RESUMEN
SETTINGS: Partners In Health Rwanda, in collaboration with the Ministry of Health, leads a multipronged approach to develop research capacity among health workers, particularly in rural areas. OBJECTIVES: To describe the characteristics of participants and to assess the impact of an introductory research seminar series in three district hospitals in rural Rwanda. DESIGN: This was a retrospective cohort study of seminar participants. Data were sourced from personnel records, assessment sheets and feedback forms. RESULTS: A total of 126 participants, including 70 (56%) clinical and 56 (44%) non-clinical staff, attended the research seminar series; 61 (48%) received certification. Among those certified, the median assessment score on assignments was 79%. Participants read significantly more articles at 6 and 12 months (median 2 and 4 respectively, compared to 1 at baseline, P < 0.01). There was also a significant increase (P ⩽ 0.05) in self-reported involvement in research studies (28%, baseline; 59%, 12 months) and attendance at other research training (36%, baseline; 65%, 12 months). CONCLUSION: The introductory research seminar series provided an important opportunity for engagement in research among clinical and non-clinical staff. Such an activity is a key component of a comprehensive research capacity building programme at rural sites, and serves as an entry point for more advanced research training.
Contexte : Partners In Health Rwanda, en collaboration avec le Ministère de la Santé, mène une approche multiple afin de développer les capacités de recherche du personnel de santé, surtout dans les zones rurales.Objectifs : Décrire les caractéristiques des participants et évaluer l'impact d'une série de séminaires d'introduction à la recherche dans trois hôpitaux de district ruraux du Rwanda.Schéma : Etude rétrospective de cohorte des participants au séminaire. Les données ont été recueillies à partir de dossiers personnels, de formulaires d'évaluation et de rétroaction.Résultats : Des 126 participants qui ont assisté à la série de séminaires de recherche, 70 (56%) étaient cliniciens et 56 (44%) personnel non-clinicien. Soixante et un (48%) ont obtenu leur certificat. Parmi ces derniers, le score médian d'évaluation des travaux était de 79%. Les participants lisaient beaucoup plus d'articles à 6 et 12 mois (médiane = 2 et 4 respectivement, comparé à 1 au départ, P < 0,01). On notait également une augmentation significative (P ⩽ 0,05) de l'implication dans des travaux de recherche rapportée par les intéressés eux-mêmes (28% au départ contre 59% à 12 mois) ainsi que de la participation à d'autres formations relatives à la recherche (36% au départ contre 65% à 12 mois).Conclusion : La série de séminaires d'introduction à la recherche a fourni une opportunité majeure d'engagement dans la recherche du personnel clinicien et non clinicien. Une telle activité est un élément clé d'un programme complet de renforcement des capacités de recherche dans les zones rurales et sert de point d'entrée pour des formations à la recherche plus avancées.
Marco de referencia: La organización Partners In Health de Rwanda, en colaboración con el Ministerio de Salud, dirige un proyecto multidimensional de creación de capacidad de investigación, dirigida a los profesionales que se ocupan de la salud, especialmente en las zonas rurales.Objetivos: Describir las características de los participantes y evaluar el efecto de la realización de una serie de seminarios introductorios a la investigación, en tres hospitales distritales de zonas rurales en Rwanda.Método: Fue este un estudio retrospectivo de cohortes de los participantes a los seminarios. Se obtuvieron datos a partir de los registros personales, las hojas de evaluación y los formularios de retroalimentación.Resultados: Participaron a la serie de seminarios 126 personas, de las cuales 70 pertenecían al personal asistencial (56%) y 56 a personal de otras esferas (44%). Sesenta y un participantes recibieron la certificación (48%). De las personas certificadas, la mediana de puntuación de la evaluación fue 79%. Los participantes leyeron más artículos a los seis y a los doce meses de la intervención (mediana = 1 y 4 respectivamente; P < 0,01) que al comienzo de la misma (mediana = 1; P ⩽ 0,05). Se observó además un aumento significativo de la intervención autorreferida en estudios de investigación (28% al comienzo y 59% a los 12 meses) y de la participación en otras capacitaciones científicas (36% al comienzo y 65% a los 12 meses).Conclusión: La serie de seminarios introductorios a la investigación ofreció al personal asistencial y a otros miembros del personal una importante oportunidad de participar en las actividades científicas. Este tipo de intervención constituye un componente primordial del programa integral de creación de capacidad de investigación en los centros rurales y representa una puerta de entrada a las capacitaciones científicas más avanzadas.
