RESUMO
Synthetic opioids have played a significant role in the current opioid crisis in the United States (U.S.) and Canada and are a matter of concern worldwide. New psychoactive opioids (NPOs) are classified in the internationally recognized new psychoactive substances (NPSs) category. This group comprises compounds that may have been synthesized decades ago but appeared only recently in the illicit drug market. Such is the case of fentanyl, fentanyl analogs, and non-fentanyl opioids. Most NPOs have effects similar to morphine, including euphoria and analgesia, and can produce fatal respiratory depression. Here, we present an overview of the systemic and molecular effects of main NPOs, their classification, and their pharmacological properties. We first review the fentanyl group of NPOs, including the four compounds of clinical use (fentanyl, alfentanil, sufentanil, and remifentanil) and the veterinary drug carfentanil. We also provide essential information on non-medical fentanyl analogs and other synthetic opioids such as brorphine, etonitazene, and MT-45, used as adulterants in commonly misused drugs. This paper also summarizes the scarce literature on the use of NPOs in Mexico. It concludes with a brief review of the challenges to prevention and treatment posed by NPOs and some recommendations to face them.
Assuntos
Analgésicos Opioides , Humanos , Estados Unidos , Analgésicos Opioides/efeitos adversos , Remifentanil , Canadá , MéxicoRESUMO
ABSTRACT Synthetic opioids have played a significant role in the current opioid crisis in the United States (U.S.) and Canada and are a matter of concern worldwide. New psychoactive opioids (NPOs) are classified in the internationally recognized new psychoactive substances (NPSs) category. This group comprises compounds that may have been synthesized decades ago but appeared only recently in the illicit drug market. Such is the case of fentanyl, fentanyl analogs, and non-fentanyl opioids. Most NPOs have effects similar to morphine, including euphoria and analgesia, and can produce fatal respiratory depression. Here, we present an overview of the systemic and molecular effects of main NPOs, their classification, and their pharmacological properties. We first review the fentanyl group of NPOs, including the four compounds of clinical use (fentanyl, alfentanil, sufentanil, and remifentanil) and the veterinary drug carfentanil. We also provide essential information on non-medical fentanyl analogs and other synthetic opioids such as brorphine, etonitazene, and MT-45, used as adulterants in commonly misused drugs. This paper also summarizes the scarce literature on the use of NPOs in Mexico. It concludes with a brief review of the challenges to prevention and treatment posed by NPOs and some recommendations to face them.
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Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1ß, CCL2, PGE2, among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.
Assuntos
Terapia de Alvo Molecular , Neoplasias/genética , Neurogênese/genética , Evasão Tumoral/genética , Comunicação Celular/genética , Humanos , Células Matadoras Naturais/imunologia , Neoplasias/complicações , Neoplasias/terapia , Evasão Tumoral/imunologiaRESUMO
El amplio espectro de aberraciones cromosómicas observable en los trastornos del neurodesarrollo no siempre puede ser caracterizado por análisis cromosómico. El objetivo del trabajo fue determinar la etiología genética de estos trastornos en pacientes con afecciones neurológicas congénitas y sospecha clínica de un síndrome genético, aplicando un algoritmo de estudio clínico-molecular. En 71 de 111 niños analizados, se hallaron aberraciones submicroscópicas asociadas a síndromes de microdeleción-microduplicación: DiGeorge (22 casos), Prader-Willi (26 casos), Angelman (2 casos), Williams-Beuren (17 casos), Smith-Magenis (1 caso), Miller-Dieker (1 caso) y síndrome cri du chat (1 caso). Adicionalmente, se detectó una inserción desbalanceada de novo de la región 17p12p11.2, en el punto 5p13.1, en un niño de tres años. La utilización del método clínico unido a técnicas moleculares, como hibridación fluorescente in situ, ha permitido, en la mayoría de los casos, el diagnóstico certero de pacientes y/o familias con trastornos del neurodesarrollo.
