Pharmacotherapy in congestive heart failure: COX-2 inhibition: a cautionary note in congestive heart failure

NSAIDs have been a mainstay of therapy for rheumatologic diseases for a number of years. Unfortunately, their use was accompanied by sometimes unacceptable gastrointestinal and/or renal side effects. Therefore, safer treatment options were sought. In the process of such a search, selective cyclo-oxygenase-2 inhibitors were identified. Drugs in this class have anti-inflammatory properties similar to NSAIDs and did not produce anywhere near the same pattern of NSAID-related gastrotoxicity. The enthusiasm for this class of drugs would appear, at least on the surface, to be well grounded. However, establishing the renal side effect profile of the selective cyclo-oxygenase-2 inhibitors would appear to be a work in progress. Formal studies with selective cyclo-oxygenase-2 inhibitors have not been conducted in the congestive heart failure population. Information does though exist for other patient cohorts--similarly "prostaglandin-dependent" for their integrity of renal function, such as the elderly and sodium-deplete individual. These data would strongly suggest that the selective cyclo-oxygenase-2 inhibitors could decrease glomerular filtration rate and stimulate salt and water retention, comparable to what occurs with nonselective NSAIDs. To date, no compelling information exists, which supports the notion that differences exist among the currently available selective cyclo-oxygenase-2 inhibitors--celecoxib and--in the potential to negatively impact renal function in this and similarly compromised patient populations. (c)2000 by CHF, Inc.     

Pharmacotherapy in congestive heart failure: Hyperkalemia in congestive heart failure

Hyperkalemia is not an uncommon occurrence in the congestive heart failure patient, particularly when renal failure coexists. Hyperkalemia in CHF is typically medication-related. Its occurrence is inevitably linked to the simultaneous ingestion of angiotensin-converting enzyme inhibitors and beta-blockers, and more recently, aldosterone receptor antagonists, such as spironolactone. The most devastating consequence of hyperkalemia is its cardiotoxicity that can be fairly insidious in its rate of development. The therapy of hyperkalemia in congestive heart failure can involve both acute and semiacute management phases. Acute hyperkalemia management includes measures that block the adverse membrane effects of hyperkalemia, such as intravenous calcium administration, and efforts to shift potassium intracellularly, such as occurs with intravenous bicarbonate and/or inhaled beta-agonists. Semiacute management of hyperkalemia includes measures to increase urinary potassium excretion and administration of binding resins, such as Kayexalate?. Prevention is the cornerstone of hyperkalemia management in the heart failure patient and requires that careful attention be directed to both identifying exogenous sources of potassium and pinpointing the maximum tolerable dose of either an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. (c)2001 by CHF, Inc.     

静脉注射途径移植骨髓基质细胞的特点

目的:探讨在大鼠脑缺血的情况下经尾静脉注射移植骨髓基质细胞的可行性,为骨髓基质细胞脑移植治疗提供一种简捷、安全、有效的途径。方法:实验于2005-10/2006-08在北华大学医学院实验中心完成。取1～2个月龄SD大鼠双侧股骨和胫骨,体外分离培养大鼠骨髓基质细胞。取体质量为280～320g的SD大鼠25只,采用颈内动脉线栓法制作大脑中动脉梗死模型,造模成功后在25只大鼠中随机盲抓分为2组:骨髓基质细胞移植组(n=15)、对照组(n=10)。骨髓基质细胞移植组经静脉缓慢推入含Hoeschst33342标记的骨髓基质细胞细胞悬液1mL(2.0×107个细胞),对照组用同样方法经尾静脉注入等量不含骨髓基质细胞的DMEM培养液作为对照。分别于移植后1d、7d、14d时间点对两组大鼠进行神经功能损害严重程度评分及大脑组织切片观察比较。结果:25只大鼠均进入结果分析。①各代细胞90%以上表达巢蛋白阳性。②与对照组相比,骨髓基质细胞移植组大鼠运动、神经功能恢复明显[骨髓基质细胞移植组:(6.10±2.96),(3.30±1.83),(2.10±1.20)分;对照组:(7.43±1.51),(6.14±1.35),(4.43±1.40)分,P<0.05]。③骨髓基质细胞移植组大鼠脑组织结构较清晰、完整;对照组大鼠脑组织破坏溶解,组织结构松散,细胞结构不完整,胞浆疏松,染色变浅,间质水肿。结论:通过静脉注射进行骨髓基质细胞移植,方法简便、安全,对神经损伤动物组织重建及神经功能有确切的修复效果。     

Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and functions as a specific IL-3 receptor antagonist

