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De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10-8; exome-wide threshold: 2.5 × 10-6). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10-13) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.
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Exoma/genética , Éxons/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Epilepsias Mioclônicas Progressivas/genética , Semaforinas/genética , Adolescente , Adulto , Alelos , Animais , Feminino , Heterozigoto , Humanos , Masculino , Degradação do RNAm Mediada por Códon sem Sentido/genética , Convulsões/genética , Adulto Jovem , Peixe-Zebra/genéticaRESUMO
Atopic dermatitis itch may cause sleep disturbance and impair quality of life. For patients finding topical therapy difficult to continue, it is important to control itch and reduce scratching. This study developed algorithms to measure nocturnal sleep and scratch, using an actigraph device worn on the back of the hand, and assessed smartphone application feedback to improve adherence with therapy. In the first trial, actigraph measurements in 5 participants who wore the device were highly correlated with measurements by a sleep-monitoring device beneath the mattress. Total actigraph-measured scratching duration for each hour of sleep was highly correlated with measurements by a person rating infrared video-recording of the sleepers. In the second trial, 40 patients with atopic dermatitis were randomly allocated into an intervention group that used the actigraph and smartphone application, and a control group that did not. Both groups were instructed to use the same moisturizer. Dermatology Life Quality Index scores decreased significantly from baseline and were lower than those in the control group at week 8. It is suggested that the device and associated smartphone application reinforced therapy adherence, moisturizer use, and contributed to improved quality of life in patients with atopic dermatitis.
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Dermatite Atópica , Transtornos do Sono-Vigília , Humanos , Dermatite Atópica/diagnóstico , Dermatite Atópica/terapia , Dermatite Atópica/complicações , Qualidade de Vida , Prurido/etiologia , Prurido/complicações , Sono , Transtornos do Sono-Vigília/diagnóstico , Transtornos do Sono-Vigília/etiologia , Índice de Gravidade de DoençaRESUMO
A 79-year-old man presented with subacute onset of dementia. Brain magnetic resonance imaging revealed leukoencephalopathy in the posterior lobes with presence of microbleeds. Although clinical manifestation suggested a diagnosis of leukoencephalopathy associated with cerebral amyloid angiopathy (CAA), the patient died of sudden rupture of an aneurysm of the thoracic aorta two months after the onset of dementia. Autopsy revealed pathological features of advanced-stage Alzheimer's disease. Immunohistochemistry for amyloid-ß revealed CAA mainly affecting arteries but not capillaries. Klüver-Barrera staining revealed white matter edema predominantly in the occipital lobes without ischemic changes. Perivascular cuffing was found to be sparse, but there was no evidence of angiitis. Pathological findings suggest that leukoencephalopathy was caused by the disruption of the blood-brain barrier rather than ischemia. Because the present patient died before immunotherapy, his neuropathological findings could reflect the pathomechanism of the acute stage of leukoencephalopathy with CAA.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Leucoencefalopatias , Substância Branca , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Edema/complicações , Edema/patologia , Humanos , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Substância Branca/patologiaRESUMO
The aim of this study is to elucidate the relationship between 2 different types of severity-indicating parameters (i.e. between subjective and objective severity-indicating parametersin patients with atopic dermatitis. The disease severity of 55 patients with atopic dermatitis was assessed using 7 subjective parameters indicating severity, including visual analogue scale for itch, Patient-Oriented Eczema Measure, 5-D itch scale, Dermatology Life Quality Index, Eczema Area and Severity Index, body surface area, and Investigator Global Assessment, and 8 objective parameters indicating severity, including eosinophil relative count, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and thymus and activation-regulated chemokine. Five subjective parameters reflecting itch correlated significantly with eosinophil relative count, but not with neutrophil-to-lymphocyte ratio. In contrast, 2 subjective parameters, mainly reflecting the degree of inflammation and area of affected regions, correlated significantly with neutrophil-to-lymphocyte ratio. The eosinophil relative count may correlate with the degree of itch, while the neutrophil-to-lymphocyte ratio may correlate with the degree of inflammation and the area of the affected region. The eosinophil relative count and neutrophil-to-lymphocyte ratio may thus be stand-alone parameters from each other in the assessment of the severity of atopic dermatitis.
