RESUMEN
PURPOSE: The aim of this study was to assess the reliability of peri-fascial oedema as a sonographic criterion for selecting the most appropriate treatment (ultrasound-guided corticosteroid injection or ultrasound-guided extracorporeal shock wave therapy) of idiopathic plantar fasciitis (IPF). MATERIALS AND METHODS: Sixty-four patients with a clinical diagnosis of unilateral refractory IPF, treated conservatively for at least 8 weeks, were studied with high-resolution ultrasound (HRUS). Pain intensity was evaluated with a visual analogue scale (VAS). HRUS was used to confirm IPF and identify the presence of peri-fascial oedema. Patients with an HRUS diagnosis of IPF were grouped according to the presence (A) or absence (B) of peri-fascial oedema and then randomly allocated to treatment with corticosteroid injection (1) or extracorporeal shock wave therapy (2). Clinical and HRUS follow-up was performed 6 weeks after treatment. RESULTS: HRUS confirmed IPF in 68,97% of patients and identified peri-fascial oedema in 53.33%. Clinical and sonographic improvements were observed in 87.5% and 37.5% of patients in subgroups A1 and A2, respectively, and in 35.71% and 92.85% of those in subgroups B1 and B2, respectively. CONCLUSIONS: The presence of peri-fascial oedema may represent an effective criterion for guiding treatment decisions towards HRUS-guided corticosteroid injection.
Asunto(s)
Fascitis Plantar/diagnóstico por imagen , Fascitis Plantar/terapia , Glucocorticoides/administración & dosificación , Ondas de Choque de Alta Energía/uso terapéutico , Terapia por Ultrasonido , Ultrasonografía Intervencional , Fascitis Plantar/tratamiento farmacológico , Femenino , Humanos , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Satisfacción del Paciente , Sicilia , Resultado del Tratamiento , Terapia por Ultrasonido/métodosRESUMEN
PURPOSE: This study was undertaken to assess the diagnostic accuracy of high-resolution ultrasonography (HRUS) in the detection of meniscal cysts. MATERIALS AND METHODS: Over a 2-year period, 1,857 patients underwent magnetic resonance imaging (MRI) of the knee for traumatic or degenerative disorders. All patients with MRI evidence of a meniscal cyst were studied by HRUS. HRUS was also performed on an equal number of patients without MRI evidence of meniscal cyst who were used as a control group. All HRUS examinations were conducted by a radiologist blinded to the MRI findings. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of HRUS were assessed with reference to MRI. All patients underwent surgery, and the resected masses were studied by histological examination. RESULTS: MRI allowed identification of a meniscal cyst in 52 patients. HRUS enabled correct detection of the meniscal cyst in 49/52 cases. In the control group, HRUS excluded the presence of meniscal cysts in all cases. HRUS had a sensitivity, specificity, PPV and NPV of 94.23%, 100%, 100% and 94.54%, respectively, for the detection of meniscal cysts. CONCLUSIONS: HRUS is a fairly reliable technique in the detection, characterisation and differentiation of the different forms of meniscal cyst.
Asunto(s)
Quistes/diagnóstico por imagen , Meniscos Tibiales/diagnóstico por imagen , Adulto , Quistes/patología , Quistes/cirugía , Femenino , Humanos , Rodilla , Masculino , Meniscos Tibiales/patología , Meniscos Tibiales/cirugía , Sensibilidad y Especificidad , Resultado del Tratamiento , UltrasonografíaRESUMEN
Realistic numerical models of human subjects and their surrounding environment represent the basic points of radiofrequency (RF) electromagnetic dosimetry. This also involves differentiating the human models in men and women, possibly with different body shapes and postures. In this context, the aims of this paper are, firstly, to propose a female dielectric anatomical model (fDAM) and, secondly, to compare the power absorption distributions of a male and a female model from 0.1 to 4 GHz. For realizing the fDAM, a magnetic resonance imaging tomographer to acquire images and a recent technique which avoids the discrete segmentation of body tissues into different types have been used. Simulations have been performed with the FDTD method by using a novel filtering-based subgridding algorithm. The latter is applied here for the first time to dosimetry, allowing an abrupt mesh refinement by a factor of up to 7. The results show that the whole-body-averaged specific absorption rate (WBA-SAR) of the female model is higher than that of the male counterpart, mainly because of a thicker subcutaneous fat layer. In contrast, the maximum averaged SAR over 1 g (1gA-SAR) and 10 g (10gA-SAR) does not depend on gender, because it occurs in regions where no subcutaneous fat layer is present.
