RESUMO
INTRODUCTION: A plausible mechanism that may contribute to drug resistance in epilepsy is the failure of drugs to reach the brain tissue, caused by changes in the activity of ABC transporters. The main argument in favour of this hypothesis is that resistance occurs against a wide variety of antiepileptic drugs with different mechanisms of action, suggesting a non-specific underlying phenomenon that limits the effectiveness of drug treatments. DEVELOPMENT: A review of the literature on ABC transporters, their role in the normal physiology of the blood-brain barrier and drug resistance in epilepsy, both in human studies and in animal models, is conducted. Studies of genetic variants in the ABCB1 and ABCC2 genes, which code for these transporters, and recent genomic studies in epilepsy and related pathologies are also reviewed, followed by a discussion of their scope and limitations. CONCLUSIONS: To date, the association of genetic variants of ABC transporters with resistance to anticonvulsant drugs remains a matter of debate. The increasingly widespread use and accessibility of modern sequencing technologies is expected to allow the establishment of genetic markers that provide a precision medicine based approach to the treatment of epilepsy.
TITLE: Transportadores ABC y resistencia a fármacos en la epilepsia: plausibilidad biológica, farmacogenética y medicina de precisión.Introducción. Un mecanismo plausible que puede contribuir a la resistencia a fármacos en la epilepsia es la falta de llegada de los fármacos al tejido encefálico, causado por cambios en la actividad de los transportadores ABC. El principal argumento a favor de esta hipótesis es que la resistencia ocurre frente a una gran variedad de fármacos antiepilépticos con distintos mecanismos de acción, lo que sugiere un fenómeno subyacente no específico que limita la efectividad de los tratamientos farmacológicos. Desarrollo. Se realiza una revisión bibliográfica de los transportadores ABC, su papel en la fisiología normal de la barrera hematoencefálica y en la resistencia a fármacos en la epilepsia, tanto en estudios en humanos como en modelos animales. Se revisan además los estudios de variantes genéticas en los genes ABCB1 y ABCC2, que codifican para estos transportadores, y los recientes estudios genómicos en la epilepsia y patologías afines, discutiendo sus alcances y limitaciones. Conclusiones. Hasta ahora, la asociación de variantes genéticas de transportadores ABC con la resistencia a fármacos anticonvulsivantes sigue siendo materia de debate. Se espera que la creciente masificación y accesibilidad a tecnologías de secuenciación modernas permitan establecer marcadores genéticos que otorguen una aproximación de medicina de precisión para el tratamiento de la epilepsia.
Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Resistência a Medicamentos/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Transportadores de Cassetes de Ligação de ATP/genética , Barreira Hematoencefálica/fisiologia , Humanos , Proteína 2 Associada à Farmacorresistência Múltipla , Farmacogenética , Polimorfismo Genético , Medicina de PrecisãoRESUMO
Steroid sex hormones produce physiological effects in reproductive tissues and also in nonreproductive tissues, such as the brain, particularly in cortical, limbic and midbrain areas. Dopamine (DA) neurones involved in processes such as prolactin secretion (tuberoinfundibular system), motor circuit regulation (nigrostriatal system) and driving of motivated behaviour (mesocorticolimbic system) are specially regulated by sex hormones. Indeed, sex hormones promote neurochemical and behavioural effects induced by drugs of abuse by tuning midbrain DA neurones in adult animals. However, the long-term effects induced by neonatal exposure to sex hormones on dopaminergic neurotransmission have not been fully studied. The present study aimed to determine whether a single neonatal exposure with oestradiol valerate (EV) results in a programming of dopaminergic neurotransmission in the nucleus accumbens (NAcc) of adult female rats. To answer this question, electrophysiological, neurochemical, cellular, molecular and behavioural techniques were used. The data show that frequency but not amplitude of the spontaneous excitatory postsynaptic current is significantly increased in NAcc medium spiny neurones of EV-treated rats. In addition, DA content and release are both increased in the NAcc of EV-treated rats, caused by an increased synthesis of this neurotransmitter. These results are functionally associated with a higher percentage of EV-treated rats conditioned to morphine, a drug of abuse, compared to controls. In conclusion, neonatal programming with oestradiol increases NAcc dopaminergic neurotransmission in adulthood, which may be associated with increased reinforcing effects of drugs of abuse.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Dopamina/metabolismo , Estradiol/farmacologia , Morfina/farmacologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Estrogênios/farmacologia , Feminino , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex-dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra-hypothalamic system in sensitised male and female rats. Adult male and female Sprague-Dawley rats underwent an AMPH-locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH-induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region-specific interactions between AMPH and the extra-hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure.
