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1.
Neuropathology ; 2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34779072

RESUMO

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The cardinal neuropathological features of PD include selective and progressive loss of pigmented neurons in the substantia nigra, deficiencies in dopaminergic signaling in the striatum, and occurrence of phosphorylated α-synuclein-identified Lewy bodies in the nervous system. Parkinsonism, the clinical presentation of movement disorders seen in PD, is a feature shared commonly by other pathologically distinct neurodegenerative diseases, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Consequently, it is sometimes difficult to distinguish PD from such parkinsonism-related neurological disorders. In addition, parkinsonism is not always a feature of certain neurodegenerative diseases, and it can sometimes develop as a result of various forms of drug intoxication or cerebrovascular disease. Here, we describe the clinicopathological features of three patients (cases 1, 2, and 3) diagnosed as having PSP, MSA, and PD, respectively, in each of whom the postmortem histopathological diagnosis differed from the final clinical diagnosis. Neuropathologically, they had suffered from coexistent disorders: PD, MSA, and argyrophilic grain disease (case 1); PD (case 2); and vascular parkinsonism (case 3). The variety of patients showing features of parkinsonism underlines the importance of careful long-term follow up followed by postmortem neuropathological evaluation.

2.
Front Psychol ; 12: 576089, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675829

RESUMO

Background: Body image self-discrepancy reflects a preference for weight loss regardless of normal body size and is a distorted cognition that may be a precursor to eating disorders. The aim of this study was to investigate factors associated with body image self-discrepancy among healthy junior high school students in Japan. Method: This cross-sectional study was conducted at one junior high school in Saitama, Japan, in December 2016. After excluding obese participants (defined as 20% above their ideal weight), 304 students (mean age, 13.9years; n=181 girls, 59.5%) who fell into underweight (n=22, 7.2%) and normal weight categories were selected. Body image self-discrepancy was measured using the Contour Drawing Rating Scale which includes eight separate figures representing body sizes. We then calculated the difference by subtracting ideal from current body sizes and defined body image self-discrepancy if the difference >1. Results: Girls constituted 92% (n=49) of the 53 students with body image self-discrepancy. In all students, multivariable stepwise models demonstrated that female gender (OR, 6.92, 95% CI: 2.33-20.51), a calorie-restricted diet (OR, 5.18, 95% CI: 2.22-12.05), and psychological symptoms (OR, 1.47, 95% CI: 1.15-1.87) were significantly associated with an increased risk of body image self-discrepancy. Specifically for girls, an increased risk of body image self-discrepancy was associated with calorie-restricted suppers and psychological symptoms. Conclusion: Body image self-discrepancy among healthy adolescents in Japan was found to be closely linked to being a girl, having a calorie-restricted diet, and having psychological symptoms.

3.
Clin J Gastroenterol ; 14(4): 975-979, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33835417

RESUMO

Black esophagus is a rare condition referred from acute necrosis of the esophagus, with characteristic endoscopic finings of circumferential black appearance of the mucosa. Black esophagus is associated with systemic dysfunction, such as massive bleeding, or severe dehydration. Although the duodenal mucosa is also susceptible to ischemia, reports of black esophagus with duodenal involvement, such as bleeding or perforation, are limited. Here, we present the case of a 61-year-old male who developed the typical black esophagus with duodenal involvement following severe dehydration. The patient was treated conservatively and recovered from the acute phase. In the chronic stage, transthoracic esophagectomy was performed because of esophageal stricture, and the patient then returned to his daily life. Although the etiological mechanism of acute esophageal necrosis is unknown, it is thought to be associated with the presence of an underlying severe systemic condition. Our case is not exceptional for these systemic conditions demonstrating extreme dehydration. However, it remains unclear why our case showed duodenal involvement. Although the reason is unknown, the presence of a celiac aneurysm located near the bifurcation to duodenal blood flow might explain the impaired blood flow to the duodenum.