Asunto(s)
Ondas de Radio , Radiometría/métodos , Absorción , Tejido Adiposo/patología , Adulto , Algoritmos , Peso Corporal , Femenino , Cabeza , Humanos , Imagen por Resonancia Magnética , Masculino , Modelos Anatómicos , Modelos Teóricos , Fantasmas de Imagen , Postura , Dosis de Radiación , Factores SexualesRESUMEN
Numerical human models for electromagnetic dosimetry are commonly obtained by segmentation of CT or MRI images and complex permittivity values are ascribed to each issue according to literature values. The aim of this study is to provide an alternative semi-automatic method by which non-segmented images, obtained by a MRI tomographer, can be automatically related to the complex permittivity values through two frequency dependent transfer functions. In this way permittivity and conductivity vary with continuity--even in the same tissue--reflecting the intrinsic realistic spatial dispersion of such parameters. A female human model impinged by a plane wave is tested using finite-difference time-domain algorithm and the results of the total body and layer-averaged specific absorption rate are reported.
Asunto(s)
Algoritmos , Campos Electromagnéticos , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Modelos Biológicos , Ondas de Radio , Radiometría/métodos , Adulto , Carga Corporal (Radioterapia) , Simulación por Computador , Impedancia Eléctrica , Femenino , Humanos , Imagen por Resonancia Magnética/instrumentación , Modelos Anatómicos , Fantasmas de Imagen , Dosis de Radiación , Monitoreo de Radiación/métodos , Efectividad Biológica Relativa , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
Complex permittivity values have a dominant role in the overall consideration of interaction between radiofrequency electromagnetic fields and living matter, and in related applications such as electromagnetic dosimetry. There are still some concerns about the accuracy of published data and about their variability due to the heterogeneous nature of biological tissues. The aim of this study is to provide an alternative semi-automatic method by which numerical dielectric human models for dosimetric studies can be obtained. Magnetic resonance imaging (MRI) tomography was used to acquire images. A new technique was employed to correct nonuniformities in the images and frequency-dependent transfer functions to correlate image intensity with complex permittivity were used. The proposed method provides frequency-dependent models in which permittivity and conductivity vary with continuity--even in the same tissue--reflecting the intrinsic realistic spatial dispersion of such parameters. The human model is tested with an FDTD (finite difference time domain) algorithm at different frequencies; the results of layer-averaged and whole-body-averaged SAR (specific absorption rate) are compared with published work, and reasonable agreement has been found. Due to the short time needed to obtain a whole body model, this semi-automatic method may be suitable for efficient study of various conditions that can determine large differences in the SAR distribution, such as body shape, posture, fat-to-muscle ratio, height and weight.
Asunto(s)
Algoritmos , Antropometría/métodos , Impedancia Eléctrica , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Modelos Anatómicos , Modelos Biológicos , Recuento Corporal Total/métodos , Carga Corporal (Radioterapia) , Simulación por Computador , Humanos , Imagen por Resonancia Magnética/instrumentación , Microondas , Fantasmas de Imagen , Dosis de Radiación , Radiometría/métodos , Raphanus , Efectividad Biológica Relativa , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The effects of prenatal CO exposure (150 ppm from days 0 to 20 of pregnancy) on the postnatal development of hippocampal neuronal NO synthase (nNOS) and haem-oxygenase (HO-2) isoform activities in 15-, 30- and 90-d-old rats were investigated. Unlike HO-2, hippocampal nNOS activity increased from postnatal days 15-90 in controls. Prenatal CO produced a long-lasting decrease in either nNOS or HO-2. The results suggest that the altered developmental profile of hippocampal nNOS and HO-2 activities could be involved in cognitive deficits and long-term potentiation dysfunction exhibited by rats prenatally exposed to CO levels resulting in carboxyhaemoglobin (HbCO) levels equivalent to those observed in human cigarette smokers.