The wide range of chromosome aberrations seen in neurodevelopmental disorders may not always be characterized by means of a chromosome analysis. The objective of this study was to determine the genetic etiology of these disorders in patients with congenital neurological conditions and clinical suspicion of a genetic disorder using a clinical and molecular testing algorithm. Among 111 studied children, 71 showed submicroscopic chromosome aberrations associated with microdeletion/microduplication syndromes: DiGeorge (22 cases), Prader-Willi (26 cases), Angelman (2 cases), Williams-Beuren (17 cases), Smith-Magenis (1 case), Miller-Dieker (1 case), and cri du chat syndrome (1 case). Additionally, a de novo trisomy 17p12p11.2 due to an unbalanced insertion into 5p13.1 was identified in a 3-year-old child. In most cases, the use of a clinical method together with molecular techniques, such as fluorescence in situ hybridization, has allowed to make an accurate diagnosis in patients and/or families with neurodevelopmental disorders.
Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Transtornos do Neurodesenvolvimento/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Síndrome , Algoritmos , Deficiências do Desenvolvimento , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Procedimentos Clínicos , Transtornos do Neurodesenvolvimento/etiologia , Aconselhamento GenéticoRESUMO
The wide range of chromosome aberrations seen in neurodevelopmental disorders may not always be characterized by means of a chromosome analysis. The objective of this study was to determine the genetic etiology of these disorders in patients with congenital neurological conditions and clinical suspicion of a genetic disorder using a clinical and molecular testing algorithm. Among 111 studied children, 71 showed submicroscopic chromosome aberrations associated with microdeletion/microduplication syndromes: DiGeorge (22 cases), Prader-Willi (26 cases), Angelman (2 cases), WilliamsBeuren (17 cases), Smith-Magenis (1 case), Miller-Dieker (1 case), and cri du chat syndrome (1 case). Additionally, a de novo trisomy 17p12p11.2 due to an unbalanced insertion into 5p13.1 was identified in a 3-year-old child. In most cases, the use of a clinical method together with molecular techniques, such as fluorescence in situ hybridization, has allowed to make an accurate diagnosis in patients and/or families with neurodevelopmental disorders.
El amplio espectro de aberraciones cromosómicas observable en los trastornos del neurodesarrollo no siempre puede ser caracterizado por análisis cromosómico. El objetivo del trabajo fue determinar la etiología genética de estos trastornos en pacientes con afecciones neurológicas congénitas y sospecha clínica de un síndrome genético, aplicando un algoritmo de estudio clínico-molecular. En 71 de 111 niños analizados, se hallaron aberraciones submicroscópicas asociadas a síndromes de microdeleción-microduplicación: DiGeorge (22 casos), Prader-Willi (26 casos), Angelman (2 casos), Williams-Beuren (17 casos), Smith-Magenis (1 caso), Miller-Dieker (1 caso) y síndrome cri du chat (1 caso). Adicionalmente, se detectó una inserción desbalanceada de novo de la región 17p12p11.2, en el punto 5p13.1, en un niño de tres años. La utilización del método clínico unido a técnicas moleculares, como hibridación fluorescente in situ, ha permitido, en la mayoría de los casos, el diagnóstico certero de pacientes y/o familias con trastornos del neurodesarrollo.
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Introducción. La calidad de vida relacionada con la salud se define como la percepción subjetiva e influenciada por el estado de salud actual sobre la capacidad para realizar aquellas actividades importantes para un individuo, la cual puede verse afectada en el adulto mayor por procesos de envejecimiento. Objetivo. Caracterizar la calidad de vida relacionada con la salud y las posibles asociaciones con factores antropométricos y sociodemográficos de la población adulta mayor. Materiales y métodos. Se realizó un estudio descriptivo con intención analítica y de corte transversal en el que se evaluó la calidad de vida relacionada con la salud en adultos mayores. La población de estudio estuvo constituida por 145 personas con edades entre los 70 y 92 años que participaron voluntariamente en el estudio y a quienes se les aplicó el cuestionario SF-36 con preguntas sociales y demográficas, además se realizó toma de medidas de talla y peso. Con la información recolectada se procedió a realizar un análisis univariado. Resultados. El 60,7 % de los participantes presentó una buena calidad de vida relacionada con salud. Dentro de las características sociodemográficas se encontró que el 63,4 % eran mujeres, el 67,6 % pertenecían a estrato medio-alto, el 67,6 % tenía escolaridad básica-media, el 81,4 % pertenecía al régimen contributivo y el 48,3 % tenía sobrepeso. Conclusiones. Es necesario implementar programas de protección y cubrimiento en seguridad social al adulto mayor que beneficien especialmente al género femenino, a adultos mayores de edades avanzadas y a los pertenecientes al régimen subsidiado de seguridad social.
