Fentanyl and other New Psychoactive Synthetic Opioids. Challenges to Prevention and Treatment.

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.

Fentanyl and other New Psychoactive Synthetic Opioids. Challenges to Prevention and Treatment

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.

Chronic early-life lead exposure sensitizes adolescent rats to cocaine: Role of the dopaminergic system.

Exposure to heavy metals has been associated with psychiatric disorders and recent studies suggest an association between childhood lead (Pb2+) intoxication and schizophrenia (SZ). In animal models, Pb2+ exposure recapitulates key neuropathological and dopaminergic system alterations present in SZ. Given the high comorbidity of mental disorders such as SZ and substance abuse, coupled with evidence showing that Pb2+ exposure affects addiction circuits, we hypothesized that early life Pb2+ exposure could sensitize neuronal systems relevant to SZ and substance abuse. To this goal, we examined the effects of chronic developmental Pb2+ exposure on the acute locomotor response to cocaine (0, 5, and 15 mg kg-1) and behavioral sensitization. We also examined the role of the dopaminergic system in the psychostimulant effects of cocaine, and measured D1-dopamine receptor (D1R) levels in the rat brain using [3H]-SCH23390 quantitative receptor autoradiography, as well as the ability of the D1R antagonist SCH23390 to block the cocaine effects on locomotor activation. These studies were performed in male and female rats at different developmental ages consisting of juveniles (postnatal, PN14), early-adolescent (PN28), late adolescent (PN50), and adults (PN120). Our results show that chronic developmental Pb2+ exposure increases the acute locomotor response to the higher dose of cocaine in Pb2+-exposed male adolescent (PN28 and PN50) rats, and to the lower dose of cocaine in adolescent female rats. No changes in the locomotor activity were detected in adult rats. Behavioral sensitization experiments showed a sustained sensitization in early adolescent Pb2+-exposed male but not female rats. The cocaine-induced effects on locomotor activity were abrogated by injection of a D1R antagonist suggesting the involvement of this dopamine receptor subtype. Furthermore, Pb2+-induced increases D1R levels in several brain regions were prominent in juveniles and early adolescence but not in late adolescence or in adults. In summary, early chronic developmental Pb2+ exposure results in age and sex-dependent effect on the locomotor response to cocaine, suggesting differential susceptibilities to the neurotoxic effects of Pb2+ exposure. Our data provides further support to the notion that Pb2+ exposure is an environmental risk factor for psychiatric disorders and substance abuse.

Chronic developmental lead exposure increases µ-opiate receptor levels in the adolescent rat brain.

Childhood lead (Pb2+) intoxication is a global public health problem best known for producing deficits in learning and poor school performance. Human and preclinical studies have suggested an association between childhood Pb2+ intoxication and proclivity to substance abuse and delinquent behavior. While environmental factors have been implicated in opioid addiction, less is known about the role of exposure to environmental pollutants on the brain opioid system. Opioid receptors are involved in the biological effects of opioids and other drugs of abuse. In this study, we examine the effect of chronic developmental Pb2+ exposure (1500 ppm in the diet) on µ-opioid receptor (MOR) levels in the rat brain using [3H]-d-Ala2-MePhe4-Gly-ol5 enkephalin ([3H]-DAMGO) quantitative receptor autoradiography at different developmental stages (juvenile, early-adolescent, late adolescent and adult) in male and female rats. Our results indicate that chronic developmental Pb2+ exposure increases the levels of [3H]-DAMGO specific binding to MOR in juvenile and early adolescent Pb2+-exposed male and female rat brain with no changes in late-adolescent (PN50) and minor changes in Pb2+-exposed adult male rats (PN120). Specifically, at PN14, Pb2+-exposed males had an increase in MOR binding in the lateral posthalamic nuclei (LPTN), and Pb2+-exposed females had increased MOR binding in LPTN, medial thalamus, and hypothalamus. At PN28, Pb2+-exposed males had increased MOR levels in the striatum, stria medullaris of the thalamus, LPTN, medial thalamus, and basolateral amygdala, while Pb2+-exposed females showed an increase in nucleus accumbens core, LPTN, and medial thalamus. No changes were detected in any brain region of male and female rats at PN50, and at PN120 there was a decrease in MOR binding of Pb2+-exposed males in the medial thalamus. Our findings demonstrate age and gender specific effects of MOR levels in the rat brain as a result of chronic developmental Pb2+ exposure. These results indicate that the major changes in brain MOR levels were during pre-adolescence and early adolescence, a developmental period in which there is higher engagement in reward and drug-seeking behaviors in humans. In summary, we show that chronic exposure to Pb2+, an ubiquitous and well-known environmental contaminant and neurotoxicant, alters MOR levels in brain regions associated with addiction circuits in the adolescent period, these findings have important implications for opioid drug use and abuse.

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies.

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.

Algoritmo para el diagnóstico de pacientes con trastornos del neurodesarrollo y sospecha de un síndrome genético / Algorithm for the diagnosis of patients with neurodevelopmental disorders and suspicion of a genetic syndrome

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.