Asunto(s)
Monóxido de Carbono/toxicidad , Hemo Oxigenasa (Desciclizante)/metabolismo , Hipocampo/enzimología , Hipocampo/crecimiento & desarrollo , Óxido Nítrico Sintasa/metabolismo , Animales , Femenino , Hemoglobinas/metabolismo , Hipocampo/efectos de los fármacos , Isoenzimas/metabolismo , Óxido Nítrico Sintasa de Tipo I , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas WistarRESUMEN
Based on the numerical determination of the complete irradiation volume of a commercial RBS antenna--performed using the FDTD method and the Kirchhoff integral formula for near to far field transformation--open site estimations of the electric field are made and compared with experimentally measured values. To describe the actual behaviour of the radiation field, the inherently complex phasic nature of plane waves is taken into account, together with their two independent states of polarisation. This information is contained in the radiation pattern previously deduced. Moreover, a reflected contribution from flat ground is introduced, along with the line-of-sight ray. Amplitude and phase of the reflected wave are calculated using Fresnel formulae for stratified ground and two polarisation states, i.e. normal and parallel to the plane of incidence. Good agreement with measured values is achieved only by using such assumptions.
Asunto(s)
Campos Electromagnéticos , Exposición a Riesgos Ambientales/análisis , Modelos Teóricos , Ondas de Radio , Dispersión de Radiación , Humanos , Análisis Numérico Asistido por Computador , Dosis de Radiación , Radiometría/métodosRESUMEN
The aim of the present study was to investigate whether functional changes at CA3-CA1 synapses in the hippocampus could underlie learning and memory deficits produced in rat offspring by a prenatal exposure model simulating the carbon monoxide (CO) exposure observed in human cigarette smokers. Electrophysiological endpoints, including long-term potentiation, were examined in 15- to 30-day-old male rats whose mothers were exposed, from day 0 to day 20 of gestation, to 150 ppm of CO resulting in blood levels of carboxyhemoglobin comparable to those found in human cigarette smokers. Evoked field excitatory postsynaptic potentials were measured in the stratum radiatum in hippocampal slices. Results show that before tetanus, input/output functions, presynaptic volley, and paired-pulse facilitation were not affected in CO-exposed offspring, indicating that basal synaptic excitability and terminal Ca(2+) influx were not influenced by prenatal exposure to this gas. Conversely, evoked field excitatory postsynaptic potentials potentiation in response to tetanization was reduced by about 23% and decayed rapidly to baseline values in slices from CO-exposed animals. No changes between and within groups were observed in paired-pulse facilitation after tetanus. The selective impairment of long-term potentiation expression exhibited by CO-exposed rats was paralleled by a significant decrease in heme-oxygenase 2 and neuronal nitric-oxide synthase in the hippocampus. No changes in either enzymatic activity were found in frontal cortex and cerebellum. These electrophysiological and biochemical alterations might account for cognitive deficits previously observed in rats exposed prenatally to CO. Our findings could have clinical implications for the offspring of mothers who smoke during pregnancy.
Asunto(s)
Monóxido de Carbono/toxicidad , Potenciación a Largo Plazo/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Células Piramidales/efectos de los fármacos , Animales , Carboxihemoglobina/metabolismo , Cerebelo/efectos de los fármacos , Cerebelo/enzimología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/enzimología , Hemo Oxigenasa (Desciclizante)/metabolismo , Masculino , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo I , Embarazo , Células Piramidales/enzimología , Células Piramidales/fisiología , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacosRESUMEN
Low (up to 100 nM) and high (approximately 100 microM) concentrations of lanthanides and Ca2+-ions, respectively, stimulated [3H]tyramine binding ([3H]TY) to rat striatal membranes, a putative marker for the vesicular transporter of dopamine. On the other hand, lanthanides (approximately 100 microM) inhibited or stimulated TY binding in striatal and extrastriatal (cortex, cerebellum) tissues, respectively. The binding increases by lanthanum (La3+) appeared to depend on endogenous Ca2+, whereas, those induced in EDTA-pretreated membranes were Ca2+-independent. The La3+-induced, apparent increase in the Bmax for [3H]TY binding seemed to reflect a retarded rate of dissociation of the ligand from its targets, rather than a larger availability of functionally-relevant, vesicular transport-related TY sites. This indicates uncertain mechanisms of present La3+ effects.