Introduction: Quality of life is related to health, thus defined as the subjective perception of an individual Ìs current capacity to carry out meaningful activities. Such perception is influenced by the current state of health which is turn affected by aging processes. Objective: To characterize the quality of life related to health and its possible associations with the anthropometric and sociodemographic characteristics. Methodology: A cross-sectional study was carried out to assess health-related quality of life in the elderly. The study counted 145 participants, ranging from the ages between sixty and ni- nety-two, who voluntarily participated in the study; A health- related quality of life questionnaire (SF-36) with social and demographic questions was administered. Height and weight measurements were also taken. With this information, a univariate analysis was carried out. Results: For the total result of the SF-36 questionnaire, it was found that 60.7% of the participants presented a good quality of life related to health.63.4% of the participants in this study were women and, 67.6% of the overall sample were placed as having upper-middle income. Also, most of the participants were found to have basic schooling (67.6). Regarding social security, 81.4% of the sample belonged to social security health plans and (48.3%) was found to have overweight. Conclusions: As a result of the analysis carried out, recommendations such as the implementation of social security protection and coverage programs for the elderly, specifically benefitting the females, older adults and those belonging to the subsidized social security system, can be provided.
Introdução. A qualidade de vida relacionada à saúde é definida como a percepção subjetiva e influenciada pelo estado atual de saúde sobre a capacidade de realizar as atividades importantes de uma pessoa, frequentemente afetadas pelo processo de envelhecimento. Objetivo. Caracterizar a qualidade de vida relacionada à saúde e possíveis associações com fatores antropométricos e sociodemográficos na população idosa. Materiais e métodos. Foi realizado um estudo descritivo com intenção analítica e um estudo transversal, avaliando a qualidade de vida relacionada à saúde em idosos. A população do estudo foi composta por 145 pessoas com idades entre 70 e 92 anos, que participaram voluntariamente do estudo e para quem foi aplicado o questionário SF-36 com questões sociais e demográficas, além de medidas de altura e peso. Com as informações coletadas, foi realizada uma análise univariada. Resultados. 60,7% dos participantes apresentaram boa qualidade de vida relacionada à saúde. Entre as características sociodemográficas, verificou-se que 63,4% eram mulheres, 67,6% pertenciam à classe média alta, 67,7% possuíam ensino médio-médio (67,6), 81,4% pertenciam ao sistema contributivo e 48,3% estavam acima do peso. Conclusões. É necessário implementar programas de proteção e cobertura da previdência social para idosos que beneficiem especialmente o sexo feminino, idosos de idade avançada e pertencentes ao sistema subsidiado.
Assuntos
Humanos , Idoso , Idoso de 80 Anos ou mais , Nível de Saúde , População , Qualidade de Vida , Envelhecimento , ColômbiaRESUMO
Methylmercury (MeHg) is an environmental neurotoxicant that inhibits neuronal migration. This process requires several cyclic steps involving the formation of membrane protrusions (lamellipodia and filopodia) and focal adhesion turnover. FAK and Src are critical proteins that regulate both processes. The FAK-Src complex promotes the activation of Rac1 and Cdc42, two GTPases involved in the remodeling of the actin cytoskeletal network. Here, we studied the effect of MeHg (1, 10, 100, 500 and 1000nM) on cell migration, the formation of cell protrusions, focal adhesion location and the activation of FAK, Src, Rac1 and Cdc42 using the SH-SY5Y neuroblastoma cell line stimulated with PDGF-BB (PDGF). The data show that MeHg (1-500nM) inhibited PDGF-stimulated cell migration. In PDGF-stimulated cells, MeHg (100-1000nM) decreased protrusions and increased the size of the p-FAKY397 clusters. MeHg also inhibited PDGF-induced FAK and Src activation and, at 100nM, MeHg inhibited the activation of Rac1 and Cdc42. Altogether, the findings show that low concentrations of MeHg inhibit SH-SY5Y cell migration by disrupting the activation and disassembly of FAK. This negatively affects the activation of Src, Rac1 and Cdc42, all of which are critical proteins for the regulation of cell movement. These effects could be related to the MeHg-mediated inhibition of PDGF-induced formation of lamellipodia and filopodia, focal adhesion disassembly and PDGF-induced movement.