Assuntos
Duodeno , Estenose Esofágica , Doença Aguda , Humanos , Masculino , Pessoa de Meia-Idade , Necrose
4.
Mov Disord ; 36(7): 1634-1643, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33570211

RESUMO

BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Variações do Número de Cópias de DNA , Ubiquitina-Proteína Ligases , Variações do Número de Cópias de DNA/genética , Homozigoto , Humanos , Mutação/genética , Deleção de Sequência , Ubiquitina-Proteína Ligases/genética
5.
J Pharmacol Sci ; 145(2): 198-201, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33451754

RESUMO

The orexinergic system plays a significant role in regulating proper sleep/wake maintenance. Dual orexin receptor antagonist (DORA) is widely prescribed for insomnia symptoms. The antagonist acts on orexin 1 and 2 receptors located in certain brain areas, including the locus coeruleus and dorsal raphe. Nevertheless, its effects on monoamine-related gene expression remain unclear. Here, we measured the expression levels of monoamine-related genes in DORA-treated mice. DORA treatment significantly affected overall levels of noradrenalin transporter/monoamine oxidases A mRNA expression in the hippocampus. Our findings suggest that DORA contributes to noradrenalin-related gene expression regulation in the central nervous system.


Assuntos
Azepinas/farmacologia , Benzimidazóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Antagonistas dos Receptores de Orexina/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Masculino , Camundongos Endogâmicos C57BL
6.
J Neuropathol Exp Neurol ; 80(2): 129-136, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33249504

RESUMO

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.


Assuntos
Diferenciação Celular/fisiologia , Neoplasias Cerebelares/metabolismo , Proteínas Hedgehog/metabolismo , Meduloblastoma/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Wnt/metabolismo , Proteína Gli3 com Dedos de Zinco/metabolismo , Neoplasias Cerebelares/genética , Proteínas Hedgehog/genética , Humanos , Meduloblastoma/genética , Proteínas do Tecido Nervoso/genética , Transdução de Sinais/fisiologia , Proteínas Wnt/genética , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína Gli3 com Dedos de Zinco/genética
7.
Neuropathology ; 41(3): 174-182, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33205528

RESUMO

Progressive supranuclear palsy (PSP) presents with a wide variety of signs/symptoms, making early initial diagnosis difficult. We investigated the clinical and neuropathological features of five patients with autopsy-proven PSP of short duration, ranging from 11 to 41 months (average, 26.2 months) due to unexpected death, focusing particularly on the distribution and severity of neuronal loss as well as neuronal and glial tau pathology in the affected brain. Clinical features were studied retrospectively through careful review of the medical records, and neuropathological examinations were carried out, along with tau immunohistochemistry using a monoclonal antibody AT8. These patients were diagnosed as having probable PSP (n = 4) and suggestive PSP (n = 1), respectively. In all cases, neuronal loss was evident in the substantia nigra, subthalamic nucleus, globus pallidus, and locus ceruleus. AT8-identified tau lesions, that is, pretangles/neurofibrillary tangles (PTs/NFTs), tufted astrocytes (TAs), and coiled bodies/neuropil threads (CBs/NTs), were distributed widely in the brain regions, especially in patients with longer disease duration. All cases showed variation in the regional tau burden among PTs/NFTs, TAs, and CBs/NTs. There was also a tendency for tau deposition to be more predominant in neuronal cells in the brainstem and cerebellum and in glial cells in the cerebral cortex and subcortical gray matter. These findings suggest that in PSP, the initial signs/symptoms are associated with degeneration and subsequent death of neurons with pathological tau deposition, and that the tau deposition in neuronal cells is independent of that in glial cells.