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Dermatite Atópica , Eczema , Dermatite Atópica/diagnóstico , Eosinófilos , Humanos , Linfócitos , Neutrófilos , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND AIM: A major reason impeding the growth of endoscopic ultrasound (EUS) in Asia is the lack of training availability. We aimed to prospectively evaluate the effectiveness of a short-term structured EUS training program in improving the knowledge and skill of EUS among trainees. METHODS: The study was conducted in six workshops in six countries including Sri Lanka, Pakistan, Thailand, Vietnam, Singapore and Philippines, within a year. Trainees were evaluated using written and skill tests before and after completion of the training. RESULTS: Pre- and post-workshop written tests from a total of 62 trainees were analyzed. Compared with pre-training, the trainees improved significantly in the overall mean (± SD) scores after the training (66.0 ± 0.3% to 77.5 ± 0.2%, P < 0.0001). Thirty-one trainees were randomly selected to undergo a skill test before and after the course. Compared with pre-training, the proportions of trainees who succeeded in locating each structure post-training were: celiac axis (36-80.5%), pancreatic body (51.5-80.5%), pancreatic body and tail (42-77.5%), splenic vein and artery (48.5-84%), left kidney (60-83%), and spleen (47-83%). Overall, there was a significant improvement in the proportion of trainees' successful localization of structures post-training compared to before training (P < 0.0001). CONCLUSION: Following a structured training program, trainees' knowledge and skills in EUS improved significantly. Structured training courses appear to be an effective way of imparting EUS knowledge and skills to aspiring endosonographers in the Asian region.
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Competência Clínica , Simulação por Computador , Educação de Pós-Graduação em Medicina/organização & administração , Endossonografia , Ásia , Estudos de Coortes , Currículo , Endoscopia Gastrointestinal/educação , Feminino , Humanos , Masculino , Modelos Educacionais , Avaliação de Programas e Projetos de Saúde , Estudos ProspectivosRESUMO
Although coronavirus disease 2019 (COVID-19) mainly exhibits respiratory symptoms, neurological symptoms are also reported, with headache being the most common neurological symptom. Headache associated with COVID-19 is widely reported. However, there are few precise case reports concerning headaches in patients with a history of migraine, tension headaches, or cluster headaches associated with COVID-19. Herein, we report a case of a woman with a history of cluster headaches who showed an unusually severe bout 10 days before typical COVID-19 symptoms. Such a case has not been reported until now.
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This case report provides evidence that Waldenström's macroglobulinemia may cause cutaneous manifestations represented as papules/nodules through the development of light chain amyloidosis. Here, we report a case of a 67-year-old man.
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A 69-year-old woman presented with progressive limb weakness lasting 50 years. She denied any congenital disorders or a family history of neuromuscular disease. At ages 29, 46, and 58 years, she underwent hospitalization and evaluations including electromyogram (EMG) and muscle biopsy, but the results were inconclusive. As a result, she received a tentative diagnosis of myopathy of unknown etiology. However, at the age of 69 years, a computed tomography (CT) scan of her skeletal muscles revealed severe involvement of the triceps brachii, iliopsoas, and gastrocnemius muscles, along with preservation of the biceps brachii, gluteus maximus, and tibialis anterior muscles, which was consistent with spinal muscular atrophy (SMA). Finally, genetic testing revealed the deletion of the survival of the motor neuron 1 (SMN1) gene, confirming the diagnosis of SMA type 3. As our case suggests, SMA patients with prolonged disease duration could be underdiagnosed even after EMG and muscle biopsy. A skeletal CT scan could be useful for the diagnosis of SMA patients compared with MRI.
