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41.
CMT4A: identification of a Hispanic GDAP1 founder mutation 总被引:5,自引:0,他引:5
Boerkoel CF Takashima H Nakagawa M Izumo S Armstrong D Butler I Mancias P Papasozomenos SC Stern LZ Lupski JR 《Annals of neurology》2003,53(3):400-405
Mutations of the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) cause autosomal recessive Charcot-Marie-Tooth disease type 4A. We report four additional families with recessive mutations (487C-->T, Q163X; 359G-->A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina. 相似文献
42.
We have previously demonstrated that pressure-overload hypertrophy in adult sheep is associated with myocardial dysfunction whereas that in young lambs is associated with normal contractility. To probe for possible mechanisms of these age-dependent differences, we assessed mRNA expression of genes encoding critical components of myocardial Ca(2+) handling in the same animal model. We studied left ventricular myocardium of young and adult sheep with short-term (48 h) and long-term (6 wk) pressure overload induced by ascending aortic constriction. Six weeks of pressure overload induced the significant left ventricular hypertrophy (36 and 39% increase in left ventricular/body weight ratio in lambs and sheep, respectively). The Ca(2+) ATPase and Na(+)/Ca(2+) exchanger mRNA decreased with pressure overload only in the adult (p < 0.05). Ca(2+) channel mRNA was slightly increased by pressure overload regardless of age (p < 0.05). Calsequestrin, sarcoplasmic reticulum Ca(2+) release channel, or myosin heavy-chain mRNA levels did not significantly differ. In adult sheep after 6 wk of pressure overload, decreases in load-adjusted midwall shortening (systolic dysfunction) and prolongation of relaxation time constant (diastolic dysfunction) correlated with decreases in Ca(2+)-ATPase mRNA. The sarcoplasmic reticulum Ca(2+)-ATPase protein level and Ca(2+) uptake activity of isolated sarcoplasmic reticulum vesicles were depressed only in the adult with pressure-overload hypertrophy but not in the young. We demonstrated age-dependent differences in mRNA expression of Ca(2+)-handling protein genes in response to pressure overload, which preceded the occurrence of hypertrophy and myocardial dysfunction. Thus, altered expression of Ca(2+)-handling protein genes may be one of the primary responses to pressure overload rather than a phenomenon secondary to myocardial hypertrophy. 相似文献
43.
Transactivation of core binding factor alpha1 as a basic mechanism to trigger parathyroid hormone-induced osteogenesis 总被引:4,自引:0,他引:4
Fujita T Fukuyama R Izumo N Hirai T Meguro T Nakamuta H Koida M 《Japanese journal of pharmacology》2001,86(4):405-416
During 28-day culture of bone marrow- and calvaria-derived osteoblasts, the constant presence of parathyroid hormone (PTH)(1-34) retarded differentiation and nodule formation (NF) in a dose-dependent fashion (C-phase). In contrast, addition of PTH(1-34) in late stage cultures (from day 10 to 21) accelerated NF (A-phase). The stable production of such an A-phase allowed us to study the mechanism of bone anabolic action of PTH(1-34). Subcellular localization studies of core binding factor alpha1 (Cbfa1) and reporter assays provided the results indicating that in the A-phase, PTH(1-34) triggers its bone anabolic action via enhancement of Cbfa1 transactivation. RT-PCR and Northern blot analyses revealed that alkaline phosphatase, osteocalcin and bone sialoprotein expression decreased in the C-phase and increased in the A-phase; however, expression of other bone proteins (Cbfa1, PTH/PTH-related peptide-receptor, osteopontin, collagen I alpha1, collagen I alpha2, vitamin K-dependent gamma-glutamyl carboxylase) did not change in a phase transition-related manner. Ovariectomized osteopenic mice, treated with PTH(1-34) (4 and 40 microg/kg, s.c., every other day, 4 or 6 weeks), recovered lost bone, displayed elevated nuclear localization of Cbfal in tibiae without alteration of its cytosolic level and exhibited upregulation of expressions of the same set of proteins (alkaline phosphatase, osteocalcin and bone sialoprotein) in femora. These results obtained by a concerted study in vitro and in vivo suggest that PTH triggers its osteogenic action via promotion of the transactivation of Cbfa1. 相似文献
44.
