Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c- myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.     

Cytotoxic T-cell responses show more restricted specificity for self than for non-self H-2D-coded antigens

The specificity of recognition of H-2 antigens by various subsets of Tc cells was investigated with respect to the two separate molecules known to be coded in the H-2D(d) region (a) D which carries the private specificity H-2.4 and (b) D’which carries the public specificity H-2.28. BALB/c.H-2(db) mutant mice express D but not D’ on their cell surfaces, whereas wild-type BALB/c mice express both D and D’. H-2 restricted Tc cells specific for viral-plus- H-2D(d)-coded antigens on infected self cells, or minor H-plus-H-2D(d)-coded antigens on H-2-compatible cells apparently recognize D, but do not detectably recognize D. In contrast, BALB/c-H-2(db) anti-BALB/c Tc cell responses do recognize D’ (the only known antigen which is not shared by mutant and wild-type); furthermore, D’ is also detectably recognized by a significant proportion of the Tc cells that respond in MLR to H-2D(d)-coded antigens. In these latter responses, D’ was recognized separately from D, i.e., the response was not “H-2 restricted”. These results indicate that H-2 restricted Tc cell responses to modified-self cells are more specific for self H-2D(d)-coded antigens then are allogeneic Tc cell responses directed at the same antigens, in that haplotype-unique (private) specificity recognition (of the D molecule) exclusively occurs only in the former, not the latter case. The implications of this specificity of H-2 restricted responses for possible processes of somatic selection of anti-self recognition structures on progenitor Tc cells are briefly discussed.     

Circulating glycosaminoglycan anticoagulants associated with suramin treatment

A complex coagulopathy appeared in three women receiving suramin as treatment for metastatic adrenocortical carcinoma. Although hepatocellular dysfunction accounted for some of the abnormality, a unique feature of the coagulopathy was the presence of an inhibitor of the thrombin clotting time. The potency of this circulating anticoagulant increased markedly during exacerbations of hepatic injury. The anticoagulant was removed from plasma samples from two of the patients by passage over a column of diethylaminoethyl (DEAE)- Sephacel. It eluted from the DEAE at salt concentrations that removed "high-charge" glycosaminoglycans. Elimination of the purified anticoagulant activity in vitro required a combination of heparitinase and chondroitinase ABC, suggesting that the activity was mediated by both heparan sulfate and dermatan sulfate. Suramin is hypothesized to inhibit enzymes that normally degrade glycosaminoglycans, resulting in accumulation of these substances, which are released from the liver into the circulation during periods of hepatic injury.     

Transesophageal two- and three-dimensional echocardiographic diagnosis of combined left ventricular pseudoaneurysm and ventricular septal rupture

Two- (2-D) and three-dimensional (3-D) transesophageal echocardiography (TEE) were useful in making the diagnosis of combined left ventricular pseudoaneurysm and ventricular septal rupture in an elderly patient presenting with mediastinitis and worsening heart failure following coronary artery bypass graft surgery. The diagnosis was not suspected clinically. Three-dimensional TEE served to increase the confidence level with which the diagnosis of this combined lesion was made. Additionally, 3-D TEE proved superior to 2-D TEE in assessing the size of the left ventricular rupture site.     

Inferior vena cava filters: a framework for evidence-based use

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Multiple peripheral arterial and aortic aneurysms in Behcet’s syndrome—a case report

Behcet’s syndrome is an inflammatory disorder of unknown cause, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Behcet’s syndrome with predominant vascular involvement is known as vasculo-Behcet. Arterial complications occur in only 1 to 7% of patients with Behcet’s syndrome. In most reports, arterial lesions are isolated. We report a case of Behcet’s syndrome that, over 6 years, developed multiple aneurysms in peripheral arteries and aorta without any coexisting venous thrombosis. An increased awareness of Behcet’s syndrome and its vascular complications is essential. This is highlighted by the fact that our patient had to undergo four surgeries and many years of diagnostic uncertainty before reaching at the final diagnosis.     

Antiphospholipid antibody syndrome presenting with disseminated bleeding and spinal subdural hemorrhage

STUDY DESIGN: Case report. OBJECTIVES: To report a rare cause of spinal subdural hematoma. SETTING: A tertiary care university hospital in Andhra Pradesh, India. METHODS: Detailed evaluation and reporting of a case admitted in the hospital. RESULTS: A case of antiphospholipid antibody syndrome (APS) was found to present with spontaneous spinal subdural hematoma and paraplegia. This is a very rare presentation of APS. CONCLUSION: This article describes a rare case of APS presenting with disseminated bleeding and spontaneous spinal subdural hematoma, resulting in paraplegia.     

Modulation of cardiovascular remodeling with statins: fact or fiction?

The concept of cardiac remodeling implies a complex mixture of myocardial ischemia, and increased wall stress that results in molecular, cellular and interstitial changes in the heart. Clinically, cardiac remodeling is manifested as a change in size, shape and function of the heart. Morphologically the key feature of remodeling is myocyte hypertrophy, myocyte loss from necrosis or apoptosis, as well as interstitial cell growth especially fibroblast proliferation leading to myocardial fibrosis. Cardiac remodeling is influenced by hemodynamic load, neurohumoral activation, and other factors that can further affect the remodeling process. Despite advances in the management of heart failure, morbidity and mortality still present major health care issues in these patients. Statins (HMG Coenzyme A reductase inhibitors) play a key role in the management of ischemic heart disease. Recent studies indicate that statins may modulate cardiac remodeling by affecting signals that cause fibroblast growth, and myocyte hypertrophy and loss. In this paper we review the mechanisms of cardiac remodeling and the mechanisms of potential beneficial effects of statins on cardiac remodeling.