Tratamiento con TRIAC en pacientes pediátricos con deficiencia de MCT8 / Treatment with TRIAC in pediatric patients with MCT8

Los transportadores de monocarboxilatos (MCT) permiten el ingreso celular de hormonas tiroideas, especialmente en el sistema nervioso central (SNC), donde son indispensables para el neurodesarrollo. La deficiencia de MCT8 produce la combinación de hipotiroidismo en SNC e hipertiroidismo periférico, caracterizada por T3 elevada. El único tratamiento actualmente disponible es el ácido 3,3',5-triyodotiroacético (TRIAC), un análogo de hormonas tiroideas que tiene como objetivo mejorar la tirotoxicosis periférica y prevenir la progresión del deterioro neurológico. En el presente artículo, se evalúan las características clínicas, imagenológicas, bioquímicas y genéticas de 4 pacientes con deficiencia de MCT8 tratados con TRIAC hasta la fecha, las dosis utilizadas y la respuesta al tratamiento.

Monocarboxylate transporters (MCTs) allow the cellular entry of thyroid hormones, especially into the central nervous system (CNS), where they are crucial for neurodevelopment. MCT8 deficiency results in the combination of hypothyroidism in the CNS and peripheral hyperthyroidism, characterized by elevated T3 levels. The only treatment currently available is 3,3',5-triiodothyroacetic acid (TRIAC), a thyroid hormone analogue aimed at improving peripheral thyrotoxicosis and preventing the progression of neurological impairment. Here we assess the clinical, imaging, biochemical, and genetic characteristics of 4 patients with MCT8 deficiency who have received TRIAC to date, the doses used, and the response to treatment.

Asociación entre los polimorfismos genéticos de nucleótido único en genes transportadores ABC con la epilepsia farmacorresistente en la población española / Association between single nucleotide genetic polymorphisms in ABC transporter genes with drug-resistant epilepsy in the Spanish population

Introducción: El 30% de los pacientes con epilepsia no responde al tratamiento farmacológico. La presencia de polimorfismos genéticos de nucleótido único (SNP) en el individuo puede influir en la variabilidad de respuesta al tratamiento farmacológico. La hipótesis de transportadores plantea que la presencia de SNP en los genes que codifican las proteínas ABC repercutiría en la biodisponibilidad de los fármacos anticrisis en el foco epileptógeno, lo que ocasionaría refractariedad. El objetivo del presente estudio fue evaluar la asociación de 13 polimorfismos en los genes ABCB1, ABCC2, ABCC5 y ABCG2 con la epilepsia farmacorresistente (EFR) en población española. Sujetos y métodos: Se realizó un estudio de casos y controles que incluyó a 327 pacientes con epilepsia: 227 farmacorresistentes y 100 farmacocontrolados según los criterios de la Liga Internacional contra la Epilepsia. En el ADN de leucocitos de sangre periférica extraído se estudiaron los polimorfismos en los genes transportadores ABC. Se utilizó la plataforma tecnológica iPlex® Gold y Mass ARRAY. Se compararon las frecuencias alélicas y genotípicas del grupo de casos y del de controles, el valor de p, la odds ratio y los intervalos de confianza al 95%. Resultados: La frecuencia alélica y genotípica del presente estudio fue similar a la comunicada en las bases de datos poblacionales. En los SNP estudiados no se encontraron diferencias significativas (p > 0,05) en todos los modelos de herencia analizados. Conclusiones: Nuestros resultados sugieren que no existe asociación entre los polimorfismos analizados en los genes ABC con la EFR en población española. Sin embargo, otros estudios adicionales confirmarán o descartarán estos resultados.(AU)

Introduction: Almost a third of all patients with epilepsy (30%) fail to respond to pharmacological treatment. The presence of single nucleotide polymorphisms (SNPs) in the individual may influence the variability of the response to drug treatment. The transporter hypothesis posits that the presence of SNPs in the genes encoding ABC proteins would affect the bioavailability of antiseizure drugs at the epileptogenic focus, giving rise to refractoriness. The aim of the present study was to evaluate the association of 13 polymorphisms in the ABCB1, ABCC2, ABCC5 and ABCG2 genes with drug-resistant epilepsy (DRE) in a Spanish population. Subjects and methods: A case-control study was conducted involving 327 patients with epilepsy: 227 resistant to drug therapy and 100 in whom their medication enabled them to control their symptoms, according to International League Against Epilepsy criteria. In the peripheral blood leukocyte DNA that was extracted, polymorphisms in the ABC transporter genes were studied. The iPlex® Gold and Mass ARRAY technology platform was used. The allele and genotypic frequencies of the case and control groups, p-value, odds ratio and 95% confidence intervals were compared. Results: The allele and genotypic frequency of the present study was similar to that reported in population-based databases. For the SNPs studied, no significant differences (p > 0.05) were found in any of the inheritance models analysed. Conclusions: Our results suggest that there is no association between the polymorphisms analysed in the ABC genes and DRE in the Spanish population. Nevertheless, further studies will confirm or refute these results.(AU)

Gitelman syndrome, a rare cause of refractory hypokalemia. A case report / Símdrome de Gitelman, causa rara de hipopotasemia refractaria. Reporte de caso

Abstract Introduction: Gitelman syndrome is a rare hereditary primary renal tubular disorder, with a prevalence of approximately 1 to 10 cases per 40 000 people. It does not have specific symptoms, so its diagnosis depends on high clinical suspicion by the treating physical and a sequential approach to hypokalemia, especially in young patients. Thus, a diagnostic algorithm is proposed at the end of this report. Case presentation: A 23-year-old woman with a history of hospitalization due to hypokalemia presented to the emergency service with intermittent cramping in her lower limbs, which was exacerbated by gastrointestinal symptoms. Laboratory tests reported the following findings: metabolic alkalosis, elevated levels of potassium, magnesium, chloride and sodium in urine, and reduced levels of calcium in urine. Thus, potassium supplementation and eplerenone administration were started, obtaining the complete resolution of symptoms. At her last follow-up appointment, the patient was asymptomatic, and her serum electrolyte levels were normal. In addition, during her hospital stay and due to the high suspicion of Gitelman syndrome, a genetic study was performed, which reported a mutation of the SCL12A3 gene, confirming the diagnosis. Conclusion: The sequential approach to a patient with recurrent hypokalemia is very important to reach an accurate diagnosis among a wide range of differential diagnoses.

Resumen Introducción. El síndrome de Gitelman es un trastorno tubular renal primario hereditario poco frecuente, con una prevalencia aproximada de 1 a 10 casos por cada 40 000 personas; su sintomatologia es inespecífica, por lo que su diagnóstico depende de la alta sospecha clínica por parte del médico tratante y de un abordaje secuencial de la hipopotasemia, sobre todo en pacientes jóvenes, para lo cual se propone un algoritmo diagnóstico al final de este reporte. Presentación de caso. Mujer de 23 años con antecedente de hospitalización por hipopotasemia, quien consultó por calambres musculares intermitentes en miembros inferiores, los cuales se agudizaron debido a síntomas gastrointestinales. En los exámenes de laboratorio se reportaron los siguientes hallazgos: alcalosis metabólica, niveles elevados de potasio, magnesio, cloro y sodio en orina, y niveles reducidos de calcio en orina, por lo que se inició suplementación de potasio y manejo con eplerenona, obteniéndose resolución completa de los síntomas. En su último control, la paciente se encontraba asintomática y sus niveles séricos de electrolitos eran normales. Además, durante la hospitalización, y debido a la alta sospecha de síndrome de Gitelman, se solicitó estudio genético que reportó mutación del gen SCL12A3, confirmándose el diagnóstico. Conclusión. El abordaje secuencial de un paciente con hipopotasemia recurrente es de gran importancia para realizar un diagnóstico certero ante una amplia gama de diagnósticos diferenciales.