Algorithm for the diagnosis of patients with neurodevelopmental disorders and suspicion of a genetic syndrome. / Algoritmo para el diagnóstico de pacientes con trastornos del neurodesarrollo y sospecha de un síndrome genético.

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.

Asociación entre calidad de vida relacionada con salud y factores sociodemográficos y antropométricos en una institución de salud de Medellín, Colombia / Association between quality of life related to health and sociodemographical and anthropometric factors in a colombian health institution / Associação entre qualidade de vida relacionada à saúde e fatores sociodemográficos e antropométricos em uma instituição de saúde colombiana

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 ́s 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.

MeHg affects the activation of FAK, Src, Rac1 and Cdc42, critical proteins for cell movement in PDGF-stimulated SH-SY5Y neuroblastoma cells.

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.

Disruption of behavior and brain metabolism in artificially reared rats.

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.

Exposure to p,p'-DDE Induces Morphological Changes and Activation of the PKCα-p38-C/EBPß Pathway in Human Promyelocytic HL-60 Cells.

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.

Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors.

Purinergic P2X4 receptors (P2X4Rs) belong to the P2X superfamily of ion channels regulated by ATP. We recently demonstrated that P2X4R knockout (KO) mice exhibited deficits in sensorimotor gating, social interaction, and ethanol drinking behavior. Dopamine (DA) dysfunction may underlie these behavioral changes, but there is no direct evidence for P2X4Rs' role in DA neurotransmission. To test this hypothesis, we measured markers of DA function and dependent behaviors in P2X4R KO mice. P2X4R KO mice exhibited altered density of pre-synaptic markers including tyrosine hydroxylase, dopamine transporter; post-synaptic markers including dopamine receptors and phosphorylation of downstream targets including dopamine and cyclic-AMP regulated phosphoprotein of 32 kDa and cyclic-AMP-response element binding protein in different parts of the striatum. Ivermectin, an allosteric modulator of P2X4Rs, significantly affected dopamine and cyclic AMP regulated phosphoprotein of 32 kDa and extracellular regulated kinase1/2 phosphorylation in the striatum. Sensorimotor gating deficits in P2X4R KO mice were rescued by DA antagonists. Using the 6-hydroxydopamine model of DA depletion, P2X4R KO mice exhibited an attenuated levodopa (L-DOPA)-induced motor behavior, whereas ivermectin enhanced this behavior. Collectively, these findings identified an important role for P2X4Rs in maintaining DA homeostasis and illustrate how this association is important for CNS functions including motor control and sensorimotor gating. We propose that P2X4 receptors (P2X4Rs) regulate dopamine (DA) homeostasis and associated behaviors. Pre-synaptic and post-synaptic DA markers were significantly altered in the dorsal and ventral striatum of P2X4R KO mice, implicating altered DA neurotransmission. Sensorimotor gating deficits in P2X4R KO mice were rescued by DA antagonists. Ivermectin (IVM), a positive modulator of P2X4Rs, enhanced levodopa (L-DOPA)-induced motor behavior. These studies highlight potential interactions between P2X4Rs and DA system.

Early Developmental Low-Dose Methylmercury Exposure Alters Learning and Memory in Periadolescent but Not Young Adult Rats.

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.

Propuesta de programa de la residencia de neurología en Cuba / A proposal of residency neurology program in Cuba

Objetivo: Proponer modificaciones para estandarizar y actualizar el programa de la especialidad de neurología en Cuba.Desarrollo: Los cambios mundiales en la neurología han traído consigo la necesidad de un análisis profundo, integral y actualizado de laorganización y los contenidos del programa de la especialidad de neurología en Cuba. En las últimas dos décadas varias instituciones docentes han hecho ajustes imprescindibles, pero no uniformes, al programa al programa vigente desde el año 1979 para garantizar la adecuada formación del especialista en neurología. Este documento pretende servir de referencia con respecto a: 1) Denominación oficial de la especialidad y requisitos de la titulación; 2) Definición de la especialidad y rasgos de su evolución histórica; 3) Objetivos generales y competencias de la formación; 4) Estrategia docente, 5) Distribución y duración de los períodos de formación; 6) Contenidos específicosde formación (incluyendo los objetivos); 7) Bibliografía recomendada; 8) Lugares y recursos de formación; y 9) Sistema de evaluación. Se han revisado varios programas de residencia de otros países, los documentos nacionales al respecto, y varios artículos sobre el tema.Conclusiones: El análisis crítico por los profesores y residentes en relación a los objetivos, estrategias y contenidos incluidos en este artículo contribuirá a que el programa de residencia de neurología cumpla los estándares más exigentes y la misión de lograr la excelencia en el cuidado del paciente, la educación y la investigación(AU)

