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1.
Intern Med ; 61(16): 2517-2521, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35110481

RESUMO

Autosomal recessive spinocerebellar ataxia of type 10 (SCAR10) is a very rare neurodegenerative disease caused by mutations in the TMEM16K (ANO10) gene. This disorder is characterized by slowly progressive cerebellar ataxia and pyramidal signs inconstantly associated with cognitive decline, polyneuropathy, epilepsy, and vesicorectal dysfunction. To date, more than 40 cases have been reported in Europe. In contrast, only three cases have been identified in Asian countries. We herein report the third Japanese case of SCAR10 harboring a novel homozygous deletion mutation (c.616delG, p.Glu206Lysfs*17). This case presented with adult-onset slowly progressive spastic ataxia with cerebellar atrophy and mild cognitive decline.


Assuntos
Atrofia Óptica , Ataxias Espinocerebelares , Adulto , Homozigoto , Humanos , Japão , Mutação/genética , Atrofia Óptica/genética , Deleção de Sequência , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética
2.
Drug Metab Pharmacokinet ; 41: 100422, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34717268

RESUMO

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.


Assuntos
Etnicidade , Rilpivirina , Adulto , Povo Asiático , Voluntários Saudáveis , Humanos , Rilpivirina/efeitos adversos , População Branca
3.
Intern Med ; 60(24): 3963-3967, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34121011

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare progressive neurodegenerative disease caused by either homozygous or compound heterozygous mutations in the SACS gene. The original ARSACS cases found in Quebec showed very homogenous phenotypes characterized by cerebellar ataxia, spasticity, and polyneuropathy. However, many cases with atypical phenotypes have been found in other regions and ethnic groups. We herein present a Japanese patient with atypical ARSACS who showed cerebellar ataxia and polyneuropathy, but no spasticity. She carried novel compound heterozygous mutations (p.Lys4326Glu and p.Leu1412Lysfs*16) in the SACS gene. The brain MRI findings were useful for making a diagnosis of ARSACS.


Assuntos
Proteínas de Choque Térmico , Ataxias Espinocerebelares , Feminino , Proteínas de Choque Térmico/genética , Homozigoto , Humanos , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/genética , Mutação , Ataxias Espinocerebelares/congênito , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética
4.
Case Rep Neurol ; 13(1): 84-91, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708099

RESUMO

Spastic paraplegia type 4 (SPG4) is the most common type of hereditary spastic paraplegia (HSP) caused by the mutations in the SPAST gene, which encodes a microtubule-severing protein named spastin. Spastin regulates the number and mobility of microtubules and is essential for axonal outgrowth and neuronal morphogenesis. Herein, we report a patient with SPG4 harboring a novel donor splice site mutation in the SPAST gene (c.1616+1dupG). Although SPG4 usually manifests itself as a pure form of HSP, this patient exhibited a slow progressive cognitive decline and also developed narcolepsy type 2 (narcolepsy without cataplexy) prior to the onset of SPG4. Recently, cognitive decline has attracted attention as a main non-motor symptom of SPG4. However, this is the first reported case of a patient developing both SPG4 and narcolepsy, although it remains unclear whether the manifestation of the two diseases is a coincidence or an association. In this report, we describe the clinical symptoms and genetic background of the patient.

5.
Intern Med ; 59(10): 1309-1313, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32101834

RESUMO

Homozygous or compound heterozygous mutations in the high-temperature requirement A serine protease 1 gene (HTRA1) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a very rare hereditary cerebral small-vessel disease (SVD). Recently, the relationship between some heterozygous HTRA1 mutations, most of which are missense, and the occurrence of cerebral SVD has been reported. We herein report a patient with cerebral SVD carrying a heterozygous nonsense p.R302X mutation in HTRA1. This patient had a family history of cerebral infarction. This report suggests that a heterozygous p.R302X mutation in HTRA1 causes an autosomal dominant cerebral SVD.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Doenças de Pequenos Vasos Cerebrais/patologia , Códon sem Sentido , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
6.
Ann Neurol ; 87(2): 302-312, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31773773