Unusual clinical phenotype of Stargardt disease / Fenótipo clínico incomum da doença de Stargardt

ABSTRACT Mutations in the ABCA4 gene are a common cause of Stargardt disease; however, other retinal phenotypes have also been associated with mutations in this gene. We describe an observational case report of an unusual clinical phenotype of Stargardt disease. The ophthalmological examination included best corrected visual acuity, color and autofluorescence photography, fluorescein angiography, optical coherence tomography, and electrophysiology tests. Targeted next-generation sequencing of 99 genes associated with inherited retinal dystrophies was performed in the index patient. A 48-year-old woman presented with a best corrected visual acuity of 20/25 and 20/20. Fundoscopy revealed perifoveal yellow flecked-like lesions. Fluorescein angiography and fundus autofluorescence findings were consistent with pattern dystrophy. Pattern electroretinogram demonstrated bilateral decrease of p50 values. Genetic testing identified two heterozygous missense mutations, c.428C>T, p.(Pro143Leu) and c.3113C>T, p.(Ala.1038Val), in the ABCA4 gene. Based on our results, we believe that these particular mutations in the ABCA4 gene could be associated with a specific disease phenotype characterized by funduscopic appearance similar to pattern dystrophy. A detailed characterization of the retinal phenotype in patients carrying specific mutations in ABCA4 is crucial to understand disease expression and ensure optimal clinical care for patients with inherited retinal dystrophies.

RESUMO Mutações no gene ABCA4 são causa comum da doença de Stargardt, mas outros fenótipos da retina também foram associados a mutações nesse gene. Apresentamos um relato de caso observacional de um fenótipo clínico incomum da doença de Stargardt. O exame oftalmológico incluiu a acuidade visual com melhor correção, fotografia em cores e com autofluorescência, angiofluoresceinografia, tomografia de coerência óptica e testes de eletrofisiologia. Na paciente em questão, realizou-se o sequenciamento de próxima geração de 99 genes associados a distrofias retinais hereditárias. Tratava-se de uma mulher de 48 anos com melhor acuidade visual corrigida de 20/25 e 20/20. A fundoscopia revelou lesões puntiformes amarelas perifoveais. Os resultados da angiofluoresceinografia e da autofluorescência do fundo de olho foram consistentes com distrofia em padrão. A eletrorretinografia por padrões mostrou diminuição bilateral dos valores de p50. Os testes genéticos revelaram duas mutações missense heterozigóticas, c.428C>T, p. (Pro143Leu) e c.3113C>T, p. (Ala.1038Val), no gene ABCA4. Nossos resultados nos fazem pensar que essas mutações específicas em ABCA4 talvez possam estar associadas a um fenótipo específico da doença, caracterizado por uma aparência fundoscópica semelhante à da distrofia em padrão. Uma caracterização detalhada do fenótipo da retina em pacientes portadores de mutações específicas em ABCA4 é crucial para compreender a expressão da doença e para garantir o tratamento clínico ideal para pacientes com distrofias retinais hereditárias.

Alteración en la expresión de proteínas transportadoras de colesterol y moléculas inmunomoduladoras en pacientes con VIH-1 / Altered expression of cholesterol transport proteins and immunomodulators molecules in HIV-1 infected patients

Debido a que la terapia antirretroviral no logra controlar la activación inmune asociada a la infección por VIH-1, el estudio de moléculas inmunomoduladoras puede proporcionar alternativas para su control. En este sentido, el propósito de este estudio fue evaluar la expresión transcripcional de moléculas asociadas con el metabolismo del colesterol-HDL (C-HDL) y con la respuesta inflamatoria mediada por el inflamasoma NLRP3 en pacientes infectados con VIH-1. En este estudio transversal, se incluyeron 23 pacientes VIH-1 sin tratamiento antirretroviral, con diferentes estadios de progresión, 7 de los cuales son controladores (Carga viral <2000 copias/mL) y 16 progresores (Carga viral >2000 copias/mL), además de 7 controles sanos. En células mononucleares de sangre periférica, se cuantificaron los niveles de la expresión transcripcional de ABCA-1, ABCA-3, Caspasa-5 y TXNIP mediante RT-PCR. Se evaluó la asociación de estos parámetros con variables demográficas y de laboratorio, y se encontró que los individuos VIH-1 progresores mostraron niveles significativamente menores de TXNIP y ABCA-3, sugiriendo que durante la infección por VIH-1 se produce una alteración en la expresión de estas moléculas. Dada la complejidad de las interacciones inmuno-metabólicas durante la infección por VIH-1, se necesitan estudios adicionales para establecer los mecanismos precisos involucrados en estas alteraciones

Because antiretroviral therapy fails to control the immune activation that occurs during HIV-1 infection, the study of immunomodulatory molecules may provide alternative strategies for their control. In this sense, the aim of the research was to evaluate the transcriptional expression of molecules associated with the metabolism of high-density lipoproteins and with the inflammatory response mediated by the NLRP3 inflammasome in patients infected with HIV-1. This is a cross-sectional study, which included 23 HIV-1 patients without antiretroviral treatment, with different stages of progression, 7 of which are controllers (Viral load <2000 copies/mL) and 16 progressors (Viral load >2000 copies/mL), in addition to 7 healthy controls. In peripheral blood mononuclear cells, the levels of transcriptional expression of ABCA-1, ABCA-3, Caspase-5 and TXNIP were quantified by RT-PCR. The association of these parameters with laboratory and demographic variables was evaluated and it was found that HIV-1 progressing individuals showed significantly lower levels of TXNIP and ABCA-3, suggesting that during HIV-1 infection there is an alteration in the expression of these molecules. Given the complexity of the immuno-metabolic interactions during HIV-1 infection, additional studies are needed to establish the precise mechanisms involved in these alterations

Synergistic interactions between ß-lapachone and fluconazole in the inhibition of CaCdr2p and CaMdr1p in Candida albicans.

BACKGROUND: Mortality rate of invasive Candida infections is raising mainly amongst immunocompromised patients. These infections are hard-to-treat mainly due to the increasing incidence of resistance. The overexpression of ATP-binding cassette and major facilitator superfamily transporters is the main responsible for the failure of antifungal therapies. In a Saccharomyces cerevisiae model, ß-lapachone inhibited Pdr5p, a transporter homologous to those found in Candida albicans. AIMS: To determine whether ß-lapachone reverses the resistance phenotype mediated by efflux transporters in C. albicans clinical isolates. METHODS: The antifungal activity of ß-lapachone combined with fluconazole was measured by agarose chemosensitization and microdilution assays. CaCdr2p and CaMdr1p activities were evaluated through fluorescent dyes accumulation. ATPase activity was assessed using transporter-enriched plasma membranes. RESULTS: ß-lapachone reverted antifungal resistance of S. cerevisiae and C. albicans strains overexpressing CaCdr2p and CaMdr1p transporters by inhibiting these proteins activities. CaCdr2p ATPase activity was not impaired by the compound. CONCLUSIONS: ß-lapachone is a promising drug candidate to be used as an adjuvant in the treatment of candidiasis caused by fluconazole-resistant C. albicans strains.