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Ischemic cerebrovascular disease is an important cause of physical disability and dementia. Oligodendrocytes (OLGs), which differentiate from oligodendrocyte precursor cells (OPCs), are crucial for remyelination of the damaged brain and functional recovery. Breast carcinoma amplified sequence 1 (BCAS1) has recently been shown to be highly expressed in newly formed pre-myelinating oligodendrocytes (pre-mOLGs), while its expression level is reduced in mature OLGs. In this study, we analyzed BCAS1 expression by immunohistochemical analysis of human post-mortem brain tissue from six stroke patients (death within 2 months after stroke onset) and eight small vessel disease (SVD) patients. Control post-mortem brain tissue was from eight age-matched patients without any obvious central nervous system (CNS) pathology. The Olig2 expression in the area corresponding to the same section of the BCAS1-stained slice was analyzed to determine the total oligodendrocyte lineage. The percentage of differentiating OPCs in the oligodendrocyte lineage was calculated as the ratio of BCAS1+ to Olig2+ cells (BCAS1+/Olig2+). The stroke and SVD cases showed demyelination with decreased expression of myelin basic protein (MBP, a mature OLG marker). The stroke cases showed significantly increased numbers of early-stage BCAS1+ cells with an immature morphology and Olig2+ cells (pan-oligodendrocyte lineages) in the peri-infarct areas in both the cortex and white matter, but showed no increase in the number of late-stage BCAS1+ cells with a mature morphology. In contrast, the SVD cases showed no significant increase in Olig2+ and BCAS1+ cells. These results indicated that remyelination dysfunction could be attributed to insufficient maturation of OPCs in stroke and impaired recruitment of OPCs in SVD.
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AVC Isquêmico , Células Precursoras de Oligodendrócitos , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/patologia , Diferenciação Celular/fisiologia , Oligodendroglia/metabolismo , Acidente Vascular Cerebral/patologia , Bainha de Mielina/metabolismo , Proteínas de Neoplasias/metabolismoRESUMO
BACKGROUND: Recurrent cervical internal carotid artery vasospasm syndrome (RCICVS) causes cerebral infarction, ocular symptoms, and occasionally chest pain accompanied by coronary artery vasospasm. The etiology and optimal treatment remain unclear. OBSERVATIONS: The authors report a patient with drug-resistant RCICVS who underwent carotid artery stenting (CAS). Magnetic resonance angiography revealed recurrent vasospasm in the cervical segment of the internal carotid artery (ICA). Vessel wall imaging during an ischemic attack revealed vascular wall thickening of the ICA, similar to that in reversible cerebral vasoconstriction syndrome. The superior cervical ganglion was identified at the anteromedial side of the stenosis site. Coronary artery stenosis was also detected. After CAS, the symptoms of cerebral ischemia were prevented for 2 years, but bilateral ocular and chest symptoms did occur. LESSONS: Vessel wall imaging findings suggest that RCICVS is a sympathetic nervous system-related disease. CAS could be an effective treatment for drug-resistant RCICVS to prevent cerebral ischemic events.
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Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disease characterized by neurofibromas with infiltration of mast cells. Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR) and basophil-to-lymphocyte ratio (BLR) are examined as markers for various diseases. However, these parameters have not yet been assessed for NF1. This study therefore examined these parameters in NF1 patients. We recruited 153 NF patients (78 males, 75 females) and 51 control patients (31 males, 20 females). Complete blood counts were performed, then NLR, LMR, PLR and BLR were calculated. Neutrophil count was significantly higher in male NF1 patients than in male controls. Lymphocyte count was significantly lower in NF1 patients than in controls for both sexes. Monocyte count was significantly higher in male NF1 patients than in male controls. Basophil count was significantly higher in male NF1 patients than in male controls. NLR, PLR and BLR were significantly higher in NF1 patients than in controls for both sexes. LMR was significantly lower in NF1 patients than in controls for both sexes. NF1 shows high NLR, PLR and BLR and low lymphocyte count and LMR.
