Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia

Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non- DS children when treated with protocols containing 1-beta-D- arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein- Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of l-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 micromol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 micromol/L ara-C, respectively). Elevated ara-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase. Further study of the mechanisms (ie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients.     

Dependence of the permanent deformation of red blood cell membranes on spectrin dimer-tetramer equilibrium: implication for permanent membrane deformation of irreversibly sickled cells

Red blood cells (RBCs) in sickle cell anemia, transformed into a sickled shape by prolonged deoxygenation, or normal RBCs deformed by a prolonged micropipette aspiration become permanently stabilized in their abnormal shape. This semisolid plastic behavior is thought to involve an irreversible reorganization of the membrane skeleton, but the exact nature of this skeletal rearrangement is not known. In this study, we first asked whether the irreversible deformation is associated with a permanent stretching of the skeletal network, and then whether it is due to a rearrangement of skeletal components involving a disruption of pre-existing protein associations and the subsequent reassociation of new protein contacts. Having found no ultrastructural evidence of stretching of the skeletal lattice in membranes derived from permanently deformed RBCs, we addressed the possibility of reorganization of the proteins of the membrane skeleton. We examined the temperature dependence of irreversible cell deformation to see if it correlated with the known temperature dependence of spectrin tetramers to dimer dissociation and reassociation. Testing the shape irreversibility of both deoxygenated reversibly sickled cells and Nucleopore-aspirated normal cells, we found that both types of cells became permanently deformed when the prolonged incubation of applied force or deoxygenation was performed at 37 degrees C, the temperature at which spectrin tetramers were free to dissociate and reassociate. In contrast, both types of cells were able to regain their original discocytic shape if the prolonged incubation was performed at the lower temperature: at less than 13 degrees C instead of 37 degrees C. Furthermore, normal RBCs were incubated with inosine and pyruvate to elevate intracellular 2,3-diphosphoglycerate, the polyanion shown to destabilize spectrin-actin-protein 4.1 association. This did not result in a promotion of irreversible deformation of these cells. We conclude that the irreversible cell deformation observed at physiologic temperature is associated with a skeletal rearrangement through dissociation of spectrin tetramers to dimers and a subsequent reassociation of dimers to tetramers in the new (deformed) configuration. These findings may explain a permanent stabilization of irreversibly sickled cells in their abnormal shape in vivo.     

Radiology interventions in patients receiving low molecular weight heparin: Timing is critical

Recent advances in diagnosis and treatment of venous thromboembolism have been associated with increasing use of low molecular weight heparins (LMWH) for treatment and prophylaxis of this disease. Despite this trend for more widespread use of LMWH, little is known of their safety in patients undergoing radiology interventions. Differences between LMWH and unfractionated heparin and the implications of these differences on use of LMWH in the setting of radiological interventions are outlined.     

氧瓶燃烧-紫外分光光度法测定硒灵胶囊中硒的含量

目的：控制本品中硒的含量。方法：采用氧瓶燃烧法使本样品中的主要成份硒酯多糖成四阶硒离子,并与２,３－二氨基萘（ＤＮＡ）络合生成４,５－苄苯并硒二唑,然后采用紫外分光光度法测定其含量,结果：硒的浓度在０．２～２．０μｇ／ｍｌ之间线性范围良好。结论：该法具有简便,快速,准确的优点。     

Technology assessment: relationship to coverage issues--a case for temporary coverage decisions

Making appropriate coverage decisions has the potential of impacting patient outcomes. In both the public and private sectors, great diversity exists in the methodology and process used to make coverage decisions. Because definitional issues are important, they are described in this article. The underpinning of coverage decisions are a commitment to certain methodological principles, including embracing evidence-based medicine. The role of the federal government and local entities in regard to evidence production and process as well as methodology used to formulate policy decisions is complex and requires resolution. A temporary coverage decision can be a helpful tool when no consensus exists.     

Lysosomal glycogen storage disease with normal acid maltase

Two unrelated 16-year-old boys had mental retardation, cardiomegaly, and proximal myopathy. One also had hepatomegaly. Histochemistry and electronmicroscopy of muscle biopsies showed lysosomal glycogen storage resembling acid maltase deficiency. Biochemical studies of skeletal muscle showed increased content of glycogen of normal structure; acid alpha-glucosidase activity in both urine and muscle was normal. Other enzymes of glycogen metabolism were also normal. The cause of this apparently generalized glycogenosis with no demonstrable enzyme defect is unknown.     

Telephone transmission of radiographic images

A new system for telecommunication of radiographic images using readily available telephone transmission circuitry is described. The resulting video images were satisfactory for accurate interpretation in 80% of the cases tested. The system is moderately priced and has facilitated maintenance of radiodiagnostic interpretive services at a satellite office form the central hospital location.     

胃癌前病变中DNA甲基化状态与叶酸

DNA甲基化异常是胃癌发生的重要机制之一,为了能尽早发现并纠正DNA甲基化异常,阻止胃癌的发生,胃黏膜癌前病变中DNA甲基化状态的研究日益受到重视．众多研究表明,胃黏膜癌前病变中多种基因中存在甲基化异常,而且基因的甲基化异常程度与年龄、性别有关,还与胃黏膜上皮细胞是否存在活动性炎症、肠化及幽门螺杆菌感染有关．叶酸缺乏可导致DNA甲基化的紊乱和DNA修复机制效率的减弱, 叶酸摄入量不足患胃癌的相对危险度增高;胃黏膜癌前病变患者体内叶酸不足,黏膜细胞总基因组DNA甲基化水平下降;经叶酸治疗后,体内叶酸升高,黏膜细胞总基因组DNA 甲基化水平上升,异型增生、肠上皮化生明显改善．因此,叶酸缺乏与胃黏膜癌前病变的发生、发展有关,及时纠正叶酸不足,可逆转胃黏膜的病理改变,减少胃癌的发生．