8.
Biologicals ; 68: 32-39, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33023810

RESUMO

In Japan, the practical application of completely cell-based seasonal influenza vaccines is under consideration. Considering the good correlation between the immunogenicity of egg-based influenza vaccines and the hemagglutinin (HA) content determined by the single radial immunodiffusion (SRD) assay, we determined the potency of the first cell-based quadrivalent vaccine experimentally generated in Japan using the SRD assay in this study. A primary liquid standard (PLS) and reference antigen were generated from the purified vaccine virus, and a sheep antiserum was produced against the HA of the vaccine virus. Since the purity of the PLS affects the reliability of vaccine potency testing, the purification steps are significant. We successfully prepared a purified PLS nearly free of cell debris. The HA content in the PLS was first estimated from the total amount of viral protein and the percentage of HA content determined by SDS-PAGE analysis. The HA content in the reference antigen was calibrated to that in the PLS via the SRD assay. The vaccine potency, that is, the HA content in each vaccine, was finally measured using the corresponding reference antigen. Ultimately, the measured vaccine potency of the monovalent vaccine was similar to that of the quadrivalent vaccine.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Estações do Ano , Tecnologia Farmacêutica/métodos , Potência de Vacina , Animais , Anticorpos Antivirais/imunologia , Cães , Humanos , Soros Imunes/imunologia , Vacinas contra Influenza/normas , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Padrões de Referência , Ovinos , Tecnologia Farmacêutica/normas
9.
J Pharmacol Sci ; 144(1): 57-59, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32624301

RESUMO

Some psychiatric diseases are associated with disruptions in the circadian clock system. Ziprasidone (ZIP), a second-generation antipsychotic, is widely used for psychiatry-related pharmacotherapy but its mechanism has not been clearly elucidated. We measured clock gene fluctuation patterns in the hippocampus and the amygdala in ZIP-treated mice. ZIP significantly increased Per1, Per2, and Bmal1 mRNA 2 h after the lights were turned off (ZT14) in the hippocampus, but not in the amygdala. These results suggest that ZIP might affect clock gene regulation, which could represent the pathway underlying symptom amelioration.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Antipsicóticos/farmacologia , Relógios Biológicos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Expressão Gênica/efeitos dos fármacos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Piperazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiazóis/farmacologia , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/metabolismo , Luz , Masculino , Camundongos Endogâmicos C57BL
10.
Neurotoxicology ; 78: 88-98, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092311

RESUMO

BACKGROUND: Human exposure to mercury (Hg) is widespread and both organic and inorganic Hg are routinely found in the human brain. Millions of people are exposed to methyl Hg (MeHg) due to the consumption of fish and to inorganic Hg from dental amalgams, small scale gold mining operations, use of Hg containing products, or their occupations. Neuropathology information associated with exposures to different species of Hg is primarily based on case reports of single individuals or collections of case studies involving a single species of Hg at toxic exposure levels such as occurred in Japan and Iraq. METHODS/RESULTS: This study brings together information on the neuropathological findings and deposition of Hg in the central nervous system of people exposed to different species of Hg at varying concentrations. The low dose exposures were lifetime exposures while the high dose exposures were generally acute or short term by different exposure routes with survival lasting various lengths of time. Total and inorganic Hg deposits were identified in formalin-fixed, paraffin embedded tissues from both low and high exposure Hg cases. Low concentration exposures were studied in adult brains from Rochester, New York (n = 4) and the Republic of Seychelles (n = 17). Rochester specimens had mean total Hg concentrations of 16-18 ppb in the calcarine, rolandic, and cerebellar cortices. Inorganic Hg averaged between 5-6 ppb or 30-37% for the cerebral and cerebellar cortices of the Rochester subjects. Total Hg was approximately 10-fold higher in specimens from Seychelles, where consumption of ocean fish is high and consequently results in exposure to MeHg. The predominant Hg species was MeHg in both the Rochester and Seychelles brain specimens. Histologically, cerebral and cerebellar cortices from Rochester and Seychelles specimens were indistinguishable. High concentration exposures were studied in brains from four adults who were autopsied at variable time periods after exposure to organic Hg (methyl or dimethyl) or inorganic Hg (inhaled vapor or intravenous injection of metallic Hg). In contrast to the Seychellois adults, these individuals had acute or subacute exposures to lethal or significantly higher concentrations. The pattern of Hg deposition differed between subjects with high organic Hg exposure and high inorganic Hg exposure. In the organic Hg cases, glia (astrocytes and microglia) and endothelial cells accumulated more Hg than neurons and there were minimal Hg deposits in cerebellar granule and Purkinje cells, anterior horn motor neurons, and neocortical pyramidal neurons. In the inorganic Hg cases, Hg was seen predominantly in neurons, vascular walls, brainstem, and cerebellar and cerebral deep gray nuclei. The presence of inorganic Hg in neural and neural supporting cells in the four high exposure Hg cases was not closely correlated with cellular pathology; particularly in the inorganic Hg cases. CONCLUSIONS: Different Hg species are associated with differing neuropathological patterns. No neuropathological abnormalities were present in the brains of either Rochester or Seychelles residents despite substantial differences in dietary MeHg exposure. Increasing concentrations of inorganic Hg were present in the brain of relatively low exposure subjects with increasing age.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Exposição Ambiental , Compostos de Metilmercúrio/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/patologia , Animais , Química Encefálica/efeitos dos fármacos , Peixes , Humanos , Seicheles
11.
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 Amiotrófica Lateral/patologia , Globo Pálido/patologia , Substância Negra/patologia , Núcleo Subtalâmico/patologia , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/classificação , Feminino , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Vias Neurais/patologia , Proteinopatias TDP-43/classificação , Proteinopatias TDP-43/patologia
12.
Influenza Other Respir Viruses ; 14(2): 204-209, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31651085