Asunto(s)
Adrenérgicos/farmacología , Cuerpo Estriado/química , Cuerpo Estriado/metabolismo , Metales de Tierras Raras/farmacología , Tiramina/farmacología , Adenosina Trifosfato/farmacología , Adrenérgicos/metabolismo , Animales , Calcio/metabolismo , Calcio/farmacología , Cerebelo/química , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Quelantes/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Ácido Edético/farmacología , Gadolinio/farmacología , Masculino , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Vesículas Sinápticas/química , Vesículas Sinápticas/metabolismo , Tritio , Tiramina/metabolismoRESUMEN
Dithiocarbamate compounds are widely used agricultural fungicides that display low acute toxicity in mammals and that may become neurotoxic after prolonged exposure. Mancozeb, among other dithiocarbamates tested, proved to be the most potent (Ki= 0.27 microM) at noncompetitively inhibiting the in vitro ATP-dependent uptake of [3H]glutamate in rat cortical vesicles. Furthermore, mancozeb partially (20%) inhibited the ATP-dependent uptake of [14C]methylamine, used as an index for the vesicular transmembrane proton gradient (DeltapH), and evoked its efflux from organelles previously incubated with the 3H-labeled marker. Meanwhile, the vesicular uptake of 36chloride- anions whose concentrations regulate the transmembrane potential gradient (DeltapsiSV) was not impaired. The dithiocarbamate effects on the vesicular transport of [3H]glutamate thus appeared to involve mainly the DeltapH gradient rather than the potential gradient. Dithiocarbamate metabolites, the potent neurotoxin carbon disulfide included, did not affect the uptake process, thus implying the relevance for inhibition of the persistence, if any, of parent compounds in the brain. The present novel and potent in vitro interferences of selected dithiocarbamate pesticides with the vesicular transport of glutamate, if representative of in vivo alterations, may play some role in the probably complex origin of dithiocarbamate neurotoxicity.
Asunto(s)
Ácido Glutámico/metabolismo , Plaguicidas/farmacología , Vesículas Sinápticas/efectos de los fármacos , Tiocarbamatos/farmacología , Adenosina Trifosfato/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cloruros/metabolismo , Técnicas In Vitro , Masculino , Maneb/farmacología , Metilaminas/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Vesículas Sinápticas/metabolismo , Zineb/farmacologíaRESUMEN
We aimed to ascertain whether pyrethroid insecticides could influence the vesicular transport of the excitatory amino acid glutamate. The incubation of rat cortical synaptic vesicles with resmethrin and permethrin, consistently stimulated both ATP-dependent and -independent uptake of [3H]glutamate, while not evoking depletion of its vesicular content. Both processes were counteracted by valinomycin, a dissipator of the transmembrane potential gradient (deltapsi(sv)). Meanwhile, the vesicular influx of 36Cl- anions was impaired by pyrethroid concentrations which did not affect the ATP-dependent uptake of [14C]methylamine, as a marker for the proton gradient (deltapH). Thus, the stimulation of glutamate transport appeared to involve mainly the deltapsi(sv). A self-attenuating effect of selected pyrethroids on putatively enhanced excitatory transmission in severe intoxication is suggested.
Asunto(s)
Ácido Glutámico/farmacocinética , Piretrinas/metabolismo , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Radioisótopos de Carbono , Cloruros/farmacocinética , Insecticidas/farmacología , Ionóforos/farmacología , Masculino , Metilaminas/farmacocinética , Permetrina , Piretrinas/farmacología , Ratas , Ratas Sprague-Dawley , Tritio , Valinomicina/farmacologíaRESUMEN
Intoxication with the alcohol-aversive drug disulfiram (Antabuse) and related dithiocarbamates may provoke neuropathies and, in some cases, damage the basal ganglia. Rats received a single administration of disulfiram (7 and 500 mg kg-1 i.p.) and equimolar doses (4 and 290 mg kg-1 i.p.) of its metabolite diethyldithiocarbamate (DDC), roughly corresponding to the daily maximum dose in alcohol abusers or to an estimated nonlethal overdose, respectively. The striatal, extracellular levels of glutamate in freely moving rats previously implanted with a microdialysis probe increased after low and intoxicating doses of disulfiram (126 +/- 3% and 154 +/- 10% of basal values, respectively) and DDC as well (135 +/- 10% and 215 +/- 14%, respectively), a partially Ca++-dependent effect. The prolonged (>7 hr) disulfiram-induced increase in glutamate observed in vivo may reflect the in vitro disulfiram-evoked release of glutamate from striato-cortical synaptic vesicles, where the drug nonspecifically inhibited (Ki approximately 4 microM) the uptake function and abolished the transmembrane proton gradient (DeltapH). In contrast, DDC did not seem to affect DeltapH. The prompt DDC-provoked increase in extracellular levels of glutamate was prevented by 7-nitroindazole, an in vivo specific inhibitor of neuronal nitric oxide synthase, which suggests that the thiol metabolite also acts via the nitric oxide synthesis. At variance, the short-acting 7-nitroindazole did not prevent the sustained in vivo effects of disulfiram and of DDC putatively formed with time. These findings provide new evidence for differential mechanisms underlying disulfiram- and DDC-induced increases in striatal glutamate release. Present glutamatergic changes, although not appearing dramatic enough to represent the only cause for neuronal damage from disulfiram overdose, might contribute to the drug neurotoxicity.
