antiproliferative activity of palladium (II) complexes with and without the ligands MePhPzTSC and Ph2PzTSC and with and without beta-cyclodextrin in MCF-7 cells and compared them to that of cisplatin. All combinations showed antiproliferative activity; however, the activity was greater for the combinations that included beta-cyclodextrin: ([Pd (MePhPzTSC) 2] • ß-CD and [Pd (Ph2PzTSC) 2] • ß-CD), at concentrations of 0.14 and 0.49 μM, respectively. The IC50 for this complex was 5-fold lower than that of the ligand-free combinations (1.4 and 2.9 μM, respectively). The IC50 for free palladium (II) complex was 0.571.24 μM and that for cisplatin was 6.87 μM.Conclusions: Beta-cyclodextrin significantly enhanced the cytotoxic activities of palladium (II) complexes and thiosemicarbazones probably by improving their solubility and bioavailability. The addition of beta-cyclodextrin is a possible strategy for designing new anticancer drugs.Introducción. Las tiosemicarbazonas y sus complejos de paladio (II) poseen actividad antineoplásica con pocos efectos secundarios, por lo cual se las considera como una nueva alternativa terapéutica. Sin embargo, existen diferencias en los rangos de la concentración inhibitoria media (CI50) asociada a la divergencia estructural y la solubilidad de los complejos, así como a la sensibilidad de los blancos celulares. La inclusión de fármacos en la beta-ciclodextrina con fines terapéuticos ha mejorado su solubilidad y estabilidad, pero los efectos de su combinación con los complejos de paladio (II) y las tiosemicarbazonas no se han comprobado aún.Objetivo. Estudiar el efecto citotóxico de los complejos de paladio en la beta-ciclodextrina.Materiales y métodos. La actividad citotóxica de los complejos de paladio en la beta-ciclodextrina se evaluó en la línea celular de cáncer de mama (MCF-7), empleando el método de la sulforodamina B.Resultados. Los ligandos MePhPzTSC y Ph2PzTSC, sus complejos de paladio (II) libres e incluidos en la beta-ciclodextrina y el cisplatino mostraron actividad citotóxica en la línea celular MCF-7; sin embargo, la citotoxicidad fue mayor con la inclusión en la beta-ciclodextrina ([Pd(MePhPzTSC)2]•ß-CD y [Pd(Ph2PzTSC)2]•ß-CD). La concentración inhibitoria media (CI50) para estos complejos se obtuvo en concentraciones de 0,14 y 0,49 μM, y con dosis hasta cinco veces inferiores comparadas con las concentraciones de los ligandos libres (1,4 y 2,9 μM), de los complejos de paladio (II) libres (0,57 y 1,24 μM) y del cisplatino (6,87 μM).Conclusiones. El uso de la beta-ciclodextrina mejoró significativamente la actividad citotóxica de las tiosemicarbazonas y sus complejos de paladio (II), lo cual probablemente está asociado al incremento de la solubilidad y biodisponibilidad del compuesto, estrategia que se puede sugerir para el diseño de futuros fármacos antineoplásicos

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Mosaicismo en el sindrome de Cri Du Chat

El Síndrome del maullido de gato (Cri du Chat) consiste en una deleción del brazo corto del cromosoma 5. Los hallazgos clínicos comunes encontrados en este síndrome son: Microcefalia, puente nasal ancho, hipertelorismo, pliegues epícanticos, hendiduras palpebrales descendentes, pabellones auriculares de inserción baja, micrognatia, dermatoglifos anormales, retraso psicomotor y del crecimiento. Corresponde a un síndrome infrecuente, con una incidencia de 1 en 50000 nacidos vivos. Solo el 3% de los casos se debe a mosaicismo. En la actualidad, no se han reportado casos de Síndrome de Cri du Chat con dos líneas celulares en Venezuela. Se presenta el caso de un paciente masculino, de 6 meses de edad quien consulta por Síndrome Convulsivo. Antecedentes personales: Producto de unión no consanguínea, primera gesta, pre-termino (34 semanas), controlado sin complicaciones. A los 28 días de nacido presenta convulsión focal motora e hipoactividad. Evaluación Genética: Al examen físico se observa microcefalia, hipertelorismo, micrognatia, llanto de tono muy agudo, talón prominente. Es evaluado a los 6 meses y se observa retardo ponto-estatural e hipotonía generalizada. El cariotipo reporta: 46 XY y 46XY del (5p) en 15% de las metafases evaluadas. Por la infrecuencia del mosaicismo como causa de este síndrome, se presentan las características clínicas y hallazgos citogenéticos de este paciente en comparación con las características de dos pacientes que portan la delección debido a otra causa. Los tres pacientes fueron admitidos a la unidad de Genética Médica de la Universidad de Los Andes, en la ciudad de Mérida; Venezuela

Estudio de prefactibilidad para la implementación de servicios exequiales para mascotas en la ciudad de Bogotá.

