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2.
Neurology ; 59(11): 1689-93, 2002 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-12473753

RESUMO

BACKGROUND: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal-recessive disorder with preferential involvement of the tibialis anterior muscle that starts in young adulthood and spares quadriceps muscles. The disease locus has been mapped to chromosome 9p1-q1, the same region as the hereditary inclusion body myopathy (HIBM) locus. HIBM was originally described as rimmed vacuole myopathy sparing the quadriceps; therefore, the two diseases have been suspected to be allelic. Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). OBJECTIVE: To determine whether DMRV and HIBM are allelic. METHODS: The GNE gene was sequenced in 34 patients with DMRV. The epimerase activity in lymphocytes from eight DMRV patients was also measured. RESULTS: The authors identified 27 unrelated DMRV patients with homozygous or compound-heterozygous mutations in the GNE gene. DMRV patients had markedly decreased epimerase activity. CONCLUSIONS: DMRV is allelic to HIBM. Various mutations are associated with DMRV in Japan. The loss-of-function mutations in the GNE gene appear to cause DMRV/HIBM.


Assuntos
Carboidratos Epimerases/genética , Proteínas de Escherichia coli , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Miosite de Corpos de Inclusão/genética , Miosite de Corpos de Inclusão/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Alelos , DNA/genética , DNA/isolamento & purificação , Eletroforese em Gel de Poliacrilamida , Ligação Genética/genética , Testes Genéticos , Humanos , Leucócitos/enzimologia , Músculo Esquelético/enzimologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/enzimologia , Mutação/genética , Miosite de Corpos de Inclusão/enzimologia , Vacúolos/ultraestrutura
3.
Neurology ; 59(11): 1791-3, 2002 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-12473774

RESUMO

The tau N279K mutation was identified in four separately ascertained families in the United States, Japan, and France and in another recently discovered affected individual in Japan. The authors analyzed genealogical and clinical records and DNA samples. Average age at onset was 43 years; survival time was 7 years. All families exhibited similar clinical features, with parkinsonism, dementia, and supranuclear palsy uniformly seen. A founder effect indicated by a shared disease haplotype was seen only in two Japanese families. The N279K mutation can develop independently in different parts of the world.


Assuntos
Cromossomos Humanos Par 17/genética , Demência/genética , Mutação/genética , Doença de Parkinson/genética , Proteínas tau/genética , Adulto , Antiparkinsonianos/uso terapêutico , DNA/genética , Demência/fisiopatologia , Efeito Fundador , França , Lobo Frontal , Humanos , Japão , Levodopa/uso terapêutico , Masculino , Repetições de Microssatélites/genética , Biologia Molecular , Degeneração Neural/genética , Doença de Parkinson/fisiopatologia , Penetrância , Lobo Temporal , Estados Unidos
4.
J Hum Genet ; 46(11): 649-55, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11721884

RESUMO

Autosomal recessive distal myopathy or Nonaka distal myopathy (NM) is characterized by its unique distribution of muscular weakness and wasting. The patients present with spared quadriceps muscles even in a late stage of the disease. The hamstring and tibialis anterior muscles are affected severely in early adulthood. We have localized the NM gene to the region between markers D9S319 and D9S276 on chromosome 9 by linkage analysis. To further refine the localization of the NM gene, we conducted homozygosity and linkage disequilibrium analysis for 14 patients from 11 NM families using 18 polymorphic markers. All of the patients from consanguineous NM families were found to be homozygous for six markers located within the region between markers D9S2178 and D9S1859. We also provided evidence for significant allelic associations between the NM region and five marker loci. Examination of the haplotype analysis identified a predominant ancestral haplotype comprising the associated alleles 199-160-154-109 (marker order: D9S2179-D9S2180-D9S2181-D9S1804), present in 60% of NM chromosomes and in 0% of parent chromosomes. On the basis of the data obtained in this study, the majority of NM chromosomes were derived from a single ancestral founder, and the NM gene is probably located within the 1.5-Mb region between markers D9S2178 and D9S1791.