RESUMO

BACKGROUND: Cell-based influenza vaccines can solve the problem of the frequent occurrence of egg adaptation-associated antigenic changes observed in egg-based vaccines. Seed viruses for cell-based vaccines can be prepared from clinical specimens by cell culture; however, clinical samples risk harboring respiratory viruses other than influenza virus. Therefore, it is necessary to investigate the patterns of co-infection in clinical samples and explore whether cell culture technology can selectively propagate influenza viruses from samples containing other respiratory viruses. METHODS: A total of 341 clinical specimens were collected from patients with influenza or influenza-like illness and analyzed by ResPlex II assay to detect 18 respiratory viruses. The patterns of co-infection were statistically analyzed with Fisher's exact test. The samples with double or triple infections were passaged in suspension MDCK cells (MDCK-S), adherent MDCK cells (MDCK-A), and LLC-MK2D cells. Cell-passaged samples were analyzed by ResPlex II assay again to investigate whether each cell line could amplify influenza viruses and eliminate other respiratory viruses. RESULTS: Double infections were detected in 8.5% and triple infections in 0.9% of the collected clinical specimens. We identified four pairs of viruses with significant correlation. For all samples with double and triple infection, MDCK-S and MDCK-A could selectively propagate influenza viruses, while eliminating all contaminating viruses. In contrast, LLC-MK2D showed lower isolation efficiency for influenza virus and higher isolation efficiency for coxsackievirus/echovirus than MDCK-S and MDCK-A. CONCLUSIONS: Both MDCK-S and MDCK-A are considered suitable for the preparation of influenza vaccine seed viruses without adventitious agents or egg-adaptation mutations.


Assuntos
Células Madin Darby de Rim Canino/virologia , Orthomyxoviridae/isolamento & purificação , Cultura de Vírus/métodos , Animais , Linhagem Celular , Cães , Humanos , Orthomyxoviridae/crescimento & desenvolvimento , Vacinas Virais
13.
Vaccine ; 37(43): 6526-6534, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31500967

