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Zachary A. Hing Tal Schiller Andrew Wu Nobuko Hamasaki‐Katagiri Evi Budo Struble Estelle Russek‐Cohen Chava Kimchi‐Sarfaty 《British journal of haematology》2013,160(6):825-837
Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare, recessively inherited genetic disorder with varying clinical presentation that is caused by ADAMTS13 mutations. Several studies have found limited associations between ADAMTS13 mutations and cTTP phenotype. The use of in silico tools that examine multiple mutation characteristics may better predict phenotype. We analysed 118 ADAMTS13 mutations found in 144 cTTP patients reported in the literature and examined associations of several mutation characteristics, including N‐terminal proximity, the evolutionary conservation of the affected amino acid position, as well as amino acid charge/phosphorylation and genetic codon usage to disease phenotype. Structure‐altering mutations were examined for their impact on ADAMTS13 function based on existing ADAMTS13 crystallographic data (AA 77‐685). Our in silico data indicate that: (i) The position of the mutation in the N‐ or C‐terminus, (ii) evolutionary conservation and (iii) codon usage of the affected mutation position are associated with disease parameters, such as age of onset, organ damage and fresh frozen plasma prophylaxis. In conclusion, the usage of multiple in silico tools presents a promising strategy in refining predictions for the diverse presentation of cTTP. Enhancing our utilization of in silico tools to find genotype‐phenotype associations will create better‐tailored approaches for individual patient treatment. 相似文献
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Masato Mizuashi M.D. Takaki Suetake M.D. Setsuya Aiba M.D. Hachiro Tagami M.D. 《Pediatric dermatology》2010,27(3):305-306
Abstract: A 2‐year‐old Japanese boy had a congenital gray‐blue macule involving the right helix along with a few melanotic spots on both sclerae. Histopathology showed dermal melanocytosis. Q‐switched alexandrite laser treatment induced a good cosmetic response. This patient shows the overlap between Ota and Ito nevi, and we suggest dermal melanocytosis is better used as a generic term for these unusual pigmentations. 相似文献
25.
Yamaguchi N Fujimori Y Fujibayashi Y Kasumoto I Okamura H Nakanishi K Hara H 《Annals of hematology》2005,84(7):423-428
Interferon (IFN)-gamma is produced by T cells and natural killer cells and activates monocytes and dendritic cells (DCs). Recently, IFN-gamma has been shown to be produced by mouse DCs following stimulation with interleukin (IL)-12, which is markedly augmented by the addition of IL-18. We here analyzed whether human DCs secrete IFN-gamma in response to IL-12 and/or IL-18. Human immature DCs, generated from cord blood CD14(+) monocytes by treating with granulocyte-macrophage colony-stimulating factor and IL-4, were incubated with IL-12 and/or IL-18 and assayed for IFN-gamma production. IL-12, but not IL-18, weakly induced IFN-gamma production, while IL-12 together with IL-18 induced high levels of IFN-gamma production. Similar results were obtained with mature DCs, although levels of IFN-gamma production were less than those in immature DCs. Also with mature and immature DCs, IL-12 upregulated the expression of IL-18 receptor alpha (Ralpha), and costimulation with IL-12 and IL-18 upregulated CD40 expression. Anti-IL-18Ralpha antibody abrogated both the IFN-gamma induction and the CD40 upregulation by IL-12 plus IL-18. These findings suggest that IL-12 upregulates IL-18Ralpha expression on human DCs and acts synergistically with IL-18 to induce high levels of IFN-gamma, which subsequently enhances CD40 expression on DCs in an autocrine manner. 相似文献
26.
CETP is a determinant of serum LDL-cholesterol but not HDL-cholesterol in healthy Japanese 总被引:2,自引:0,他引:2
Makoto Kinoshita Tamio Teramoto Nobuko Shimazu Kazuko Kaneko Masato Ohta Toru Koike Shigemi Hosogaya Yukio Ozaki Shoji Kume Masami Yamanaka 《Atherosclerosis》1996,120(1-2):75-82
Cholesteryl ester transfer protein (CETP) is one of the factors that regulate plasma levels of HDL-cholesterol. To identify the factors that may regulate CETP activity, and to determine to what extent CETP is correlated with physiologic concentrations of lipoprotein, we performed an epidemiologic study in 586 healthy volunteers (317 males and 269 females, mean age 52.2 ± 10.9 years). CETP activity in these subjects was 192.96 ± 48.73 (mean ± S.D.) nmol/ml/h and distributed to a wide range (60–450 nmol/ml/h). Using multiple regression analysis, we found significant positive correlations between CETP activity and LDL-cholesterol (P < 0.03), apolipoprotein (apo) E (P < 0.005) and LCAT activity (P < 0.001). CETP activities showed significant negative correlation with apo A-I (P < 0.03). However, CETP activity showed no significant correlation either with HDL cholesterol or with apo B. One-way layout analysis of variance showed that alcohol drinking and cigarette smoking significantly reduced CETP activity, but there was no significant association between CETP activity and body mass index. Although CETP activities were significantly higher in females than in males (P < 0.001), multiple regression analysis showed no correlation between CETP activity and age in either the males or the females. Our results suggest that CETP activity regulates the concentration of apo A-I and LDL-cholesterol, and that such activity may be influenced by gender, alcohol consumption and cigarette smoking. 相似文献
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Yuki Sumazaki Watanabe Tomofumi Miura Ayumi Okizaki Keita Tagami Yoshihisa Matsumoto Maiko Fujimori Tatsuya Morita Hiroya Kinoshita 《Journal of pain and symptom management》2018,55(4):1159-1164
Context
The achievement of a personalized pain goal (PPG) is advocated as an individualized pain relief indicator.Objectives
Pain relief indicators, including PPG, pain intensity (PI), and interference with daily activities (interference), were compared herein.Methods
This was a single-center cross-sectional study. Adult patients with cancer on opioid medications who visited the outpatient clinic at the National Cancer Center Hospital East between March and September 2015 were consecutively enrolled. Patients conducted a self-report questionnaire, including reports of average PI, interference, PPG, and the need for further analgesic treatment. We compared the proportion of patients achieving PPG (PI ≤ PPG) and other pain relief indicators including PI ≤3 or interference ≤3 and the percentage of patients who did not need further analgesic treatment among those who fulfilled each pain relief indicator.Results
A total of 347 patients (median age 64; 38% females) were analyzed. Median (interquartile range [IQR]) of PPG, PI, and interference was 2 (IQR 1–3), 2 (IQR 1–4), and 2 (IQR 0–5), respectively. The proportion of patients achieving PPG was 45.3% and significantly lower than those with PI ≤3 (69.0%; P < 0.001) and interference ≤3 (70.2%; P < 0.001). Eighty percent of patients achieving PPG did not need further analgesic treatment, whereas 70.8% of patients with PI ≤3 (P < 0.001) and 73.3% with interference ≤3 did need further analgesic treatment (P < 0.001).Conclusion
The achievement of PPG was a stricter pain relief indicator than PI and interference and may reflect a real need for pain control. 相似文献29.