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Neurofibromatose 1 , Feminino , Humanos , Masculino , Estudos Retrospectivos , Contagem de Linfócitos , Linfócitos , Neutrófilos , Monócitos , Contagem de Células SanguíneasRESUMO
Neurofibromatosis type 1 (NF1), or von Recklinghausen disease, is an autosomal dominant disease that presents with various symptoms, including café-au-lait spots and neurofibromas. NF1 patients occasionally suffer from renal artery vasculopathy, which impairs renal function, while results of a previous report suggested that male NF1 patients have a low creatinine level in peripheral blood. The assessment of renal function in NF1 patients remains inadequate. In this study, renal function in NF1 was assessed. We recruited 308 patients consisting of 149 NF1 patients (77 males and 72 females) and 159 control patients (102 males and 57 females). Creatinine, blood urea nitrogen and haemoglobin A1c in peripheral blood as well as protein, occult blood and sugar in urine were examined. In addition, the estimated glomerular filtration rate was calculated. The mean age and body mass index did not differ significantly between the NF1 patients and controls for both sexes. For both sexes, i) the mean creatinine value was significantly lower in the NF1 patients than in the controls; ii) the mean blood urea nitrogen value did not differ significantly between the NF1 patients and controls; iii) the mean blood urea nitrogen-to-creatinine ratio was significantly higher in the NF1 patients than in the controls; iv) the mean estimated glomerular filtration rate was significantly higher in the NF1 patients than in the controls; and v) the mean haemoglobin A1c value was significantly lower in the NF1 patients than in the controls. In conclusion, NF1 patients may have improved renal function. The clinical significances should be further examined.
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INTRODUCTION: Alzheimer's disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. METHODS AND ANALYSIS: This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. ETHICS AND DISSEMINATION: The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process. TRIAL REGISTRATION NUMBER: jRCT2041200008, NCT04413344.
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Doença de Alzheimer , Bromocriptina , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Bromocriptina/efeitos adversos , Método Duplo-Cego , Reposicionamento de Medicamentos , Humanos , Mutação , Presenilina-1/genética , Resultado do TratamentoRESUMO
Imatinib mesylate seemed to inhibit development of cutaneous neurofibromas (c-NFs) and promote growth of pre-existing c-NFs in our neurofibromatosis type 1 case. This report potentially provides new findings in the effects of imatinib mesylate.
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INTRODUCTION: Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease characterized by eczema and pruritus, and frequently impairs sleep quality. Although cyclosporine improves symptoms of AD, objective evaluation of sleep in patients with AD treated with cyclosporine has not been reported. This study was conducted to elucidate the effects of cyclosporine on sleep quality for patients with AD. METHODS: Twelve patients with moderate-to-severe AD were recruited. Nocturnal sleep quality was evaluated for 7 days using a sleep analyzer, which patients wore at the waist before and after cyclosporine was administered at 2.0-4.0 mg/kg per day. Seven parameters of sleep quality were measured before and after cyclosporine administration for a period of 7 days for each patient. RESULTS: The administration of cyclosporine significantly improved total sleep time in four cases, sleep latency in two cases, wake after sleep onset in six cases, number of awakenings in two cases, sleep efficiency in seven cases, number of awakenings for more than 8 min in three cases, and number of position changes recorded every 2 min in three cases. The mean values of sleep latency significantly decreased after cyclosporine administration (P = 0.023). The mean value of sleep efficiency significantly increased after the administration (P = 0.002). CONCLUSION: Cyclosporine improves sleep quality in patients with moderate-to-severe AD.