Matsuzaki T Nakagawa M Nagai M Usuku K Higuchi I Arimura K Kubota H Izumo S Akiba S Osame M 《Journal of neurovirology》2001,7(3):228-234
To clarify clinical and laboratory findings that may be related to the pathomechanism of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we analyzed these findings in 239 patients with HAM/TSP, including 64 patients followed up for 10 years after their first examinations, with special interest in the HTLV-I proviral load in peripheral blood mononuclear cells (PBMCs). The proviral load in PBMCs did not differ in terms of modes of HTLV-I transmission. However, the proviral load in patients with age of disease onset greater than 65 years tended to be higher than those with a younger age of onset. In the 64 patients followed up for 10 years, the clinical symptoms deteriorated in 36 patients (56%), unchanged in 26 patients (41%), and improved in 2 patients (3%). HTLV-I proviral load also appeared to be related to the deterioration of motor disability in these patients. To our knowledge, the present study is the first longitudinal study concerning the relationship between the clinical course of HAM/TSP and HTLV-I proviral load. It is suggested that HTLV-I proviral load is related to the progression of motor disability and is an important factor to predict prognosis of patients with HAM/TSP. 相似文献
45.
We investigated the localization and extent of beta-amyloid precursor protein (APP) immunoreactivity as a sensitive marker for impairment of fast axonal transport in the spinal cords of patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). The results from this study show that APP, used as a marker of early axonal damage in HAM/TSP lesions, is more intensively expressed in areas of active-inflammatory lesions than those of inactive-chronic lesions. The close localization to the areas containing inflammation (activation of macrophage/microglia) is striking and suggests that axonal damage is closely associated with inflammation in active-chronic lesions. Although inflammatory cell infiltration in the central nervous system (CNS) is rarely found in inactive-chronic lesions, a few clusters of APP+ axons are found in the spinal cord white matter in some cases. The presence of APP+ axons without relation to inflammatory cells in inactive-chronic lesions, suggest that soluble neurotoxic factors might induce axonal changes in the CNS of HAM/TSP. The occasional myelinated fibers in the anterior and posterior spinal roots in lower thoracic to lumbar levels had APP+ axons, suggesting that spinal nerve roots can be affected in HAM/TSP, especially in lower thoracic to lumbar levels. Impairment of fast axonal transport may contribute to the development of disability in patients with HAM/TSP. 相似文献
46.
47.
I. Higuchi S. Izumo M. Kuriyama M. Suehara M. Nakagawa H. Fukunaga M. Osame S. Ohtsubo K. Miyata 《Acta neuropathologica》1989,79(3):300-304
Summary Pathological examinations were carried out on the skeletal muscle of a patient with germanium intoxication. The prominent histochemical finding was vacuolar myopathy with lipid excess, increased acid phosphatase activity and decreased cytochrome c oxidase activity. Ultrastructural lesions revealed a mitochondrial abnormality, autophagic vacuoles and accumulation of high electron-dense materials in deformed mitochondria and at the periphery of lipid droplets. Furthermore, the toxic effect of germanium on skeletal muscle was confirmed by the experimentally induced germanium myopathy, which showed autophagic degeneration, decreased cytochrome c oxidase activity and a mitochondrial abnormality with high electron-dense materials. 相似文献
48.
