Anxiogenic doses of rapamycin prevent URB597-induced anti-stress effects in socially defeated mice.

Repeated exposure to psychosocial stress modulates the endocannabinoid system, particularly anandamide (AEA) signaling in brain regions associated with emotional distress. The mTOR protein regulates various neuroplastic processes in the brain disrupted by stress, including adult hippocampal neurogenesis. This kinase has been implicated in multiple effects of cannabinoid drugs and the anti-stress behavioral effects of psychoactive drugs. Therefore, our hypothesis is that enhancing AEA signaling via pharmacological inhibition of the fatty acid amide hydrolase (FAAH) enzyme induces an anti-stress behavioral effect through an mTOR-dependent mechanism. To test this hypothesis, male C57Bl6 mice were exposed to social defeat stress (SDS) for 7 days and received daily treatment with either vehicle or different doses of the FAAH inhibitor, URB597 (0.1; 0.3; 1 mg/Kg), alone or combined with rapamycin. The results suggested that URB597 induced an inverted U-shaped dose-response curve in mice subjected to SDS (with the intermediate dose of 0.3 mg/kg being anxiolytic, and the higher tested dose of 1 mg/Kg being anxiogenic). In a second independent experiment, rapamycin treatment induced an anxiogenic-like response in control mice. However, in the presence of rapamycin, the anxiolytic dose of URB597 treatment failed to reduce stress-induced anxiety behaviors in mice. SDS exposure altered the hippocampal expression of the mTOR scaffold protein Raptor. Furthermore, the anxiogenic dose of URB597 decreased the absolute number of migrating doublecortin (DCX)-positive cells in the dentate gyrus, suggesting an anti-anxiety effect independent of newly generated/immature neurons. Therefore, our results indicate that in mice exposed to repeated psychosocial stress, URB597 fails to counteract the anxiogenic-like response induced by the pharmacological dampening of mTOR signaling.

The chronic pharmacological antagonism of the CB1 receptor is not involved in the behavioral effects of antidepressants administered in mice submitted to chronic unpredictable stress.

Several pieces of evidence suggest that the monoaminergic theory of depression cannot fully explain all behavioral and neuroplastic changes observed after antidepressant chronic treatment. Other molecular targets, such as the endocannabinoid system, have been associated with the chronic effects of these drugs. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the antidepressants (AD) Escitalopram (ESC) or venlafaxine (VFX) in chronically stressed mice depend on CB1 receptor activation. Male mice submitted to the chronic unpredictable stress (CUS) paradigm for 21 days were treated with Esc (10 mg/kg) or VFX (20 mg/kg) once a day in the presence or not of AM251 (0.3 mg/kg), a CB1 receptor antagonist/inverse agonist. At the end of the CUS paradigm, we conducted behavior tests to evaluate depressive- and anxiety-like behaviors. Our results demonstrated that chronic blockade of the CB1 receptor does not attenuate the antidepressant- or the anxiolytic-like effects of ESC nor VFX. ESC increased the expression of CB1 in the hippocampus, but AM251 did not change the pro-proliferative effects of ESC in the dentate gyrus or the increased expression of synaptophysin induced by this AD in the hippocampus. Our results suggest that CB1 receptors are not involved in behavioral and hippocampal neuroplastic effects observed after repeated antidepressant treatment in mice submitted to CUS.

Spontaneous Activity of CB2 Receptors Attenuates Stress-Induced Behavioral and Neuroplastic Deficits in Male Mice.

The monoaminergic theory of depression/anxiety disorders cannot fully explain the behavioral and neuroplastic changes observed after ADs chronic treatment. Endocannabinoid system, which comprises CB2 receptors, has been associated with the chronic effects of these drugs, especially in stressed mice. CB2-KO mice display more vulnerability to stressful stimuli. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the AD escitalopram (Esc) in chronically stressed mice depend on CB2 receptor signaling. Male mice submitted to chronic unpredictable stress (CUS) paradigm (21 days) were treated daily with AM630 (0.01; 0.03 or 0.3 mg/kg, i.p) a CB2 receptor antagonist/inverse agonist. At e 19th day of the CUS protocol, mice were submitted to Open field test and Tail-suspension test to evaluate antidepressant-like behavior. At the end of the stress protocol, mice were submitted to Novel Suppressed Feeding test (day 22nd) to evaluate anxiety-like behavior. In a second series of experiments, male mice treated with Esc (10 mg/kg, daily, 21 days) in the presence or not of AM630 (0.30 mg/kg) were submitted to the same round of behavioral tests in the same conditions as performed in the dose-response curve protocol. Animals were then euthanized under deep anesthesia, and their brains/hippocampi removed for immunohistochemistry (Doublecortin-DCX) or Western Blot assay. Our results demonstrated that chronic treatment with AM630, a CB2 antagonist/inverse agonist, induces anxiolytic-like effects in stressed mice. Moreover, chronic reduction of CB2 receptor endogenous activity by AM630 attenuated the neuroplastic (potentiating stress-induced decreased expression of pro-BDNF, but enhanced pmTOR and DAGL expression in the hippocampus reduced in stressed mice), the antidepressant- but not the anxiolytic-like effects of Esc. AM630 alone or in combination with Esc decreased the expression of DCX + cell in both the subgranular and granular layers of the dentate gyrus (DG), indicating a general reduction of DCX + neuroblasts and a decrease in their migration through the DG layers. We suggest that the antidepressant-like behavior and the pro-neurogenic effect, but not the anxiolytic like behavior, promoted by Esc in stressed mice are, at least in part, mediated by CB2 receptors.