Assuntos
Anfetamina/administração & dosagem , Arginina Vasopressina/metabolismo , Complexo Nuclear Corticomedial/metabolismo , Núcleos Septais/metabolismo , Caracteres Sexuais , Animais , Comportamento Animal/efeitos dos fármacos , Estro , Feminino , Locomoção/efeitos dos fármacos , Masculino , Ratos Sprague-DawleyRESUMO
A kinetic description of Alfvén-cyclotron magnetic fluctuations for anisotropic electron-proton quasistable plasmas is studied. An analytical treatment, based on the fluctuation-dissipation theorem, consistently shows that spontaneous fluctuations in plasmas with stable distributions significantly contribute to the observed magnetic fluctuations in the solar wind, as seen, for example, in [S. D. Bale et al., Phys. Rev. Lett. 103, 211101 (2009)], even far below from the instability thresholds. Furthermore, these results, which do not require any adjustable parameters or wave excitations, are consistent with the results provided by hybrid simulations. It is expected that this analysis contributes to our understanding of the nature of magnetic fluctuations in the solar wind.
RESUMO
Chagas'disease has a great epidemiological relevance. Most of infected children are asymptomatics, with low mortality rate. The most frequent clinical findings are hepatomegaly and splenomegaly Parasitological methods: fresh smears, microStrout and Hemoculture, sequentially performed, detect the parasite in almost 100% of infected children. The gold standard for immunodiagnosis are serological curves, due to the interference of maternal IgG. Infected children maintain their antibody levels , whereas non infected became negatives. IgM test show false positive and false negative results. In children acutely infected during the first year of life and in cases of congenital infection, we observed high serum levels of soluble receptors of TNFalpha, IL-2 and sCD8, with significantly post treatment decrease. In a prospective 30 years research, we observed high therapeutic efficacy when children were treated before 3 years of life with benznidazol or nifurtimox, with good clinical evolution, together with parasitological and serological negativization.
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Gravidez , Humanos , Feminino , Animais , Doença de Chagas/congênito , Transmissão Vertical de Doenças Infecciosas , Complicações Parasitárias na Gravidez , Anticorpos Antiprotozoários/sangue , Argentina/epidemiologia , Doença de Chagas/diagnóstico , Doença de Chagas/epidemiologia , Doença de Chagas/terapia , Seguimentos , Transmissão Vertical de Doenças Infecciosas , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Estudos Prospectivos , Trypanosoma cruzi/isolamento & purificação , XenodiagnósticoRESUMO
Se presenta un reporte de cuatro casos de colecistitis xantogranulomatosa, de un total de 1920 biopsias de pacientes colecistectomizados en el servicio de cirugía del Hospital de Quilpué, entre los años 1993 y 2002. Esto constituye un 0,2 por ciento del total de vesículas extirpadas. Tres casos corresponden al sexo masculino, uno al femenino; con una edad promedio de 62 años. El diagnóstico preoperatorio fue de ictericia obstructiva en tres casos y en dos de ellos, el diagnóstico macroscópico intraoperatorio fue de cáncer vesicular. El estudio histopatológico demostró una colecistitis xantogranulomatosa, sin evidencia de malignidad.
