Tandem transplantation with peripheral autologous hematopoietic blood stem cells in treatment of oncologic and hematologic malignancies. Initial results of the Donauspital, Vienna

10 patients were subjected to tandem transplantation for breast cancer (n = 3), ovarian cancer (n = 2) and multiple myeloma (n = 5), at the Second Department of Medicine, Donauspital, Vienna. The breast cancer patients were in stages 2 and 3, respectively, at diagnosis and entered complete remission thereafter. 2 of them developed lymph node metastasis and additional local recurrence, the 3rd patient presented with distant metastasis. The 2 patients with ovarian cancer were in stages Figo III and IV, respectively, at the time of diagnosis, and showed minimal residual disease at second-look-operation. 5 patients with multiple myeloma were in stage 3 pretransplant. Peripheral stem cells were obtained after either high-dose cyclophosphamide or FEC induction and application of cytokines. In 4 patients, tandem transplantation has been completed. 1 patient with multiple myeloma, who had received total body irradiation in combination with chemotherapy for the 2nd transplant, succumbed from idiopathic interstitial pneumonia. No severe clinical complications were observed in all other patients. All patients with solid tumors entered complete remission after the 1st transplantation. 3 of them completed tandem transplantation. Of these, 2 remain in continuous complete remission, the 3rd patient relapsed in lymph nodes day 485. In patients who received only 1 course of high dose chemotherapy with stem cell transplantation, relapses occurred on days 29 and 75, respectively. All patients with multiple myeloma entered only partial remission. We conclude that supralethal chemotherapy with peripheral blood stem cell support is a safe procedure that may at least induce prolonged remissions in solid tumors and hematologic malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification and characterization of novel antimicrobial decapeptides generated by combinatorial chemistry

Novel combinatorial libraries consisting of simplified amino acid sequences were designed to screen for peptides active against the Candida albicans membrane. A novel decapeptide, KKVVFKVKFK, that had a unique primary amino acid sequence was identified in this work. This peptide irreversibly inhibited the growth of C. albicans and showed a broad range of antibacterial activity but no hemolytic activity. Circular dichroism spectra revealed that the predominant secondary structure of this peptide strongly depended on the membrane-mimetic environments; the peptide preferred to form an amphipathic alpha-helical structure in the presence of 50% trifluoroethanol, while it preferred to adopt a distorted alpha-helical structure in the presence of sodium dodecyl sulfate micelles. Experiments in which dye was released from vesicles indicated that this novel antimicrobial peptide killed microorganisms through the action on the membrane as its primary target. Replacement of amino acids in this active decapeptide on the basis of information from the libraries could provide unique information about factors affecting its antimicrobial activity such as its secondary structure, net positive charge, and hydrophobicity.     

Crystal structure of a murine alpha-class glutathione S-transferase involved in cellular defense against oxidative stress

STATEMENT OF PROBLEM: The electric alloy brazed joints of removable partial denture alloys have failed frequently after routine usage. PURPOSE: A technique providing higher joint strengths was investigated. This investigation compared the tensile strengths of electric-brazed and laser-welded joints for a cobalt-chromium removable partial denture alloy. MATERIAL AND METHODS: Twenty-four cobalt-chromium standard tensile testing rods were prepared and divided into three groups of eight. All specimens in the control group (group 1) were left in the as-cast condition. Groups 2 and 3 were the test specimens, which were sectioned at the center of the rod. Eight specimens were joined by using electric brazing, and the remaining specimens were joined by using laser welding. After joining, each joint was ground to a uniform diameter, then tested to tensile failure on an Instron universal testing machine. Failure loads were recorded and fracture stress calculated. Statistical analysis was applied. RESULTS: The student-Newman-Keuls test showed a highly significant difference between the joint strengths of the as-cast control specimens, the electric-brazed and laser-welded joints. CONCLUSIONS: The tensile strengths of the as-cast joints were higher than those for the laser-welded joints, and both were higher than the electric-brazed joint strengths.     

Increase of intracellular calcium is the essential signal for the expression of CD40 ligand

CD40 ligand (CD40L) is present on activated but not on resting T cells. In contrast to the activation markers CD25 and CD71, a strong CD40L expression could be induced by calcium ionophore alone but not by phorbol 12-myristate 13-acetate (PMA). Ionomycin induced a very early mRNA and protein surface expression of CD40L within the first 2 h, whereas CD25 and CD71 did not appear earlier than 6 h after stimulation. The mitogens phytohemagglutinin and concanavalin A induced little CD40L, but together with PMA, a markedly increased CD40L expression was observed. In T cells stimulated with immobilized anti-CD3, co-stimulation with anti-CD28 or PMA induced an earlier and higher maximal CD40L expression. CD40L expression of purified T cells was higher and more prolonged compared to that of T cells in unseparated peripheral blood mononuclear cells. We conclude that the expression of CD40L on T cells is profoundly different from other early activation markers with regard to signal requirements, kinetics and the role of accessory cells in the system.     

Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL

The subendothelial accumulation of macrophage-derived foam cells is one of the hallmarks of atherosclerosis. The recruitment of monocytes to the intima requires the interaction of locally produced chemokines with specific cell surface receptors, including the receptor (CCR2) for monocyte chemoattractant protein-1 (MCP-1). We have previously reported that monocyte CCR2 gene expression and function are effectively downregulated by proinflammatory cytokines. In this study we identified low density lipoprotein (LDL) as a positive regulator of CCR2 expression. Monocyte CCR2 expression was dramatically increased in hypercholesterolemic patients compared with normocholesterolemic controls. Similarly, incubation of human THP-1 monocytes with LDL induced a rapid increase in CCR2 mRNA and protein. By 24 hours the number of cell surface receptors was doubled, causing a 3-fold increase in the chemotactic response to MCP-1. The increase in CCR2 expression and chemotaxis was promoted by native LDL but not by oxidized LDL. Oxidized LDL rapidly downregulated CCR2 expression, whereas reductively methylated LDL, which does not bind to the LDL receptor, had only modest effects on CCR2 expression. A neutralizing anti-LDL receptor antibody prevented the effect of LDL, suggesting that binding and internalization of LDL were essential for CCR2 upregulation. The induction of CCR2 expression appeared to be mediated by LDL-derived cholesterol, because cells treated with free cholesterol also showed increased CCR2 expression. These data suggest that elevated plasma LDL levels in conditions such as hypercholesterolemia enhance monocyte CCR2 expression and chemotactic response and potentially contribute to increased monocyte recruitment to the vessel wall in chronic inflammation and atherogenesis.     

Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells

Eighty-two patients with traumatic anterior shoulder instability were treated with an arthroscopic transglenoid multiple suture technique (Caspari's method) and followed-up for more than 2 years. A retrospective analysis of the clinical outcome was performed to determine the factors related to poor results. The mean age at operation was 21 years (range, 13 to 50 years) and the mean follow-up period was 40 months (range, 24 to 70 months). According to the status of the ligament-labrum complex and the glenoid bone defect, the Bankart lesions were classified into five types arthroscopically. There were 21 shoulders of type 1, 33 shoulders of type 2, 22 shoulders of type 3, and 6 shoulders of type 5. Twenty-four of the patients played contact sports before the operation. The clinical outcome was assessed by Rowe's criteria (1978). To analyze the factors related to a poor outcome, a multivariate analysis was done to assess the influence of 12 clinical factors (age at operation, age at first dislocation, sex, dominant side, disease duration, number of dislocations, sporting activity before operation, inferior joint laxity, thickness of the ligament-labrum complex, type of Bankart lesion, number of sutures, and method of suture fixation). Fifty-five of 82 patients had an excellent outcome, 14 had a good result, and 13 had a poor result. According to postoperative instability, redislocation was seen in 13 patients (16%), resubluxation in 2 patients (2%), with a recurrence rate of 18%. The mean limitation of external rotation at 90 degrees abduction was 6.0 degrees (range, 0 degrees to 30 degrees), and there was a 10 degrees loss of external rotation in 10 patients. The factors significantly related to recurrence were a type 3 Bankart lesion, playing contact sports preoperatively, a thin ligament-labrum complex, and repair with less than four sutures. In conclusion, a 18% rate of recurrence is not acceptable. To obtain a better clinical outcome, very careful selection of patients for this technique is necessary. Our analysis of the factors related to a poor outcome may help to decide what the proper indications are for this technique.     

Familial thrombocytosis in infancy presenting with a leukaemoid reaction

Familial thrombocytosis (FT) is a hereditary disorder probably involving the regulation of megakaryopoiesis. This report is the first documented case of FT in infancy. The clinical course was complicated by a leukaemoid reaction which lasted for several months, in combination with failure to thrive and hepatosplenomegaly. At the age of 5 years the patient, with the exception of thrombocytosis, is healthy and without medication.     

Ceftriaxone in the outpatient treatment of cancer patients with fever and neutropenia

A study was performed in low-risk cancer patients with chemotherapy-induced febrile neutropenia to determine the safety and efficacy of ceftriaxone given in an outpatient setting. A total of 126 episodes of febrile neutropenia in 120 clinically stable outpatients were treated with intravenous ceftriaxone alone (n=100) or in combination with other antibiotics (n=26). The mean neutrophil count was 460/mm3; severe neutropenia (< 100/mm3) was observed in 18 episodes. The initial treatment with ceftriaxone (alone or in combination) was successful in 99 episodes (78%). Ninety-five episodes (76%) were successfully treated in an outpatient setting only; admission to hospital was necessary in 31 episodes (24%), but no infection-related death was observed. Ceftriaxone seems to be safe and effective for outpatient therapy of patients with low-risk febrile neutropenia.