Expression of the Tn antigen in myelodysplasia, lymphoma, and leukemia

Expression of the normally cryptic blood group antigen Tn has occasionally been reported in hematologic disease, but the true frequency of this change is not known. A mouse monoclonal antibody (FBT3) and immunohistochemistry were used to examine expression of the Tn antigen. Expression was not detected in 35 normal bone marrow aspirates examined, but it was detected in 5 of 725 abnormal bone marrow aspirates, including 2 (3.6%) of 55 cases of de novo acute nonlymphocytic leukemia and 2 cases that terminated in acute nonlymphocytic leukemia. In two patients, one with acute myeloblastic leukemia and the other in blast transformation of chronic myeloid leukemia, the Tn antigen was expressed on 2 percent of blast cells. In one case of non-Hodgkin's lymphoma, 4 percent of normal myeloid cells expressed the antigen. In the other two cases, one of acute myelomonocytic leukemia and the other of myelodysplasia, only 2 to 8 percent of myeloid and erythroid cells initially were Tn positive. Subsequent serial immunohistochemical studies of bone marrow aspirates and peripheral blood in these two cases showed increasing numbers of Tn-positive erythroid and myeloid cells 8 to 12 months before polyagglutination was detected serologically. Tn-positive cells increased to > 90 percent in the terminal phase in both cases of both diseases. The results suggest that Tn expression in these two patients may have conferred a growth advantage to the cells and could be related to disease progression.     

Some observations on the Inb antigen and evidence that anti-Inb causes accelerated destruction of radiolabeled red cells

This report describes an example of anti-Inb, a red cell alloantibody directed against a high-frequency antigen, detected in a prenatal sample obtained from a Canadian woman of Asian Indian extraction. Although the antibody is IgG1, it could not be detected in the serum or on the red cells (RBCs) of her In(b+) infant. Evidence is provided that the Inb antigen is denatured by papain, ficin, trypsin, bromelin, cystein-activated papain/dithiothreitol, 6 percent aminoethylisothiouronium, and 50 mM dithiothreitol, but not by neuraminidase. Inb antigen strength appears reduced on the In(Lu) type but not on the LuLu type of Lu(a-b-) RBCs. RBCs from a patient with paroxysmal nocturnal hemoglobinuria showed normal Inb antigen strength as did Ko, Ge:-2,3, Ge:-2,-3, and Yt(a-) RBCs. A RBC survival study using 51Cr-labeled In(b+) RBCs showed 97 percent survival 90 minutes after injection but reduced survivals of 62 and 14 percent at 24 and 96 hours, respectively. These results indicate that this example of anti-Inb is unlikely to be implicated in an immediate hemolytic transfusion reaction, but that delayed extravascular hemolysis might occur.     

Growth factors and cytokines in the prevention and treatment of oral and gastrointestinal mucositis

Goals of work Growth factors and cytokines may be useful in preventing chemotherapy (CT)- and radiotherapy (RT)-induced oral and gastrointestinal mucositis. Two systematic reviews of the medical literature on growth factors and cytokines for the amelioration of CT- and RT-induced mucositis throughout the alimentary tract were performed by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology. The aim of these evidence-based scientific reviews was to critically evaluate the literature and create evidence-based guidelines for the use of growth factors and cytokines in the prevention or treatment of CT- and RT-induced mucositis.Method The two reviews covered articles on clinical trials from January 1966 through May 2002 and preclinical studies from June 2002 through May 2005, respectively. The systematic review process was based on a well-established method for evaluating scientific literature.Main results The number of articles in the first review was 29. In the second review, 23 articles were evaluated, 14 preclinical and 9 clinical studies. It was concluded from the first review that there was no sufficient evidence to provide any recommendations for clinical practice guidelines regarding growth factors and cytokines. From the second review, a guideline could be presented recommending the use of recombinant human keratinocyte growth factor-1 (palifermin) to prevent oral mucositis in patients receiving high-dose CT and total body irradiation followed by stem cell transplantation for haematological malignancies. A guideline could also be provided suggesting that granulocyte macrophage colony-stimulating factor mouthwash not be used for the prevention of oral mucositis in the transplant setting with high-dose CT and autologous or allogeneic stem cell transplantation.Conclusions These systematic reviews have provided clarity and shown exciting new results. Further studies will provide new options for this debilitating side-effect of cancer therapy.     