Elaborar el estudio de prefactibilidad, recopilando información y tomando en cuenta diferentes variables que permitan realizar un análisis preliminar y de esta manera minimizar el riesgo para la creación de una empresa de servicios exequiales de mascotas ubicada en la ciudad de Bogotá.Debido al desarrollo y alto crecimiento de servicios fúnebres para mascotas en Colombia, las nuevas tendencias en el mercado de las mascotas permiten generar una gran oportunidad a las empresas funerarias en diversificar su portafolio de servicios y fortalecer sus ventas en previsión exequial a través de la atención profesionalizada en servicios funerarios para mascotas. Esta línea de negocio puede funcionar también como una estrategia de venta para las afiliaciones exequiales mediante la aceptación de la mascota como un miembro de la familia, lo que generará nuevas afiliaciones de previsión exequial y mayor fidelización para con la empresa. Es por esto por lo que, se necesita de mucha promoción, sensibilidad, concientización, creatividad e innovación para poder vender al cliente, por lo tanto, se recomienda utilizar estrategias de promoción incentivando a la compra de estos servicios a través de beneficios adicionales para el comprador. A corto plazo para generar reconocimiento en la comunidad y el perfil de nuestro comprador, se deberá ejecutar el plan de promoción informativo, con el cual buscara los clientes objetivos, utilizando estrategias en Marketing digital y alianzas estratégicas. Las redes sociales juegan un papel importante, por medio de ellas se tendrá actualizado a los clientes, se generarán mecanismos para aumentar la comunidad virtual y así poder dar a conocer la marca. Es importante la constante innovación y participación de la nueva línea de negocio en todo el ciclo de vida de la mascota (servicios y productos que pueda utilizar en vida y en su muerte), para romper el paradigma que se está vendiendo un seguro de muerte, sino al contrario, se está vendiendo una protección y bienestar para la familia, que incluye a su mascota.Due to the development and high growth of funeral services for pets in Colombia, the new trends in the pet market allow a great opportunity for funeral companies to diversify their portfolio of services and strengthen their sales in funeral provision through care Professionalized in funeral services for pets. This line of business can also function as a sales strategy for funeral affiliations by accepting the pet as a member of the family, which will generate new funeral funeral affiliations and greater loyalty to the company. This is why, it takes a lot of promotion, sensitivity, awareness, creativity and innovation to be able to sell to the client, therefore, it is recommended to use promotion strategies encouraging the purchase of these services through additional benefits for the buyer. In the short term to generate recognition in the community and the profile of our buyer, the informative promotion plan must be executed, with which it will search for the target clients, using strategies in digital Marketing and strategic alliances. Social networks play an important role, through them customers will be updated, mechanisms will be generated to increase the virtual community and thus be able to publicize the brand. The constant innovation and participation of the new business line throughout the pet's life cycle (services and products that can be used in life and in death) is important to break the paradigm that death insurance is being sold, on the contrary, a protection and well-being for the family is being sold, which includes your pet

Estudio de prefactibilidad para la implementación de servicios exequiales para mascotas en la ciudad de Bogotá.

Elaborar el estudio de prefactibilidad, recopilando información y tomando en cuenta diferentes variables que permitan realizar un análisis preliminar y de esta manera minimizar el riesgo para la creación de una empresa de servicios exequiales de mascotas ubicada en la ciudad de Bogotá.Debido al desarrollo y alto crecimiento de servicios fúnebres para mascotas en Colombia, las nuevas tendencias en el mercado de las mascotas permiten generar una gran oportunidad a las empresas funerarias en diversificar su portafolio de servicios y fortalecer sus ventas en previsión exequial a través de la atención profesionalizada en servicios funerarios para mascotas. Esta línea de negocio puede funcionar también como una estrategia de venta para las afiliaciones exequiales mediante la aceptación de la mascota como un miembro de la familia, lo que generará nuevas afiliaciones de previsión exequial y mayor fidelización para con la empresa. Es por esto por lo que, se necesita de mucha promoción, sensibilidad, concientización, creatividad e innovación para poder vender al cliente, por lo tanto, se recomienda utilizar estrategias de promoción incentivando a la compra de estos servicios a través de beneficios adicionales para el comprador. A corto plazo para generar reconocimiento en la comunidad y el perfil de nuestro comprador, se deberá ejecutar el plan de promoción informativo, con el cual buscara los clientes objetivos, utilizando estrategias en Marketing digital y alianzas estratégicas. Las redes sociales juegan un papel importante, por medio de ellas se tendrá actualizado a los clientes, se generarán mecanismos para aumentar la comunidad virtual y así poder dar a conocer la marca. Es importante la constante innovación y participación de la nueva línea de negocio en todo el ciclo de vida de la mascota (servicios y productos que pueda utilizar en vida y en su muerte), para romper el paradigma que se está vendiendo un seguro de muerte, sino al contrario, se está vendiendo una protección y bienestar para la familia, que incluye a su mascota.Due to the development and high growth of funeral services for pets in Colombia, the new trends in the pet market allow a great opportunity for funeral companies to diversify their portfolio of services and strengthen their sales in funeral provision through care Professionalized in funeral services for pets. This line of business can also function as a sales strategy for funeral affiliations by accepting the pet as a member of the family, which will generate new funeral funeral affiliations and greater loyalty to the company. This is why, it takes a lot of promotion, sensitivity, awareness, creativity and innovation to be able to sell to the client, therefore, it is recommended to use promotion strategies encouraging the purchase of these services through additional benefits for the buyer. In the short term to generate recognition in the community and the profile of our buyer, the informative promotion plan must be executed, with which it will search for the target clients, using strategies in digital Marketing and strategic alliances. Social networks play an important role, through them customers will be updated, mechanisms will be generated to increase the virtual community and thus be able to publicize the brand. The constant innovation and participation of the new business line throughout the pet's life cycle (services and products that can be used in life and in death) is important to break the paradigm that death insurance is being sold, on the contrary, a protection and well-being for the family is being sold, which includes your pet