Assuntos
Humanos , Masculino , Feminino , Idoso , Colecistite/cirurgia , Colecistite/diagnóstico , Neoplasias da Vesícula Biliar , Granuloma/cirurgia , Xantomatose/cirurgia , Xantomatose/diagnóstico , ColectomiaRESUMO
To ascertain the role of extracellular adenosine 5'-triphosphate (ATP) receptors in human placenta circulation, we identified and pharmacologically characterized the P2X receptor population in its superficial vessels. Total RNA was extracted from segments of chorionic and umbilical arteries and veins of terminal placentae delivered by vaginal or Caesarian births. Polymerase chain reaction (PCR), followed by sequencing of the products, identified the presence of P2X 1, 4, 5, 6, and 7mRNAs in smooth muscle from chorionic and umbilical arteries and veins. Umbilical vessels proximal to the fetus expressed the same population of P2X subtypes, except for the P2X(5), but additionally expressed the P2X(2). Rings of chorionic vessels contracted upon addition of nucleotides and analogs with the following relative rank order of potencies in arteries and veins: alpha,beta-methyleneATP>beta,gamma-methyleneATP>PNP>ATP=diBzATP>2-MeSATP>ADP>AMP; in umbilical vessels alpha,beta-methyleneATP was at least 100-fold more potent than ATP. Nucleotide potency was less than that of PGF(2alpha) or endothelin-2, but had the same magnitude as serotonin. ATP-desensitized receptors evidenced cross desensitization to alpha,beta-methyleneATP, 2-MeSATP and diBzATP, effect not observed when desensitization was elicited by alpha,beta-methyleneATP, confirming the presence of various P2X receptor subtypes in the smooth muscles of these vessels. The vasocontractile efficacy of alpha,beta-methyleneATP was unaltered by endothelium removal, while that of ATP was significantly attenuated and those elicited by 2-MeSATP were blunted, indicating the presence of additional endothelial nucleotide receptors. These results suggest that P2X receptors participate in the humoral regulation of placental blood flow.
Assuntos
Córion/metabolismo , Músculo Liso Vascular/metabolismo , Receptores Purinérgicos P2/metabolismo , Artérias Umbilicais/metabolismo , Cordão Umbilical/metabolismo , Veias Umbilicais/metabolismo , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Adulto , Córion/irrigação sanguínea , Córion/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Troca Materno-Fetal/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Reação em Cadeia da Polimerase , Gravidez , RNA Mensageiro/metabolismo , Receptores Purinérgicos P2/genética , Artérias Umbilicais/efeitos dos fármacos , Cordão Umbilical/efeitos dos fármacos , Veias Umbilicais/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
Previous human and animal studies have shown that specific memories arise during prenatal life as a function of fetal processing of chemosensory stimuli present in the amniotic fluid. Furthermore, the animal literature indicates that fetal exposure to alcohol modifies subsequent neonatal and infantile responsiveness toward the sensory attributes of the drug. The main goal of the present study was to analyze whether differential maternal alcohol consumption during pregnancy affects neonatal reactivity to ethanol odor. To achieve this goal, an initial experiment examined how healthy human neonates respond to olfactory stimuli. In this first experiment, newborns (postpartum age: 24-48 h) were evaluated in terms of motor responsiveness elicited by repetitive stimulation with either alcohol or lemon odors. Infants exhibited a marked increase in duration of overall body and head and facial activity when the odorants were first presented. In four successive trials, behavioral responsiveness progressively declined until reaching baseline values. The introduction of a novel odorant served to dishabituate the motor responses under analysis. In the second experiment newborn's reactivity to the mentioned odorants was evaluated as a function of maternal self-reported patterns of consumption of alcohol during gestation. Mothers were classified as frequent or infrequent drinkers. Babies born to frequent drinkers exhibited heightened reactivity toward ethanol odor when compared to newborns delivered by infrequent drinkers. No differences emerged when comparing the responses of both groups of infants elicited by a non-ethanol stimulus such as lemon. The results coupled with prior human and animal research suggest the possibility of intrauterine experience with alcohol odor that yields a sensory memory likely to be retrieved immediately after birth.