RESUMEN
AIM: Encapsulating peritoneal sclerosis (EPS) is arguably the most serious complication of chronic peritoneal dialysis (PD) therapy with extremely high mortality rates. We aimed to establish the rates of EPS and factors associated with its development in a single center. METHODS: We retrospectively reviewed the records of all our PD patients from 1 January 1989 until 31 December 2008. All suspected cases were confirmed at laparotomy. Multifactorial models adjusted for potentially confounding variables such as age and sex. RESULTS: Eleven cases of EPS were identified giving a prevalence rate of 1.98%. Median duration on PD was substantially longer in affected versus unaffected patients (42.5 months versus 13.8 months; p = 0.0002). EPS patients had experienced a mean of 3.54 previous cases of peritonitis (1 infection per year versus 0.71 per year in unaffected patients; p = 0.075). Six patients died (54.5%) due to intra-abdominal sepsis including all five who presented with small bowel obstruction. Three patients had an omentectomy and adhesiolysis performed with a successful outcome. CONCLUSION: Our study reinforces the link between duration on PD and EPS. While mortality was high in our cohort, emerging surgical techniques demonstrate a favorable outcome that can be achieved even in severely affected cases.
Asunto(s)
Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Fibrosis Peritoneal/etiología , Adulto , Femenino , Humanos , Irlanda/epidemiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Diálisis Peritoneal Ambulatoria Continua/mortalidad , Fibrosis Peritoneal/mortalidad , Fibrosis Peritoneal/terapia , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Estadísticas no ParamétricasRESUMEN
Improved prostate cancer cure rates have been attributed to higher radiotherapy dose prescriptions delivered more safely by modern conformal/intensity-modulated radiotherapy (IMRT) methods. As the dose becomes more concentrated conformally on the prostate, the volume of the rectum "at risk" for damage becomes smaller and more focal on the anterior rectal wall between the upper and lower axial limits of the planning target volume (PTV). The rectal dose-volume histogram (DVH) traditionally studies the whole volume of the rectum, and such definition for "avoidance" planning presupposes that rectal tolerance depends on "whole organ" radiation tolerance (as might, for example, lung or kidney). However, rectal morbidity with modern prostate radiotherapy is determined by anterior rectal wall tolerance between the superior and inferior limits of the PTV; this, we argue, is not dependent on whole organ tolerance. Recent published studies attempting to improve rectal DVH definition have studied the rectal wall only and concluded that rectal wall DVH is more relevant than whole rectum. In this manuscript, it is first demonstrated that a large and more relevant difference exists when comparing whole rectal DVH to "PTV limits" rectal DVH. Secondly, when considering "PTV limits" rectal DVH, the wall vs whole perimeter comparison differs little. Furthermore, by adopting a "PTV limits" DVH, the inferior right quartile of the DVH accurately reflects the dose distribution to the most vulnerable section of the anterior rectal wall. With improving IMRT technologies, scrutiny of this part of the rectal DVH will most accurately predict rectal sparing - reflected in this manuscript by the less precipitous decline of the TomoTherapy DVH vs the three-dimensional conformal DVH towards the maximum dose point received by the rectum.