RESUMO

Suspension Madin-Darby canine kidney (MDCK) cells (MDCK-N), adherent MDCK cells (MDCK-C), and adherent rhesus monkey kidney LLC-MK2 cells (LLC-MK2D) were systematically evaluated for the preparation of influenza vaccine seed viruses for humans on the basis of primary virus isolation efficiency, growth ability, genetic stability of the hemagglutinin (HA) and neuraminidase (NA) genes, and antigenic properties in hemagglutination inhibition (HI) test of each virus isolate upon further passages. All the subtypes/lineages of influenza viruses (A(H1N1), A(H1N1)pdm09, A(H3N2), B-Victoria, and B-Yamagata) were successfully isolated from clinical specimens by using MDCK-N and MDCK-C, whereas LLC-MK2D did not support virus replication well. Serial passages of A(H1N1) viruses in MDCK-N and MDCK-C induced genetic mutations of HA that resulted in moderate antigenic changes in the HI test. All A(H1N1)pdm09 isolates from MDCK-C acquired amino acid substitutions at the site from K153 to N156 of the HA protein, which resulted in striking antigenic alteration. In contrast, only 30% of MDCK-N isolates showed amino acid changes at this site. The frequency of MDCK-N isolates with less than two-fold reduction in the HI titer was as high as 70%. A(H3N2) and B-Yamagata isolates showed high antigenic stability and no specific amino acid substitution during passages in MDCK-N and MDCK-C. B-Victoria isolates from MDCK-N and MDCK-C acquired genetic changes at HA glycosylation sites that greatly affected their antigenicity. When these cell isolates were applied to passages in hen eggs, A(H1N1), B-Victoria, and B-Yamagata viruses grew well in eggs, while none of the cell isolates of A(H3N2) viruses did. Thus, we demonstrate that MDCK-N might be useful for the preparation of influenza vaccine seed viruses.


Assuntos
Vírus da Influenza A/classificação , Vírus da Influenza A/fisiologia , Cultura de Vírus/métodos , Replicação Viral , Animais , Linhagem Celular , Cães , Hemaglutininas Virais/genética , Vacinas contra Influenza , Rim/citologia , Rim/virologia , Macaca mulatta , Células Madin Darby de Rim Canino , Mutação , Neuraminidase/genética , RNA Viral/genética
14.
Brain Pathol ; 29(6): 803-812, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31006160

RESUMO

Posttranslational modifications by phosphorylation, ubiquitination, neddylation and other pathways have emerged as major regulators of cellular functions. NEDD8 ultimate buster 1, NUB1, is an adaptor protein, which negatively regulates the levels of the ubiquitin-like protein NEDD8 as well as neddylated proteins through proteasomal degradation. We previously reported that NUB1 is highly involved in the pathogenesis of synucleinopathy including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). In general, since phosphorylation is strongly related to the alteration of protein propensity, we examined if the fundamental function of NUB1 can be modulated by its phosphorylation. We created a series of phosphomimic mutants of NUB1. Among them, we found that phosphorylation of NUB1 at S46 (P-NUB46) efficiently degrades aggregates using a cell-based assay. Immunohistochemical studies have shown that specific antibodies against P-NUB46 reacted with Lewy bodies in PD and DLB but not with glial cytoplasmic inclusions in MSA. Moreover, P-NUB46 levels were significantly higher in the brains of patients with DLB than in control brains, and P-NUB46 was extracted in an insoluble fraction of DLB. These findings suggest that the phosphorylation of NUB1 is modulated during the pathological process of Lewy body disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Corpos de Lewy/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Humanos , Corpos de Inclusão/patologia , Corpos de Lewy/patologia , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Masculino , Atrofia de Múltiplos Sistemas/patologia , Proteína NEDD8/metabolismo , Neuroglia/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fosforilação
15.
Neurobiol Dis ; 127: 339-349, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910745

RESUMO

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder clinically characterized by autonomic failure in addition to various combinations of symptoms of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Despite extensive research, the mechanisms underlying the progression of MSA remain unknown. Animal models of human diseases that recapitulate their clinical, biochemical and pathological features are indispensable for increasing our understanding of their underlying molecular mechanisms, which allows preclinical studies to be advanced. Because the onset of MSA occurs in middle age, an animal model that first manifests abnormal protein aggregates in adulthood would be most appropriate. We therefore used the Cre-loxP system to express inducible α-synuclein (Syn), a major component of the pathological hallmark of MSA, to generate a mouse model of MSA. Beginning in adulthood, these MSA model mice express excessive levels of Syn in oligodendrocytes, resulting in abnormal Syn accumulation and modifications similar to those observed in human MSA pathology. Additionally, MSA model mice exhibit some clinical features of MSA, including decreased motor activity. These findings suggest that this new mouse model of MSA represents a useful tool for analyzing the pathophysiological alterations that underlie the progression of this disease.


