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81.
Saito M Nishikomori R Kambe N Fujisawa A Tanizaki H Takeichi K Imagawa T Iehara T Takada H Matsubayashi T Tanaka H Kawashima H Kawakami K Kagami S Okafuji I Yoshioka T Adachi S Heike T Miyachi Y Nakahata T 《Blood》2008,111(4):2132-2141
Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutation-negative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients. 相似文献
82.
Kanako Sugawara Youichi Tajima Ikuo Kawashima Takahiro Tsukimura Seiji Saito Kazuki Ohno Kunihiko Iwamoto Toshihide Kobayashi Kohji Itoh Hitoshi Sakuraba 《Molecular genetics and metabolism》2009,96(4):233-238
Enzyme enhancement therapy (EET) for Fabry disease involving imino sugars has been developed and attracted interest. It is thought that imino sugars act as pharmacological chaperones for wild-type and mutant α-galactosidases (GLAs) in cells, but the mechanisms underlying the molecular interactions between the imino sugars and the enzyme have not been clarified yet. We examined various kinds of imino sugars and found that galactostatin bisulfite (GBS) inhibited GLA in vitro and increased the enzyme activity in cultured Fabry fibroblasts as in the case of 1-deoxygalactonojirimycin (DGJ). Then, we analyzed the molecular interactions between the imino sugars and recombinant human GLA by means of isothermal titration calorimetry and surface plasmon resonance biosensor assays, and first determined the thermodynamic and binding-kinetics parameters of imino sugar and GLA complex formation. The results revealed that DGJ bound to the enzyme more strongly than GBS, the binding of DGJ to the enzyme protein being enthalpy-driven. In the case of GBS, the reaction was mainly enthalpy-driven, but there was a possibility that entropy-driven factors were involved in the binding. Structural analysis in silico revealed that both the chemicals fit into the active-site pocket and undergo hydrogen bonding with residues comprising the active-site pocket including the catalytic ones. The side chain of GBS was oriented towards the entrance of the active-site pocket, and thus it could be in contact with residues comprising the wall of the active-site pocket. Thermodynamic, kinetic and structural studies should provide us with a lot of information for improving EET for Fabry disease. 相似文献
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W Koyano H Shibata K Nakazato H Haga Y Suyama T Matsuzaki 《Journal of gerontology》1988,43(2):S41-S45
The prevalence of disability in instrumental activities of daily living (IADL) was assessed for seven items of activity -- among them, using public transportation, using the telephone, and shopping -- in 7,735 elderly residents living in an urban Japanese community. The prevalence of disability generally was low (ranging from 6.1% in heating water to 15.9% in preparing meals), but increased significantly with age. The prevalence was higher, controlling by age, in females than in males, with the exception of preparing meals. 相似文献
86.
Takashi Tsukahara Masaru Tamura Hiromichi Yamazaki Hideyuki Kurihara Shigeru Matsuzaki 《Journal of cancer research and clinical oncology》1992,118(3):171-175
Summary The effects of -difluoromethylornithine (DFMO), radiation and the therapy of their combination were investigated in rats bearing G-XII glioma. DFMO treatment as well as radiation therapy prolonged the survival period when compared to the results in non-treated control rats. The combination therapy showed a greater effect on the survival rate than the single therapies, the effect being additive. The concentration of putrescine, spermidine, andN
1-acetylspermidine in tumor tissues was lowered by DFMO, while that of spermine was slightly elevated. Radiation decreased the concentration of all the polyamines, putrescine, spermidine, spermine andN
1-acetylspermidine. The concomitant treatment with DFMO and radiation further decreased the concentrations of putrescine andN
1-acetylspermidine in tumor tissues. The survival period of glioma-bearing rats is inversely correlated with the tissue levels of putrescine plusN
1-acetylspermidine.Abbreviations DFMO
-difluoromethylornithine
- BrdUrd
bromodeoxyuridine 相似文献
87.
M Matsuzaki S Ono Y Tomochika H Michishige N Tanaka F Okuda R Kusukawa 《Japanese circulation journal》1992,56(6):592-602
We assessed atherosclerotic lesions in the thoracic aorta in 166 consecutive patients (aged 56 +/- 13 years) by transesophageal echocardiography, and investigated the influences of hypertension, hypercholesterolemia and age on the prevalence of such lesions. Satisfactory images were obtained of all the thoracic aorta, except for a small part of the ascending aorta, by use of a biplane transesophageal probe. We defined atherosclerotic lesions as increased echogenicity of the intima (intimal thickening), raised plaque, calcification, ulceration, or aneurysms. Lesions were observed in 97 patients (58%). The incidence of lesions in patients with hypertension (81%) or hypercholesterolemia (80%) was significantly greater than in those without both conditions (37%, p less than 0.005). The incidence of lesions was significantly increased among patients over 60 years old compared with that in patients under 60 (76% vs 42%, p less than 0.005). Patients without either hypertension or hypercholesterolemia showed a marked increase in the incidence of lesions with age (16% at less than 60 yrs vs. 67% at greater than 60 yrs), and no significant influence of these conditions on the incidence of lesions was found in patients over 60. We conclude that hypertension and hypercholesterolemia might be important risk factors for the development of atherosclerotic lesions in the thoracic aorta in relatively younger patients. Age appears to become a more important determinant of such lesions in Japanese patients over 60 years old irrespective of blood pressure and serum cholesterol levels. 相似文献
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