Human myeloid alpha 3-fucosyltransferase is involved in the expression of the sialyl-Lewis(x) determinant, a ligand for E- and P-selectin

The sialyl-Lex determinant (NeuAc alpha 2-->3Gal beta 1-->4[Fuc alpha- 1-->3]GlcNAc) has been identified as a major ligand in the selectin- mediated adhesion of neutrophils and monocytes to activated endothelium or platelets. This carbohydrate epitope is formed by the sequential action of alpha 3-sialyltransferase and alpha 3-fucosyltransferase on N- acetyllactosamine (Gal beta 1-->4GlcNAc) disaccharide termini of glycoconjugates. We have addressed the role of the human myeloid alpha 3-fucosyltransferase in the expression of this epitope at the leucocyte surface by determining its activity in human-mouse leukemic cell hybrids (WEGLI), normal human granulocytes and chronic myeloid leukemia (CML) cells using sialylated and desialylated glycoproteins and oligosaccharides as acceptor substrates. In contrast to what has been reported for the myeloid-type enzyme, we found that the alpha 3- fucosyltransferase of the cells studied can use sialylated acceptors be it that the activity is several times lower than with asialo- substrates. Characterization of the product obtained with a sialylated oligosaccharide indicated that the enzyme can catalyze the formation of the sialyl-Le(x) structure. Flow cytometry of the WEGLI cells using a sialyl-Le(x)-specific monoclonal antibody (MoAb) showed that these cells indeed express sialyl-Lex at their surface, provided that they contain human chromosome 11. Earlier the presence of this chromosome had been correlated with the expression of alpha 3-fucosyltransferase activity. In addition to sialyl-Le(x), WEGLI cells containing chromosome 11 showed high-expression levels of related structures recognized by antibodies VIM-2 and VIM-8, suggesting that fucose addition can occur at both distal and proximal GlcNAc residues in poly- N-acetyl-lactosaminoglycan sequences. Based on the human chromosome contents it could be ruled out that the alpha 3-fucosyltransferase of WEGLI cells is a Lewis-type alpha 3/4- or plasma-type alpha 3- fucosyltransferase, the genes of which have been mapped to chromosome 19. It is concluded that the enzyme studied is of the myeloid-type and indeed is involved in the synthesis of sialyl-Le(x) (and also VIM-2 and VIM-8 structures) in leukocytes provided that its expression is at a sufficiently high level.     

开通闭塞冠状动脉策略的全球性研究 GUSTO—Ⅱb（亚组研究）

病人资料 3 289例因急性冠脉综合征而接受溶栓治疗的患者,2274例接受t－PA治疗,1015例接受链激酶治疗。     

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.     

硼替佐米联合地塞米松与沙利度胺治疗多发性骨髓瘤的效果

目的比较硼替佐米＋地塞米松＋沙利度胺（BDT）方案与长春地辛＋表柔比星＋地塞米松＋沙利度胺（VADT）方案治疗多发性骨髓瘤（MM）的临床效果。方法MM病人67例,应用BDT方案治疗30例,VADT方案治疗37例,均治疗4个疗程,比较两组治疗前、治疗后β2-微球蛋白、免疫球蛋白、骨髓瘤细胞的变化,并比较两组疗效。结果BDT组及VADT组化疗后β2-微球蛋白、免疫球蛋白、骨髓瘤细胞均低于化疗前,差异有显著性（t=2．837～7．562,P％0．05）。BDT组完全缓解（CR）占13．0％,接近完全缓解（ncR）占20．0％,部分缓解（PR）占53．0％,微小反应（MR）占6．7％,总有效率93．3％;VADT组CR占3．0％,nCR占10．8％,PR占40．5％,MR占16．2％,总有效率70．3％,两组疗效比较,差异有显著性（Hc=51．67,P〈0．05）。结论BDT方案治疗MM效果优于VADT方案,且起效快,可改善病人的预后。     