Assuntos
Cromossomos Humanos Par 9 , Genes Recessivos , Desequilíbrio de Ligação , Distrofias Musculares/genética , Adulto , Alelos , Mapeamento Cromossômico , Consanguinidade , Primers do DNA , Feminino , Marcadores Genéticos , Haplótipos/genética , Homozigoto , Humanos , Masculino , Distrofias Musculares/classificação , Polimorfismo Genético
9.
J Neurol Sci ; 182(2): 167-70, 2001 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11137523

RESUMO

We describe a 64-year-old man with 'citrullinemia type II' whose serum citrulline levels fluctuated between normal and abnormally high during episodic manifesting periods. Elevations of the serum threonine/serine ratio and pancreatic secretory trypsin inhibitor level are very useful diagnostic markers. Our patient's cerebrospinal fluid citrulline level was also elevated, and T1-weighted magnetic resonance images revealed high-intensity signals at the bilateral internal capsule and the cerebral peduncles. Single-photon emission computed tomography of his brain showed reduced bilateral temporal lobar blood flow. Even if the serum citrulline level is within the normal range, citrullinemia should be considered in adult patients without primary liver dysfunction who show episodic consciousness disturbance, psychotic symptoms or both.


Assuntos
Citrulina/sangue , Citrulinemia/sangue , Citrulinemia/patologia , Citrulinemia/fisiopatologia , Amônia/sangue , Biomarcadores/sangue , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Serina/sangue , Treonina/sangue , Inibidor da Tripsina Pancreática de Kazal/sangue
10.
Neurology ; 54(9): 1787-95, 2000 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-10802785

RESUMO

OBJECTIVE: To characterize the clinical diagnostic features, neuropathologic phenotype of tau deposition, and subunit structure of tau filaments in patients who had an asparagine-to-lysine substitution at codon 279 (the N279K missense mutation) of the gene for microtubule-associated tau protein. BACKGROUND: The N279K mutation is a causative genetic defect for pallidopontonigral degeneration in an American kindred that presents with frontotemporal dementia (FTD) and parkinsonism. METHODS: The authors analyzed retrospectively the clinical symptoms of two Japanese brothers who carry this mutation. Postmortem neuropathologic and electron microscopic studies, and Western blot analysis of insoluble tau were performed to correlate tau-mediated lesions with neurologic deficits. RESULTS: Both patients exhibited impairment in recent memory, parkinsonism, and corticospinal disturbances in addition to FTD. Parkinsonism in one patient was responsive temporarily to l-dopa. There was intense tau deposition in the medial temporal cortices and upper and lower motor neurons with accompanying corticospinal tract degeneration. Two distinct tau isoforms with four microtubule-binding repeats, in hyperphosphorylated forms, were the primary constituents of insoluble tau, which aggregated to the filamentous component, termed "paired tubules," in neurons, oligodendrocytes, and astrocytes. The elemental filaments were hollow tubules measuring 11 to 12 nm in diameter, two of which adhered to each other along their longitudinal axes to form "paired tubules." CONCLUSIONS: Early memory loss and pyramidal signs, which are atypical of FTD, can be presenting symptoms in this disorder. The authors demonstrated that the subunit structure of tau filaments is a pair of hollow tubules despite the prevailing twisted ribbon model.


Assuntos
Substituição de Aminoácidos/genética , Códon/genética , Demência/genética , Mutação de Sentido Incorreto/genética , Transtornos Parkinsonianos/genética , Proteínas tau/genética , Asparagina/genética , Demência/diagnóstico , Demência/patologia , Diagnóstico Diferencial , Lobo Frontal/patologia , Humanos , Lisina/genética , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Neurônios Motores/patologia , Exame Neurológico , Testes Neuropsicológicos , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/patologia , Linhagem , Tratos Piramidais/patologia , Estudos Retrospectivos , Lobo Temporal/patologia
11.
J Nucl Med ; 40(10): 1583-9, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10520695

