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91.
Factor V and factor VIII are homologous cofactors in the blood coagulation cascade that have the domain structure A1-A2-B-A3-C1-C2, of which the B domain has extensively diverged. In transfected COS-1 monkey cells, expression of factor VIII is approximately 10-fold less efficient than that of factor V, primarily because of inefficient protein secretion and, to a lesser extent, reduced mRNA expression. To study the functional significance and effect of the B domain on expression and activity, chimeric cDNAs were constructed in which the B domains of factor V and factor VIII were exchanged. Expression of a factor VIII chimera harboring the B-domain of factor V yielded a fully functional factor VIII molecule that was expressed twofold more efficiently than wild-type factor VIII because of increased mRNA expression. Thus, sequences within the factor VIII B domain were not responsible for the inefficient secretion of factor VIII compared with factor V. Expression of a factor V chimera harboring the B domain of factor VIII was slightly reduced compared with wild-type factor V, although the secreted molecule had significantly reduced procoagulant activity correlating with dissociated heavy and light chains and resistance to thrombin activation. Interestingly, the factor V chimera containing the factor VIII B domain was efficiently activated by Russell's viper venum (RVV). A factor V B domain deletion (residues 710- 1545) molecule also exhibited significantly reduced procoagulant activity caused by resistance to thrombin cleavage and activation, although this molecule was activatable by RVV. These results show that, in contrast to factor VIII, thrombin activation of factor V requires sequences within the B domain. In addition, thrombin activation of factor V occurs through a different mechanism than activation by RVV. 相似文献
92.
Brennan FM; Browne KA; Green PA; Jaspar JM; Maini RN; Feldmann M 《Rheumatology (Oxford, England)》1997,36(6):643-650
Matrix metalloproteinase (MMP)-1 and MMP-3 levels were measured in serum
samples from rheumatoid arthritis (RA) patients undergoing a double-blinded
placebo-controlled trial with the chimaeric anti-tumour necrosis factor
(TNF)-alpha antibody cA2. Both MMP-1 (P < 0.015), but to a larger extent
MMP-3 (P < 0.001) levels were elevated in all RA patients prior to the
commencement of the trial compared with normal control sera. Following cA2
therapy, MMP-1 and MMP-3 levels were assessed in the placebo, and 1 and 10
mg/kg cA2-treated groups at 7, 14, 21 and 28 days. In both the 1 and the 10
mg/kg cA2-treated groups, a significant decrease in serum MMP-3 levels at
all time points was observed, reducing maximally to 41% of pre-infusion
values at day 7. MMP-1 levels were also reduced, but less dramatically than
MMP-3, to 85% of pre-infusion values after 14 days in the 10 mg/kg cA2
treated group. In a separate non-placebo-controlled study, we also
evaluated the tissue inhibitor of metalloproteinase (TIMP)-1 levels in
plasma following cA2 infusion. Pre-infusion TIMP-1 levels were above the
normal control range, but were significantly reduced (P < 0.035) 14 days
after infusion to 72% of pre-infusion values. This study confirms previous
reports that MMP-3 levels are elevated and correlate with measures of
inflammation in RA, and furthermore demonstrate that serum MMP-3 and MMP-1
levels are downmodulated following anti-TNF-alpha antibody therapy. Whilst
serum MMP-3 levels correlated with C-reactive protein (CRP) both prior to
and following anti-TNF-alpha antibody therapy, it remains to be
demonstrated that serum MMP-3 and/or MMP-1 levels reflect the cartilage and
bone resorptive processes which are evident in this disease.
相似文献
93.