Fuzzy modeling of volumetric efficiency and specific energy consumption in agricultural screw conveyors / Modelagem fuzzy de eficiência volumétrica e consumo específico de energia em transportadores agrícolas de parafuso

ABSTRACT: Vertical screw conveyors have low energy efficiency but this is generally acceptable within the normally low power range. Previously, a fuzzy logic approach was used to model volumetric efficiency and specific energy consumption in screw conveyors. The performance of conveyors in different working conditions and the geometry of the screw were studied. It was reported that increasing the screw speed, pitch, and loading angle also increases specific energy consumption. In this study, an intelligent fuzzy model based on the Mamdani approach was developed to predict volumetric efficiency and specific energy consumption. The model inputs included the slope, speed, and pitch of screw conveyors. The fuzzy model consists of 27 rules in which three parameters, namely the goodness of fit (η), relative error (ε), and coefficient of correlation (R), are used to evaluate the model. The goodness of fit, relative error, and coefficient of correlation values were 0.986, 5.28%, and 0.99, respectively, for volumetric efficiency and 0.987, 4.93%, and 0.99, respectively, for specific energy consumption. Results revealed that the developed model is capable of predicting volumetric efficiency and specific energy consumption in barley transport under different working conditions with high accuracy.

RESUMO: Os transportadores de parafuso verticais têm baixa eficiência energética, mas isso geralmente é aceitável dentro da faixa de potência normalmente baixa. Anteriormente, uma abordagem lógica fuzzy era usada para modelar a eficiência volumétrica e o consumo específico de energia em transportadores de parafuso. O desempenho dos transportadores em diferentes condições de trabalho e a geometria do parafuso foram estudados. Verificou-se que aumentar a velocidade do parafuso, a inclinação e o ângulo de carga também aumenta o consumo de energia específico. Neste estudo, um modelo fuzzy inteligente baseado na abordagem de Mamdani é desenvolvido para prever a eficiência volumétrica e o consumo específico de energia. As entradas do modelo incluem a inclinação, velocidade e inclinação dos transportadores de parafuso. O modelo fuzzy consiste em 27 regras, nas quais três parâmetros, a saber, qualidade do ajuste (η), erro relativo (ε) e coeficiente de correlação (R), são usados para avaliar o modelo. Os valores de ajuste, erro relativo e coeficiente de correlação são de 0,986, 5,28% e 0,99, respectivamente, para eficiência volumétrica e 0,987, 4,93% e 0,99, respectivamente, para consumo específico de energia. Os resultados revelam que o modelo desenvolvido é capaz de prever eficiência volumétrica e consumo específico de energia no transporte de cevada sob diferentes condições de trabalho com alta precisão.

Terapia complementaria a la insulina en el tratamiento de niños y adolescentes con diabetes mellitus tipo 1- (DM1) / Therapies complementaries to insulin in the treatment of children and adolescents with type 1 diabetes mellitus (T1DM)

La diabetes mellitus tipo 1 (DM1), es una enfermedad crónica caracterizada por la deficiencia de insulina debido a la pérdida de células ß pancreáticas, las alteraciones hormonales en la DM 1 no se limitan a la deficiencia de insulina; existiendo también secreción inadecuadada de glucagón en el período postprandial. Aunque el control glucémico con terapias intensivas con insulina ha reducido la incidencia de complicaciones microvascular y macrovasculares. La mayoría de las personas con DM1 tienen un control glucémico subóptimo; Por lo tanto, el uso de farmacoterapia adyuvante para mejorar el control ha sido de interés clínico. El uso de estos nuevos medicamentos brindaría la oportunidad de imitar más de cerca la fisiología pancreática normal, y contrarrestar otros mecanismos fisiopatológicos diferentes a Insulinopenia; contribuyendo a lograr un mejor control metabólico y expectativa de vida.

Type 1 diabetes mellitus (T1DM), is a chronic disease characterized by insulin deficiency due to the loss of pancreatic ß cells, the hormonal alterations in T1DM are not limited to insulin deficiency; there is also a deregulated glucagon secretion in the postprandial period. Although glycemic control with intensive therapies with insulin has reduced the incidence of microvascular and macrovascular complications, most people with T1DM1 glycemic control; therefore, the use of adjuvant pharmacotherapy to improve control has been of clinical interest. The use of these new drugs would offer the opportunity to imitate more closely the normal pancreatic physiology, and to counteract other physiopathological mechanisms different from insulinopenia; contributing to achieve better metabolic control and life expectancy.

Diferencias de género en presión arterial, función renal y respuesta a la dieta hipersódica en ratas Wistar / Gender differences in blood pressure, renal function and response to a high-sodium diet in Wistar rats

Introducción: Es conocido que el sexo es un condicionante de la regulación renal de sodio y de la presión arterial. Material y métodos: Se estudiaron ratas Wistar machos y hembras a los 150 días de vida, con dieta normo o hipersódica (NaCl 1% v.o.) en los últimos cinco. Se determinaron presión arterial media (PAM), natriuresis, filtrado glomerular (VFG), flujo plasmático renal (FPR) y aldosterona plasmática. Se estudió la expresión Na+,K+-ATPasa total (t-NKA) y defosforilada (d-NKA), citocromo P4504A (CYP4A), cotransportadores Na+,K+,2Cl- tipo 2 (NKCC2) y Na+/Cl- (NCC) y por PCR el ARNm de la cadena α1 de NKA (Atp1a1) en corteza y médula renal. Resultados: La PAM fue mayor y la natriuresis menor en los machos bajo ambas dietas. Con ingesta hipersódica la aldosterona bajó en ambos sexos, el VFG fue menor en hembras y el FPR aumentó en machos (4,09 ± 0,17 vs 2,81 ± 0,12 ml/min/gR; p<0,01 vs dieta normosódica). La t-NKA, d-NKA y Atp1a1 en médula fue mayor en machos con ambas dietas. Con ingesta hipersódica, t-NKA en médula y d-NKA en corteza y médula disminuyeron en hembras y solamente d-NKA disminuyó en médula de machos. Asimismo, aumentó CYP4A y disminuyó NKCC2 y NCC en hembras, mientras que aumentó NKCC2, sin cambios en NCC, en machos. Conclusión: El sexo condiciona la presión arterial y el balance de sodio, disminuyendo su reabsorción en hembras y aumentando el FPR en machos. Esto sugiere posibilidades de estudio diferenciales según sexo en trastornos del metabolismo del sodio