RESUMO

UNLABELLED: This study investigated alterations in regional cerebral blood flow (rCBF) in patients with Parkinson's disease using statistical parametric mapping (SPM). METHODS: Noninvasive rCBF measurements using 99mTc-ethyl cysteinate dimer (ECD) SPECT were performed on 28 patients with Parkinson's disease and 48 age-matched healthy volunteers. The Parkinson's disease patients were divided into two groups, 16 patients with Hoehn and Yahr stage I or II and 12 patients with Hoehn and Yahr stage III or IV. We used the raw data (absolute rCBF parametric maps) and the adjusted rCBF images in relative flow distribution (normalization of global CBF for each subject to 50 mL/100 g/min with proportional scaling) to compare these groups with SPM. RESULTS: In patients with stage I or II Parkinson's disease, we found a diffuse decrease in absolute rCBF in the whole brain with sparing of the central gray matter, hippocampus and right lower temporal lobe compared with healthy volunteers. Adjusted rCBF increased in both putamina and the right hippocampus. In patients with stage III or IV disease, rCBF decreased throughout the whole brain. Adjusted rCBF increased bilaterally in the putamina, globi pallidi, hippocampi and cerebellar hemispheres (dentate nuclei) and in the left ventrolateral thalamus, right insula and right inferior temporal gyrus. CONCLUSION: SPM analysis showed that significant rCBF changes in Parkinson's disease accompanied disease progression and related to disease pathophysiology in the functional architecture of thalamocortex-basal ganglia circuits and related systems.


Assuntos
Encéfalo/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Idoso , Encéfalo/irrigação sanguínea , Mapeamento Encefálico , Circulação Cerebrovascular , Cisteína/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Organotecnécio , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Compostos Radiofarmacêuticos , Fluxo Sanguíneo Regional , Software
12.
Brain Res ; 843(1-2): 53-61, 1999 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-10528110

RESUMO

The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid (NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB). The microtubule-associated protein tau is an integral component of filaments of neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons is rare. Double-immunofluorescence study and peroxidase-immunohistochemical study in serial sections, performed to examine the co-localization of tau- and NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different epitopes of tau including phosphorylation-dependent and independent ones were present in a minority of LBs, but more often than previously considered. A tau (tau2)-epitope was localized to filaments in the outer layers of brainstem-type LBs by immunoelectron microscopy. Therefore, we conclude that tau is incorporated into filaments in certain LBs. Extensive investigation has enabled us to classify this co-localization into four types: type 1, LBs with ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP- and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and tau-immunoreactive dystrophic neurites. This study raises a new question whether aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the collapse of intraneuronal organization of microtubules due to NACP-filament aggregation in neuronal perikarya and axons.


Assuntos
Encéfalo/patologia , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Epitopos/análise , Feminino , Humanos , Imuno-Histoquímica , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/análise , Doença de Parkinson/patologia , Fosfoproteínas/análise , Fosfoproteínas/metabolismo , Fosforilação , Sinucleínas , alfa-Sinucleína , Proteínas tau/análise
13.
Nihon Ronen Igakkai Zasshi ; 36(6): 396-403, 1999 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-10513210

RESUMO

We developed a questionnaire for the study of background factors and quality of life (QOL) in elderly patients with cerebral vascular disease (CVD) and Parkinson's disease (PD). The questionnaire covered the background factors and four sections such as physical, functional, psychological and social health sections. Each section had 15 questions and disease-specific questions for CVD or PD were included in the physical health section. We analyzed 107 patients with CVD (76 elderly patients, aged 65 or more, 31 non-elderly patients under 65) and 136 patients with PD (91 elderly, 45 non-elderly). In the background section, of a total of 243 patients with CVD and PD, the elderly patients needed the assistance of their spouse and their sons wives more frequently than non-elderly patients. With regard to rehabilitation, non-elderly CVD patients had rehabilitation more frequently than the elderly CVD patients, while a higher percentage of elderly patients with PD had rehabilitation training more frequently than the non-elderly PD patients. In the QOL section, there was no difference between elderly and non-elderly CVD patients, while elderly PD patients were statistically more significantly disabled physically and weak-minded psychologically. The physical disabilities of the elderly PD patients in this statistical investigation included slow motion, stooped posture, frozen gait, difficulty in turning and standing up, constipation and dysuria. The psychological problems of elder PD patients included forgetfulness and a feeling of aging. These patients had significantly fewer consultations by family and relatives than the non-elderly PD patients. The overall tendency of QOL in patients with CVD and PD was similar to that of PD patients.