Unintentional pediatric cannabis exposures after legalization of recreational cannabis in Canada.

Research letter: Previous studies have documented increases in cannabis exposures among young children after legalization of recreational cannabis. We evaluated changes in pediatric emergency department (ED) visits and hospitalizations due to cannabis exposures associated with these changes

Inmunodeficiencias primarias: inmunopatogenia, infecciones asociadas y estrategias terapéuticas

Las inmunodeficiencias primarias (IDP) son un grupo de defectos genéticos que generan alteración en los mecanismos de defensa tanto innatos como adaptativos, asociados con: 1) ausencia de uno o varios de los componentes celulares, 2) incapacidad para la comunicación de los elementos de la respuesta inmune, así como también en el reconocimiento de antígenos extraños, propios o modificados e 3) incapacidad para la activación de los mecanismos efectores, bien sea por dificultad para alcanzar los tejidos afectados; para promover la polarización de la respuesta inmune tanto proinflamatoria como reguladora; o para liberar mediadores encargados de la destrucción de los agentes invasores. Este complejo grupo de enfermedades condicionan no solo a una susceptibilidad elevada para sufrir infecciones por diferentes agentes infecciosos, sino también a la alteración de los mecanismos homeostáticos y de vigilancia que evitan el desarrollo de enfermedades autoinflamatorias y neoplásicas. En esta revisión se describen parte de estos defectos, sus consecuencias y el abordaje inicial para el estudio y manejo de las infecciones recurrentes. Primary immunodeficiencies: immunopathogenesis, associated infections and therapeutic strategies Abstract Primary immunodeficiencies disorders (PID) are a group of genetic defects that affect both innate and adaptive immune response. PID are associated with: 1) absence of cellular components, 2) impaired connection among components of the immune response, as well as in the recognition of foreign, self or modified antigens, and 3) inappropriate modulation of effectors mechanisms either by inability to reach affected tissues, to promote proinflammatory and regulatory polarization, or perform the clearance of invading agents. PID not only increases the susceptibility to infections by different microorganisms, but also alters the homeostatic mechanisms and immune surveillance, that prevent autoinflammatory and neoplastic diseases. This review describes some of these defects, its consequences and the initial approach to the study and management of recurrent infections

Desarrollo de un ensayo casero para la detección de IgG contra el core del virus de la Hepatitis B

Hepatitis B infection affects individuals worldwide, especially in Latin America. Serological assay for HBV antibodies and antigen detection, are critical for HBV diagnostic and treatment. Available commercial ELISA kits are expensive and in our country not always are readily available. The aim of this study was develop a homemade ELISA kit for serological detection IgG anti-HBV core (IgG anti-HBc) accessible for our patients. 114 samples were analyzed: 17 from seronegatives individuals, 48 from seropositives patients and 49 belonging to indigenous population from Mérida State. Exposure to HBV was determined using the Murex anti-HBc test (DiaSorin, UK). Homemade ELISA shows 100% specificity and del 100 % sensitivity, and was in very good agreement with serological status, Kappa= 1 (CI 95%: 0,767-1), X2 (p<0,001). In indigenous population (Wayuu and mestizos), overall IgG anti-HBc prevalence was 22%. Taking into account these results, homemade IgG anti-HBc ELISA is efficacious and low cost usefully, for HBV diagnosis