Introduction: It is known that sex is a determinant of renal sodium regulation and blood pressure. Methods: Male and female Wistar rats, which were 150 days old and a diet with normal or high levels of sodium (NaCl 1% v.o.), were studied for the last five days. Mean blood pressure (MBP), natriuresis, glomerular filtration rate (GFR), renal plasma flow (RPF) and plasma aldosterone level were established. The following were studied: expressions of total Na+,K+,-ATPase (t-NKA); dephosphorylated NKA (d-NKA); cytochrome P4504A (CYP4A); Na+K+-2Cl- (NKCC2) and Na+/Cl- (NCC) cotransporters. The mRNA expression of the NKA α1 (Atp1a1) chain was examined through PCR analysis in the renal cortex and marrow. Results: Male rats having both types of diet showed higher MBP and lower natriuresis. High sodium intake triggered lower aldosterone levels in both sexes; GFR was lower in females and RPF was higher in males (4.09 ± 0.17 vs. 2.81 ± 0.12 ml/min/gr; p<0.01 vs. diet with a normal sodium level). Marrow t-NKA, d-NKA and Atp1a1 were higher in males on both diets. High sodium intake caused lower marrow t-NKA as well as lower cortex and marrow d-NKA in females. In the case of males, only marrow d-NKA decreased. Furthermore, females showed a higher level of CYP4A and lower levels of NKCC2 and NCC, whereas males showed higher levels of NKCC2 and no variations in NCC. Conclusion: Sex conditions blood pressure and sodium balance, reducing resorption in females and increasing RPF in males. This suggests the possibility of studying sodium metabolism disorders differently according to sex

Effect of Extracellular Zinc Chelator on Rat Retinal Ganglion Cell Number, and Taurine and Zinc Transporters in These Cells / Efecto de un quelante de zinc extracelular sobre el número de células ganglionares en retina de rata, y transportadores de taurina y de zinc en estas células

RESUMEN La deficiencia de zinc en humanos produce disminución de antioxidantes, asociados a taurina, en la retina y se relaciona con adaptación anormal a la oscuridad, cataratas, ceguera y degeneración macular. Existe escasa evidencia acerca del efecto del zinc sobre el sistema de taurina en retina de mamíferos, por lo cual estudiamos el efecto del zinc sobre el transportador de taurina (TAUT) y los transportadores de zinc (ZnT-1 y 3) usando el quelante de zinc extracelular, ácido dietileno-triamino-penta-acético (DTPA), mediante inmunocitoquímica e inmunohistoquímica fluorescentes en células ganglionares (CG) y en las capas de la retina de ratas. Tres días después de la administración de DTPA (10μM) se utilizaron anticuerpos primarios y secundarios conjugados con rodamina o fluoresceína-5-isotiocianato (FITC) según fuera el caso. Para el marcaje inmunocitoquímico se contaron trescientas células por condición y la intensidad de fluorescencia se midió como densidad óptica integrada (DOI) en cuatro áreas por cada capa del tejido. El DTPA produjo una disminución en un 32 % y 29 % de las CG del total de células marcadas con los anticuerpos contra glicoproteína Thy 1.1 y γ-sinucleína, respectivamente. También produjo una disminución significativa de la distribución de TAUT en un 27 y 28 % respecto a los controles. DTPA disminuyó la localización de ZnT-1 y ZnT-3 en las capas de retina (células ganglionares, CCG y en las plexiformes externa e interna, CPE y CPI). El estudio de estos transportadores en la retina resulta relevante para entender las interacciones de taurina y de zinc en esta estructura.

ABSTRACT Zinc deficiency in humans causes decreased antioxidants in the retina and is related with abnormal darkness adaptation, cataracts, blindness, and macular degeneration. There is little information about the effects of zinc on the taurine system in mammalian retinal cells. Therefore, we studied the effect of zinc on the taurine transporter (TAUT) and zinc transporters (ZnT-1 and 3) using the extracellular zinc chelator, diethylenetriaminepentaacetic acid (DTPA) by fluorescence immunocytochemistry and immunohistochemistry in the ganglion cells (CG) and cell layers of the retina of rats. Three days after administration ofDTPA (10μM) primary antibodies and secondary antibodies conjugated with rhodamine or fluorescein isothiocyanate (FITC) were used as required. For immunocytochemical labeling approximately three hundred cells per condition were counted. For immunohistochemical labeling, the fluorescence intensity was measured as integrated optical density (DOI) in four areas for each layer of tissue. DTPA produced a decrease of 32 % and 29 % in GC of the total cells labeled with antibody against glycoprotein Thy 1.1 and γ-synuclein, respectively. It also produced a significant decrease in TAUT localization in 27 and 28 % compared to controls. DTPA produced a decrease in the localization of ZnT-1 and ZnT-3 in the retina layers (ganglion cells, GCC and the outer and inner plexiform, CEP and CIP). The study of these molecules in the retina is relevant to understanding the interactions of taurine and zinc in this structure.

Papel de la superfamilia ABC en la resistencia farmacológica / Role of the superfamily of ABC transports in pharmacological resistance / Papel da superfamília ABC na resistência a drogas / Rôle de la superfamille ABC dans la résistance pharmacologique

Resumen Objetivo: Actualizar los conocimientos acerca de los transportadores de la superfamilia ABC vinculados con la resistencia farmacológica. Materiales y métodos: Se realizó un estudio donde se aplicó el método cualitativo, mediante una revisión bibliográfica y documental sobre el tema en fuentes de datos digitales. Se usaron los descriptores DeCs-MeSH: transportadores ABC, superfamilia ABC, resistencia farmacológica, ATP binding- cassette. Se revisaron artículos publicados sobre el tema, a través de los buscadores habituales (Google, PubMed, Cochrane, Future Medicine, Scielo, entre otros), teniendo en cuenta la calidad y la actualidad de ellos. Resultados: Se destaca la importancia clínica de estos transportadores que se relacionan con la aterosclerosis, enfermedades hepáticas, enfermedad de Alzheimer, entre otras. Esto los convierte en dianas atractivas para el diseño de nuevos medicamentos; pero al mismo tiempo, pueden expulsarlos de la célula, haciéndola resistente como a los antitumorales, antimicrobianos y antivirales. Conclusiones: Los transportadores ABC tienen una función central en los efectos adversos que diferentes sustancias, entre ellas los fármacos, tienen sobre la célula. Además, el polimorfismo genético en esta superfamilia se asocia con alteraciones farmacocinéticas que pueden desencadenar resistencia farmacológica; el impacto de estas modificaciones es el centro de recientes investigaciones que las sitúan como posible blanco terapéutico.

Abstract Objective: To update the knowledge about the ABC transporters superfamily linked to drug resistance. Materials and methods: A qualitative study where the method was applied, using a bibliographical and documentary review on the subject of digital data sources was conducted. ABC transporters, ABC superfamily, and drug resistance, binding- ATP cassette: the DECS-MeSH descriptors were using published articles on the subject through the usual search engines (Google, PubMed, Cochrane, Future Medicine, Scielo, among others), counting on the quality and timeliness of them were review. Results: The clinical significance of these transporters is stress as they relate to atherosclerosis, liver disease, Alzheimer's disease, among other conditions. This makes them attractive targets for new drug design; but at the same time, they can expel the cell making it resistant as antitumor, antimicrobial and antiviral. Conclusions: ABC transporters have central role in the adverse effects of different substances, including drugs, have on the cell. In addition, the genetic polymorphism in this superfamily is associated with pharmacokinetic changes that can trigger drug resistance; the impact of these changes is the focus of recent research that place them as a possible therapeutic target.