Beating-heart percutaneous mitral valve repair using a transcatheter endovascular suturing device in an animal model.

BACKGROUND: The edge-to-edge (Alfieri) technique for mitral valve repair is a versatile method of treating mitral insufficiency. Because of its simplicity, it has been applied in minimally invasive surgery, and recently, in the design of endovascular closed-heart devices. AIM: The purpose of this study was to evaluate the acute in-vivo safety and feasibility of a novel percutaneous mitral valve repair system based on Alfieri technique in an animal model. METHODS: Under general anesthesia, 11 pigs (90-100 kgs), underwent percutaneous Alfeiri procedure. The right femoral vein was punctured and the mitral valve was approached via a standard transeptal puncture. Combined intracardiac echo and fluoroscopic guidance was used. The procedure included: the positioning of a guide catheter for multiple access to the left atrium and for directing devices; the use of a therapy device to capture the free edge of the mitral valve leaflets using vacuum, and to deliver the suture to the valve and finally the fixation with a Nitinol suture clip, and trimming of the suture with a fastener catheter. RESULTS: Leaflet capture, suture placement, and suture-clip deployment was successful in all 11 animals. There were no acute cardiac or access site complications. Procedural time (from wire in left atrium to completion of the procedure was 18 +/- 9 min (range 9-30 min). Blood loss was 67 +/- 44 ml (range 0-125 ml). A double orifice configuration was visible by echocardiography at the end of the procedure in all animals. CONCLUSION: This acute animal study demonstrated the feasibility of a beating heart percutaneous Alfieri procedure in a non-diseased porcine valve using an endovascular suturing device to safely access the mitral valve, place a stitch through the mitral valve leaflets, and deploy a suture-clip that reproduces the surgical technique. Clinical application of this device in humans needs to be evaluated.     

Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor

The mechanism by which activated protein C stimulates fibrinolysis was studied in a simple radiolabeled clot lysis assay system containing purified tissue-type plasminogen activator, bovine endothelial plasminogen activator inhibitor (PAI), plasminogen, 125I-fibrinogen and thrombin. Fibrinolysis was greatly enhanced by the addition of purified bovine activated protein C; however, in the absence of PAI, activated protein C did not stimulate clot lysis, thus implicating this inhibitor in the mechanism. In clot lysis assay systems containing washed human platelets as a source of PAI, bovine-activated protein C-dependent fibrinolysis was associated with a marked decrease in PAI activity as detected using reverse fibrin autography. Bovine-activated protein C also decreased PAI activity of whole blood and of serum. In contrast to the bovine molecule, human-activated protein C was much less profibrinolytic in these clot lysis assay systems and much less potent in causing the neutralization of PAI. This species specificity of activated protein C in clot lysis assays reflect the known in vivo profibrinolytic species specificity. When purified bovine-activated protein C was mixed with purified PAI, complex formation was demonstrated using immunoblotting techniques after polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. These observations suggest that a major mechanism for bovine protein C- dependent fibrinolysis in in vitro clot lysis assays involves a direct neutralization of PAI by activated protein C.     

Effect of granulocyte-macrophage colony-stimulating factor on lymphokine-activated killer cell induction

The treatment of cancer with lymphokine-activated killer (LAK) cells in conjunction with high-dose interleukin-2 (IL-2) has been limited by the toxicity of IL-2 and the narrow range of tumors that respond to therapy. Cytokines that are capable of augmenting lower doses of IL-2 are, therefore, a major focus of research. We report here that granulocyte-macrophage colony-stimulating factor (GM-CSF) can augment low-dose IL-2 LAK induction from murine splenocytes. Anti-tumor necrosis factor alpha (anti-TNF alpha) or anti-interferon gamma (anti- IFN gamma) monoclonal antibodies did not inhibit (IL-2 + GM-CSF)- induced LAK generation, indicating that GM-CSF augmentation does not require TNF alpha or IFN gamma activity. Depletion of natural killer cells before culture did not inhibit low-dose IL-2-induced LAK generation or the ability of GM-CSF to augment LAK generation. In contrast, depletion of both CD4+ and CD8+ T cells before culture inhibited the generation of LAK activity. However, depletion of only CD4+ T cells, or only CD8+ T cells, did not inhibit the generation of IL-2 or (IL-2 + GM-CSF) LAK activity. These results suggest that LAK precursors are present in both the CD4+ and CD8+ T-cell populations and suggest that the addition of GM-CSF to low-dose IL-2 may result in the generation of T-derived LAK cells.     

