尿道原発と考えられた悪性リンパ腫の1例

82歳女.主訴は排尿困難と残尿感.膀胱底部から尿道周囲にかけて鶏卵大の腫瘤を認め, 生検で非ホジキンリンパ腫と診断された.他臓器に病変を認めなかった為, 尿道原発の悪性リンパ腫と診断し放射線療法を施行した.治療後, 腫瘍は著明に縮小したが肺転移が出現した.エトポシド単剤による化学療法を追加したが, 放射線治療後5ヵ月で腫瘍の急激な増加を認め癌死したA patient with a primary malignant lymphoma surrounding the female urethra is reported. Despite the good response of the primary tumor to radiotherapy, the patient died shortly after diagnosis due to disseminated disease. We reviewed 16 cases of this rare entity reported previously

High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly

Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome. One hundred twenty-three patients with carnal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire transthyretin gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four patients (34.0%) with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabeling with antitransthyretin antibody. Direct DNA sequencing of the entire transthyretin gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio, 15.8; 95% confidence interval, 3.3-75.7), and age and male sex were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.ArticleHUMAN PATHOLOGY. 42(11):1785-1791 (2011)journal articl

Cerebral hemorrhage in Fabry's disease

Fabry's disease is an X-linked lysosomal storage disorder resulting from alpha-galactosidase A deficiency. Although ischemic stroke is recognized as an important manifestation of Fabry's disease, hemorrhagic stroke is considered to be rare. Here, we report our recent clinical experience with three hemizygous male patients with Fabry's disease who developed cerebral hemorrhage. One patient had classic type Fabry's disease with p.Ala37Val mutation and others had cerebrovascular variant with p.Glu66Gln mutation. Degeneration of the cerebral small arteries secondary to deposition of glycosphingolipids and aging, in addition to hypertension and antiplatelet/anticoagulant agents, are considered to be contributing factors for hemorrhage. Fabry's disease is frequently associated with not only ischemic but also hemorrhagic stroke, especially in elderly patients. Journal of Human Genetics ( 2010) 55, 259-261; doi:10.1038/jhg.2010.18; published online 19 March 2010ArticleJOURNAL OF HUMAN GENETICS. 55(4):259-261 (2010)journal articl

Nesfatin-1 evokes Ca2+ signaling in isolated vagal afferent neurons via Ca2+ influx through N-type channels

金沢大学医薬保健研究域医学系Nesfatin-1, processed from nucleobindin 2, is an anorexigenic peptide expressed in the brain and several peripheral tissues including the stomach and pancreas. Peripheral, as well as intracerebroventricular, administration of nesfatin-1 suppresses feeding behavior, though underlying mechanisms are unknown. In this study, we examined effects of nesfatin-1 on cytosolic Ca2+ concentration ([Ca2+]i) in the neurons isolated from the vagal afferent nodose ganglion of mice. Nesfatin-1 at 10-10-10-8 M increased [Ca2+]i in the isolated neurons in a concentration-dependent manner, and at 10-8 M it increased [Ca2+]i in 33 out of 263 (12.5%) neurons. These responses were inhibited under Ca2+-free conditions and by N-type Ca2+ channel blocker, ω-conotoxin GVIA. All the nesfatin-1-responsive neurons also exhibited [Ca2+]i responses to capsaicin and cholecystokinin-8. These results provide direct evidence that nesfatin-1 activates vagal afferent neurons by stimulating Ca2+ influx through N-type channels, demonstrating the machinery through which peripheral nesfatin-1 can convey signals to the brain. © 2009 Elsevier Inc. All rights reserved

偏光分解顕微鏡を用いたアルコール性肝線維症の線維化の量的・質的評価系の開発

Liver fibrosis is assessed mainly by conventional staining or second harmonic generation (SHG) microscopy, which can only provide collagen content in fibrotic area. We propose to use polarization-resolved SHG (PR-SHG) microscopy to quantify liver fibrosis in terms of collagen fiber orientation and crystallization. Liver samples obtained from autopsy cases with fibrosis stage of F0–F4 were evaluated with an SHG microscope, and 12 consecutive PR-SHG images were acquired while changing the polarization azimuth angle of the irradiated laser from 0° to 165° in 15° increments using polarizer. The fiber orientation angle (φ) and degree (ρ) of collagen were estimated from the images. The SHG-positive area increased as the fibrosis stage progressed, which was well consistent with Sirius Red staining. The value of φ was random regardless of fibrosis stage. The mean value of ρ (ρ-mean), which represents collagen fiber crystallinity, varied more as fibrosis progressed to stage F3, and converged to a significantly higher value in F4 than in other stages. Spatial dispersion of ρ (ρ-entropy) also showed increased variation in the stage F3 and decreased variation in the stage F4. It was shown that PR-SHG could provide new information on the properties of collagen fibers in human liver fibrosis

