克罗恩病内科治疗的新进展

对于活动期克罗恩病(CD)的治疗,日本是以营养疗法为首选;欧美则根据随机对照试验(RCF)的结果以类固醇激素为主,其差异可能与治疗期间,胃肠道营养剂的组成,QOL(生活质量)以及医疗保险制度等不同有关.近年来开发出较以往常用药物(柳氮磺胺吡啶及强的松)副作用少的新制剂.此外,根据疾病的具体情况,可以选择抗CD4抗体;抗TNF-α抗体;外源性给予IL-10;抗粘附分子疗法;白细胞去除疗法;免疫调节疗法;肝素抗凝,EPA等疗法.     

Monoclonal antibody to human high-molecular-weight kininogen recognizes its prekallikrein binding site and inhibits its coagulant activity

We developed a mouse monoclonal antibody (MoAb 115-21) to human high- molecular-weight kininogen (HK) that recognizes its prekallikrein binding site (residues 565 through 595 of HK). The corresponding synthesized 31-amino acid peptide (peptide IV) was recently shown to retain native HK's prekallikrein binding property. The same peptide bound factor XI also, although less avidly. Our MoAb recognizes purified HK, peptide IV, and the light chain moiety of HK (where the peptide IV resides), as shown by enzyme-linked immunosorbent assay (ELISA) and Western blotting experiments. The apparent dissociation constant for the HK and MoAb 115-21 interaction was 2.2 nmol/L. It does not recognize low-molecular-weight kininogen (LK) with which HK shares its heavy chain moiety or any antigens in human plasma congenitally deficient in kininogens. The binding of MoAb 115-21 to purified light chain of HK was competitively inhibited by peptide IV. In addition, the antibody inhibits HK-dependent clotting activity of normal human plasma and dextran sulfate-mediated activation of prekallikrein in plasma and retards cleavage of HK in normal plasma after contact activation with dextran sulfate. Also, purified Fab fragments of MoAb 115-21 inhibited the HK-dependent coagulant activity and dextran sulfate-mediated prekallikrein activation in normal plasma. Since the kd for HK-MoAb 115- 21 interaction is ten times lower than that of HK-prekallikrein, our data suggest that binding of MoAb 115-21 to HK's peptide IV site increases the free prekallikrein concentration in plasma and thus results in the decreased efficiency of factor XIIa-mediated activation of prekallikrein. Decreased levels of kallikrein thus formed may be responsible for the inhibition of HK-dependent clotting activity and the decrease in rate and extent of HK cleavage in normal plasma on contact activation with dextran sulfate. MoAb 115-21 may thus prove very useful, especially with its high affinity for HK, in further delineation of the role of HK and prekallikrein in contact activation and kinin-related human pathology.     

Bone marrow disorders: characterization with quantitative MR imaging

Thirty patients with various hematologic disorders and 15 healthy control subjects underwent quantitative magnetic resonance (MR) imaging of the lumbar spine with spin-echo techniques. Images of patients with infiltrative bone marrow disorders showed significantly more prolonged T1 times than those of control subjects (P less than .001). It was not possible to distinguish different diffuse infiltrative bone marrow disorders on the basis of T1 values. Aplastic anemia could be distinguished from normality because of significantly shortened T1 (P less than .001). A significant correlation was seen between T1 and bone marrow cellularity (r = .74, P less than .001). T2 was of no value in the characterization of bone marrow disorders. Quantitative MR imaging dose not improve the diagnostic potential of bone marrow imaging in the detection of diffuse marrow infiltrates.     

What is the role for improved long-term antiplatelet therapy after percutaneous coronary intervention?

Background

Coronary stent placement has replaced balloon angioplasty as the percutaneous coronary intervention (PCI) method of choice, primarily because of its lower restenosis rate. Compared with aspirin (ASA) monotherapy or ASA plus warfarin, the ticlopidine and ASA combination is superior in reducing thrombotic events after stenting. Clopidogrel plus ASA appears to be at least as effective as ticlopidine and ASA. Intravenous glycoprotein IIb/IIIa inhibitors effectively prevent periprocedural thrombotic complications, but their short duration of action and parenteral dosing don’t allow for long-term protection. This review aimed to answer how long after PCI with a stent patients are at risk for recurrent thrombotic events and what the optimal way to prevent them is.

Results

Classically, ASA has been prescribed indefinitely, whereas adenosine diphosphate receptor antagonists have been discontinued after 2 to 4 weeks. However, the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial found that long-term dual antiplatelet therapy with clopidogrel and ASA was more effective than ASA alone in preventing major cardiovascular events in patients with acute coronary syndrome, including those treated with PCI.

Conclusion

Results from additional ongoing studies are needed to clarify the role of long-term dual oral antiplatelet therapy in preventing ischemic events in patients who have undergone PCI.     

The severe combined immunodeficient-human peripheral blood stem cell (SCID-huPBSC) mouse: a xenotransplant model for huPBSC-initiated hematopoiesis

Mononuclear cells (MNCs) containing peripheral blood stem cells (PBSCs) were obtained from solid-tumor patients undergoing mobilizing chemotherapy followed by granulocyte colony-stimulating factor for PBSC transplantation-supported dose-intensified anticancer chemotherapy and were transplanted into unconditioned "nonleaky" young severe combined immunodeficient mice. Multilineage engraftment was shown by flow cytometry and immunocytochemistry using monoclonal antibodies to various human cell surface antigens as well as identification of human immunoglobulin in murine sera. Within a dose range of MNCs suitable for transplantation (10 to 36 x 10(6) cells/graft) the number of CD34+ cells injected (optimal at > 0.7 x 10(6)/graft) determined the yield of human cells produced in recipient animals. Engraftment of hu PBSC preparations resulted in prolonged generation of physiologic levels of human cytokines including interleukin-3 (IL-3), IL-6, and granulocyte- macrophage colony-stimulating factor, which were detectable in the murine blood over a period of at least 4 months. In vivo survival of immature human progenitor cells was preserved even 9 months after transplantation. Because human IL-3 is known to stimulate early hematopoiesis, a rat fibroblast cell line was stably transfected with a retroviral vector carrying the human IL-3 gene and cotransplanted subcutaneously as additional source of growth factor. Cotransplants of this cell line producing sustained in vivo levels of circulating human IL-3 for at least 12 weeks significantly accelerated the process of engraftment of huPBSC and spurred the spread of mature human cells to the murine spleen, liver, thymus, and peripheral blood. Cotransplants of allogeneic human bone marrow stromal cells derived from long-term cultures resulted in a comparable--though less prominent--support of engraftment.