From the Cover: Distemper,extinction, and vaccination of the Amur tiger

Canine distemper virus (CDV) has recently emerged as an extinction threat for the endangered Amur tiger (Panthera tigris altaica). CDV is vaccine-preventable, and control strategies could require vaccination of domestic dogs and/or wildlife populations. However, vaccination of endangered wildlife remains controversial, which has led to a focus on interventions in domestic dogs, often assumed to be the source of infection. Effective decision making requires an understanding of the true reservoir dynamics, which poses substantial challenges in remote areas with diverse host communities. We carried out serological, demographic, and phylogenetic studies of dog and wildlife populations in the Russian Far East to show that a number of wildlife species are more important than dogs, both in maintaining CDV and as sources of infection for tigers. Critically, therefore, because CDV circulates among multiple wildlife sources, dog vaccination alone would not be effective at protecting tigers. We show, however, that low-coverage vaccination of tigers themselves is feasible and would produce substantive reductions in extinction risks. Vaccination of endangered wildlife provides a valuable component of conservation strategies for endangered species.

Tigers (Panthera tigris), among the world’s most iconic carnivore species, are highly threatened. Having once occupied vast swathes of Asia from Turkey to the Sea of Japan, fewer than 3,500 tigers now survive with breeding populations in just eight countries, all of which are fragmented and acutely vulnerable to extinction (1). The Amur tiger subspecies (P. tigris altaica) numbers fewer than 550 individuals in two discrete populations in the Russian Far East and neighboring areas of China.     

A comparison between activated protein C and des-1-41-light chain- activated protein C in reactions with type 1 plasminogen activator inhibitor

This study investigates the role of the gamma-carboxyglutamic acid (gla) containing domain of activated protein C in interactions with both platelet-derived and purified type 1 plasminogen activator inhibitor (PAI-1). The activity of human platelet PAI-1 was neutralized to the same extent by bovine activated protein C and bovine des-1-41- light chain-activated protein C. Both forms of activated protein C formed SDS-stable, divalent-cation independent complexes with platelet PAI-1, as demonstrated by immunoblotting using antibodies directed to either protein C or PAI-1. Since activated protein C neutralized PAI-1, the potential inhibition of the enzyme by PAI-1 was studied. Purified PAI-1 inhibited the amidolytic activity of bovine-activated protein C and bovine des-1-41-light chain-activated protein C with a k2 of 2.85 X 10(4) M-1 sec-1 for both proteins. These data suggest that the gla domain of activated protein C is not required for neutralization of PAI- 1 activity, for complex formation with PAI-1, or for inhibition of the amidolytic activity of activated protein C by PAI-1.     

The molecular basis of alpha thalassemia in India. Its interaction with the sickle cell gene

The alpha globin genotype of a total of 282 Indians from Orissa state has been analyzed. The overall alpha thalassemia gene frequency is 0.29, most frequently caused by the -alpha 3.7 and -alpha 4.2 deletions. In one family a novel -alpha 3.5 deletion removing the alpha 1 globin gene with some of its flanking sequences has been found, suggesting further sequence homology of the alpha globin gene cluster 3' to the alpha 1 globin gene. Patients with sickle cell disease and alpha thalassemia had higher hemoglobin (Hb) levels, RBC counts, and Hb A2 levels, and lower reticulocyte counts, MCV, MCH, and Hb F levels than those with a normal alpha genotype. The frequency of splenomegaly was not influenced by the alpha globin genotype. A higher prevalence of alpha thalassemia was found in patients greater than or equal to 10 years of age than in the younger group, suggesting a possible advantageous effect of alpha thalassemia on the survival of patients with sickle cell disease.