Assuntos
Transtornos Cerebrovasculares/psicologia , Transtornos Parkinsonianos/psicologia , Qualidade de Vida , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
15.
Acta Neuropathol ; 97(6): 565-76, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10378375

RESUMO

We performed a detailed study of swollen neurite aggregation surrounding extracellular neurofibrillary tangles (ghost tangles, GTs) in brains of patients with progressive supranuclear palsy (PSP) by immunohistochemistry and electron microscopy (EM). The complex structures, designated as tangle-associated neuritic clusters (TANCs), were found in the hippocampus and parahippocampal cortex in all five PSP brains examined. TANCs measured from 20 to 40 microm across; twice as large as nearby neurons. Each neurite was globular or fusiform in shape, measured up to 10 microm in diameter, and was found between loosened fascicles of GTs or along their outer rims. There were several subsets of neurites that were argyrophilic or immunoreactive against antibodies to either phosphorylated tau protein, phosphorylated neurofilaments, ubiquitin, or synaptophysin. On EM, TANCs consisted of numerous axon terminals of varying size, which were filled with flocculate dense bodies, vesicular profiles, and synaptic vesicles, as well as normal-looking and degenerating cell organelles. Some axons had 13- to 15-nm-thick straight tubules that showed tau immunoreactivity; however, there was little neurofilament accumulation. Most of the swollen axon terminals conformed to the ultrastructural features of either reactive or degenerating terminals. The neurites identified by immunohistochemistry only represented a minority of the swollen axons visualized by EM. Tubules of GTs were dispersed in the extracellular space, but no amyloid fibrils were found. TANCs may constitute a distinctive form of neuronal degeneration in PSP cortices. We hypothesize that axon terminal accumulation may occur in response to GT-formation.


Assuntos
Hipocampo/patologia , Neuritos/patologia , Emaranhados Neurofibrilares/patologia , Paralisia Supranuclear Progressiva/patologia , Idoso , Feminino , Hipocampo/ultraestrutura , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Neuritos/ultraestrutura , Emaranhados Neurofibrilares/ultraestrutura
16.
Acta Neurol Scand ; 99(4): 209-12, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10225349

RESUMO

UNLABELLED: The purpose of the present study was to assess the relationship between clinical characteristics of spinocerebellar ataxia type 6 (SCA6) and CAG repeat length. MATERIALS AND METHODS: We examined clinical symptoms of 54 patients with SCA6. CAG repeat length was compared among subgroups divided by clinical manifestations. RESULTS: The major symptom was progressive cerebellar ataxia. Truncal or limb ataxia, dysarthria, and nystagmus were observed in more than 80% of the patients. In analysis of CAG repeat length in patients with different types of nystagmus, CAG repeat length was the longest when both upbeat and downbeat nystagmus existed (P < 0.01). In addition, CAG repeat length was longer when the initial symptom was ataxic gait and was shorter when the initial symptom was dysarthria or ocular symptom (P < 0.05). CONCLUSION: Clinical features of SCA6 might be influenced by the length of abnormal CAG repeat.


Assuntos
Degenerações Espinocerebelares/genética , Repetições de Trinucleotídeos/genética , Adulto , Idoso , Progressão da Doença , Feminino , Marcha , Humanos , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/complicações , Nistagmo Patológico/diagnóstico , Transtornos da Motilidade Ocular/complicações , Degenerações Espinocerebelares/complicações , Degenerações Espinocerebelares/diagnóstico , Inquéritos e Questionários
17.
Neurology ; 52(2): 260-5, 1999 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9932941

RESUMO

OBJECTIVE: The authors studied the pathomechanisms of the characteristics associated with Gerstmann-Sträussler-Scheinker disease (GSS). BACKGROUND: GSS, associated with a missense mutation at codon 102 of the prion protein (PrP) gene (GSS102), is a hereditary disorder that presents with progressive ataxia and dementia, and is characterized by the loss of deep tendon reflexes and painful dysesthesias of the legs in its early stage. METHODS: The authors conducted immunohistochemical studies of the spinal cord and peripheral nervous system in one of two patients from a Japanese family with GSS102 in comparison with patients with GSS105. RESULTS: The authors found intense PrP immunoreactivities mainly in the posterior horn of the spinal cord, but not in the dorsal root ganglia or peripheral nerves. In addition to PrP amyloid plaques, synaptic-type, fine granular PrP deposits were distributed in the spinal posterior horns. In contrast to the GSS102 patient, the spinal cords of the GSS105 patients showed no granular PrP deposits. CONCLUSIONS: The PrP abnormalities in synaptic structures of the spinal posterior horn may cause synaptic dysfunction that leads to loss of deep tendon reflexes and painful dysesthesias in patients with GSS102.


