RESUMEN
BACKGROUND: Oxidative stress is involved in the progression of Parkinson's disease (PD). Recent studies have confirmed that molecular hydrogen (H2) functions as a highly effective antioxidant in cultured cells and animal models. Drinking H2-dissolved water (H2-water) reduced oxidative stress and improved Parkinson's features in model animals. METHODS: In this a placebo-controlled, randomized, double-blind, parallel-group clinical pilot study, the authors assessed the efficacy of H2 -water in Japanese patients with levodopa-medicated PD. Participants drank 1,000 mL/day of H2-water or pseudo water for 48 weeks. RESULTS: Total Unified Parkinson's Disease Rating Scale (UPDRS) scores in the H2-water group (n=9) improved (median, -1.0; mean ± standard deviation, -5.7 ± 8.4), whereas UPDRS scores in the placebo group (n=8) worsened (median, 4.5; mean ± standard deviation, 4.1 ± 9.2). Despite the minimal number of patients and the short duration of the trial, the difference was significant (P<0.05). CONCLUSIONS: The results indicated that drinking H2-water was safe and well tolerated, and a significant improvement in total UPDRS scores for patients in the H2-water group was demonstrated.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Hidrógeno/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Método Doble Ciego , Femenino , Humanos , Japón , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Proyectos Piloto , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Agua/administración & dosificaciónRESUMEN
To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.
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Estudios de Asociación Genética , Variación Genética/genética , Heterocigoto , Homocigoto , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Factores de Edad , Edad de Inicio , Femenino , Frecuencia de los Genes , Corazón/diagnóstico por imagen , Humanos , Masculino , Mediastino/diagnóstico por imagen , Mediastino/patología , Imagen de Perfusión Miocárdica , Miocardio/patología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/patologíaAsunto(s)
Dopamina , Distonía , Oxidorreductasas de Alcohol , Distonía/complicaciones , Distonía/genética , Humanos , SerotoninaRESUMEN
3-Nitropropionic acid (3-NPA) is a suicide inactivator of succinate dehydrogenase (SDH), commonly used as a pharmacological model of Huntington's disease in rodents. Several studies have shown that a single administration of 3-NPA given systemically provides subsequent ischemic tolerance. The present study has tested the hypothesis that 3-NPA is capable of inducing tolerance in a model of permanent focal cerebral ischemia and whether 3-NPA can be truly applicable as a tolerance-inducer to ischemia. Rats given 3-NPA intraperitoneally revealed that the mortality of 3-NPA of 15, 20, and 25 mg/kg groups was 20.5, 38.8, and 83.3%, respectively. All rats survived without behavioral sequelae at smaller doses. Three days after 3-NPA preconditioning, the rats showing no behavioral changes underwent the permanent middle cerebral artery occlusion. The groups treated with 10 and 15 mg/kg of 3-NPA showed significantly reduced neurological deficits and infarction volumes in comparison with the control group, whereas the groups treated with 5 and 20 mg/kg of 3-NPA revealed no tolerance effects. When the regional SDH activity (% of control) was photometrically semi-quantified, it was observed that the activity was reduced to 90.8, 76.1, 67.8, and 64.3% in the outer layers of the cerebral cortex, and to 79.4, 67.5, 63.2, and 62.9% in the striatum 1 h after 3-NPA application (5, 10, 15, 20 mg/kg), respectively. In conclusion, although the preconditioning with 3-NPA is clearly shown in the setting of permanent ischemia, the preconditioning with this mitochondrial toxin demonstrated a rather narrow safety margin (critical threshold).
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Isquemia Encefálica/tratamiento farmacológico , Convulsivantes/farmacología , Precondicionamiento Isquémico/métodos , Propionatos/farmacología , Animales , Isquemia Encefálica/mortalidad , Isquemia Encefálica/patología , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Masculino , Nitrocompuestos , Ratas , Ratas Sprague-Dawley , Succinato Deshidrogenasa/antagonistas & inhibidoresRESUMEN
A 74-year-old man became unable to walk two days following the initiation of administration of oral distigmine bromide, 10 mg per day, for his constipation. Neurological examination revealed bradykinesia, rigidity and fine postural tremor without laterality. T2 weighted MRI showed mild front-temporal atrophy and multiple hyperintensities in both deep white matters. His symptoms fully improved one week after discontinuance of distigmine bromide. This is the first case report of distigmine bromide induced Parkinsonism.