Assuntos
Consumo de Bebidas Alcoólicas , Etanol , Troca Materno-Fetal , Odorantes , Estimulação Física , Adulto , Comportamento , Feminino , Humanos , Recém-Nascido , Masculino , Atividade Motora , GravidezRESUMO
Presenta el caso de un adenosarcoma de Muller originado en una endometriosis extragonadal. En la descripción de este caso, hacemos énfasis en los antecedentes ginecológicos y quirúrgico de la paciente, en la forma de presentación de la enfermedad, en la investigación clínica, en los hallazgos quirúrgicos y en las características macro y microscópicas de la tumoración resecada. Establecemos nuestro criterio que nos lleva a afirmar la transformación maligna del quiste endometriosico. Se realiza además, una revisión bibliográfica de los pocos casos reportados en la literatura mundial, pudiendo ser este, el primer caso reportado en nuestro país.
Assuntos
Humanos , Feminino , Adulto , Adenossarcoma , Endometriose , Tumor Mulleriano Misto , Institutos de Câncer , EquadorRESUMO
Sera from 210 patients with Acute Poststreptococcal Glomerulonephritis (APSGN) and 14 patients with streptococcal impetigo without glomerular disease were tested for the presence of IgG-ANCA using an indirect immunofluorescence assay (IIF) on ethanol fixed normal human neutrophils. In the group of nephritic patients, ANCA were detected by IIF in 9% (18 out of 210 cases) in an atypical diffuse cytoplasmic pattern (a-ANCA) in 14 cases and in a (p-ANCA) perinuclear staining in the remaining 4 cases. Longitudinal studies performed on six IIF positive patients, showed persistence of the phenomenon for up to six months, without relationship with activity of disease. No patient with streptococcal impetigo showed positivity on the IIF assay. Positive sera were analyzed on ELISA plates for their IgG reactivity against specific purified ANCA antigens: Proteinase-3 (PR3), Myeloperoxidase (MPO). Cathepsin-G and Bactericidal/Permeability Increasing Protein (BPI). Anti-MPO antibodies were present in 4 cases (3 a-ANCA and 1 p-ANCA). No reactivity was identified against PR-3, BPI and Catepsin-G in any of the samples. The presence of ANCA was significantly associated with a more severe glomerular disease as assessed by the serum creatinine and the crescents formation. Further studies are required to identify other antigenic specificities of these autoantibodies. Their absence in the streptococcal impetigo control group might suggest that their presence in APSGN could play some pathogenic role in kidney disease.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/análise , Autoantígenos/imunologia , Epitopos/imunologia , Glomerulonefrite/imunologia , Infecções Estreptocócicas/complicações , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Glomerulonefrite/microbiologia , Glomerulonefrite/patologia , Humanos , Impetigo/imunologia , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The early detection of peripheral neuropathy in diabetics is important since it is the main risk factor for lower limb trophic lesions in diabetics. AIM: To assess the relationship between feet thermal sensation threshold and metabolic control in ambulatory non-insulin-dependent diabetics. PATIENTS AND METHODS: A random sample of 34 non-insulin-dependent diabetics followed for more than five years in a special clinic, out of 368 patients, was selected. Warmth sensation thresholds were measured in the dorsum of both feet using a MSTP-III thermostimulator. The average value of all glycosylated hemoglobins obtained during the 9.7 +/- 5.3 years of follow up for each patient was calculated. A multiple stepwise regression analysis was performed between thermal sensation as the dependent variable and glycosylated hemoglobin, fasting blood glucose, age and diabetes duration. RESULTS: The regression model disclosed glycosylated hemoglobin as the only independent predictor of warmth sensation threshold (partial r = 0.385; p = 0.043). Fifteen diabetic patients with good metabolic control, defined as those with a mean glycosylated hemoglobin of less than 9.5%, had a warmth sensation threshold of 35.6 +/- 3.7 degrees C, whereas 19 diabetics with a had control (glycosylated hemoglobin > or = 9.5%) had a threshold of 39 +/- 3.8 degrees C (p = 0.017). CONCLUSIONS: In this group of diabetics, there is a relationship between the severity of distal polyneuropathy and the metabolic control, assessed with glycosylated hemoglobin levels.