Resumo Objectivo: Atualizar o conhecimento sobre os transportadores de superfamilia ABC ligada a resistência a drogas. Materiais e métodos: Foi realizado um estudo qualitativo, através de uma revisão da literatura e documental sobre o tema em fontes de dados digitais. Foram utilizados os descritores DeCs-MeSH: transportadores ABC, superfamilia ABC, resistência farmacológica, ATP binding- cassette. Foram pesquisados artigos sobre o tema, através dos motores de busca (Google, PubMed, Cochrane, Future Medicine, Scielo, entre outros), tendo em conta a qualidade e a sua atualidade. Resultados: Destacou-se a importãncia clínica destes transportadores que se relacionam com a aterosclerose, doen9as hepáticas, de Alzheimer, entre outras. Isso os torna alvos atraentes para o design de novos fármacos, mas ao mesmo tempo, os fármacos podem ser expulsos da célula, tornando-a resistente aos antitumorais, antimicrobianos e antivirais. Conclusões: Os transportadores ABC têm uma função central nos efeitos adversos que diferentes substãncias, tais como os fármacos, possuem sobre a célula. Além disso, o polimorfismo genético desta superfamilia está associado as alterações farmacocinéticas que podem desencadear a resistência aos medicamentos; o impacto dessas mudanças é o centro de pesquisas recentes que os coloca como um possível alvo terapéutico.

Résumé Objectif: Actualiser les connaissances sur les transporteurs de la superfamille ABC liés a la résistance pharmacologique. Matériaux et méthodes: Une étude qualitative a été réalisée au moyen d'une recherche bibliographique et documentaire dans différentes sources de données numériques avec les moteurs de recherche habituels (Google, PubMed, Cochrane, Medicine Future, Scielo, entre autres). Les descripteurs DeCs-MeSH utilisés ont été: transporteurs ABC, superfamille ABC, résistance pharmacologique, ATP binding- cassette. Un certain nombre d'articles relatifs au sujet ont été sélectionnés en fonction de leur qualité et de leur actualité. Résultats: Les résultats mettent en avant l'importance clinique de ces transporteurs du fait de leur relation avec l'athérosclérose, certaines maladies hépatiques, la maladie d'Alzheimer, et d'autres affections. Cela en fait des cibles attrayantes pour la conception de nouveaux médicaments; mais en meme temps, ils peuvent expulser des médicaments de la cellule et la rendre résistante aux antitumoraux, antimicrobiens et antiviraux, par exemple. Conclusions: Les transporteurs ABC jouent un role central dans les conséquences néfastes de différentes substances, y compris les médicaments, sur la cellule. En outre, le polymorphisme génétique dans cette superfamille est associé a des modifications pharmacocinétiques qui peuvent déclencher une résistance aux médicaments; l'impact de ces modifications est l'objet de recherches récentes qui les placent comme cible thérapeutique possible.

Candidate genes for performance in horses, including monocarboxylate transporters / Genes candidatos para desempenho em equinos, incluindo transportadores de monocarboxilatos

Some horse breeds are highly selected for athletic activities. The athletic potential of each animal can be measured by its performance in sports. High athletic performance depends on the animal capacity to produce energy through aerobic and anaerobic metabolic pathways, among other factors. Transmembrane proteins called monocarboxylate transporters, mainly the isoform 1 (MCT1) and its ancillary protein CD147, can help the organism to adapt to physiological stress caused by physical exercise, transporting lactate and H+ ions. Horse breeds are selected for different purposes so we might expect differences in the amount of those proteins and in the genotypic frequencies for genes that play a significant role in the performance of the animals. The study of MCT1 and CD147 gene polymorphisms, which can affect the formation of the proteins and transport of lactate and H+, can provide enough information to be used for selection of athletic horses increasingly resistant to intense exercise. Two other candidate genes, the PDK4 and DMRT3, have been associated with athletic potential and indicated as possible markers for performance in horses. The oxidation of fatty acids is highly effective in generating ATP and is controlled by the expression of PDK4 (pyruvate dehydrogenase kinase, isozyme 4) in skeletal muscle during and after exercise. The doublesex and mab-3 related transcription factor 3 (DMRT3) gene encodes an important transcription factor in the setting of spinal cord circuits controlling movement in vertebrates and may be associated with gait performance in horses. This review describes how the monocarboxylate transporters work during physical exercise in athletic horses and the influence of polymorphisms in candidate genes for athletic performance in horses.(AU)

Algumas raças de equinos são altamente selecionadas para atividades desportivas. O potencial atlético de cada animal pode ser medido pelo seu desempenho nas competições equestres. Um alto potencial atlético depende, entre outros fatores, da capacidade do animal de produzir energia através dos metabolismos aeróbio e anaeróbio. As proteínas transmembrana chamadas transportadores de monoxarboxilato, principalmente a isoforma 1 (MCT1) e sua proteína auxiliar CD147, podem ajudam o organismo a se adaptar ao estresse fisiológico causado pelo exercício físico, transportando íons lactato e H+. Algumas raças de equinos são selecionadas para diferentes objetivos, portanto é provável que existam diferenças nas quantidades de transportadores monocarboxilatos e na frequência genotípica dos seus respectivos genes. O estudo de polimorfismos nos genes das proteínas MCT1 e CD147, afetando a sua formação e o transporte dos íons lactato e H+, podem fornecer informações suficientes para a seleção de equinos com capacidade de serem altamente treinados e resistentes a intensos exercícios. Dois outros genes candidatos que têm sido relacionados com potencial atlético e utilizados como possíveis marcadores para desempenho em equinos são o PDK4 e o DMRT3. A oxidação de ácidos graxos é altamente efetiva para produção de ATP e é controlada pela expressão do gene PDK4 (pyruvate dehydrogenase kinase, isozyme 4) no musculo esquelético durante e após do exercício físico. O gene DMRT3 (doublesex and mab-3 related transcription factor 3) codifica um importante fator de transcrição no controle dos movimentos em vertebrados e pode ser associado com a marcha em algumas raças de equinos. Esta revisão descreve como agem os transportadores de monocarboxilatos durante o exercício físico em equinos atletas e qual a influência de alguns polimorfismos em genes candidatos para o desempenho atlético em equinos.(AU)

Development and formulation of azospirillum lipoferum and pseudomonas fluorescens as effective biological agents for enhanced agro-productivity / Desenvolvimento e formulação de azospirillum lipoferum e pseudomonas fluorescens enquanto agentes biológicos eficazes para uma agro-produtividade melhorada

Biofertilizer is a group of beneficial microorganisms used for improving the productivity of soil by fixing atmospheric nitrogen or by solubilizing soil phosphorus. They also stimulate plant growth through synthesis of growth promoting substances. In this present study, Azospirillum lipoferum is grown in Nitrogen free Bromothymol blue (Nfb) medium and Pseudomonas fluorescens in King's B medium. Bioprocess condition was optimized for both of the culture and found that Pseudomonas fluorescens has shown highest growth at 300C in pH 8 after 72 hours of incubation where as Azospirillum lipoferum showed highest cell concentration at 310C in pH 7, with incubation period of 72 hours. The optimized culture is mixed with different formulations of powder and liquid carrier such as Saw dust, Rice husk, Date seed powder, Matka khad, Jiwamrit and Beejamrit respectively. Shelf life study for 0, 30, 60, 90 and 120 days by cell counting and spread plate method showed that shelf life of the biofertilizer produced from Powder and liquid carriers had high amount of viable microbial population up to 120 days storage. Among biofertilizer based bio inoculants, Saw dust showed maximum population of 77x109cfu/ml for Azospirillum lipoferum and 72 x 109 CFU/ml for Pseudomonas strain on 120th day and the liquid carrier Matka khad showed 85x109 cfu/ml for Azospirillum lipoferum and 78 x 109 CFU/ml for Pseudomonas fluorescens.