Asunto(s)
Disuasivos de Alcohol/envenenamiento , Antídotos/envenenamiento , Disulfiram/envenenamiento , Ácido Glutámico/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Ditiocarba/envenenamiento , Masculino , Metilaminas/metabolismo , Ratas , Ratas Sprague-Dawley , Corteza Visual/efectos de los fármacos , Corteza Visual/fisiologíaRESUMEN
A set of substituted benzamides, characterized by the presence of a bulky quinolizidine moiety, were subjected to binding assays for 5-HT3 and D2 receptors on membranes obtained from the bovine area postrema ([3H]-GR65630) and the rat striatum ([3H]-spiperone) respectively. These benzamides resulted unsuitable for the recognition of D2 receptors, while a few of them, devoid of 5-HT4 receptor activity, had consistent affinity for central 5-HT3 receptors, inhibiting also potently the ethanol-induced dopamine efflux from the mesolimbic dopamine terminal region. However they failed in attenuating voluntary alcohol consumption in rats, as observed with several other chemically unrelated 5-HT3 antagonists. Thus the 5-HT3-mediated inhibition of alcohol-induced striatal release of dopamine by substituted benzamides is not a requisite for affecting ethanol intake.
Asunto(s)
Consumo de Bebidas Alcohólicas , Benzamidas/farmacología , Dopamina/metabolismo , Etanol/antagonistas & inhibidores , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Animales , Benzamidas/química , Benzamidas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Etanol/farmacología , Masculino , Estructura Molecular , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Serotonina 5-HT3 , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/metabolismoAsunto(s)
Envejecimiento , Encéfalo/efectos de los fármacos , Exposición a Riesgos Ambientales , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Neurotoxinas/toxicidad , Animales , Proteínas Portadoras/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Humanos , Proteínas del Tejido Nervioso/efectos de los fármacos , Vesículas Sinápticas/efectos de los fármacos , TritioRESUMEN
Acute intoxication and chronic therapy with the alcohol consumption deterrent dithiocarbamate disulfiram have been associated with several neurological complications perhaps involving the impairment of neurotransmitter pathways. In this study we have tested the hypothesis that dopaminergic malfunction is a critical component in disulfiram-evoked neurotoxicity. Disulfiram antagonized the in vitro striatal binding of [3H]tyramine, a putative marker of the vesicular transporter for dopamine, and the uptake of [3H]dopamine into striatal synaptic vesicles, with inhibitory constants (Ki) in the range of reported blood dithiocarbamate levels in treated alcoholics. Furthermore, disulfiram provoked a loss of radioactivity from [3H]dopamine-preloaded striatal vesicles, when added directly to the incubation mixture. Several metal-containing fungicide analogs were also potent displacers of specifically bound [3H]tyramine. Diethyldithiocarbamate (DDC), the major metabolite of disulfiram, had none of these effects. The intraperitoneal injection of a high dose of disulfiram and DDC into rats, mimicking acute intoxication, induced in vivo overflow of striatal dopamine from both a reserpine-sensitive (vesicular) and an alpha-methyl-p-tyrosine-sensitive (cytoplasmic) pool. The vesicular component of in vivo dopamine release resulted mainly from a direct activity of disulfiram, on the organelles (interaction with the carrier for dopamine plus membrane permeabilization) and indirectly through the mediation of serotonergic 5-HT3 receptors. DDC acted poorly at the vesicle membrane, and the in vivo releasing effect of dopamine was only partially prevented by the inhibition of 5-HT3 receptors, thus suggesting the role of additional mechanisms. It is concluded that disulfiram intoxication may acutely disrupt dopamine balance, an effect probably underlying some of the central neurotoxic, extrapyramidal symptoms associated with dithiocarbamate overdose.
