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To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.
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BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.
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Linfoma Difuso de Grandes Células B , Medula Espinal , Humanos , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Sistema Nervoso Central , Encéfalo/patologia , BiópsiaRESUMO
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.
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Ataxia Cerebelar , Ataxias Espinocerebelares , Masculino , Humanos , Pessoa de Meia-Idade , Adulto , Movimentos Oculares , Autopsia , Ataxia Cerebelar/patologia , Vias Visuais/patologia , População do Leste Asiático , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Corpos de Inclusão Intranuclear/patologia , Atrofia/patologiaRESUMO
The patient exhibited plantarflexion during walking at the age of five. He then developed writer's cramp at the age of six, dysphonia at 15 years, and action-induced dystonia with left knee elevation and trunk swinging when walking at 16 years, which subsequently spread to the right leg at 19 years. Levodopa therapy was ineffective for dystonia. Brain MRI showed no abnormalities. He was diagnosed with DYT28 after detecting a novel heterozygous mutation (c.433C>T, p.Arg145*) in the KMT2B gene using whole-exome sequencing at age 39. Furthermore, the patient's parents exhibited normal alleles, confirming the de novo status of KMT2B gene mutation. We should consider DYT28 in addition to DYT1 and DYT5 in patients who developed leg dystonia in childhood.
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Distonia , Distúrbios Distônicos , Masculino , Humanos , Adulto , Adolescente , Distonia/genética , Distonia/diagnóstico , Histona-Lisina N-Metiltransferase/genética , Distúrbios Distônicos/genética , Mutação , AlelosRESUMO
Heat shock protein family B member 8, encoded by HSPB8, is an essential component of the chaperone-assisted selective autophagy complex, which maintains muscle function by degrading damaged proteins in the cells. Mutations in HSPB8 have been reported to cause Charcot-Marie-Tooth type 2L, distal hereditary motor neuropathy IIa, and rimmed vacuolar myopathies (RVM). In this study, we identified a novel heterozygous frameshift variant c.525_529del in HSPB8 in a large Japanese family with RVM, using whole exome sequencing. Three affected individuals had severe respiratory failure, which has not been addressed by previous studies. Muscle atrophy in the paraspinal muscles was also a clinical feature of the individuals affected with RVM in this study. The frameshift mutation was located in the last coding exon, and the mutated protein was predicted to harbor an isoleucine-leucine-valine (ILV) sequence, which corresponds to the IXI/V (isoleucine, X amino acids, and isoleucine or valine) motif. The IXI/V motif is essential for assembly into larger oligomers in other small heat shock proteins and all frameshift mutants of HSPB8 were predicted to share the ILV sequence in the C-terminal extension. The in silico prediction tools showed low protein solubility and increased aggregation propensity for the region around the ILV sequence. The IXI/V motif might be associated with the pathogenesis of HSPB8-related RVM.
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Miopatias Distais/genética , Predisposição Genética para Doença , Proteínas de Choque Térmico/genética , Chaperonas Moleculares/genética , Atrofia Muscular/genética , Adulto , Miopatias Distais/diagnóstico , Miopatias Distais/patologia , Feminino , Deleção de Genes , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/diagnóstico , Atrofia Muscular/patologia , Músculos Paraespinais/patologia , Sequenciamento do ExomaRESUMO
A 77-year-old man with a history of lung cancer at the age of 71 developed involuntary right leg movement for a month. Neurological examination revealed a right-sided hemi-chorea. Autoimmune disease was suspected owing to the presence of oligoclonal bands and the elevated IgG-index in the cerebrospinal fluid. We detected anti-SRY-Related HMG-Box Gene 1 (SOX1) antibodies, known to be serological markers of Lambert-Eaton syndrome with small cell lung cancer, but not tumors. The results of tests for antiphospholipid, anti-LGI1, and anti-CASPR2 antibodies associated with non-paraneoplastic autoimmune chorea were all negative. This is the first suggestive case of autoimmune chorea in which anti-SOX1 antibodies were detected.