Glial Cells and Their Contribution to the Mechanisms of Action of Cannabidiol in Neuropsychiatric Disorders.

Cannabidiol (CBD) is a phytocannabinoid with a broad-range of therapeutic potential in several conditions, including neurological (epilepsy, neurodegenerative diseases, traumatic and ischemic brain injuries) and psychiatric disorders (schizophrenia, addiction, major depressive disorder, and anxiety). The pharmacological mechanisms responsible for these effects are still unclear, and more than 60 potential molecular targets have been described. Regarding neuropsychiatric disorders, most studies investigating these mechanisms have focused on neuronal cells. However, glial cells (astrocytes, oligodendrocytes, microglia) also play a crucial role in keeping the homeostasis of the central nervous system. Changes in glial functions have been associated with neuropathological conditions, including those for which CBD is proposed to be useful. Mostly in vitro studies have indicated that CBD modulate the activation of proinflammatory pathways, energy metabolism, calcium homeostasis, and the proliferative rate of glial cells. Likewise, some of the molecular targets proposed for CBD actions are f expressed in glial cells, including pharmacological receptors such as CB1, CB2, PPAR-γ, and 5-HT1A. In the present review, we discuss the currently available evidence suggesting that part of the CBD effects are mediated by interference with glial cell function. We also propose additional studies that need to be performed to unveil the contribution of glial cells to CBD effects in neuropsychiatric disorders.

Efeitos dos anabolizantes sobre a densidade de neurônios dos núcleos da base / Effects of anabolic agents on the neuron density of the basal nuclei / Efectos de los anabolizantes en la densidad de las neuronas de los núcleos basales

RESUMO Objetivos: Pouco se sabe sobre a atuação dos esteroides androgênicos anabolizantes (EAA) no cérebro humano e, por isso, resolvemos estudar a perda neuronal causada pelo uso e abuso de EAA em camundongos. Métodos: Utilizamos 60 camundongos da linhagem Swiss, sendo 30 machos e 30 fêmeas, divididos em três grupos: 20 animais foram tratados com Deposteron® (cipionato de testosterona); outros 20 animais foram tratados com Winstrol Depot® (stanozolol); os últimos 20 animais foram tratados com solução salina. Todos foram submetidos à natação por 15 minutos. Finalizado o tratamento, os animais foram sacrificados pelo método de inalação de Halotano. Os encéfalos foram retirados e armazenados em solução de formaldeído a 4% por 24 horas. De cada encéfalo foram retiradas amostras homotípicas da região média do cérebro em cortes frontais para que pudéssemos avaliar as áreas estabelecidas para este estudo. Resultados: As análises da estimativa dos perfis celulares mostraram que houve uma diminuição do número de perfis no núcleo pálido dos animais machos tratados com Winstrol Depot®. Conclusão: Esses resultados nos permitem inferir que o uso inadequado e sem orientação médica de EAA pode levar a degenerações celulares.

ABSTRACT Objectives: Little is known about the action of anabolic-androgenic steroids (AAS) on the human brain and, therefore, we decided to study the neuronal loss caused by use and abuse of AAS in mice. Methods: We used 60 Swiss mice, 30 males and 30 females, divided into three groups: 20 animals treated with Deposteron® (testosterone cypionate); another 20 animals were treated with Winstrol Depot® (stanozolol); the last 20 animals were treated with saline solution. All the animals were submitted to swimming for 15 minutes. After the treatment, the animals were euthanized by halothane inhalation (Halotano) method. The brains were removed and stored in 4% formal-dehyde solution for 24 hours. From each brain, homotypic samples were taken from the middle region of the brain in frontal cuts so that we could evaluate the areas established for this study. Results: Analyzes of the estimated cell profiles showed that there was a decrease in the number of profiles in the pallidal nucleus of the male animals treated with Winstrol Depot®. Conclusion: These results allow us to infer that inadequate and non-medical use of AAS can lead to cellular degeneration.

RESUMEN Objetivos: Poco se sabe acerca del efecto de la acción de los esteroides anabólicos androgénicos (EAA) en el cerebro humano y, por este motivo, decidimos estudiar la pérdida neuronal causada por el uso y abuso de EAA en ratones. Métodos: Utilizamos 60 ratones de linaje Swiss, siendo 30 machos y 30 hembras, divididos en tres grupos: 20 animales fueron tratados con Deposteron® (cipionato de testosterona); otros 20 animales fueron tratados con Winstrol Depot® (stanozolol); los últimos 20 animales fueron tratados con solución salina. Todos fueron sometidos a natación durante 15 minutos. Terminado el tratamiento, los animales fue-ron sacrificados por el método de inhalación de Halotano. Los cerebros fueron retirados y almacenados en solución de formaldehído al 4% durante 24 horas. De cada cerebro fueron retiradas muestras homotípicas de la región media del cerebro en cortes frontales, así que pudimos evaluar las áreas establecidas para este estudio. Resultados: El análisis de la estimación de los perfiles celulares mostró que hubo una disminución en el número de perfiles en el globo pálido de los animales machos tratados con Winstrol Depot®. Conclusión: Estos resultados permiten inferir que el uso inadecuado y sin orientación médica de EAA puede conducir a la degeneración celular.