Asunto(s)
Disuasivos de Alcohol/toxicidad , Antídotos/toxicidad , Cuerpo Estriado/efectos de los fármacos , Disulfiram/toxicidad , Ditiocarba/toxicidad , Dopamina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Disuasivos de Alcohol/administración & dosificación , Animales , Antídotos/administración & dosificación , Unión Competitiva , Bovinos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cuerpo Estriado/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Disulfiram/administración & dosificación , Ditiocarba/administración & dosificación , Inhibidores Enzimáticos/farmacología , Inyecciones Intraperitoneales , Masculino , Metiltirosinas/farmacología , Orgánulos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT3 , Reserpina/farmacología , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , Tiramina/metabolismo , alfa-MetiltirosinaRESUMEN
The displacement of [3H]SCH-23390 and of [3H]spiperone from striatal, dopamine D1- and D2-type receptors by several quinolizidinyl-derivatives of bi- and tricyclic systems was investigated. All tested compounds did not affect SCH-23390 binding and exhibited only weak activity on spiperone binding to D2 binding sites (Ki = 1.9 microM). Therefore the good deconditioning activity (CAR blockade in rats) of 6-chloro-1-lupinyl-3-methyl-quinoxalinone (18) must rely on interactions with other kinds of receptors.
Asunto(s)
Quinolizinas/farmacología , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Animales , Benzazepinas/farmacología , Unión Competitiva/efectos de los fármacos , Técnicas In Vitro , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Ratas , Espiperona/farmacologíaRESUMEN
This study defined the ability of a large sample of heterogeneous pesticides and neurotoxins to interact with the [3H]tyramine-labelled vesicular transporter of dopamine in rat striatum. Botanical (with rotenone as the most potent), and organochlorine (Kepone) insecticides, as well as fungicides (Zineb), as a whole, consistently inhibited [3H]tyramine binding, with Ki values ranging from 5 nM to 10 microM. ATP/Mg(2+)-dependent [3H]tyramine uptake to purified striatal synaptic vesicles was also inhibited by rotenone. Organophosphate and carbamate insecticides, and miscellaneous herbicides poorly antagonized [3H]tyramine binding, yielding Ki values exceeding 10 microM. Several, though not all, of the best recognized central neurotoxins tested were major binding antagonists. Their rank order of potency was 1-methyl-4-phenylpyridinium ion (MPP+) > trimethyltin > or = 6-hydroxydopamine > N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) > 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with Ki values ranging from 35 nM to 3 microM. Overall, the potent interaction of selected pesticides and chemicals with the vesicular transporter for dopamine, although, by itself, not synonymous with neurotoxicity, would argue for a likely impairment of transmitter homeostasis, or the putative formation of neurodegenerative toxin pools.
Asunto(s)
Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Neostriado/metabolismo , Proteínas del Tejido Nervioso/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Neurotoxinas/farmacología , Plaguicidas/farmacología , Tiramina/metabolismo , Animales , Carbamatos , Dopamina/fisiología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Fungicidas Industriales/farmacología , Herbicidas/farmacología , Insecticidas/farmacología , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Neostriado/efectos de los fármacos , Compuestos Organofosforados , Ratas , Ratas Sprague-Dawley , Rotenona/farmacologíaRESUMEN
A number of Ca(2+)-, K(+)-, and Na(+)-channel modulators has been tested with respect to their effects on [3H]tyramine (TY) binding, as a putative marker for the vesicular dopamine (DA) transporter in striatal membrane preparations containing vesicle ghosts. Among organic Ca(2+)-channel modulators, the diphenylalkylamines tested consistently inhibited TY binding: the order of potency was prenylamine > lidoflazine > flunarizine > cinnarizine, with Ki values of 0.1, 0.2, 0.5 and 1.2 microM, respectively. Low (up to 100 nM) concentrations of prenylamine did competitively inhibit TY binding, and higher concentrations provoked a mixed-type inhibition. Furthermore, LIGAND-analysis of competition curves revealed a high- and a low-affinity binding site for prenylamine and flunarizine. The TY binding process was also sensitive to selected K(+)- and Na(+)-channel modulators. Since several Ca(2+)-antagonists are known to affect H(+)-ATPase and the bioenergetics of catecholamine storage vesicles in chromaffin granules, thus affecting monoamine storage, the energy requirements for the formation of the