Assuntos
Encéfalo/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Oligodendroglia/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Oligodendroglia/patologia , Fosforilação , alfa-Sinucleína/genética
16.
J Virol Methods ; 267: 53-58, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30831121

RESUMO

Influenza virus and respiratory syncytial virus cause acute upper and lower respiratory tract infections, especially in children and the elderly. Early treatment for these infections is thought to be important, so simple and sensitive detection methods are needed for use at clinical sites. Therefore, in this study, real-time reverse transcription loop-mediated isothermal amplification assays with quenching primer for influenza virus and respiratory syncytial virus were developed. Evaluation of a total of 113 clinical specimens compared to real-time RT-PCR assays showed that the novel assays could distinguish between the types and subtypes of influenza virus and respiratory syncytial virus and had 100% diagnostic specificity. The diagnostic sensitivity of each assay exceeded 85.0% and the assays showed sufficient clinical accuracy. Furthermore, positive results could be obtained in around 15 min using the novel assays in cases with high concentrations of virus. The developed assays should be useful for identifying influenza virus and respiratory syncytial virus cases not only in experimental laboratories but also in hospital and quarantine laboratories.


Assuntos
Primers do DNA/genética , Orthomyxoviridae/isolamento & purificação , Vírus Sincicial Respiratório Humano/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Humanos , Influenza Humana/diagnóstico , Influenza Humana/virologia , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/virologia , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/virologia , Sensibilidade e Especificidade , Temperatura
17.
Neurol Med Chir (Tokyo) ; 59(3): 89-97, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30787232

RESUMO

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific cell surface antigen often expressed in glioblastoma and has drawn much attention as a possible therapeutic target. We performed immunohistochemistry on histology sections of surgical specimens taken from 67 cases with glioblastoma, isocitrate dehydrogenase-wild type, and evaluated the morphological characteristics and distribution of the EGFRvIII-positive tumor cells. We then evaluated the localization of EGFRvIII-expression within the tumor and peritumoral areas. EGFRvIII immunopositivity was detected in 15 specimens taken from 13 patients, including two recurrent specimens taken from the same patient at relapse. Immunofluorescence staining demonstrated that EGFRvIII-positive cells were present in cells positive for glial fibrillary acidic protein (GFAP), and some showed astrocytic differentiation with multiple fine processes and others did not shown. The EGFRvIII-positive cells were located in cellular areas of the tumor, but not in the invading zone. In the two recurrent cases, EGFRvIII-positive cells were markedly decreased in one case and retained in the other. With regard to overall survival, univariate analysis indicated that EGFRvIII-expression in patients with glioblastoma was not significantly associated with a favorable outcome. Double-labeling immunofluorescence staining of EGFRvIII and GFAP showed that processes of large, well differentiated, GFAP-positive glia extend to and surround less differentiated, EGFRvIII-positive glial cells in cellular areas of tumor. However, in the tumor periphery, EGFRvIII-positive tumor cells were not observed. This finding suggests that EGFRvIII is involved in tumor proliferation, but that invading glioma cells lose their EGFRvIII expression.


Assuntos
Neoplasias Encefálicas/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Estudos de Coortes , Feminino , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
18.
J Med Virol ; 91(7): 1232-1238, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30735248

RESUMO

Human rhinoviruses (RVs) belong to the genus Enterovirus of the family Picornaviridae, and are classified into RV-A, -B, and -C species. Two assays were developed to detect RVs by a real-time fluorescent reverse transcription loop-mediated isothermal amplification method: one was designed based on the 5'-untranslated regions (UTRs) of RV-A and -B, and the other was designed based on the 5'-UTR of RV-C. The competence of both assays for the diagnosis of RV infection was tested using isolated viruses and compared with real-time reverse transcription polymerase chain reaction assays on clinical specimens. Neither assay demonstrated cross-reactivity with other tested enteroviruses, and they detected 19 out of 21 tested RV-As and seven out of eight tested RV-Cs. The specificity of the assays was 100% for the detection of RVs and their sensitivity for RV-A and RV-C was 86.3% and 77.3%, respectively, on clinical specimens by the combined use of both assays. Considering that both developed assays were highly specific and detected the majority of recently circulating RVs, they are helpful for the diagnosis of RV infection. Consequently, the results generated by these assays will enhance the surveillance of respiratory illness and the study of the roles of RVs associated with clinical features and disease severity.