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The susceptibility to neurological and psychiatric disorders reveals sexual dimorphism in the structure and function of human brains. Recent evidence has also demonstrated the sex-related differences in cellular components of the brain, including neurons, microglia, astrocytes, and endothelial cells. Oligodendrocyte precursor cells (OPCs) regulate the neuronal system in various ways and play crucial roles in brain homeostasis beyond their well-known role as a reservoir for mature oligodendrocytes. Although recent studies have shown regional diversities and heterogeneities of OPCs, sex-related differences in OPCs are largely unknown. Here, we revealed transcriptomic differences in OPCs isolated from male and female neonatal rat brains. Furthermore, we demonstrated sex-dependent differences in OPCs regarding proliferation, migration, differentiation, tolerance against ischemic stress, energy metabolism, and the ability to regulate the blood-brain barrier integrity.
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Células Precursoras de Oligodendrócitos , Diferenciação Celular , Células Endoteliais , Feminino , Humanos , Masculino , Oligodendroglia , Caracteres Sexuais , TranscriptomaRESUMO
Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-synuclein-immunoreactive inclusions in oligodendrocytes. Although the myelinating process of oligodendrocytes can be observed in adult human brains, little is known regarding the presence of α-synuclein pathology in immature oligodendrocytes and how their maturation and myelination are affected in MSA brains. Recently, breast carcinoma amplified sequence 1 (BCAS1) has been found to be specifically expressed in immature oligodendrocytes undergoing maturation and myelination. Here, we analyzed the altered dynamics of oligodendroglial maturation in both MSA brains and primary oligodendroglial cell cultures which were incubated with α-synuclein pre-formed fibrils. The numbers of BCAS1-expressing oligodendrocytes that displayed a matured morphology negatively correlated with the density of pathological inclusions in MSA brains but not with that in Parkinson's disease and diffuse Lewy body disease. In addition, a portion of the BCAS1-expressing oligodendrocyte population showed cytoplasmic inclusions, which were labeled with antibodies against phosphorylated α-synuclein and cleaved caspase-9. Further in vitro examination indicated that the α-synuclein pre-formed fibrils induced cytoplasmic inclusions in the majority of BCAS1-expressing oligodendrocytes. In contrast, the majority of BCAS1-non-expressing mature oligodendrocytes did not develop inclusions on day 4 after maturation induction. Furthermore, exposure of α-synuclein pre-formed fibrils in the BCAS1-positive phase caused a reduction in oligodendroglial cell viability. Our results indicated that oligodendroglial maturation and myelination are impaired in the BCAS1-positive phase of MSA brains, which may lead to the insufficient replacement of defective oligodendrocytes. In vitro, the high susceptibility of BCAS1-expressing primary oligodendrocytes to the extracellular α-synuclein pre-formed fibrils suggests the involvement of insufficient oligodendroglial maturation in MSA disease progression and support the hypothesis that the BCAS1-positive oligodendrocyte lineage cells are prone to take up aggregated α-synuclein in vivo.
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Atrofia de Múltiplos Sistemas/patologia , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/patologia , alfa-Sinucleína/metabolismo , alfa-Sinucleína/toxicidade , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Humanos , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Ratos , Ratos Sprague-DawleyRESUMO
A 73-year-old women visited emergency department because of sudden right hemiplegia. She had a history of duodenum papilla cancer terminal stage and multiple liver metastasis. On admission, diffusion weighted images revealed high intensity area at left middle cerebral artery territory. In addition, 3D-TOF MRA depicted proximal part of the left internal carotid artery. We performed endovascular thrombectomy because low platelet count met contraindication of intravenous recombinant tissue plasminogen activator therapy. Although we could get partial recanalization of middle cerebral artery occlusion after thrombectomy, the patient eventually died due to multiple organ failure. Autopsy findings showed white thrombus on mitral valve and also left middle cerebral artery occluded by similar white thrombus without infective findings. The patient was finally diagnosed with nonbacterial thrombotic endocarditis due to white thrombus on the mitral valve. We should select appropriate mechanical thrombectomy devices with a case of cerebral infarction due to nonbacterial thrombotic endocarditis because its thrombus is often white thrombus and would be hard.