RESUMEN
OBJECTIVE: To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD). BACKGROUND: Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients. METHODS: The study participants consisted of 112 PD patients (median age 72.5 years [inter-quartile range: IQR 65-79]; mean disease duration 8.44 years [standard deviation: 7.33]; median Hoehn and Yahr stage 3 [IQR 2-3.75]) taking one of three types of non-ergot extended-release DAs (rotigotine 32; pramipexole 44; ropinirole 36) with or without L-dopa (median daily total dosage of antiparkinsonian drugs 525.5 mg [IQR 376.25-658] levodopa equivalent dose [LED]). Participants were assessed using the PD Sleep Scale-2 (PDSS-2). RESULTS: For the whole PD patient cohort, the PDSS-2 sleep disturbance domain score and the scores for item 1 assessing sleep quality and item 8 assessing nocturia were positively correlated with daily total dosage of antiparkinsonian drugs and dosage of L-dopa, but not with the dosage of DAs. Sub-analysis according to DA treatment revealed that DA dosage was not correlated with item 1 or 8 score in any of the subgroups. The LED ratio of rotigotine to the total dosage of antiparkinsonian drugs was inversely correlated with the item 1 score. CONCLUSIONS: These data suggest that antiparkinsonian drugs, in particular L-dopa, adversely affect nocturnal sleep in PD patients, especially in terms of sleep quality and nocturia. Thus, adjusting both the total dosage of antiparkinsonian drugs and the dose-ratio of L-dopa might be key actions for alleviating poor sleep quality in patients with PD. Among DAs, we found a clear positive correlation between the dose-ratio of rotigotine and sleep quality. Thus, partial L-dopa replacement with rotigotine could improve sleep quality in patients with PD.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Sueño , Anciano , Antiparkinsonianos/farmacología , Estudios Transversales , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Humanos , Indoles/farmacología , Indoles/uso terapéutico , Levodopa/farmacología , Levodopa/uso terapéutico , Pramipexol/farmacología , Pramipexol/uso terapéutico , Análisis de Regresión , Estudios Retrospectivos , Sueño/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
A 45-year-old man presented with fever, progressive mutism and memory loss, was admitted to our hospital. MR imaging and angiography suggested multiple foci of infarctions and vasculitis without Gadrinium-enhancement. CSF examination revealed pleocytosis with mononuclear cell dominance and elevated protein content. Adenosine deaminase activity was accelerated, and no malignant cell was found. Whole body CT imaging and Garium-scintigraphy were normal. Under the clinical diagnosis of tuberculous meningitis, anti-tubercular drugs with steroid were administered, resulting in marked attenuation of his neurological impairments. Four months later, his symptoms aggravated and restudy of Garium-scintigraphy revealed enhanced accumulation in the submandibular and abdominal lymphnodes. A lymph node biopsy revealed diffuse large B-cell lymphoma cells. In such a case of this clinical statue, careful and repeated observations should be required to establish the correct diagnosis of occult lymphoma.
Asunto(s)
Linfoma de Células B Grandes Difuso/diagnóstico , Neoplasias Meníngeas/diagnóstico , Tuberculosis Meníngea , Infarto Cerebral/diagnóstico , Infarto Cerebral/etiología , Diagnóstico Diferencial , Diagnóstico por Imagen , Humanos , Leucocitosis/diagnóstico , Leucocitosis/etiología , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/patología , Masculino , Neoplasias Meníngeas/patología , Persona de Mediana Edad , Vasculitis/diagnóstico , Vasculitis/etiologíaRESUMEN
It is essential that we know the real situation of at-home patients with amyotrophic lateral sclerosis (ALS) in order to improve their medical support system. We indirectly investigated the daily living status of ALS patients and their families at home by conducting on individual questionnaires survey for nurses working at public health centers in Aichi prefecture, Japan. Detailed information about 136 cases was obtained, and we could clarify the need for variety of communication methods, plasticity of medical interrelations and care between neurologists and home doctors, incomplete utilization of social resources including various official support, overwork among single caregivers, and underdeveloped immature individual medical care support programs for them. Thus it might be important that we should promote the sure utilization of social resources and programming the individual medical care support in their earlier stages. And moreover, we should also consider constructing a general support system for at-home patients with ALS, in which each professional would owe the dividing responsibility, without role duplications. These strategies would lead to overall the better quality of life among ALS patients, and their families.
Asunto(s)
Esclerosis Amiotrófica Lateral , Servicios de Atención de Salud a Domicilio/estadística & datos numéricos , Planificación de Atención al Paciente , Actividades Cotidianas , Adulto , Anciano , Anciano de 80 o más Años , Cuidadores , Femenino , Recursos en Salud , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Cuidados Intermitentes/estadística & datos numéricosRESUMEN
The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.
Asunto(s)
Benzoquinonas/administración & dosificación , Lactamas Macrocíclicas/administración & dosificación , Neuronas Motoras/metabolismo , Atrofia Muscular Espinal/tratamiento farmacológico , Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores Androgénicos/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Neuronas Motoras/efectos de los fármacos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Complejo de la Endopetidasa Proteasomal/genética , Receptores Androgénicos/genética , Ubiquitina/genética , Ubiquitina/metabolismoRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.
Asunto(s)
Sistema Nervioso Central/metabolismo , Terapia Genética/métodos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Receptores Androgénicos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Sistema Nervioso Central/fisiopatología , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Femenino , Regulación de la Expresión Génica/fisiología , Predisposición Genética a la Enfermedad/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Atrofia Muscular Espinal/terapia , Mutación/genética , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/terapia , Fenotipo , Complejo de la Endopetidasa Proteasomal/metabolismo , Pliegue de Proteína , Receptores Androgénicos/genéticaRESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease caused by an expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the androgen receptor (AR) gene. To elucidate the pathogenesis of polyglutamine-mediated motor neuron dysfunction, we investigated histopathological and biological alterations in a transgenic mouse model of SBMA carrying human pathogenic AR. In affected mice, neurofilaments and synaptophysin accumulated at the distal motor axon. A similar intramuscular accumulation of neurofilament was detected in the skeletal muscle of SBMA patients. Fluoro-gold labeling and sciatic nerve ligation demonstrated an impaired retrograde axonal transport in the transgenic mice. The mRNA level of dynactin 1, an axon motor for retrograde transport, was significantly reduced in the SBMA mice resulting from pathogenic AR-induced transcriptional dysregulation. These pathological events were observed before the onset of neurological symptoms, but were reversed by castration, which prevents nuclear accumulation of pathogenic AR. Overexpression of dynactin 1 mitigated neuronal toxicity of the pathogenic AR in a cell culture model of SBMA. These observations indicate that polyglutamine-dependent transcriptional dysregulation of dynactin 1 plays a crucial role in the reversible neuronal dysfunction in the early stage of SBMA.