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Autoanticorpos/sangue , Autoimunidade , Coreia/etiologia , Coreia/imunologia , Fatores de Transcrição SOXB1/imunologia , Idoso , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Coreia/diagnóstico , Imagem de Difusão por Ressonância Magnética , Humanos , Síndrome Miastênica de Lambert-Eaton/complicações , Neoplasias Pulmonares/complicações , Masculino , Carcinoma de Pequenas Células do Pulmão/complicaçõesRESUMO
BACKGROUND: Recurrent hydrocephalus may occur as a complication of neurosarcoidosis with chronic inflammation. We present a case that required a combination of multistage endoscopic diversion of the cerebrospinal fluid pathway and shunt surgery. CASE DESCRIPTION: A 34-year-old man presented with progressive nausea and vomiting. Magnetic resonance imaging revealed hydrocephalus with leptomeningeal enhancement along the base of the fourth ventricle and the bilateral foramina of Luschka. Concurrent endoscopic third ventriculostomy and biopsy were performed. The diagnosis was neurosarcoidosis. Immediately after the procedure, the endoscopic third ventriculostomy stoma was occluded, and a right ventriculoperitoneal shunt was urgently performed. However, left unilateral hydrocephalus developed during the late phase of immunosuppressive therapy for neurosarcoidosis. Endoscopic septostomy with repositioning of the ventricular catheter was indicated. Intraoperative findings included a white pasty tissue with nodules that covered the ventricular wall close to the foramen of Monro and sealed the side holes of the catheter. Chemotherapy with a tumor necrosis factor-α inhibitor was initiated after the surgical procedure. The patient had an uneventful course without recurrence of hydrocephalus for >6 months. CONCLUSIONS: Endoscopic diversion of the cerebrospinal fluid pathway should be actively considered for treating hydrocephalus without a shunt and performing biopsy simultaneously. Even if a subsequent shunt is needed, complex hydrocephalus can be avoided with a combination of endoscopic techniques.
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Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/cirurgia , Endoscopia/métodos , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Sarcoidose/complicações , Sarcoidose/cirurgia , Adulto , Doenças do Sistema Nervoso Central/tratamento farmacológico , Ventrículos Cerebrais/cirurgia , Humanos , Hidrocefalia/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Masculino , Reoperação , Sarcoidose/tratamento farmacológico , Terceiro Ventrículo/diagnóstico por imagem , Terceiro Ventrículo/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Derivação Ventriculoperitoneal , VentriculostomiaRESUMO
A 38-year-old man presented with primary position upbeat nystagmus accompanied by peripheral neuropathy. The serum vitamin B12 level was low along with high plasma homocysteine level, indicating vitamin B12 deficiency. Cyanocobalamin supplementation showed partial clinical and electrophysiological improvement. Although brain magnetic resonance imaging did not show any abnormal intensity lesions, the electrophysiological findings suggested that a pontomedullary medial lesion was responsible for the upbeat nystagmus. To our knowledge, this is the first case of upbeat nystagmus with low serum vitamin B12. Physicians need to recognize the possibility of vitamin B12 deficiency as a cause of upbeat nystagmus.
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Nistagmo Patológico , Deficiência de Vitamina B 12 , Adulto , Humanos , Imageamento por Ressonância Magnética , Masculino , Nistagmo Patológico/diagnóstico , Vitamina B 12 , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/diagnósticoRESUMO
Amyotrophic Lateral Sclerosis is the most common motor neuron degenerative disease in adults, and TARDBP gene mutations have been reported to be involved in the pathogenesis. We present here how we generated the human induced pluripotent stem cell (hiPSC) line KEIOi001-A/SM4-4-5 from the peripheral blood of a 63-year-old male patient presenting the c.1035C > G heterozygous SNP mutation in the TARDBP gene locus. The established hiPSC line does not express the exogenous reprogramming factors oriP nor EBNA1 and shows no karyotypic abnormalities, while it expresses pluripotent stem cell markers, presents the SNP mutation and is capable of three-germ layers differentiation in vitro.
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A 67-year-old man developed weakness and atrophy of the anterior compartment of the lower leg at age 53 years, followed by weakness of proximal muscles of the upper limb. His father had difficulties in walking in his thirties and died of heart disease at age 45 years. He also had mild respiratory weakness without cardiac involvement. Muscle histology showed spheroid or cytoplasmic bodies-like inclusions with moth-eaten appearance and irregular intramyofibrillar network. Electron microscopy revealed abnormally thickened and disorganized Z lines (Z line streaming) between the surrounding myofibrils and electron-dense globular deposits. These pathological findings apparently suggested myofibrillar myopathy. However, genetic analysis revealed a mutation (c.5566G>A, p.E1856K) in MYH7 gene, that is responsible for Laing-type distal myopathy (LDM). This mutation was previously reported in a study from Austria. This is the first report of LDM in the Japanese population .