We have recently described a marrow stroma-dependent long-term culture system that supports differentiation of CD34+ human marrow primitive progenitors into natural killer (NK) cells. We postulate that CD7 expression may be an early event in commitment of hematopoietic progenitors to the NK lineage. Here we compare the characteristics of CD34+7- and CD34+7+ marrow cells cultivated in the stroma-based NK culture system. These CD34+ populations were further compared with a marrow derived, more committed, CD34-7+ progenitor to emphasize the continuum of NK development and to highlight differences between progenitors in our assays. No progenitor proliferated when plated in media without stroma, underscoring the importance of stroma in NK differentiation. Plating progenitor populations in interleukin-2 containing media directly on preestablished, allogeneic, irradiated marrow stroma for 5 weeks resulted in CD56+CD3- NK cells; however, characteristics of the cultured populations differed. Fold expansion and cloning efficiency of the CD34+7+ population, determined by a functional limiting dilution assay was significantly higher than of the CD34+7- or CD34+7+ populations. This suggests that the CD34+7+ population is highly enriched for an NK progenitor and a possible intermediate in NK lineage differentiation. Further dividing the CD34+7+ population by the relative fluorescence of CD7 into CD34+7+dim and CD34+7+bright populations showed that the CD34+7+bright population exhibited a significantly higher cloning frequency than parallel experiments with CD34+7+dim cells (11.8% +/- 2.4% v 2.4% +/- 0.7%, n = 6; P = .005). Plating of the more primitive CD34+7- population in a transwell system (which separates progenitors from stroma by a microporous membrane) prevents differentiation into NK cells. In contrast, plating of CD34+7+ progenitors in transwells resulted in generation of NK cells. These data suggest that primitive, but not more mature NK progenitors may require direct contact with stroma for the initial differentiation steps. Finally, differentiation of the NK progenitors in this stroma-dependent model results in expression of CD2 not present on any of the starting populations. This observation suggests that marrow stroma can stimulate CD2 expression on NK progenitors in a previously undescribed fashion that may be analogous to the thymic effect on CD2 expression in immature T lymphocytes. These observations identify early steps in the commitment of primitive marrow CD34+ hematopoietic progenitors to a lymphoid lineage and underscore the importance of coexpression of CD7 with CD34 as an early lymphoid commitment characteristic and direct progenitor-stroma interactions in this process. 相似文献
94.
Identification of the molecular defect in the erythrocyte membrane skeleton of some kindreds with hereditary spherocytosis 总被引:12,自引:0,他引:12
We have localized the molecular alteration in the membrane skeleton of two of four kindreds with hereditary spherocytosis (HS) to an alteration in the spectrin-protein-4.1 interaction due to a defective spectrin molecule. The defective spectrin-protein-4.1 interaction in these kindreds (referred to as type I HS) leads to a weakened spectrin- protein-4.1-actin ternary complex, which in turn may lead to the friable membrane skeleton and suggested membrane instability related to this disorder. Type I HS spectrin binds approximately 63% as much protein-4.1 as normal spectrin (with equal affinity). This defect does not correlate with splenic function or erythrocyte age in the circulation. However, the approximately 37% reduction in binding of protein-4.1 to HS spectrin approaches the theoretical value of 50% expected in this autosomal dominant disorder. All other type I membrane skeletal interactions (spectrin-syndein, spectrin heterodimer- heterodimer, syndein-band-3) were found to be normal. It would appear therefore that the defective HS spectrin-protein-4.1 interaction in type I hereditary spherocytosis may be the primary molecular defect rather than a secondary phenomena. 相似文献
95.
Splenectomized mice treated for 7 days with pegylated recombinant rat stem cell factor (rrSCF-PEG) showed a dose-dependent increase in peripheral blood progenitor cells (PBPC) that have enhanced in vivo repopulating potential. A dose of rrSCF-PEG at 25 micrograms/kg/d for 7 days produced no significant increase in PBPC. However, when this dose of rrSCF-PEG was combined with an optimal dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 200 micrograms/kg/d), a synergistic increase in PBPC was observed. Compared with treatment with rhG-CSF alone, the combination of rrSCF-PEG plus rhG-CSF resulted in a synergistic increase in peripheral white blood cells, in the incidence and absolute numbers of PBPC, and in the incidence and absolute numbers of circulating cells with in vivo repopulating potential. These data suggest that low doses of SCF, which would have minimal, if any, effects in vivo, can synergize with optimal doses of rhG-CSF to enhance the mobilization of PBPC stimulated by rhG-CSF alone. 相似文献
96.