TY/carrier complex were here assessed, assuming similarity between chromaffin granules and synaptic vesicles. TY binding, though not reflecting endovesicle-sequestered TY, was indeed strongly sensitive (with Ki coefficients in the fM or low nM range) to the dissipation of the vesicular transmembrane proton concentration (delta pH), electrical (delta psi), and proton electrochemical (delta microH+) gradients, provoked by a number of specifically targeted agents. It is concluded that Ca(2+)-channel agents of the diphenylalkylamine group may directly affect striatal TY binding due to an extrachannel-regulated competition with TY for the vesicular carrier of DA, as well indirectly, by disruption of the transmembrane energization of the reserpine-sensitive carrier.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Tiramina/metabolismo , Animales , Unión Competitiva , Carbonil Cianuro p-Trifluorometoxifenil Hidrazona/farmacología , Cationes , Membrana Celular/metabolismo , Electroquímica , Concentración de Iones de Hidrógeno , Masculino , Oligomicinas/farmacología , Canales de Potasio/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Canales de Sodio/efectos de los fármacos , TritioRESUMEN
Of 5,500 newborn infants whose family histories were screened, 900 were found to have anamnestic risk. Cord-blood IgE was evaluable in 4,677 of these newborns, of which 394 had levels > or = 1 IU/mL; 84 infants had both anamnestic risk and elevated cord-blood IgE levels. Parents of infants with anamnestic risk were informed of their child's risk of atopy. Additionally, for 391 infants at two of the three participating hospitals, a preventive diet was prescribed that recommended breastfeeding for the first 6 months of life, with maternal diet restricted to no more than 200 dL of cow milk per day, no more than one egg per week, and no tomato, fish, shellfish, nuts, or foods allergenic to the mother. Only soy formula was recommended, and introduction of solid foods was also carefully prescribed. Furthermore, doctors recommended against exposure to tobacco smoke, animal allergens, and early entrance into daycare. Evaluable infants whose parents complied with the prescribed diet were found to have a lower incidence of atopy during the first year of life (13.3%, n = 158) than infants whose parents had ignored the prescribed diet (54.7%, n = 86) or infants whose parents were offered no dietary recommendations (28.9%, n = 218). Differences between the compliant group and the two groups with unrestricted diets were significant, indicating that this prescribed diet may protect against or delay onset of food allergies during the first year of life.
Asunto(s)
Hipersensibilidad a los Alimentos/dietoterapia , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad Inmediata/dietoterapia , Hipersensibilidad Inmediata/epidemiología , Femenino , Sangre Fetal/inmunología , Hipersensibilidad a los Alimentos/inmunología , Humanos , Hipersensibilidad Inmediata/inmunología , Inmunoglobulina E/análisis , Incidencia , Alimentos Infantiles , Recién Nacido , Intercambio Materno-Fetal/inmunología , Tamizaje Neonatal , Embarazo , Estudios Prospectivos , Factores de RiesgoRESUMEN
The [3H]Tyramine (TY) binding site is proposed as a high affinity marker of the membrane carrier for dopamine (DA) in synaptic vesicles from DA-rich brain regions. Under precise assay conditions, there is neither a consistent association of TY with the neuronal, cocaine-sensitive DA transporter, nor with mitochondrial or microsomal targets. TY-labeled sites have a high affinity for selected toxins such as the Parkinsonian agent MPP+ (1-methyl-4-phenylpyridinium ion), or drugs such as diphenylalkylamine Ca(2+)-channel antagonists. The MPP+/TY site interaction, which in the striatum leads to depletion of vesicular DA, occurs in dopaminergic as well as in noradrenergic regions, though with different kinetic profiles. TY-labeled carriers for DA and noradrenaline (NA) in respective vesicles seem to be different entities, which might result in a region-specific rate of toxin sequestration and/or release from heterogeneous vesicles. Whereas MPP+ is a potent competitive-type inhibitor of [3H]TY binding, prenylamine-like Ca(2+)-channel antagonists can compete with TY for the vesicle site, in a tetrabenazine- or reserpine-like manner, and also inhibit TY binding thanks to the extra-channel directed impairment of membrane bioenergetics they are proposed to provoke. This follows from the generally-accepted assumption that similar mechanisms are operational for secretory organelles in adrenals and CNS, and from the marked sensitivity of TY binding to miscellaneous energy-disrupting agents.(ABSTRACT TRUNCATED AT 250 WORDS)