Assuntos
Dopamina , Distonia , Oxirredutases do Álcool , Distonia/complicações , Distonia/genética , Humanos , SerotoninaRESUMO
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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Estudos de Associação Genética , Variação Genética/genética , Heterozigoto , Homozigoto , Doença de Parkinson/genética , Proteínas Quinases/genética , Fatores Etários , Idade de Início , Feminino , Frequência do Gene , Coração/diagnóstico por imagem , Humanos , Masculino , Mediastino/diagnóstico por imagem , Mediastino/patologia , Imagem de Perfusão do Miocárdio , Miocárdio/patologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/epidemiologia , Doença de Parkinson/patologiaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Teste de Tolerância a Glucose , Acidente Vascular Cerebral/prevenção & controle , Tiazolidinedionas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/patologia , Diabetes Mellitus Tipo 2/complicações , Feminino , Intolerância à Glucose/complicações , Intolerância à Glucose/diagnóstico , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , PPAR gama/agonistas , Pioglitazona , Estado Pré-Diabético/complicações , Estado Pré-Diabético/diagnóstico , Estudos Prospectivos , Recidiva , Fatores de Risco , Prevenção Secundária/métodos , Acidente Vascular Cerebral/patologia , Resultado do TratamentoRESUMO
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/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Ubiquinona/análogos & derivados , Idoso , Antioxidantes/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Projetos Piloto , Resultado do Tratamento , Ubiquinona/administração & dosagem , Ubiquinona/farmacologiaAssuntos
Doenças dos Nervos Cranianos/etiologia , Nervo Oftálmico/patologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Doenças dos Nervos Cranianos/diagnóstico , Feminino , Humanos , Hipertrofia/etiologia , Hipertrofia/patologia , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnósticoRESUMO
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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Transtornos das Habilidades Motoras/diagnóstico , Transtornos das Habilidades Motoras/epidemiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos das Habilidades Motoras/fisiopatologia , Doença de Parkinson/fisiopatologia , Prevalência , Estudos Retrospectivos , Fatores de RiscoRESUMO
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.
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Antiparkinsonianos/uso terapêutico , Hidrogênio/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Idoso , Método Duplo-Cego , Feminino , Humanos , Japão , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Água/administração & dosagemRESUMO
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.
Assuntos
Autoanticorpos , Síndrome de Miller Fisher/imunologia , Receptores de Glutamato/imunologia , Feminino , Humanos , Adulto JovemRESUMO
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.
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Linfócitos T CD8-Positivos/imunologia , Hepatopatias/imunologia , Polimiosite/imunologia , Idoso , Artrite Reumatoide/complicações , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Hepatopatias/patologia , Polimiosite/complicações , Polimiosite/tratamento farmacológico , Polimiosite/patologia , Prednisolona/uso terapêuticoRESUMO
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.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/enzimologia , Encéfalo/patologia , Glutamato-Amônia Ligase/fisiologia , Precondicionamento Isquêmico/métodos , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Infarto Encefálico/etiologia , Infarto Encefálico/patologia , Convulsivantes/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Imuno-Histoquímica/métodos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Nitrocompostos/administração & dosagem , Propionatos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
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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Doença de Parkinson Secundária/induzido quimicamente , Compostos de Piridínio/efeitos adversos , Idoso , Constipação Intestinal/tratamento farmacológico , Humanos , MasculinoRESUMO
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).