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Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/prevención & control , Oncología por Radiación/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Conformacional/métodos , Humanos , Masculino , Protección Radiológica , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/métodos , Recto/efectos de la radiación , Tomografía Computarizada por Rayos XRESUMEN
UNLABELLED: Twenty pediatric users of cochlear implants were administered three tests of speech intelligibility: (1) a test of contrast perception intelligibility, (2) a test of contrast production intelligibility, and (3) a test of production sentence intelligibility. Sixty adults with normal hearing served as listener judges for the two speech production tasks, and percent correct scores were generated for each of the three tasks. Correlational analyses showed significant correlations among overall scores for the three tasks. However, scores for individual feature classes from the contrast perception task were not correlated with their corresponding contrast production feature class scores, and only some of the feature class scores were correlated significantly with sentence intelligibility. We conclude that although these three types of intelligibility are related at a gross level, relationships are more tenuous at finer levels of analysis, suggesting that the separate skills may need to be addressed separately in remediation. EDUCATIONAL OBJECTIVES: As a result of this activity, the participant will be able to differentiate various methods for assessing speech intelligibility and describe the relationships among different types of speech intelligibility in pediatric users of cochlear implants.
Asunto(s)
Implantación Coclear , Sordera/cirugía , Inteligibilidad del Habla , Percepción del Habla , Niño , Preescolar , Femenino , Humanos , Masculino , Fonética , Pruebas de Discriminación del Habla , Medición de la Producción del HablaRESUMEN
The role of nitric oxide (NO) in the long-term, amine-depleting effects of methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) was investigated in the rodent central nervous system. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) antagonized the dopamine- and serotonin-depleting effects of both METH and MDMA. The protective actions of L-NAME in METH-treated mice were reversed by prior administration of the NO generator isosorbide dinitrate. However, pretreatment with N(G)-monomethyl-L-arginine or N(G)-nitro-L-arginine, two other NO synthase inhibitors, failed to block the neurotoxic effects of METH or MDMA. L-NAME was also the only NO synthase inhibitor that antagonized the hyperthermic effects of METH, reducing colonic temperatures in mice by a mean of 3 degrees C, in comparison with control. Moreover, if the hypothermic effects of L-NAME in METH-treated mice were prevented by raising the ambient room temperature, the dopamine-depleting actions of the stimulant were fully restored. The latter findings suggest that it is the hypothermic actions of L-NAME, rather than its NO inhibitory properties, that are responsible for the prevention of neurotoxicity. Together with the results of the N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine experiments, the data suggest that NO plays little or no role in the toxic mechanism of action of METH or MDMA.
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Encéfalo/metabolismo , Catecolaminas/metabolismo , Dinitrato de Isosorbide/farmacología , Metanfetamina/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , NG-Nitroarginina Metil Éster/farmacología , Neurotoxinas , Óxido Nítrico/fisiología , Nitroarginina/farmacología , Serotonina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Análisis de Varianza , Animales , Temperatura Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Ácido Homovanílico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratones , Ratones Endogámicos , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To conduct a nationwide survey of graduating clinical laboratory science students in order to gather descriptive data and to determine how graduates felt about their profession and what their career goals were for the next 5 years. DESIGN: Survey PARTICIPANTS: A total of 866 clinical laboratory science seniors from hospital-based and university-based clinical laboratory science programs in the United States. OUTCOME MEASURES: Results of questions designed to gather descriptive data and professional goals as well as scales measuring professional attitudes about various aspects of the clinical laboratory science profession. RESULTS: Respondents indicated a high level of satisfaction with their chosen profession as indicated by the positive ratings of their clinical laboratory science program and immediate and long-term employment goals. CONCLUSION: Graduating clinical laboratory science students displayed satisfaction with their profession as evidenced by their career choices immediately following graduation, their professional goals 5 years after graduation, and their responses assessing professional attitudes.