RESUMO

OBJECTIVE: The pallidonigroluysian (PNL) system, the primary component of corticosubcortical circuits, is generally spared in amyotrophic lateral sclerosis (ALS). We evaluated the clinicopathological features of an unusual form of ALS with PNL degeneration (PNLD) and assessed whether ALS with PNLD represents a distinct ALS subtype. METHODS: From a cohort of 97 autopsied cases of sporadic ALS with phosphorylated 43kDa TAR DNA-binding protein (TDP-43) inclusions, we selected those with PNLD and analyzed their clinicopathological features. RESULTS: Eleven cases (11%) that showed PNLD were divided into 2 subtypes depending on the lesion distribution: (1) extensive type (n = 6), showing widespread TDP-43 pathology and multisystem degeneration, both involving the PNL system; and (2) limited type (n = 5), showing selective PNL and motor system involvement, thus being unclassifiable in terms of Brettschneider's staging or Nishihira's typing of ALS. The limited type showed a younger age at onset and predominant PNLD that accounted for the early development of extrapyramidal signs. The limited type exhibited the heaviest pathology in the subthalamus and external globus pallidus, suggesting that TDP-43 inclusions propagated via indirect or hyperdirect pathways, unlike ALS without PNLD, where the direct pathway is considered to convey TDP-43 aggregates from the cerebral cortex to the substantia nigra. INTERPRETATION: The PNL system can be involved in the disease process of ALS, either nonselectively as part of multisystem degeneration, or selectively. ALS with selective involvement of the PNL and motor systems exhibits unique clinicopathological features and TDP-43 propagation routes, thus representing a distinct subtype of ALS. ANN NEUROL 2020;87:302-312.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Globo Pálido/patologia , Substância Negra/patologia , Núcleo Subtalâmico/patologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/classificação , Feminino , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Proteinopatias TDP-43/classificação , Proteinopatias TDP-43/patologia
7.
J Gastroenterol ; 52(10): 1101-1111, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28324167

RESUMO

BACKGROUND: The global phase 3 studies of golimumab [PURSUIT-SC and PURSUIT-maintenance (M)], an anti-tumor necrosis factor-α (anti-TNFα) antibody, have demonstrated clinical efficacy and safety as induction and maintenance therapies in patients with moderate to severely active ulcerative colitis (UC). This study aimed to evaluate the efficacy and safety of golimumab as maintenance therapy in the Japanese population. METHODS: In this phase 3, double-blind (DB), placebo-controlled, parallel group, randomized withdrawal study, 144 Japanese patients with moderately to severely active UC received golimumab doses of 200 mg (at week 0) and 100 mg (at week 2) subcutaneously during the 6-week open-label induction phase. Patients who responded to golimumab induction therapy entered the DB maintenance (M) phase and were randomized (1:1) to receive 100 mg of golimumab subcutaneous injection (SC) or placebo every 4 weeks for 52 weeks. The primary endpoint was clinical response through M-week 54; secondary endpoints included clinical remission and mucosal healing at M-week 30 and 54. RESULTS: Among induction responders, more patients on golimumab treatment (56.3%) maintained clinical response through M-week 54 versus the placebo group (19.4%). At both M-week 30 and 54, 50% golimumab-treated patients achieved clinical remission versus the placebo group (6.5%) and a higher proportion of patients on golimumab (59.4%) experienced mucosal healing than the placebo group (16.1%). Incidence of treatment-emergent adverse events was 96.9% in the golimumab group and 71% in the placebo group. Overall, the efficacy and safety results in this study were comparable with those observed in global studies. CONCLUSIONS: Golimumab SC treatment maintained clinical efficacy through week 54 among induction responders, and no new safety signals were observed in the patients with moderate to severely active UC. CLINICAL TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov NCT01863771.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais/efeitos adversos , Povo Asiático , Colite Ulcerativa/fisiopatologia , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Índice de Gravidade de Doença , Resultado do Tratamento
8.
J Am Chem Soc ; 129(26): 8103-11, 2007 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-17567008