Biofertilizante é um grupo de microorganismos benéficos utilizados para melhorar a produtividade do solo através da fixação de azoto atmosférico ou por solubilização de fósforo no solo. Eles também estimulam o crescimento vegetal através de síntese de substâncias promotoras do crescimento. No presente estudo, Azospirillum lipoferum é cultivado em um meio de azul de bromotimol sem nitrogênio (Nfb) e Pseudomonas fluorescens num meio de King's B. A condição de bioprocesso foi optimizada para ambas as culturas e descobriram que Pseudomonas fluorescens mostraram maior crescimento a 300ºC em pH 8 após 72 horas de incubação, enquanto que Azospirillum lipoferum mostraram maior concentração de células a 310ºC em pH 7, com um período de incubação de 72 horas. A cultura optimizada é misturada com diferentes formulações de pó e veículo líquido tal como serragem, casca de arroz, pó de semente de tâmaras, Matka khad, Jiwamrit e Beejamrit respectivamente. O estudo do prazo de validade para 0, 30, 60, 90 e 120 dias por contagem celular e método de espalhamento em placa mostrou que o prazo de validade do biofertilizante produzido a partir do pó e veículos líquidos teve grande quantidade de população microbiana viável até 120 dias de armazenamento. Entre inoculantes biológicos de base biofertilizantes, a serragem mostrou população máxima de 77x109 CFU/ml para Azospirillum lipoferum e 72 x 109 CFU/ml para a estirpe Pseudomonas no 120º dia e um veículo líquido Matka khad mostrou 85x109 CFU/ml para Azospirillum lipoferum e 78x109 CFU/ml para Pseudomonas fluorescens.

Gene expression profile of ABC transporters and cytotoxic effect of ibuprofen and acetaminophen in an epithelial ovarian cancer cell line in vitro / Perfil da expressão gênica dos transportadores ABC e efeito citotóxico do ibuprofeno e acetaminofen em uma linhagem celular de câncer epitelial de ovário in vitro

PURPOSES: To determine the basic expression of ABC transporters in an epithelial ovarian cancer cell line, and to investigate whether low concentrations of acetaminophen and ibuprofen inhibited the growth of this cell line in vitro. METHODS: TOV-21 G cells were exposed to different concentrations of acetaminophen (1.5 to 15 μg/mL) and ibuprofen (2.0 to 20 μg/mL) for 24 to 48 hours. The cellular growth was assessed using a cell viability assay. Cellular morphology was determined by fluorescence microscopy. The gene expression profile of ABC transporters was determined by assessing a panel including 42 genes of the ABC transporter superfamily. RESULTS: We observed a significant decrease in TOV-21 G cell growth after exposure to 15 μg/mL of acetaminophen for 24 (p=0.02) and 48 hours (p=0.01), or to 20 μg/mL of ibuprofen for 48 hours (p=0.04). Assessing the morphology of TOV-21 G cells did not reveal evidence of extensive apoptosis. TOV-21 G cells had a reduced expression of the genes ABCA1, ABCC3, ABCC4, ABCD3, ABCD4 and ABCE1 within the ABC transporter superfamily. CONCLUSIONS: This study provides in vitro evidence of inhibitory effects of growth in therapeutic concentrations of acetaminophen and ibuprofen on TOV-21 G cells. Additionally, TOV-21 G cells presented a reduced expression of the ABCA1, ABCC3, ABCC4, ABCD3, ABCD4 and ABCE1 transporters. .

OBJETIVOS: Determinar a expressão básica dos transportadores ABC em uma linhagem celular do câncer epitelial de ovário, e investigar se o acetaminofen e o ibuprofeno em baixas concentrações são capazes de inibir o crescimento desta linhagem celular in vitro. MÉTODOS: A linhagem celular TOV-21 G foi exposta a diferentes concentrações de acetaminofen (1,5 a 15 µg/mL) e ibuprofeno (2,0 a 20 µg/mL), de 24 a 48 horas. O crescimento celular foi avaliado utilizando-se um ensaio de viabilidade celular. A morfologia celular foi determinada por meio da microscopia de fluorescência. O perfil de expressão gênica foi estabelecido por um painel de 42 genes da superfamília de transportadores ABC. RESULTADOS: Observou-se um decréscimo significativo no crescimento das células TOV-21 G expostas a 15 µg/mL de acetaminofen durante 24 (p=0,02) e 48 horas (p=0,01), ou a 20 µg/mL de ibuprofeno por 48 horas (p=0,04). Ao avaliar a morfologia das células cultivadas, não foi observada evidência de apoptose extensiva. A linhagem de células estudada subexpressa os genes de ABCA1, ABCC3, ABCC4, ABCD3, ABCD4 e ABCE1 na superfamília de transportadores ABC. CONCLUSÕES: Este estudo fornece evidências in vitro referentes aos efeitos inibidores do crescimento de concentrações terapêuticas do acetaminofen e ibuprofeno na linhagem celular testada. Além disso, as células TOV-21 G apresentaram uma expressão reduzida de genes dos transportadores ABCA1, ABCC3, ABCC4, ABCD3, ABCD4 e ABCE1. .

Longitudinal evaluation using FP-CIT in patients with parkinsonism.

OBJECTIVE: To assess a group of patients with parkinsonism using serial studies with FP-CIT, basically the initial false negative results. METHODS: Restrospective study of 92 patients (55 men and 37 women) who had undergone 2 different FP-CIT studies because of discrepancies between study results and clinical progression. The mean elapsed time between the studies was 26 months (SD: 6). We performed a semi-quantitative study using the patient's clinical history and the available literature to analyse discrepant cases with a normal initial study and subsequent pathological findings. RESULTS: A total of 184 studies were completed for 92 patients; 11 of those 92 showed discrepancies between initial and subsequent studies. Among the 11 discrepant cases, 7 showed a normal initial study and pathological findings at a later date. Analysis of the predominant clinical features that might explain this behaviour revealed that 4 of these 7 subjects presented tremor-dominant parkinsonism. Regarding the rest, 1 presented early stage parkinsonism and was treated with antidopaminergic agents; 1 was classified as probable multisystem atrophy type C, and the third showed clinical signs of atypical parkinsonism without any causes of those signs being identified. CONCLUSIONS: Serial FP-CIT studies are unnecessary in the large majority of cases, but they may be justifiable in certain clinical situations.