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Actitud del Personal de Salud , Selección de Profesión , Personal de Laboratorio Clínico/psicología , Estudiantes del Área de la Salud/psicología , Empleo , Humanos , Satisfacción en el Trabajo , Personal de Laboratorio Clínico/educación , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Several amphetamine analogues are reported to increase striatal glutamate efflux in vivo, whereas other data indicate that glutamate is capable of stimulating the efflux of dopamine (DA) in the striatum via a glutamate receptor-dependent mechanism. Based on these findings, it has been proposed that the ability of glutamate receptor-blocking drugs to antagonize the effects of amphetamine may be explained by their capacity to inhibit DA release induced by glutamate. To examine this possibility further, we investigated in vivo the ability of glutamate antagonists to inhibit DA release induced by either methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA). Both METH and MDMA increased DA efflux in the rat striatum and, in animals killed 1 week later, induced persistent depletions of DA and serotonin in tissue. Pretreatment with MK-801 or CGS 19755 blocked the neurotoxic effects of METH and MDMA but did not significantly alter striatal DA efflux induced by either stimulant. Infusion of 6-cyano-7-nitro-quinoxaline-2,3-dione into the striatum likewise did not alter METH-induced DA overflow, and none of the glutamatergic antagonists affected the basal release of DA when given alone. The findings suggest that the neuroprotective effects of NMDA antagonists do not involve an inhibition of DA release, nor do the data support the proposal that glutamate tonically stimulates striatal DA efflux in vivo. Whether phasic increases in glutamate content might stimulate DA release, however, remains to be determined.
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Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitadores , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Aminas/antagonistas & inhibidores , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ácidos Pipecólicos/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Older mice are much more susceptible to the dopamine-depleting actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an effect that has been correlated with age-related increases in the central nervous system activity of the enzyme responsible for its bioactivation, monoamine oxidase type B (MAO B). To characterize the involvement of MAO B further in the age-related effects of MPTP, a neurotoxic analog of MPTP, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'CH3-MPTP), was used. This drug produced much larger depletions of striatal dopamine in 10-month-old mice than in 2-month-old animals, which indicated that the effects of 2'CH3-MPTP, like those of MPTP, are age related. Different from MPTP, however, neither the inhibition of MAO B (selegiline) nor MAO A (clorgiline) blocked the dopamine-depleting effects of 2'CH3-MPTP; rather, the simultaneous inhibition of both forms of the enzyme was required. These data indicate that both MAO A and B participate in the bioactivation of 2'CH3-MPTP. Based on these findings, the ability of selective inhibitors of MAO A and B to block the age-related effects of 2'CH3-MPTP was investigated. 2'CH3-MPTP produced equivalent depletions of striatal dopamine in 2- and 10-month-mice after both groups were pretreated with selective inhibitors of MAO B; that is, MAO B inhibition abolished the age-dependent effects of the neurotoxin. By contrast, older mice continued to display much larger 2'CH3-MPTP-induced depletions of striatal dopamine than did younger rodents after the inhibition of MAO A.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/análogos & derivados , Envejecimiento/metabolismo , Clorgilina/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Ratones , Ratones Endogámicos C57BLRESUMEN
The calcium channel antagonists verapamil nifedipine and flunarizine all increased the threshold for convulsions induced by N-methyl-D-aspartate in rats. By contrast, only flunarizine blocked the long-term serotonin-depleting effects of 3,4-methylenedioxymethamphetamine. Flunarizine was also the only drug that antagonized methamphetamine-induced stereotypy. These findings suggest that calcium influx through L-type channels does not participate in the neurotoxic mechanism of MDMA, and that the neuroprotective actions of flunarizine are probably related to its anti-dopaminergic activity.