Objective: To review and formulate recommendations of cuban neurology residency curriculum for standardization and update.Development: World neurology practice changes cause a profound, integral and update analysis about organization and contents of neurology specialty program in Cuba. In last two decades some docents national units make necessary, but not uniform, adjustments to1979 year approved program with the purpose to achieve adequate formation of neurologists. This document pretends to serve as reference regarding: 1) Official specialty denomination and requisites of qualifications; 2) Specialty definition and some historiccharacteristic; 3) General objective and formation competences; 4) Docent strategy; 5) Distribution and duration of formation periods; 6)Specific formation contents (including objectives); 7) Recommended bibliography; 8) Formation places and resources; and 9) Evaluation system. A review was carried out about some residency programs of other countries, national documents, and various articles about this issue.Conclusions: Understanding and critical analysis for professors and residents about objectives, strategies, and contents included in this article may contribute to fulfill most exigent standards and mission of excellence for patients care, education and investigation(AU)

El concepto zona de desarrollo próximo y su manifestación en la educación médica superior cubana / The concept near development zone and its manifestation in the Cuban higher medical education

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.

El concepto zona de desarrollo próximo y su manifestación en la educación médica superior cubana / The concept near development zone and its manifestation in the Cuban higher medical education

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.(AU)

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.(AU)

Hemorragia subaracnoidea: epidemiología, etiología, fisiopatología y diagnóstico / Subarachnoid haemorrhage: epidemiology, etiology, pathophysiology and diagnosis

Objetivo: Revisar la literatura para seleccionar los aspectos más relevantes y avanzados referentes a la epidemiología, etiología, fisiopatología y diagnóstico de la hemorragia subaracnoidea (HSA).Desarrollo: La HSA constituye un desafío diagnóstico e implica intervenciones complejas, sofisticadas, multidisciplinarias y raramente rutinarias. La sospecha clínica de HSA radica en la aparición de cefalea súbita severa con pico en minutos y quepersiste más de una hora. El paciente con sospecha de HSA debe ser remitido de forma urgente a un centro hospitalario que disponga al menos de equipo de TC de cráneo, servicio de neurocirugía y cuidados intensivos especializados. El primer estudio neurológico a realizar es la TC de cráneo simple, pero su resultado negativo no excluye la HSA. Cuando el resultadode la TC de cráneo es negativo se aconseja la consulta con un especialista en Neurología o Neurocirugía para la ejecución de la punción lumbar y la interpretación de los hallazgos. En el protocolo de manejo diagnóstico es esencial un algoritmo estándar para ejecutar con urgencia la angiografía estándar y/o la angio–TC acorde al paciente concreto y la disponibilidadde dichas técnicas.Conclusiones: Se consideran puntos claves de la incidencia, factores de riesgo, causas, mecanismos fisiopatológicos y manejo diagnóstico de la HSA. Las recomendaciones son un resumen de la mejor evidencia disponible para el manejo diagnóstico de este tipo de ictus. No obstante, algunas de las áreas tratadas demandan de investigaciones futuras porque han sido controversiales o han recibido escasa atención(AU)

Objective: A literature review was carried out of more relevant and refined elements about Subarachnoid hemorrhage (SAH) epidemiology, etiology, physiopathology and diagnosis.Development: SAH is a diagnostic challenge and includes complex, sophisticated, multidisciplinary, and rarely routinely procedures. The clinical suspicion of SAH is based in a sudden onset of very severe headache that peaks within minutes and lasts more than an hour. This patient must be urgently remitted for a hospital with at least CT scan equipment, neurosurgeryservice and dedicated intensive care unit. The first neurological study to make is CT scan without contrast enhancement, but negative results are not criteria for exclusion of SAH. When CT scan is negative we recommend that cases should be consulted with neurologist or neurosurgery specialist for lumbar puncture execution and results assessments. In this diagnostic protocol is essential an algorithm for urgently execution of standard angiography and/or CT angiography based in patient context and accessibility.Conclusions: The essentials points about incidence, risk factors, causes, physiopathology and diagnostic management of SAH was considered. The recommendations are a summary of best available evidence for diagnostic management of this stroke type. Nevertheless, some topics need more investigations because are controversial or received poor attention(AU)

Mosaicismo de aneuploidías de los cromosomas sexuales en el diagnóstico prenatal / Mosaicism of aneuploidias of sexual chromosomes in prenatal diagnosis

El mosaicismo, de las aneuploidías sexuales es relativamente frecuente en el Diagnóstico Prenatal Citogenético, comparado con otros tipos de mosaicismos cromosómicos. En una serie de 16 950 amniocentesis se determinó la frecuencia de este tipo de mosaicismo en nuestro medio, su efecto en el fenotipo fetal y la influencia del porcentaje de la línea aberrada en la manifestación de malformaciones. Como resultado, se describen 18 casos de mosaicos sexuales para una frecuencia de 37,5(percent). El 50(percent) de los mismos correspondió a la aberración cromosómica 45,X/46,XX. Se detectó solo un 11,1(percent (2/18) de alteraciones fenotípicas, sin encontrar una influencia determinante del porcentaje de la línea aberrada. Se halló un alto índice de interrupciones de embarazos entre estos casos de mosaicismo de los cromosomas sexuales, lo cual no coincide con los reportes de la literatura…(AU)