老年性痴呆与血管性痴呆患者睡眠障碍的对照研究

目的:研究老年性痴呆(AD)和血管性痴呆(VD)患者睡眠障碍的特点及相关性。方法:对31例AD患者和30例VD患者采用阿森斯(Athens)失眠量表调查评分及临床资料比较分析。对研究对象进行筛选分组。从8个方面详细记录睡眠情况,按量表现规定进行评定。结果:AD患者和VD患者总体睡眠状况比较有显著性差异(t=2.251,P<0.05)。睡眠状况各因子比较,在总睡眠质量、白天情绪、白天思睡等3个方面无显著性差异(P>0.05)。在早醒、白天身体功能方面,两者有极显著差异(P<0.01)。在入睡时间、夜间苏醒、总睡眠时间等两者存在显著性差异(P<0.05)。结论:AD患者和VD患者都有睡眠障碍,AD患者在早醒、白天身体功能、夜间苏醒、总睡眠时间等方面都比VD患者差,而VD患者在入睡时间上比AD患者明显延迟。     

Evaluation of the detection of PML-RARα fusion gene in acute promyelocytic leukemia to monitor minimal residual disease

Objective To investigate the kinetics of PML-RARα fusion gene in acute promyelocytic leukemia(APL)to monitor minimal residual disease(MRD). Methods In induction therapy,consolidation and maintenance therapy courses, PML-RARα fusion gene was performed by RT-PCR. Results The long-term follow-up of 18 cases achieved complete remission (CR),two cases experienced molecular relapse. One case relapsed at 4 months after CR1 and achieved CR2 after induction therapy. However, molecular and hematology relapsed again at 2 months after CR2 and re-achieved CR3. The other case relapsed at 74 months after CR1 and achieved CR2 after induction treatment, who had survived for 106 months until the end of follow-up. Conclusion RT-PCR assay for detection of PML-RARα should be performed regularly during CR period so as to find molecular relapse eady. Hematological relapse could potentially be averted through treatment modification according to molecular monitoring results of PML-RARα.     

Bilateral extracranial aneurysm of the internal carotid artery--a case report.

The authors report a case study of a 78-year-old man with a bilateral extracranial atherosclerotic aneurysm of the internal carotid artery. The patient was treated surgically with resection of the aneurysm and restoration of the flow with a polytetrafluoroethylene (PTFE) graft. The postoperative period was uneventful. Histologic tests demonstrated almost complete destruction of the elastin fibers. The potential hazards of an aneurysm of the internal carotid artery indicate that surgical treatment is warranted.     

Dialysis efficacy during acetate-free biofiltration

Background. Acetate-free biofiltration (AFB) is a haemodiafiltration technique based on continuous post-dilution infusion of a sterile isotonic bicarbonate solution. We performed a long-term randomized prospective trial to compare dialysis efficacy and metabolic control of AFB versus bicarbonate haemodialysis (HD). Methods. The AFB group consisted of 11 and the HD group of nine patients, matched for age, sex and urea reduction rate. Biochemical parameters were obtained every 3 months for 1 year (haemoglobin, calcium, phosphate, urea, pre- and post-dialysis bicarbonate, and parathormone (PTH)) and medication was updated. Efficacy of dialysis calculated by KT/V using the dialysate sampling method was determined every 3 months. In AFB patients, the infusion rate of bicarbonate solution was adjusted individually to obtain bicarbonate values of ⩾22 mmol/l before dialysis and ⩽32 mmol/l after dialysis. In the HD group, bicarbonate was added as oral medication to match these bicarbonate concentrations. Statistical analysis was performed using ANOVA for repeated measurements. Results. Pre-dialysis serum bicarbonate levels had risen to the same extent in both groups at the end of the study period (AFB from 21.8 to 26.1 mmol/l, P<0.001, and HD from 20.8 to 24.9 mmol/l, P<0.001). Post-dialysis bicarbonate level was higher in the AFB than in the HD group (P<0.01). Calcium and phosphate levels remained stable in both groups. PTH increased in both groups (AFB from 10.6 to 23.7 pmol/l, and HD from 24.6 to 32.8 pmol/l), with a significant rise only in the AFB patients (P<0.013). Finally, haemoglobin levels and erythropoietin dosage did not change in either group. No significant differences between the two groups were observed. Conclusions. Acidosis was better corrected in AFB without the need for oral supplementation of bicarbonate. However, neither serum calcium nor phosphate levels changed. The observed increase in PTH in the AFB group remains to be clarified. Dialysis efficacy, measured as KT/V, improved during AFB.