Assuntos
Fluorescência , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico/métodos , Infecções por Picornaviridae/diagnóstico , Rhinovirus/genética , Temperatura , Regiões 5' não Traduzidas/genética , Primers do DNA , Humanos , Infecções por Picornaviridae/virologia , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade
19.
Neuropathology ; 39(2): 111-119, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30646429

RESUMO

Globular glial tauopathies (GGTs) are four-repeat tauopathies characterized by the presence of two types of tau-positive globular glial inclusions (GGIs): globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). GGTs are classified into three different neuropathological subtypes: Types I, II and III. We report two patients with GGTs - a 76-year-old woman and a 70-year-old man - in whom the disease duration was 5 and 6 years, respectively. Both patients exhibited upper and lower motor neuron signs and involuntary movements, and the latter also had dementia with frontotemporal cerebral atrophy evident on magnetic resonance imaging. Neuropathologically, in both cases, the precentral gyrus was most severely affected, and at the gray-white matter junction there was almost complete loss of Betz cells and occurrence of GOIs and coiled bodies with numerous neuropil threads. Both patients also showed neuronal loss and GGIs (mostly GOIs) in many other central nervous system regions, including the basal ganglia. Apart from the degree of regional severity, the distribution pattern was essentially the same in both cases. However, GAIs were not conspicuous in any of the affected regions. Based on the morphology and distribution pattern of the GGIs, we diagnosed the present two patients as having GGT Type II. Electron microscopic and biochemical findings in the former were consistent with the diagnosis. Type II cases are reported to be characterized by pyramidal features reflecting predominant motor cortex and corticospinal tract degeneration. The present observations suggest that a variety of neurological features, including dementia, can occur in GGT Type II reflecting widespread degeneration beyond the motor neuron system.


Assuntos
Encéfalo/patologia , Neuroglia/patologia , Tauopatias/patologia , Idoso , Astrócitos/patologia , Feminino , Humanos , Corpos de Inclusão/patologia , Masculino , Neurônios/patologia , Oligodendroglia/patologia , Medula Espinal/patologia , Proteínas tau/metabolismo
20.
Psychiatry Res ; 270: 940-946, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30551347

RESUMO

Perineuronal nets comprise chondroitin sulfate moieties and their core proteins, and their neuropathological alterations have been implicated in schizophrenia. To explore the molecular mechanism of the perineuronal net impairments in schizophrenia, we measured the immunoreactivity of chondroitin sulfate moieties, major components of perineuronal nets, in three brain regions (postmortem dorsolateral prefrontal cortex, caudate nucleus, and hippocampus) of schizophrenia patients and control subjects. Immunoblotting for chondroitin 4-sulfate and chondroitin 6-sulfate moieties revealed a significant increase in intensity of a 180 kD band of chondroitin 4-sulfate immunoreactivity in the hippocampus of patients, although we detected no significant alteration in their immunoreactivities with any other molecular sizes or in other brain regions. The levels of immunoreactivity were not correlated with postmortem interval, age, or storage time. We failed to find such an increase in a similar molecular range of the chondroitin 4-sulfate immunoreactivity in the hippocampus of the rats chronically treated with haloperidol. These results suggest that the level alteration of the chondroitin 4-sulfate moiety might contribute to the perineuronal net abnormality found in patients with schizophrenia.


Assuntos
Sulfatos de Condroitina/metabolismo , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Idoso , Animais , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Núcleo Caudado/patologia , Matriz Extracelular/metabolismo , Feminino , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos , Esquizofrenia/patologia
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