Assuntos
Movimento Celular/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Compostos de Metilmercúrio/farmacologia , Neuroblastoma/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Quinases da Família src/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases da Família src/metabolismoRESUMO
Early adverse life stress has been associated to behavioral disorders that can manifest as inappropriate or aggressive responses to social challenges. In this study, we analyzed the effects of artificial rearing on the open field and burial behavioral tests and on GFAP, c-Fos immunoreactivity, and glucose metabolism measured in anxiety-related brain areas. Artificial rearing of male rats was performed by supplying artificial milk through a cheek cannula and tactile stimulation, mimicking the mother's licking to rat pups from the fourth postnatal day until weaning. Tactile stimulation was applied twice a day, at morning and at night, by means of a camel brush on the rat anogenital area. As compared to mother reared rats, greater aggressiveness, and boldness, stereotyped behavior (burial conduct) was observed in artificially reared rats which occurred in parallel to a reduction of GFAP immunoreactivity in somatosensory cortex, c-Fos immunoreactivity at the amygdala and primary somatosensory cortex, and lower metabolism in amygdala (as measured by 2-deoxi-2-[18 fluoro]-d-glucose uptake, assessed by microPET imaging). These results could suggest that tactile and/or chemical stimuli from the mother and littermates carry relevant information for the proper development of the central nervous system, particularly in brain areas involved with emotions and social relationships of the rat. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1413-1429, 2017.
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Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Transtornos Mentais/etiologia , Estresse Psicológico/complicações , Estresse Psicológico/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Fluordesoxiglucose F18/farmacocinética , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Transtornos Mentais/diagnóstico por imagem , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Estimulação Física , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Isolamento Social/psicologia , TatoRESUMO
Dichlorodiphenyldichloroethylene (p,p'-DDE), the most persistent metabolite of dichlorodiphenyltrichloroethane (DDT), is still present in the human population. Both are present in the bone marrow of patients with bone marrow disorders, but thus far there are no studies that assess the capability of p,p'-DDE to affect myeloid cells. The aim of this study was to determine the effect of p,p'-DDE on promyelocytic cell differentiation and intracellular pathways related to this event. p,p'-DDE induced morphological changes compatible with promyelocytic differentiation in a concentration-dependent manner. The p,p'-DDE effect on [Ca2+]i, C/EBPß protein levels, PKCα and p38 activation, and the role of oxidative stress or PLA2 was assayed. Exposure to 1.9 µg/mL of p,p'-DDE increased [Ca2+]i, PKCα, p38, and C/EBPß protein levels; the increase of nuclear C/EBPß protein was dependent on p38. PKCα phosphorylation was dependent on PLA2 and p,p'-DDE-induced oxidative stress. p38 phosphorylation induced by p,p'-DDE was dependent on PLA2, PKC activation, and oxidative stress. These effects of p,p'-DDE at concentrations found in human bone marrow may induce alterations in immature myeloid cells and could affect their cellular homeostasis. In order to establish the risk from exposure to p,p'-DDE on the development of bone marrow disorders in humans, these effects deserve further study.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diclorodifenil Dicloroetileno/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células Mieloides/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Células HL-60 , Humanos , Células Mieloides/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 µg/kg/day MeHg, (3) 500 µg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.
Assuntos
Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Fatores Etários , Animais , Feminino , Humanos , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Gravidez , RatosRESUMO
La zona de desarrollo próximo es un concepto creado por Vigotsky que se refiere a la distancia que existe entre el desarrollo psíquico actual del sujeto y su desarrollo potencial. Por esta razón es un concepto de suma importancia para la educación en todos los niveles de enseñanza. El objetivo del presente artículo es describir cómo el concepto zona de desarrollo próximo se manifiesta en la educación superior médica cubana. Se explica la importancia de este concepto en los principios didácticos y se especifica cómo se utiliza en la formación de valores y mediante el uso de las tecnologías de la información y las comunicaciones. Se exponen las razones por las cuales la gestión del profesor ha de sustentarse en la ampliación de la zona de desarrollo próximo de sus estudiantes.
The concept near development zone was created by Vigotsky and refers to the distance between the present psychical development of the individual and his potential development. It is a concept of vital importance for education at all levels. The objective of the article is to describe how this concept behaves in the higher medical education in Cuba. The importance of this concept in the didactic principles were explained, as well as how it is used in the formation of values through the information and communication technologies. The reasons why the work of the professor has to be supported on the widening of the near development zone of their students were also stated.