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3,4-Metilenodioxianfetamina/análogos & derivados , Bloqueadores de los Canales de Calcio/farmacología , Serotonina/metabolismo , 3,4-Metilenodioxianfetamina/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/farmacología , Animales , Química Encefálica/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Flunarizina/farmacología , Haloperidol/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Metanfetamina/antagonistas & inhibidores , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina , Nifedipino/farmacología , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Conducta Estereotipada/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
Anisomycin and cycloheximide were used to investigate the role of protein synthesis in the mechanism of behavioral sensitization to the stereotypic effects of cocaine and amphetamine in mice. The drugs completely antagonize induction and partially block expression of the sensitization. Because these drugs were found to be neither antidopaminergic nor antiglutamatergic, it seems that they disrupt sensitization at a novel locus. The antagonism of expression is limited to that quantitative fraction of the response derived from the sensitization reaction; the acute response is unaffected by the inhibitors of protein synthesis. The results differ from those obtained with haloperidol which can completely block either the acute or sensitized response to the stimulants. These results suggest that the sensitized response is functionally different from that of the acute response. The blockage of sensitization induction by the protein synthesis inhibitors may be related to other reports that the stimulants induce the transcription of immediate early genes; however, the relationship between the activation of immediate early genes and behavioral sensitization remains to be determined.
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Anfetamina/antagonistas & inhibidores , Conducta Animal/efectos de los fármacos , Cocaína/antagonistas & inhibidores , Inhibidores de la Síntesis de la Proteína/farmacología , Anfetamina/farmacología , Animales , Anisomicina/farmacología , Cocaína/farmacología , Cicloheximida/farmacología , Inyecciones Intraperitoneales , Masculino , Ratones , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Conducta Estereotipada/efectos de los fármacosRESUMEN
Recent clinical studies suggest that selegiline (L-deprenyl) is useful in retarding the progress of Parkinson's disease, an effect that may be related to its inhibition of monoamine oxidase type B (MAO-B). Selegiline is also reported to prevent the toxic effects of the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). This article reviews recent studies on the role of MAO-B and its inhibition in this neuroprotective action of selegiline. Male C57Bl/6 mice were given DSP-4 (50 mg/kg) 1 h, 24 h, or 4 days after the administration of selegiline (10 mg/kg) or the selective MAO-B inhibitor MDL 72974 (1.25 mg/kg) and then killed 1 week later for the assay of norepinephrine in the hippocampus. The MAO-B-inhibiting effects of selegiline or MDL 72974 were also determined after these same intervals. Selegiline and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (> 95%), 24 h (> 90%), or 4 days (> 70%) after their administration. Given 1 h before, selegiline totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between selegiline and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, no activity was observed when DSP-4 was used as a substrate for MAO. All of these findings suggest that the ability of selegiline to protect against DSP-4-induced neuronal degeneration does not depend on its inhibition of MAO-B.
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Bencilaminas/toxicidad , Encéfalo/efectos de los fármacos , Isoenzimas/fisiología , Monoaminooxidasa/fisiología , Degeneración Nerviosa/efectos de los fármacos , Neurotoxinas , Selegilina/farmacología , Animales , Encéfalo/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos BALB C , Degeneración Nerviosa/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Norepinefrina/fisiologíaRESUMEN
The mechanism by which the amphetamines damage selectively nigrostriatal dopaminergic neurons in experimental animals remains uncertain. The observation that neuronal cell death during embryogenesis involves an activation of gene expression and new protein synthesis, coupled with recent reports indicating that the amphetamines are capable of inducing neuropeptide biosynthesis, offers a possible clue as to their neurotoxic mechanism of action. Based on these considerations, we evaluated the effects of two different inhibitors of protein synthesis, cycloheximide and anisomycin, on the long-term, amine-depleting effects of methamphetamine (METH) in mice and rats. Both inhibitors were found to block the amine-depleting effects of METH in these species. In other experiments, cycloheximide did not affect the functional integrity of dopaminergic or glutamatergic neurons, transmitter systems previously implicated in the neurotoxic mechanism of action of METH. These findings raise the possibility that the neuronal-damaging effects of METH are mediated via a synthesis of 'neurotoxic' proteins.