Acidosis tubular renal en niños: conceptos actuales de diagnóstico y tratamiento / Renal tubular acidosis in children: state of the art, diagnosis and treatment

Recientemente se ha detectado un sobre-diagnóstico de acidosis tubular renal (ATR) en niños mexicanos, posiblemente por errores de diagnóstico y desconocimiento de la fisiopatología y bioquímica molecular del padecimiento. El objetivo de la presente publicación es facilitar el conocimiento y la realización del diagnóstico acertado de la ATR, que es una condición clínica poco frecuente a escala mundial. La ATR es la alteración del metabolismo ácido-base producida por el defecto de reabsorción del bicarbonato en los túbulos renales proximales (ATRp o proximal tipo 2) o de la excreción de hidrogeniones en la nefrona distal (ATRd o distal tipo 1). La ATR tipo 4 (hipercaliémica) obedece a alteraciones del metabolismo de la aldosterona. La ATR puede ser primaria, secundaria, adquirida o hereditaria. Las principales alteraciones ocurren en proteínas como la anhidrasa carbónica (AC II y IV), la H+ATPasa, el intercambiador HCO3-/Cl- (AE1) y el cotransportador Na+/HCO3- (NBCe1). El diagnóstico debe incluir la demostración de acidosis metabólica hiperclorémica con hiato aniónico sanguíneo normal (en sangre arterial o arterializada), pH sanguíneo menor a 7.35 en pacientes con acidosis metabólica descompensada (aunque puede encontrarse normal en los casos con compensación completa), alteración del hiato aniónico urinario y del gradiente urinario/sanguíneo de la pCO2. En el caso de la ATR secundaria, es importante determinar el diagnóstico de la enfermedad sistémica que la origina. Con frecuencia, los criterios diagnósticos se acompañan de diversos síntomas como anorexia, poliuria, polidipsia, detención del crecimiento, raquitismo, nefrocalcinosis, litiasis renal y sordera temprana o tardía (en la ATRd). El tratamiento alcalino depende del tipo de la ATR: bicarbonato de sodio para la ATRp o bicarbonato o citrato de potasio para la ATRd. La administración de calcio y vitamina D depende del grado de la alteración ósea.

Overdiagnosis of renal tubular acidosis (RTA) has been recently detected in Mexican children, perhaps due to diagnostic errors as well as in a lack of knowledge regarding the pathophysiology and molecular biochemistry involved in this illness. The objective of the present study is to facilitate the knowledge and diagnosis of RTA, a clinical condition infrequently seen worldwide. RTA is an alteration of the acid-base equilibrium due to a bicarbonate wasting in the proximal renal tubules (proximal RTA, pRTA or type 2 RTA) or due to a distal nephron hydrogen ion excretion defect (distal RTA, dRTA or type 1 RTA). Hyperkalemic, or type 4 RTA, is due to alterations in aldosterone metabolism. RTA may be primary, secondary, acquired or hereditary and frequently presents secondary to an array of systemic diseases, usually accompanied by multiple renal tubular defects. The main defect occurs in the transmembrane transporters such as carbonic anhydrase (CA I and II), H+-ATPase, HCO3-/Cl- (AE1) exchanger and Na+/HCO3- (NBCe1) cotransporter. Diagnosis should include the presence of hyperchloremic metabolic acidosis with normal serum anion gap (done in an arterial or arterialized blood sample), lack of appetite, polyuria, thirst, growth failure, and rickets; nephrocalcinosis and renal stones (in dRTA); abnormal urine anion gap and abnormal urine/serum pCO2 gradient. Diagnosis of a primary systemic disease must be made in cases of secondary RTA. Bicarbonate or potassium citrate therapy, as well as potassium, calcium and vitamin D administration depends on the type and severity of the RTA.

[Elaboration of the SPM template for the standardization of SPECT images with 123I-Ioflupane]. / Elaboración de una plantilla de SPM para la normalización de imágenes de SPECT con 123I-Ioflupano.

PURPOSE: Statistical parametric mapping (SPM) is a widely used produced for normalization of functional images. This study has aimed to develop a normalization template of (123)I-Ioflupane SPECT-imaging DaTSCAN(®), GE Healthcare), not available in SPM5, and to validate it compared to other quantification methods. MATERIAL AND METHODS: In order to write the template we retrospectively selected 26 subjects who had no evidence of nigrostriatal degeneration and whose age distribution was similar to that of the patients in the usual practice of our Department: 2 subjects (7.6%) were < 35 years, 9 between 35-65 years (34.6%) and 15 > 65 years (57.7%). All the studies were normalized with the T1-template available in SPM5 and an average image of the value was obtained for each voxel. For validation we analyzed 60 patients: 30 with idiopathic Parkinson's disease patients (iPD) with right involvement (66.83±12.20 years) and 30 with essential tremor patients (ET) (67.27±8.33 years). Specific uptake rates (SUR) of different striatal regions were compared after image normalization with our template and the application of a semiautomated VOIs-map created with Analyze v9.0 ((©)BIR, Mayo Clinic), against two quantification methods: a) manual adjustment of a ROIs-map drawn in Analyze, and b) semi-automated method (HERMES-BRASS) with normalization and implementation of VOIs-map. RESULTS: No statistically significant differences in the iPD/ET discriminatory capacity between the three methods analyzed were observed (p<0,001). The correlation of SUR after normalization with our «template¼ was higher than that obtained by method b) (R>0,871, p<0,001). This difference was greater in patients with PD. CONCLUSIONS: Our study demonstrates the efficacy of our SPM «template¼ for (123)I-Ioflupane SPECT-imaging, obtained from normalization with «T1-template¼.

Estudo da neuroatividade da Parawixina 10, um composto isolado da peçonha da aranha Parawixia bistriata (Araneae: Araneidae), em ratos Wistar submetidos ao Status Epilepticus induzido por pilocarpina

Epilepsia é um distúrbio neurológico bastante comum, caracterizado por crises recorrentes e espontâneas, cuja prevalência na população mundial é de cerca de 1 %. À Epilepsia do Lobo Temporal (ELT) é o tipo mais frequente desta enfermidade, acometendo cerca de 40% dos pacientes e a que apresenta maior dificuldade de tratamento, pois a maioria dos pacientes deixa de responder aos medicamentos disponíveis atualmente. Além disso, estudos têm ressaltado o envolvimento do sistema glutamatérgico em crises epilépticas agudas, na plasticidade celulares associada à epileptogênese e em crises recorrentes espontâneas observadas em casos clínicos e em modelos experimentais de epilepsia. Dessa forma, a busca por novos compostos com potencial terapêutico, tanto para o tratamento das apilépsiass quanto de outras doenças neurológicas, sei faz necessária. Neste contexto, venenos animais se apresentam como fontes alternativas de compostos com ação seletiva e específica sobre estruturas do tecido nervoso. À luz destes fatos, pesquisadores do laboratório de Neurobiologia e Peçonhas (FCLRP-USP), isolaram,; dentre outros, o composto Parawixinal 10 da peçonha da aranha Parawixia bistriata, o qual aumentou a captação de glutamato em sinaptossomas cérebro-corticais de ratos. Além de ser anticonyulsivante em modelos de crises agudas induzidas por PTZ, NMDA e ácido caínico. Portanto, o principal objetivo deste estudo foi investigar os efeitos da Parawixinal0 no modelo de ELT por pilocarpina intracerebral, avaliando-se as alterações histopatólógicas, cognitivas e comportamentais. Para tanto, ratos Wistar submetidos a um Status Epilepticus (SE) de 180 mine foram tratados com diferentes doses da Parawixinal0, com riluzol...(AU)