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Enfermedad de Parkinson Secundaria/inducido químicamente , Compuestos de Piridinio/efectos adversos , Anciano , Estreñimiento/tratamiento farmacológico , Humanos , MasculinoRESUMEN
INTRODUCTION: Mitochondrial complex I deficiencies have been found in post-mortem brains of patients with Parkinson's disease (PD). Coenzyme Q10 (CoQ10) is the electron acceptor found in complexes I and II, and is a potent antioxidant. A recent trial of the oxidized form of CoQ10 for PD failed to show benefits; however, the reduced form of CoQ10 (ubiquinol-10) has shown better neuroprotective effects in animal models. METHODS: Randomized, double-blind, placebo-controlled, parallel-group pilot trials were conducted to assess the efficacy of ubiquinol-10 in Japanese patients with PD. Participants were divided into two groups: PD experiencing wearing off (Group A), and early PD, without levodopa (with or without a dopamine agonist) (Group B). Participants took 300 mg of ubiquinol-10 or placebo per day for 48 weeks (Group A) or 96 weeks (Group B). RESULTS: In Group A, total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the ubiquinol-10 group (n = 14; mean ± SD [-4.2 ± 8.2]), indicating improvement in symptoms. There was a statistically significant difference (p < 0.05) compared with the placebo group (n = 12; 2.9 ± 8.9). In Group B, UPDRS increased in the ubiquinol-10 group (n = 14; 3.9 ± 8.0), as well as in the placebo group (n = 8; 5.1 ± 10.3). CONCLUSIONS: This is the first report showing that ubiquinol-10 may significantly improve PD with wearing off, as judged by total UPDRS scores, and that ubiquinol-10 is safe and well tolerated.
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Antioxidantes/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Ubiquinona/análogos & derivados , Anciano , Antioxidantes/administración & dosificación , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/administración & dosificación , Proyectos Piloto , Resultado del Tratamiento , Ubiquinona/administración & dosificación , Ubiquinona/farmacologíaRESUMEN
AIM: Prediabetes is an independent risk factor for future stroke. However, no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes. Here we investigated the effects of pioglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist, for the reduction of recurrent stroke in patients with prediabetes. METHODS: Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack (TIA) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test. These patients were randomized to either receive or not receive pioglitazone. The primary endpoint was a recurrence of ischemic stroke. RESULTS: A total of 120 patients were enrolled in the study. Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone. The majority of patients (68.3%) were prescribed 15 mg of pioglitazone, while the remaining patients (31.7%) were treated with 30 mg of pioglitazone. Over a median follow-up period of 2.8 years, treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint (recurrence of stroke) than that observed in the control group [event rate=4.8% pioglitazone vs 10.5% control, hazard ratio=0.62, 95% confidence interval 0.13-2.35, p=0.49]. However, differences were not statistically significant. CONCLUSIONS: While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Accidente Cerebrovascular/prevención & control , Tiazolidinedionas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/patología , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/diagnóstico , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , PPAR gamma/agonistas , Pioglitazona , Estado Prediabético/complicaciones , Estado Prediabético/diagnóstico , Estudios Prospectivos , Recurrencia , Factores de Riesgo , Prevención Secundaria/métodos , Accidente Cerebrovascular/patología , Resultado del TratamientoRESUMEN
PURPOSE: We examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinson's disease (PD) (n = 1453; 650 males). METHODS: Events were analyzed using Kaplan-Meier survival curves, logistic regression, and Cox proportional-hazards models. RESULTS: The mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females (p < 0.05) and patients with late-onset PD (≥60 years, p < 0.001) were more likely to be affected. About 44.7% of patients had wearing-off 7.5 (4.7) years after the onset, and it was more common in females (p < 0.001) and patients with early-onset PD (p < 0.001). Camptocormia was found in 9.5% of patients 8.1 (6.2) years after the onset, and it was more common in females (p < 0.05) and patients with late-onset PD (p < 0.05). About 28.6% of patients developed psychosis 9.0 (5.4) years after the onset, and it was more likely to occur in patients with late-onset PD (p < 0.001). Late-onset PD and cerebrovascular disease were also associated with increased risk of pneumonia. CONCLUSIONS: Considering that very few studies have assessed numerous clinical symptoms in the same report, these data provide a useful reference for the clinical course of PD.