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Anisomicina/farmacología , Encéfalo/efectos de los fármacos , Cicloheximida/farmacología , Dopamina/metabolismo , Metanfetamina/toxicidad , Proteínas del Tejido Nervioso/biosíntesis , Animales , Masculino , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
Although the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice have been reported to increase with age, they have not been characterized in the full spectrum of ages. Thus, in spite of a considerable body of scientific literature on the subject, previous reports leave unanswered the question of whether or not the increased susceptibility of fully mature mice is part of the aging process or simply a consequence of maturation. In the present study, the age-related effects of MPTP on striatal dopamine were studied in groups of C57BL/6 mice from young maturity to old age. The major increase in the effects of MPTP occurred between 2 and 10 months of age (equivalent to adolescence and young adulthood in humans). A slight additional increase was observed between 10 and 16 months (young adulthood and middle age) and the dopamine-depleting effects of MPTP significantly declined in truly aged animals (24 months). Of note also is the fact that normal concentrations of striatal dopamine did not decline in the later ages. Additional studies indicated that while neuronal sensitivity to the effects of 1-methyl-4-phenylpyridinium (MPP+; the putative toxic metabolite of MPTP) appears to remain constant, age-related changes in the activity of striatal monoamine oxidase type B (MAO B) paralleled the dopamine-depleting effects of MPTP in the 4 age groups. Indeed, MAO B activity increased between 2 and 16 months and declined slightly, but significantly, between 16 and 24 months. This pattern of age-related changes in MAO B, striatal dopamine and the sensitivity of the nigrostriatal system to toxic insult may provide insights into factors which have been implicated in age-related neurodegeneration and idiopathic Parkinson's disease.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Envejecimiento/fisiología , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Monoaminooxidasa/metabolismo , 1-Metil-4-fenilpiridinio/farmacología , Animales , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Dextromethorphan, an agent that blocks the neuronal-damaging effects of hypoxemia in vitro, was tested for its ability to prevent the neurotoxic effects of p-chloroamphetamine (PCA). Rats were treated with either saline, PCA, dextromethorphan, or the combination of PCA and increasing doses of dextromethorphan. Dextromethorphan provided a dose-related protection against the serotonin (5-HT)-depleting effects of PCA. These observations may offer a clue as to the mechanism responsible for PCA-induced neurotoxicity.
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Dextrometorfano/farmacología , Sistema Nervioso/efectos de los fármacos , p-Cloroanfetamina/farmacología , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Hipocampo/metabolismo , Masculino , Ratas , Ratas Endogámicas , Antagonistas de la Serotonina/farmacología , p-Cloroanfetamina/antagonistas & inhibidoresRESUMEN
The MPTP-treated monkey has become an important model for the study of Parkinson's disease. However, studies on the acute evolution of the neurotoxic effects of MPTP in primates are lacking. In the present study, 17 squirrel monkeys were given a single subcutaneous injection of MPTP (2.5 mg/kg). The behavioral effects and the concentrations of dopamine (DA), dihydroxyphenylacetic acid and homovanillic acid were determined in caudate, putamen and substantia nigra 1, 3, 5 (n = 3/time point) and 10 days (n = 6) after drug administration. Two animals were studied neuropathologically 8 and 9 days after MPTP. Profound parkinsonism was evident in all animals after 1 day and neuropathological examination revealed severe nerve cell destruction in the substantia nigra. Surprisingly, although 50-75% reductions in nigral DA were observed 1 and 3 days after MPTP, caudate DA was not reduced and putaminal DA was increased at these time points. The temporal sequence of these events differs markedly from that which occurs in the MPTP-treated mouse and suggests that, in the monkey, nigral cell bodies may represent an important initial site of MPTP-induced damage. Five and 10 days after MPTP, nigral DA depletions remained greater than 60% of control and striatal DA was reduced 50-85%. At these time points, the putamen was always more affected than the caudate. This interregional pattern of striatal DA deficits is similar to that seen in idiopathic Parkinson's disease.