Osteopetrosis is a heterogeneous group of bone disorders characterized by the failure of osteoclasts to resorb bone and by several immunological defects including macrophage dysfunction. Two compounds, colony-stimulating factor-1 (CSF-1) and vitamin D-binding protein- macrophage activating factor (DBP-MAF) were used in the present study to evaluate their effects on the peritoneal population of cells and on cells within the bone marrow microenvironment in normal and incisors absent (ia) osteopetrotic rats. Previous studies in this laboratory have demonstrated that administration of DBP-MAF to newborn ia animals results in a substantial increase in bone marrow cavity size due to upregulated osteoclast function. To study the effects of these compounds on the macrophage/osteoclast precursors, DBP-MAF, CSF-1, and the combination of these compounds were given to newborn ia and normal littermate animals. Both the normal and mutant phenotypes responded similarly when treated with these compounds. Rats exhibited a profound shift toward the macrophage lineage from the neutrophil lineage when compared with vehicle-treated control animals after treatment with these compounds. In the in vivo peritoneal lavage study, animals received injections of CSF-1, DBP-MAF or DBP-MAF/CSF-1 over a 4-week period. The various types of cells in the peritoneal cavity were then enumerated. The in vitro study consisted of cells isolated from the bone marrow microenvironment and cultured on feeder layers of CSF-1, DBP-MAF, or DBP-MAF/CSF-1 for colony enumeration. The increase in macrophage numbers at the expense of neutrophil numbers could be seen in both the in vivo and in vitro experiments. The macrophage/osteoclast and neutrophil lineages have a common precursor, the granulocyte/macrophage colony-forming cell (GM-CFC). With the addition of CSF-1, the GM-CFC precursor may be induced into the macrophage/osteoclast lineage rather than the granulocyte lineage. This increased pool of cells in the macrophage/osteoclast lineage can be functionally upregulated with the subsequent addition of DBP-MAF to perform the activities of phagocytosis and bone resorption. The in vitro data also showed that DBP-MAF did not support colony development as in CSF-1 or the combination treatment. The recruitment and activation of cells into the macrophage/ osteoclast lineage may help to correct the bone and immune defects found in diseases demonstrating a significant lack of myeloid cells, as well as neutrophilia disorders and the disease, osteopetrosis. 相似文献
97.
Prague women's drinking before and after the 'velvet revolution' of 1989: a longitudinal study 总被引:1,自引:0,他引:1
Results are presented of a follow-up study in which a representative sample of 608 Prague women aged 20–49 years in 1987 at first interview was re-interviewed in 1992 3 years after the revolution that ended the 41 years of the Communist era in Czechoslovakia. The average yearly consumption of alcohol in the followed-up female sample increased between 1987–92 from a reported 3.6 litres to 4.8 litres. The percentage of heavier drinkers (with average daily consumption of over 20 g alcohol) increased from 7.2% to 14.0%. The women expressed increased tolerance of drunkenness in their attitudes to drinking. The consumption increase was mainly due to increased drinking frequency of spirits and to increased quantity of beer consumed per occasion. The consumption increase was largest in women working as free-lance and the newly emerging self-employed women; economically inactive women did not increase their consumption. Women who reported a positive impact of the socio-political changes on their personal lives and an expansion of social contacts also reported larger than average consumption increases. A coincidence of stressful, possibly self-inflicted, life events and increased alcohol use was observed and interpreted as probably a two-way influence. 相似文献
98.
目的 分析疏附县炭疽流行病学特征,为制订炭疽防控策略提供依据和参考.方法 对疏附县2005-2012年网络报告的炭疽发病资料进行描述性流行病学分析.结果 2005-2012年疏附县共报告炭疽137例,占同期全国病例总数的5.09%,年平均发病率为5.34/10万.病例全部为皮肤型炭疽,多为散发;夏秋两季高发,7月为高峰月份;男女性别比为1.36∶1,男性发病率高于女性.超过54%的病例为20岁以下儿童和青年,10-14岁高发.病例职业多为农牧民和学生,民族以维吾尔族为主(99.27%).结论 疏附县炭疽发病率极高且呈低龄化特点,应采取针对性措施进一步加强其预防控制. 相似文献
99.
Shin JH; Oestmann J; Hall D; Cardenosa G; McCarthy KA; Mrose HE; Pile- Spellman E; Rubens JR; Greene RE 《Radiology》1989,172(2):399-401
The authors compared low-dose (32% of standard exposure) storage phosphor digital imaging (system resolution: 0.2-mm pixels, 10 bits) with isovoltage 75-kVp conventional radiography (standard exposure) in the detection of subtle simulated gastric abnormalities by using air contrast barium studies. Subtle simulated abnormalities (3-7-mm polyps, 4-15-mm ulcer craters, 4-11-mm-diameter edema, and 11-12-mm linear ulcers) were produced in resected canine stomachs. Receiver operating characteristic analysis of 1,800 observations by six readers indicated that the digital images with and without high-frequency edge enhancement were equivalent to conventional radiographs (mean receiver operating characteristic areas [+/- standard deviation]: 0.76 +/- 0.06, 0.78 +/- 0.04, and 0.77 +/- 0.04, respectively). The accuracy of the diagnosis was equivalent for all three modalities. The following mean accuracies of negative and positive responses, respectively, for unenhanced digital, edge-enhanced digital, and conventional images were determined: 0.71 +/- 0.05 and 0.41 +/- 0.07, 0.71 +/- 0.04 and 0.51 +/- 0.09, and 0.68 +/- 0.04 and 0.43 +/- 0.05. It was concluded that low-dose storage phosphor air-contrast barium studies were equivalent to conventional radiography in the detection of subtle gastric abnormalities. 相似文献
100.