Mayu Shiomi Shinya Matsuzaki Satoshi Serada Koji Matsuo Chihiro Mizuta-Odani Mariko Jitsumori Ruriko Nakae Satoko Matsuzaki Satoshi Nakagawa Kosuke Hiramatsu Ai Miyoshi Eiji Kobayashi Toshihiro Kimura Yutaka Ueda Kiyoshi Yoshino Tetsuji Naka Tadashi Kimura 《Cancer science》2021,112(9):3655-3668
This study aimed to investigate the cytotoxicity of a cluster of differentiation 70 antibody-drug conjugate (CD70-ADC) against ovarian cancer in in vitro and in vivo xenograft models. CD70 expression was assessed in clinical samples by immunohistochemical analysis. Western blotting and fluorescence-activated cell sorting analyses were used to determine CD70 expression in the ovarian cancer cell lines A2780 and SKOV3, and in the cisplatin-resistant ovarian cancer cell lines A2780cisR and SKOV3cisR. CD70 expression after cisplatin exposure was determined in A2780 cells transfected with mock- or nuclear factor (NF)-κB-p65-small interfering RNA. We developed an ADC with an anti-CD70 monoclonal antibody linked to monomethyl auristatin F and investigated its cytotoxic effect. We examined 63 ovarian cancer clinical samples; 43 (68.3%) of them expressed CD70. Among patients with advanced stage disease (n = 50), those who received neoadjuvant chemotherapy were more likely to exhibit high CD70 expression compared to those who did not (55.6% [15/27] vs 17.4% [4/23], P < .01). CD70 expression was confirmed in A2780cisR, SKOV3, and SKOV3cisR cells. Notably, CD70 expression was induced after cisplatin treatment in A2780 mock cells but not in A2780-NF-κB-p65-silenced cells. CD70-ADC was cytotoxic to A2780cisR, SKOV3, and SKOV3cisR cells, with IC50 values ranging from 0.104 to 0.341 nmol/L. In A2780cisR and SKOV3cisR xenograft models, tumor growth in CD70-ADC treated mice was significantly inhibited compared to that in the control-ADC treated mice (A2780cisR: 32.0 vs 1639.0 mm3, P < .01; SKOV3cisR: 232.2 vs 584.9 mm3, P < .01). Platinum treatment induced CD70 expression in ovarian cancer cells. CD70-ADC may have potential therapeutic implications in the treatment of CD70 expressing ovarian cancer. 相似文献
49.
Yosuke Yakushiji Koka Motoyama Mayu Fukuda Hisako Takahashi Makiko Kimura Satoshi Tazoe Hiromi Iida Anna Tamai Takeshi Sakura Yoshihiro Isaka Mariko Fukumoto Keiko Yamagami Hidenori Nakagawa Michinori Shirano Masayuki Hosoi 《Journal of diabetes investigation.》2022,13(7):1277
Aims/IntroductionDiabetes mellitus is reported as a risk factor for increased coronavirus disease 2019 (COVID‐19) severity and mortality, but there have been few reports from Japan. Associations between diabetes mellitus and COVID‐19 severity and mortality were investigated in a single Japanese hospital.Materials and MethodsPatients aged ≥20 years admitted to Osaka City General Hospital for COVID‐19 treatment between April 2020 and March 2021 were included in this retrospective, observational study. Multivariable logistic regression analysis was carried out to examine whether diabetes mellitus contributes to COVID‐19‐related death and severity.ResultsOf the 262 patients included, 108 (41.2%) required invasive ventilation, and 34 (13.0%) died in hospital. The diabetes group (n = 92) was significantly older, more obese, had longer hospital stays, more severe illness and higher mortality than the non‐diabetes group (n = 170). On multivariable logistic regression analysis, age (odds ratio [OR] 1.054, 95% confidence interval [CI] 1.023–1.086), body mass index (OR 1.111, 95% CI 1.028–1.201), history of diabetes mellitus (OR 2.429, 95% CI 1.152–5.123), neutrophil count (OR 1.222, 95% CI 1.077–1.385), C‐reactive protein (OR 1.096, 95% CI 1.030–1.166) and Krebs von den Lungen‐6 (OR 1.002, 95% CI 1.000–1.003) were predictors for COVID‐19 severity (R 2 = 0.468). Meanwhile, age (OR 1.104, 95% CI 1.037–1.175) and Krebs von den Lungen‐6 (OR 1.003, 95% CI 1.001–1.005) were predictors for COVID‐19‐related death (R 2 = 0.475).ConclusionsDiabetes mellitus was a definite risk factor for COVID‐19 severity in a single Japanese hospital treating moderately‐to‐severely ill patients. 相似文献
50.
Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells 总被引:34,自引:0,他引:34
M Osame M Matsumoto K Usuku S Izumo N Ijichi H Amitani M Tara A Igata 《Annals of neurology》1987,21(2):117-122
Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified. 相似文献