RESUMO

The discovery and development of a new Lewis acid system based on a complex formed from niobium(V) methoxide and (R)-3,3'-bis(2-hydroxy-3-isopropylbenzyl)-1,1'-binaphthalene-2,2'-diol, a novel tetradentate BINOL derivative, is presented. The system was shown to be extremely effective in promoting the desymmetrative ring opening of linear and cyclic meso-epoxides using anilines as nucelophiles, delivering the corresponding (R,R) anti-amino alcohols in good to excellent yields (up to quantitative) and excellent enantioselectivity (up to 96% ee). Furthermore, the catalyst system displays a remarkable sensitivity to steric bulk at the beta-carbon of the epoxide, selectively facilitating ring opening of smaller epoxides in the presence of more sterically hindered epoxides. This property was confirmed by a series of competition reactions using a mixture of meso-2-butene oxide and another aliphatic meso-epoxide, with the result that the former, less encumbered epoxide reacted preferentially with up to 98% chemical selectivity. While it was found to be most convenient to conduct the reactions with 10 mol % catalyst loading at 0.16 M, at higher overall concentration the reaction still proceeded efficiently with as little as 0.25 mol % catalyst to give the desired products with no significant reduction in yields or enantioselectivities. In addition, the current catalyst system was also found to mediate the asymmetric ring opening of nonsymmetrical cis-2-alkene oxides with anilines to give preferentially the corresponding (2R,3R)-2-amino-3-ols arising from ring opening at the methyl terminus, in excellent yields (up to quantitative) and good to excellent regio- and enantioselectivities (up to 18:1 and >99% ee, respectively). Intriguingly, it was discovered that the same catalyst system also promoted the ring-opening desymmetrization of aziridines with aniline nucleophiles to give the corresponding (S,S) vicinal diamines in good to excellent yields and enantioselectivity (up to 95% and 84% ee [>99% ee following a single recrystallization]). Catalyst systems that promote closely related reactions with opposite stereochemical outcomes in high selectivity such as the current niobium system are extremely unusual. To the best of our knowledge, this report constitutes not only the first example of the catalytic desymmetrization of both meso-epoxides and meso-aziridines but also a rare example of such complementary stereoselectivity in a catalytic reaction.


Assuntos
Substâncias Macromoleculares/química , Nióbio/química , Catálise , Estrutura Molecular
9.
Neurosci Lett ; 335(3): 159-62, 2003 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-12531457

RESUMO

To investigate the effect of aging on the oligodendrocyte progenitor cells (OPCs) after cerebral ischemia, neuron-glia antigen 2 (NG2) chondroitin sulfate proteoglycan was examined at 1, 3 and 7 days after 90 min of transient middle cerebral artery occlusion in young and aged brains. The number of NG2 positive cells increased in the ischemic penumbra at 3 and 7 days after reperfusion, while those decreased in the ischemic core. At 7 days, the number of NG2 positive cells was significantly greater in the young than the aged brains, and the processes of NG2 positive cells enlarged and were highly branched in the young than the aged brains. These results suggest that the young brain showed a higher potential of proliferation and process branching of OPCs than the aged brains.


Assuntos
Envelhecimento/metabolismo , Antígenos/metabolismo , Isquemia Encefálica/metabolismo , Oligodendroglia/metabolismo , Proteoglicanas/metabolismo , Células-Tronco/metabolismo , Animais , Isquemia Encefálica/etiologia , Imunofluorescência , Infarto da Artéria Cerebral Média , Masculino , Mitose , Ratos , Ratos Wistar , Fatores de Tempo
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