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Trastornos de la Destreza Motora/diagnóstico , Trastornos de la Destreza Motora/epidemiología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/epidemiología , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastornos de la Destreza Motora/fisiopatología , Enfermedad de Parkinson/fisiopatología , Prevalencia , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The present study reports a young woman with acute ataxia, areflexia and ophthalmoplegia, accompanied by psychosis and involuntary movements (IVMs) from disease onset. Anti-GQ1b and anti-GT1a antibodies were detected allowing for a diagnosis of Miller Fisher syndrome (MFS). However, psychosis and IVMs are atypical MFS symptoms and often mimic symptoms of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Interestingly, the autoantibodies against full-length glutamate receptor-ε2 (GluRε2) and glutamate NR2B- and NR2A-containing heteromers (NR1/NR2) of NMDAR were also detected in the patient serum and cerebrospinal fluid. It was concluded that psychosis and IVMs in this patient were associated with autoantibodies against various GluRs.
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Autoanticuerpos , Síndrome de Miller Fisher/inmunología , Receptores de Glutamato/inmunología , Femenino , Humanos , Adulto JovenAsunto(s)
Enfermedades de los Nervios Craneales/etiología , Nervio Oftálmico/patología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Enfermedades de los Nervios Craneales/diagnóstico , Femenino , Humanos , Hipertrofia/etiología , Hipertrofia/patología , Imagenología Tridimensional , Imagen por Resonancia Magnética , Persona de Mediana Edad , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnósticoRESUMEN
Glutamine synthetase (GS), localized to astrocyte is a key enzyme in the glutamate-glutamine pathway in the brain. 3-Nitropropionic acid (3-NPA) is an irreversible inhibitor of succinate dehydrogenase in the tricarboxylic-acid cycle, and provides ischemic tolerance to the brain. So far, there have been no reports on the relationship of astrocytic GS and ischemic tolerance by chemical preconditioning. In order to test the hypothesis that astrocytes serve a pivotal role in 3-NPA-induced chemical preconditioning, we have investigated the temporal profile of GS expression in astrocyte parallel with those of glial fibrillary acidic protein and heat-shock protein 70 (HSP70). In our rat model of permanent focal ischemia, preconditioning with 3-NPA singnificantly reduced the subsequent neurological deficits and infarct volume within 24-72 hours after treatment. Immunohistochemically, protoplasmic astrocytes in the cortex and striatum were activated in terms of upregulation of GS and more abundant protoplasmic processes with 3-NPA preconditioning, however, HSP70 expression could not be induced. Thus, the activation of astrocytes and upregulation of GS play an important role in 3-NPA-induced preconditioning but HSP70 does not. In view of glutamate being imposed on the cerebral ischemic damage, the astrocytic GS may contribute to 3-NPA-induced ischemic tolerance.
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Astrocitos/efectos de los fármacos , Astrocitos/enzimología , Encéfalo/patología , Glutamato-Amoníaco Ligasa/fisiología , Precondicionamiento Isquémico/métodos , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Infarto Encefálico/etiología , Infarto Encefálico/patología , Convulsivantes/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Inmunohistoquímica/métodos , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Proteínas del Tejido Nervioso/metabolismo , Nitrocompuestos/administración & dosificación , Propionatos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
We describe a case of polymyositis (PM) with liver injury that occurred in a patient with rheumatoid arthritis (RA). A 74-year-old woman who had a 12-year history of RA was admitted to our hospital because of muscle weakness and liver dysfunction. CD8-positive T cell infiltration was found in the interstitium of both the liver and muscle. In addition to the administration of a large amount of prednisolone (PSL), high-dose intravenous immunoglobulin (IVIG) successfully improved myositis and hepatitis. Our case indicates the pathogenic potential of CD8-positive T cells in PM-associated liver injury.