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Miosinas Cardíacas/genética , Miopatias Distais/diagnóstico , Miopatias Distais/genética , Mutação , Cadeias Pesadas de Miosina/genética , Idoso , Povo Asiático , Miopatias Distais/classificação , Miopatias Distais/patologia , Heterozigoto , Humanos , Masculino , Microscopia Eletrônica , Músculo Esquelético/patologia , Músculo Esquelético/ultraestruturaRESUMO
A 52-year-old woman taking a Chinese herbal medicine for 10 months was admitted to our hospital for recurrent severe headaches, nausea and vomiting. Brain magnetic resonance imaging revealed convexity subarachnoid hemorrhage in the left occipital and parietal lobes. Brain magnetic resonance angiography (MRA) showed multifocal segmental stenosis of cerebral arteries. Clinical symptoms resolved after treatments with nicardipine and verapamil. Follow-up MRA at 31 days after the onset showed complete disappearance of multifocal stenosis of cerebral arteries, confirming the diagnosis of reversible cerebral vasoconstriction syndrome (RCVS). It was suggested that licorice and evodia fruit, which were components of a Chinese herbal medicine named tokishigyakukagoshuyushokyoto were the precipitating factors of vasoconstriction. It is important for physicians to recognize that herbal supplements could be one of the causes of RCVS. (Received January 22, 2019; Accepted April 3, 2019; Published July 1, 2019).
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Transtornos Cerebrovasculares/induzido quimicamente , Medicamentos de Ervas Chinesas/efeitos adversos , Transtornos Cerebrovasculares/diagnóstico por imagem , Feminino , Humanos , Angiografia por Ressonância Magnética , Pessoa de Meia-Idade , VasoconstriçãoRESUMO
Neuromuscular disorders associated with hyperthyroidism have several variations in their clinical phenotype, such as ophthalmopathy, periodic paralysis, and thyrotoxic myopathy. We herein report an unusual case of thyrotoxic myopathy presenting as unilateral drop foot. Histopathological examinations of the left tibialis anterior muscle showed marked variation in the fiber size, mild inflammatory cell infiltration, and necrotic and regenerated muscle fibers with predominantly type 1 fiber atrophy. Medical treatment with propylthiouracil resulted in complete improvement of the left drop foot. This case expands the phenotype of thyrotoxicosis and suggests that thyrotoxicosis be considered as a possible cause of unilateral drop foot.
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Transtornos Neurológicos da Marcha/etiologia , Doenças Musculares/etiologia , Tireotoxicose/complicações , Adolescente , Antitireóideos/uso terapêutico , Biópsia , Feminino , Transtornos Neurológicos da Marcha/diagnóstico por imagem , Transtornos Neurológicos da Marcha/patologia , Humanos , Imageamento por Ressonância Magnética , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/patologia , Necrose/etiologia , Necrose/patologia , Paralisia/etiologia , Paralisia/patologia , Propiltiouracila/uso terapêutico , Tireotoxicose/diagnóstico , Tireotoxicose/tratamento farmacológicoRESUMO
OBJECTIVE: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. METHODS: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. RESULTS: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. CONCLUSIONS: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.
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Alopecia/enzimologia , Alopecia/genética , Infarto Cerebral/enzimologia , Infarto Cerebral/genética , Heterozigoto , Leucoencefalopatias/enzimologia , Leucoencefalopatias/genética , Mutação de Sentido Incorreto , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Doenças da Coluna Vertebral/enzimologia , Doenças da Coluna Vertebral/genética , Alopecia/diagnóstico por imagem , Alopecia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/enzimologia , Encéfalo/patologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/patologia , Cromatografia em Gel , Dimerização , Família , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Análise de Sequência de DNA , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/patologiaRESUMO
A 56-year-old man, who presented with 6 years history of difficulty in walking, was diagnosed as having vascular parkinsonism on the basis of the clinical findings of parkinsonism, pyramidal sign and the brain MRI findings of multiple lacunar infarction. Although he did not have hypertension, he had hyperhomocysteinemia and homozygous methylenetetrahydrofolate reductase (MTHFR) gene variant (C677T) as risk factors for ischemic stroke. Recent studies have shown that hyperhomocysteinemia and MTHFR gene variant are associated with small-vessel disease, suggesting that these risk factors may underlie vascular parkinsonism, particularly in patients lacking hypertension and in those with a relatively younger age at onset of this disease.
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Variação Genética , Hiper-Homocisteinemia/complicações , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Idade de Início , Humanos , Hipertensão , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/etiologia , Fatores de Risco , Acidente Vascular Cerebral Lacunar/diagnóstico , Acidente Vascular Cerebral Lacunar/etiologiaRESUMO
OBJECTIVE: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. METHODS: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. RESULTS: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). INTERPRETATION: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.