Mujer anciana con el síndrome de las uñas amarillas, artritis reumatoide e hipotiroidismo / Elderly woman with yellow nail syndrome, rheumatoid arthritis and hypothyroidism

The yellow nail syndrome is a scarcely reported condition, and its physiopathology is not well understood. The main characteristics of this syndrome are yellowish discoloration of the nail plates, pulmonary changes and pleural effusion, and lymphedema of the lower limbs. Case Report An 85-year-old Brazilian woman, with history of bronchial asthma, rheumatoid arthritis and arterial hypertension, was complaining of breathlessness, lower limb edema, and intense oliguria. Over the previous 40 years she had been treated with aurothioglucose, prednisone, and NSAIDs. Yellowish nail changes developed in her hand and toe fngers, and lung and pleural changes were detected by chest radiography and computerized tomography. With evidence of classical triad, the yellow nail syndrome was characterized. Laboratory tests showed elevated levels of TSH and normal levels of free-T4, establishing the additional diagnosis of subclinical hypothyroidism. Conclusion The purpose of this report is to discuss uncommon associated conditions with yellow nails syndrome, which is considered a rare clinical entity.

El síndrome de las uñas amarillas es una condición escasamente reportada, y su fsiopatología no es bien entendida. Las principales características de este síndrome son la decoloración amarillenta de las placas de las uñas, alteraciones pulmonares y efusión pleural, y linfedema de las extremidades inferiores. Presentación de caso Mujer brasileña, 85 años de edad, con antecedentes de asma bronquial, artritis reumatoide y hipertensión arterial se quejaba de falta de aire, edema de miembros inferiores y oliguria intensa. Durante los últimos 40 años había sido tratada con aurotioglucosa, prednisona, y AINEs. Uñas amarillas desarrollaron en los dedos de manos y pies, y cambios pulmonares y pleurales fueron detectados por radiografía de tórax y tomografía computarizada. Con evidencia de la tríada clásica, se caracterizó el síndrome de las uñas amarillas. Las pruebas de laboratorio mostraron niveles elevados de TSH, con niveles normales de T4 libre, y se estableció el diagnóstico adicional de hipotiroidismo subclínico. Conclusión El propósito de este informe es analizar condiciones poco comunes asociadas con el síndrome de las uñas amarillas, que se considera una entidad clínica rara. CASE REPORT Recibido: 06 ­ November ­ 2014 Aceptado: 01 ­ December ­ 2014 Key words: Rheumatoid arthritis; Subclinical hypothyroidism; Yellow nail syndrome; Case report. Revista Médica Vozandes Volumen 25, Número 1-2, 2014 This article is licensed under a Creative Commons Attribution ­ Non Commercial ­ No Derivatives 4.0 International Licence Resumen Mujer anciana con el síndrome de las uñas amarillas, artritis reumatoide e hipotiroidismo Palabras clave: Artritis reumatoide; Hipotiroidismo subclínico; Síndrome de las uñas amarillas; Rep

Effect of fundamental frequency at voice onset on vocal attack time.

OBJECTIVE: To examine vocal attack time (VAT) values associated with the production of low, mid, and high rates of vocal fold vibration in normal speakers. STUDY DESIGN: Sound pressure (SP) and electroglottographic (EGG) recordings were obtained for eight female and five male subjects while producing multiple tokens of the sustained vowels /ɑ/, /i/, and /u/ at comfortable loudness and at mid, low (-3 semitones), and high (+6 semitones) rates of vocal fold vibration. METHODS: Generalized sinusoidal models of the SP and EGG signals were computed to compare rates of amplitude change. VAT was computed from the time lag of the cross-correlation function. RESULTS: Adjusted mean VAT for the high frequency condition was smaller than the adjusted mean VAT values for the low- and mid-frequency conditions. There was no significant difference between the mid and low frequency conditions. CONCLUSIONS: Findings reveal an association of the VAT measure with increases in vocal fold tension associated with the production of high rates of vocal fold vibration.

Núcleo de fragmento homógeno em dente com estrutura radicular debilitada / Nucleus of homogenous fragment in a tooth with a weakened radicular structure

Este trabalho tem o objetivo de demonstrar a utilização de fragmentos dentários longitudinais homógenos como núcleo de preenchimento em raízes que, por várias razões, tenham perdido estrutura dentinária interna, apresentando dilaceração significante no diâmetro do preparo e enfraquecimento das paredes circundantes. Com esta técnica, cria-se mais uma alternativa de trabalho com os materias de preenchimento que temos à nossa disposição no mercado