Analysis of an insertion mutation in a cohort of 94 patients with spinocerebellar ataxia type 31 from Nagano, Japan

Spinocerebellar ataxia type 31 (SCA31) is a recently defined subtype of autosomal dominant cerebellar ataxia (ADCA) characterized by adult-onset, pure cerebellar ataxia. The C/T substitution in the 5′-untranslated region of the puratrophin-1 gene (PLEKHG4) or a disease-specific haplotype within the 900-kb SCA31 critical region just upstream of PLEKHG4 has been used for the diagnosis of SCA31. Very recently, a disease-specific insertion containing penta-nucleotide (TGGAA)n repeats has been found in this critical region in SCA31 patients. SCA31 was highly prevalent in Nagano, Japan, where SCA31 accounts for approximately 42% of ADCA families. We screened the insertion in 94 SCA31 patients from 71 families in Nagano. All patients had a 2.6- to 3.7-kb insertion. The size of the insertion was inversely correlated with the age at onset but not associated with the progression rate after onset. (TAGAA)n repeats at the 5′-end of the insertion were variable in number, ranging from 0 (without TAGAA sequence) to 4. The number of (TAGAA)n repeats was inversely correlated to the total size of the insertion. The number of (TAGAA)n repeats was comparatively uniform within patients from the three endemic foci in Nagano. Only one patient, heterozygous for the C/T substitution in PLEKHG4, had the insertions in both alleles; they were approximately 3.0 and 4.3 kb in size. Sequencing and Southern hybridization using biotin-labeled (TGGAA)5 probe strongly indicated that the 3.0-kb insertion, but not the 4.3-kb insertion, contained (TGGAA)n stretch. We also found that 3 of 405 control individuals (0.7%) had the insertions from 1.0 to 3.5 kb in length. They were negative for the C/T substitution in PLEKHG4, and neither of the insertions contained (TGGAA)n stretch at their 5′-end by sequencing. The insertions in normal controls were clearly detected by Southern hybridization using (TAAAA)5 probe, while they were not labeled with (TGGAA)5 or (TAGAA)5 probe. These data indicate that control alleles very rarely have a nonpathogenic large insertion in the SCA31 critical region and that not only the presence of the insertion but also its size is not sufficient evidence for a disease-causing allele. We approve of the view that (TGGAA)n repeats in the insertion are indeed related to the pathogenesis of SCA31, but it remains undetermined whether a large insertion lacking (TGGAA)n is nonpathogenic

Nesfatin-1 suppresses peripheral arterial remodeling without elevating blood pressure in mice

Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin -1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2- transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease

Severity and Progression Rate of Cerebellar Ataxia in 16q-linked Autosomal Dominant Cerebellar Ataxia (16q-ADCA) in the Endemic Nagano Area of Japan

16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA) is a recently defined subtype of ADCA identified by a disease-specific C/T substitution in the 5' untranslated region of the puratrophin-1 gene. In Nagano, the central mountainous district of the main island of Japan, 16q-ADCA and spinocerebellar ataxia type 6 (SCA6) are the most and second most prevalent subtypes of ADCA, respectively. Both subtypes are classified into Harding's ADCA III, but little attention has been given to the differences in the severity and progression rate of cerebellar ataxia between 16q-ADCA and SCA6. We investigated the clinical severity and progression rate of cerebellar ataxia of 16q-ADCA patients using international cooperative ataxia rating scale and scale for the assessment and rating of ataxia and compared them with those of SCA6 patients. The age at onset was much higher in 16q-ADCA patients (60.1 +/- 9.8 years, n = 66) than in SCA6 patients (41.1 +/- 8.7 years, n = 35). Clinical features of 16q-ADCA were basically consistent with pure cerebellar ataxia, as well as in SCA6, but gaze-evoked nystagmus was observed less frequently in 16q-ADCA patients than in SCA6 patients. When compared at almost the same disease duration after onset, the severity of cerebellar ataxia was a little higher, and the progression rate seemed more rapid in 16q-ADCA patients than in SCA6 patients, but the differences were not significant.ArticleCEREBELLUM. 8(1):46-51 (2009)journal articl

High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly

Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome. One hundred twenty-three patients with carnal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire transthyretin gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four patients (34.0%) with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabeling with antitransthyretin antibody. Direct DNA sequencing of the entire transthyretin gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio, 15.8; 95% confidence interval, 3.3-75.7), and age and male sex were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.ArticleHUMAN PATHOLOGY. 42(11):1785-1791 (2011)journal articl