Epilepsy is a neurological disorder very common, characterized by spontaneous and recurrent seizures, which prevalence in world population reaches almost 1%. Temporal Lobe Epilepsy is the most frequent type, affecting approximately 40% of diagnosed patients being also the most difficult to treat since most patients do not respond to currently available medications. Moreover, several studies have stressed the glutamatergic system implication on acute epileptic seizures, cellular plasticity associated to epileptogenesis and also on spontaneous recurrent seizures observed in clinical cases and experimental models. Thereby the search of new compounds that represent therapeutical potential, either in epilepsy as well as other neurological disorders treatment. In this context, animal venoms represents alternative source of compounds with specific selective action on structures of nervous tissue. In light of these facts, researchers from Neurobiology and Venoms laboratory (FFCLRP-USP) isolated the Parawixinl0 compound, extracted from Parawixia bistriata spider venom, which demonstrated a potent in enhance glutamate uptake in synaptosornes from rat cerebral cortex, besides presenting anticonvulsant effects on convulsant chemical acute model of PTZ, NMDA, Kainic Acid. Considering these facts, the aim of this study was to investigate the Parawixinl0 effects in intracerebral pilocarpine model of TL-E, evaluating the histopathological, cognitive and behavioral alterations associated to this type of epilepsy. Thus, Wistar rats were submitted to 180 min Status Epilepticus (SE), treated throughout four consecutive days with three different Parawixinl0 doses, riluzole ...(AU)

Transportadores de lípidos biliares: una revisión actualizada / Biliary lipids transporters: an update review

Las sales biliares, colesterol y fosfatidilcolina son los lípidos más importantes de la bilis; su transporte está regulado por una red compleja de proteínas de las familias Casete de Unión a ATP y transportadora de solutos. Los transportadores de lípidos biliares son proteínas que intervienen en la fisiopatología de numerosas enfermedades del sistema gastrointestinal, por lo tanto, son importantes moléculas de estudio y en un futuro pueden ser nuevas dianas terapéuticas que eviten la prevalencia de enfermedades como hipercolesterolemia, cálculos biliares, colestasis, trastornos de la bilirrubina, entre otras. La presente revisión hace una evaluación actualizada sobre la función específica de los transportadores de lípidos biliares, su regulación genética e implicación fisiopatológica

Bile salts, cholesterol and phosphatidylcholine are the major lipids of bile; its secretion is regulated by an elaborate network of family proteins such as ATP Binding Cassette and the Solute Carrier. Biliary lipids transporters are proteins involved in physiopathology of many diseases of gastrointestinal system, therefore it are important molecules of study and the future it may be new therapeutic targets to prevent the prevalence of diseases, such as hypercholesterolemia, gallstones, cholestasis, bilirubin disorders among other. This review makes a current evaluation on the specific role of biliary lipids transporters, its genetic regulation and physiopathological implications

Efeitos da exposição à nicotina e/ou ao etanol durante a adolescência: alterações glutamatérgicas e na memória visuoespacial de camundongos / Effect of nicotine and/or etanol exposure during adolescence: glutamatergic and visuospatial memory alterations in mice

Adolescentes humanos frequentemente associam o fumo do tabaco ao consumo de bebidas alcoólicas. A despeito desta associação, pouco se sabe sobre a neurobiologia básica da coexposição no cérebro adolescente. No presente estudo, avaliamos os efeitos da exposição, que ocorreu do 30º ao 45º dia de vida pós natal (PN30 a PN45), à nicotina e/ou ao etanol durante a adolescência (PN38-45) e da retirada (PN50-57) na memória visuoespacial através do Labirinto Aquático de Morris (LAM: 6 sessões + 1 prova, 3 tentativas/sessão, latência = 2 min), em 4 grupos de camundongos Suíços machos e fêmeas: (1) exposição concomitante à NIC [solução de nicotina free base (50 μg/ml) em sacarina a 2% para beber] e ETOH [solução de etanol (25%, 2 g/kg) injetada i.p. em dias alternados]; (2) exposição à NIC; (3) exposição ao ETOH; (4) veículo (VEH). Uma vez que os resultados comportamentais podem sofrer a interferência de alterações motoras, avaliamos (a) a atividade locomotora no Teste de Campo Aberto (sessão única, 5 min) e (b) a coordenação e o equilíbrio no Teste de Locomoção Forçada sobre Cilindro Giratório (5 tentativas, latência = 2 min). Para os efeitos da exposição à NIC e/ou ao ETOH na eficiência do transporte de aminoácidos excitatórios, avaliamos a captação de [3H] D-aspartato no hipocampo. A expressão do transportador glial GLAST/EAAT1 foi avaliada por Western-blot. Durante a exposição, animais ETOH e NIC+ETOH apresentaram déficits de memória nas sessões de teste e de prova no LAM enquanto, na retirada, os grupos NIC e NIC+ETOH apresentaram prejuízos na retenção. Não houve diferenças significativas entre os grupos de tratamento em nenhum dos parâmetros testados em ambos os testes motores, tanto na exposição quanto na abstinência. Os grupos NIC, ETOH e NIC+ETOH tiveram uma diminuição significativa na captação de [3H] D-aspartato ao final do período de exposição, com uma normalização da atividade dos EAATs na retirada das drogas...

Human adolescents frequently associate tobacco smoke and alcoholic drinks. Despite this association, little is known about the basic neurobiology of co-exposure in the adolescent brain. In the present study, we assessed the effects of nicotine and/or ethanol exposure (postnatal days 30 to 45: PN30-45) during adolescence (PN38-45) and withdrawal (PN50-57) on visuospacial memory through the Morris Water Maze (MWM: 6 sessions + 1 probe, 3 trials/session, latency = 2 min), in four groups of male and female Swiss mice: (1) Concomitant NIC [nicotine free base solution (50µg/ml) in 2% saccharin to drink] and ETOH [ethanol solution (25%, 2g/kg) i.p. injected every other day] exposure; (2) NIC exposure; (3) ETOH exposure; (4) Vehicle (VEH). Once behavioral results can be affected by motor disorders, we assessed (a) locomotor activity through the Open field Test (one session, 5 min) and (b) coordination and balance through the ROTAROD Test (5 trials, latency = 2 min). To investigate the effects of NIC and/or ETOH exposure on the efficiency on excitatory amino acid transport, we assessed the [3H] D-aspartate uptake in mice hippocampus. The GLAST/EAAT1, a glial transporter, was assessed by Western-blot technique. During exposure, ETOH and NIC+ETOH animals showed deficits on memory through the session and probe trial in WMW while, during withdrawal, NIC and NIC+ETOH groups showed impairments on retention. There were no significant differences between the experimental groups in any parameters assessed in both motor tests, either during exposure and withdrawal. There was a significant decrease in the [3H] D-aspartate for NIC, ETOH and NIC+ETOH groups in the end of exposure, turning to the normal levels of EAATs activity during withdrawal...