Assuntos
Doença de Gerstmann-Straussler-Scheinker/fisiopatologia , Príons/genética , Medula Espinal/fisiopatologia , Adulto , Códon , Feminino , Humanos , Imuno-Histoquímica , Mutação de Sentido Incorreto
18.
Acta Neurol Scand ; 98(5): 364-7, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9858109

RESUMO

We report 2 familial patients with limb-girdle muscular dystrophy (LGD). The parents of patient 1 showed a consanguineous marriage and patient 2 was a paternal cousin of patient 1. Slowly progressive muscular weakness/wasting and dystrophic changes in the biopsied muscles were observed in both patients. However, a quantitative assay revealed a severely reduced myophosphorylase activity in patient 1 with normal activity in patient 2. A semi-ischemic exercise test disclosed no elevation of venous lactate in patient 1 with a normal increase in patient 2. A leukocytes DNA analysis in patient 1 did not show the gene deficits previously recognized in patients with McArdle's disease (McD). Patient 1 may only have abnormal myophosphorylase activity with dystrophic changes secondary to the myophosphorylase deficiency or coincidentally two genomic abnormalities for McD and LGD. LGD still has heterogenous etiologies and the responsible genes for these two disorders may be closely mapped.


Assuntos
Distrofias Musculares/genética , Fosforilases/deficiência , Adulto , Teste de Esforço , Humanos , Ácido Láctico/sangue , Masculino , Músculo Esquelético/patologia , Distrofias Musculares/enzimologia , Linhagem , Fosforilases/metabolismo
19.
Acta Neuropathol ; 96(5): 439-44, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9829806

RESUMO

We examined neuronal cytoplasmic inclusions (NCIs) and oligodendrocytic glial cytoplasmic inclusions (GCIs) in the pontine nuclei in multiple system atrophy (MSA) using antibodies against the non-amyloid beta component of Alzheimer's disease amyloid precursor protein (NACP/alpha-synuclein). Our immunohistochemical study revealed that anti-NACP antibodies labeled both NCIs and GCIs. Immunoelectron microscopy showed that positive reaction products were localized on the 15- to 30-nm-thick filamentous components of NCIs and GCIs. The present study demonstrates that NACP is associated with cytoplasmic inclusions of MSA, and suggests a role of NACP in abnormal filament aggregation in neuronal degeneration.


Assuntos
Corpos de Inclusão/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Oligodendroglia/metabolismo , Ponte/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão/patologia , Masculino , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/patologia , Neurofibrilas/metabolismo , Neurofibrilas/patologia , Neurônios/patologia , Oligodendroglia/patologia , Ponte/patologia , Ratos , Sinucleínas
20.
Brain Res ; 808(1): 93-100, 1998 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-9795161

RESUMO

We examined brains from Parkinson's disease and from dementia with Lewy bodies (LBs) by using antibodies to NACP/alpha-synuclein. Immunohistochemically, all of the antibodies against the amino-terminal region, NAC domain, and carboxyl-terminal region of NACP labeled not only LBs, pale bodies (PBs), and dystrophic neurites, but also fine thread-like structures in the neuronal perikarya (perikaryal threads) in the hypothalamus and brainstem nuclei. On electron microscopy, immunoreactive products were found to label the 9 to 12 nm-thick filamentous component (LB-filaments) of LBs, PBs, and perikaryal threads. The NACP-immunoreactive perikaryal threads, consisting of small bundles of LB-filaments and randomly oriented LB-filaments, presumably represent an initial stage of LB- or PB-formation. The present study indicates that the entire molecule of NACP is involved in the neuronal filament-aggregating processes of LB disorders.


Assuntos
Encéfalo/patologia , Demência/patologia , Corpos de Lewy/patologia , Proteínas do Tecido Nervoso/análise , Doença de Parkinson/patologia , Encéfalo/ultraestrutura , Tronco Encefálico/patologia , Tronco Encefálico/ultraestrutura , Epitopos/análise , Humanos , Hipotálamo/patologia , Hipotálamo/ultraestrutura , Imuno-Histoquímica , Corpos de Lewy/ultraestrutura , Microscopia Imunoeletrônica , Neuritos/patologia , Neuritos/ultraestrutura , Fosfoproteínas/análise , Sinucleínas
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