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A 60-year-old woman was admitted to our hospital because of difficulty in standing on her toes. Neurological examination showed muscle weakness in both calf muscles. Her serum creatine kinase (CK) level was slightly elevated. MRI revealed hyper-intense signals localized in both the gastrocnemius and soleus muscles. Histological examinations of biopsied muscle specimens showed a marked variation in fiber size, small angular fibers, and hypertrophic and splitting fibers, but no muscle fiber necrosis or regeneration or inflammatory cell infiltration. ATPase stained sections showed small grouped atrophy of type 1 fibers. NADH-TR stained sections showed target/targetoid fibers predominantly in type 1 fibers. Dysferlin immunoreactivity was normal. Follow-up clinical evaluation for one year showed no progression. This patient was diagnosed as having an unknown type of spinal muscular atrophy or benign calf amyotrophy. Sporadic cases characterized by elderly-onset, neurogenic muscular atrophy localized in both calf muscles, and non-progressive course are extremely rare in Japan.
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Músculo Esquelético/patologia , Atrofia Muscular/patologia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
A 21-year-old man complained of severe pain and muscle twitching localized in his right arm. Neurological examination showed muscle fasciculations in his right forearm but no myokymia or myotonia. Needle electromyography revealed fibrillation potentials in his biceps brachii muscle and extensor carpi radialis muscle at rest but no myokymic discharges. His serum anti-voltage-gated potassium channel (VGKC)-complex antibody level was significantly high (194.2pM; controls <100pM). Although anticonvulsant therapy relieved his pain, he was readmitted to our hospital because of severe pain in his left arm and both thighs three months later. A high-dose intravenous immunoglobulin (IVIG) therapy followed by steroid pulse therapy relieved his pain. This case with neither muscle cramp nor myokymia expands the phenotype of anti VGKC-complex antibody associated disorder.
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Autoanticorpos/sangue , Fasciculação/tratamento farmacológico , Fasciculação/imunologia , Dor/tratamento farmacológico , Dor/imunologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/imunologia , Extremidade Superior , Adulto , Biomarcadores/sangue , Eletromiografia/métodos , Fasciculação/diagnóstico , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Masculino , Metilprednisolona/administração & dosagem , Pulsoterapia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Genetic studies on late-onset Alzheimer's disease (AD) have repeatedly mapped susceptibility loci onto chromosome 12q13, encompassing the vitamin D receptor (VDR) gene. Epidemiology studies have indicated vitamin D insufficiency as a risk factor for AD. Given that VDR is the major mediator for vitamin D's actions, we sought to clarify the role of VDR in late-onset AD. We conducted an association study in 492 late-onset AD cases and 496 controls with 80 tagging single nucleotide polymorphisms (SNPs). The strongest association was found at a promoter SNP rs11568820 (P = 9.1 × 10(-6), odds ratio (OR) = 1.69), which resides within the transcription factor Cdx-2 binding site and the SNP has been also known as CDX2. The risk-allele at rs11568820 is associated with lower VDR promoter activity (p < 10(-11)). The overexpression of VDR or vitamin D treatment suppressed amyloid precursor protein (APP) transcription in neuroblastoma cells (p < 0.001). We provide both statistical evidence and functional data suggesting VDR confers genetic risk for AD. Our findings are consistent with epidemiology studies suggesting that vitamin D insufficiency increases the risk of developing AD.
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Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Proteínas de Homeodomínio/genética , Receptores de Calcitriol/genética , Transativadores/genética , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/genética , Idoso , Fator de Transcrição CDX2 , Comorbidade , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Prevalência , Medição de Risco , Estados Unidos/epidemiologiaAssuntos
Intoxicação por Monóxido de Carbono/complicações , Interleucina-6/líquido cefalorraquidiano , Proteína Básica da Mielina/líquido cefalorraquidiano , Síndromes Neurotóxicas/diagnóstico , Síndromes Neurotóxicas/etiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
A 49-year-old man presented with fever and pain, redness, swelling, and difficulty in walking. The serum C-reactive protein (CRP), creatin kinase (CK), and endotoxin levels were elevated. A blood culture revealed Edwardsiella tarda(E. tarda). Computed tomography (CT) showed subfascial and subcutaneous low-density areas in the lower legs, suggesting focal abscesses and edema. The patient was likely to have necrotizing fasciitis or cellulitis. He was successfully treated with several antibiotics and discharged after 43 days. Because E. tarda causes sepsis and fulminating necrotizing fasciitis with a high mortality rate in patients with an underlying illness, it should be considered a potentially important pathogen. The lack of an underlying illness may be a factor for a good outcome in this case.