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Núcleo Caudado/metabolismo , Actividad Motora/efectos de los fármacos , Putamen/metabolismo , Sustancia Negra/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/patología , Dopamina/metabolismo , Ácido Homovanílico/metabolismo , Masculino , Monoaminooxidasa/metabolismo , Putamen/efectos de los fármacos , Putamen/patología , Valores de Referencia , Saimiri , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.
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Compuestos Alílicos , Bencilaminas/antagonistas & inhibidores , Inhibidores de la Monoaminooxidasa/farmacología , Enfermedades del Sistema Nervioso/inducido químicamente , Selegilina/farmacología , Animales , Bencilaminas/metabolismo , Bencilaminas/toxicidad , Butilaminas/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Cinética , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedades del Sistema Nervioso/fisiopatología , Norepinefrina/metabolismoAsunto(s)
3,4-Metilenodioxianfetamina/análogos & derivados , Aminas Biogénicas/líquido cefalorraquídeo , Drogas de Diseño/farmacología , Trastornos Relacionados con Sustancias , 3,4-Metilenodioxianfetamina/farmacología , Adulto , Femenino , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Persona de Mediana Edad , N-Metil-3,4-metilenodioxianfetamina , Valores de ReferenciaRESUMEN
Using the systemically active, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dextrorphan, we explored the role of the NMDA receptor-calcium channel complex in the toxic mechanism of action of 3,4-methylenedioxymethamphetamine (MDMA). Rats were treated with MDMA, dextrorphan, or the combination of MDMA and increasing doses of dextrorphan, and then killed 10 days later for the assay of serotonin and dopamine in the striatum, hippocampus, and cortex. Dextrorphan totally prevented the serotonin-depleting effects of MDMA in the straitum, with a lessened but still significant blockade noted in the hippocampus and cortex. These findings may provide a clue to the molecular events underlying MDMA-induced neurotoxicity.
Asunto(s)
3,4-Metilenodioxianfetamina/antagonistas & inhibidores , Anfetaminas/antagonistas & inhibidores , Dextrorfano/farmacología , Morfinanos/farmacología , Receptores de Neurotransmisores/antagonistas & inhibidores , 3,4-Metilenodioxianfetamina/administración & dosificación , 3,4-Metilenodioxianfetamina/análogos & derivados , 3,4-Metilenodioxianfetamina/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Calcio/metabolismo , Masculino , N-Metil-3,4-metilenodioxianfetamina , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmisores/metabolismoRESUMEN
A recent approach to identifying the factors that predispose neurons to an early death in Parkinson's or Alzheimer's disease has been to study how the effect of specific neurotoxins are altered by increasing maturity. We determined the dose-related serotonin and norepinephrine-depleting effects of the selective neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), in C57BL/6 mice of 2 different ages. Norepinephrine and serotonin in the hippocampus were assayed 1 week after the intracerebroventricular (i.c.v.) administration of 5,7-DHT. 5,7-DHT produced an equivalent, dose-related depletion of hippocampal norepinephrine in both age groups. Since the effects of 5,7-DHT on noradrenergic neurons may, at least in part, depend on the monoamine oxidase (MAO)-generated formation of hydrogen peroxide and associated oxy-radicals, this result suggests that noradrenergic neurons do not become more vulnerable to oxidative stress with aging. We also found that the noradrenergic-depleting effects of 5,7-DHT were blocked by the non-selective MAO inhibitor pargyline (50 mg/kg, i.p.), while the selective MAO B inhibitor deprenyl (10 mg/kg, i.p.) failed to prevent this depletion. These latter results suggest that it is the A form of MAO that plays an important role in the mechanism of 5,7-DHT-induced noradrenergic toxicity. Somewhat unexpectedly, older mice were found to be less susceptible to the serotonin-depleting effects of 5,7-DHT. Although the mechanism by which this compound damages serotonergic neurons is uncertain, our results show that the increased susceptibility of serotonergic neurons to 5,7-DHT in young animals extends well beyond the neonatal period.