Kumar V Silvis C Nystrom G Deshpande N Vary TC Frost RA Lang CH 《Alcoholism, clinical and experimental research》2002,26(10):1574-1583
BACKGROUND: Alcohol (EtOH) alters the plasma and tissue content of insulin-like growth factor (IGF)-I, an important anabolic hormone. However, the bioavailability and bioactivity of IGF-I can also be modulated by changes in soluble proteins that bind IGF-I (IGFBPs). The purpose of the present study was to determine whether EtOH intoxication in rats alters the plasma concentration and tissue mRNA content of various IGFBPs. Based on initial results subsequent studies were performed to assess potential mechanisms by which EtOH increased IGFBP-1. METHODS: Rats were administered EtOH (75 mmol/kg) and blood and tissues collected at various times thereafter. Separate groups of rats were also pretreated with 4-methylpyrazole (4-MP; alcohol dehydrogenase inhibitor), cyanamide (inhibitor of acetaldehyde metabolism), RU486 (glucocorticoid receptor antagonist) or the tumor necrosis factor (TNF) antagonist (TNF(BP)) prior to EtOH administration. RESULTS: Acute EtOH intoxication did not alter the mRNA content of IGFBP-3, -4 or -5 in liver or kidney. However, EtOH increased IGFBP-1 in blood (5-fold), which was associated with an up-regulation of IGFBP-1 mRNA content in liver and kidney (2- to 3-fold). Likewise, the injection of the nonmetabolizable alcohol -butanol also increased IGFBP-1 in plasma, liver, and kidney. The increased IGFBP-1 in blood and tissues was not prevented by inhibiting alcohol metabolism with 4-MP. However, pretreatment with cyanamide markedly accentuated the EtOH-induced increase in IGFBP-1 in blood (20-fold), liver (3.5-fold), and kidney (12-fold), indicating that accumulation of acetaldehyde can enhance IGFBP-1 synthesis. A time course study indicated that EtOH increased plasma IGFBP-1 levels as early as 0.5-1 hr, and that this response was associated with elevated IGFBP-1 mRNA in liver but not kidney. Pretreatment with RU486 did not prevent or attenuate the EtOH-induced increase in IGFBP-1. However, the alcohol-induced increase in IGFBP-1 was attenuated by TNF(BP). CONCLUSIONS: These data suggest that the acute alcohol-induced increase in IGFBP-1 is mediated, at least in part, by TNF and is independent of EtOH metabolism and increases in endogenous glucocorticoids. 相似文献
30.
Glaucoma is defined as an optic neuropathy with characteristic changes in the optic nerve head and ultimate loss of visual field. Previous studies have suggested that (a) mechanical damage due to raised intraocular pressure and (b) a compromised tissue circulation in the optic nerve head play significant roles in the development of glaucomatous damage in the optic nerve head. Recently, we found that lomerizine, a new Ca2+ channel blocker, increased ocular circulation and protected neuronal cells against retinal neurotoxicity both in vitro and in vivo with minimal cardiovascular side effects. We examined the effect of lomerizine on the ocular circulation and compared it with those of other Ca2+ channel blockers in normal rabbits and in rabbits with an endothelin‐1‐disturbed circulation in the optic nerve head. In anesthetized rabbits, lomerizine and the other Ca2+ channel blockers increased the ocular circulation and also inhibited the hypoperfusion induced in optic nerve head tissue by an intravitreous injection of endothelin‐1. Whereas the other Ca2+ channel blockers produced changes in blood pressure and heart rate, the effects of lomerizine on these parameters were slight. In healthy humans, lomerizine increased blood velocity in the optic nerve head, without significantly altering blood pressure or heart rate. Moreover, lomerizine reduced retinal damage in rats both in vitro and in vivo, presumably through a Ca2+ channel blocking effect via an action that may involve a direct protection of retinal neurons as well as an improvement in the ocular circulation. These results indicate that lomerizine may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that involve a disturbance of the ocular circulation. 相似文献