The human interleukin-3 receptor (IL-3R) is expressed on myeloid, lymphoid, and vascular endothelial cells, where it transduces IL-3- dependent signals leading to cell activation. Although IL-3R activation may play a role in hematopoiesis and immunity, its aberrant expression or excessive stimulation may contribute to pathologic conditions such as leukemia, lymphoma, and allergic reactions. We describe here the generation and characterization of a monoclonal antibody (MoAb), 7G3, which specifically binds to the IL-3R alpha-chain and completely abolishes its function. MoAb 7G3 immunoprecipitated and recognized in Western blots the IL-3R alpha-chain expressed by transfected cells and bound to primary cells expressing IL-3R alpha. MoAb 7G3 bound the IL-3R alpha-chain with a kd of 900 pmol/L and inhibited 125I-IL-3 binding to high- and low-affinity receptors in a dose-dependent manner. Conversely, IL-3 but not granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited 125I-7G3 binding to high- and low-affinity IL- 3Rs, indicating that MoAb 7G3 and IL-3 bind to common or adjacent sites. In keeping with the inhibition of IL-3 binding, MoAb 7G3 antagonized IL-3 biologic activities, namely stimulation of TF-1 cell proliferation, basophil histamine release, and IL-6 and IL-8 secretion from human endothelial cells. Two other anti-IL-3R alpha-chain MoAbs failed to inhibit IL-3 binding or function. Epitope mapping experiments using truncated IL-3R alpha-chain mutants and IL-3R alpha/GM-CSFR alpha chimeras revealed that 31 amino acids in the N-terminus of IL-3R alpha were required for MoAb 7G3 binding. MoAb 7G3 may be of clinical significance for antagonizing IL-3 in pathologic conditions such as some myeloid leukemias, follicular B-cell lymphoma, and allergy. Furthermore, these results implicate the N-terminal domain of IL-3R alpha in IL-3 binding. Since this domain is unique to the IL-3/GM- CSF/IL-5 receptor subfamily, it may represent a novel and common binding feature in these receptors.     

Pulmonary sclerosing pneumocytoma (sclerosing haemangioma): Radical radiation therapy

We present a case of pulmonary sclerosing pneumocytoma (PSP) – (Formerly known as pulmonary sclerosing haemangioma) which was successfully treated with definitive radical external beam radiation therapy (EBRT). To our knowledge, such a treatment response has not been described in the literature.     

A tissue reconstitution model to study cancer cell‐intrinsic and ‐extrinsic factors in mammary tumourigenesis

The contribution of cancer cell‐intrinsic and ‐extrinsic factors to metastatic breast cancer is still poorly understood, hampering development of novel therapeutic strategies that decrease breast cancer mortality. Cre/loxP‐based conditional mouse models of breast cancer present unique opportunities to study sporadic tumour formation and progression in a controlled setting. Unfortunately, the generation of mouse strains carrying multiple mutant alleles needed for such studies is very time‐consuming. Moreover, conditional mouse tumour models do not permit independent manipulation of tumour cell‐intrinsic and ‐extrinsic factors. Although the latter can be achieved by cleared fat‐pad transplantation of mouse mammary epithelial cells (MMECs) from tumour suppressor gene (TSG) knockouts into wild‐type or mutant recipients, this procedure is not possible for mutations that cause embryonic lethality or preclude mammary gland development. Here we show that cleared fat‐pad transplantations with MMECs isolated from K14cre;Cdh1^F/F; Trp53^F/F mice expressing Cre recombinase under control of the cytokeratin‐14 promoter and carrying conditional null alleles for p53 and E‐cadherin (Cdh1) first resulted in the formation of phenotypically normal mammary glands, followed by the development of invasive metastatic mammary tumours. Tumour formation in the recipients mimicked tumour latency, spectrum, morphology, immunophenotype, and metastatic characteristics of the original mammary tumour model. This transplantation system, which can be expanded to other conditional TSG knockouts, permits independent genetic analysis of stromal factors and testing of additional cancer cell‐intrinsic mutations that would otherwise be embryonic lethal or require intensive breeding. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

7-甲氧基-4′-羟基-3′-二乙胺甲基异黄酮(MHDF)对大鼠血流动力学和主动脉的作用

本实验观察了MHDF对整体大鼠血流动力学和离体大鼠胸主动脉的作用。结果表明iv MHDF(3～12.8 mg/kg)能降低大鼠左心室±dp/dt_(max),V_(max),V_(pm)和LVSP,延长T-dp/dt_(max),减慢心率。MHDF还能舒张大鼠胸主动脉,ED_(50)为6.5×10~(-6)mol/L;非竞争拮抗NA和CaCl_2致主脉收缩,pD_2′为3.11±0.21和3.73±0.07;抑制高K~ 致主动脉收缩,IC_(50)为1.76×10~(-5)mol/L。提示MHDF对血管的作用与α受体阻断剂不同,而可能与钙拮抗有关。