Behçet's disease and cardiac arrhythmia

Summary Only few cases of cardiac conduction disturbances and arrhythmias have been reported in Behçet's disease. We recently observed the case of a 16-year-old woman with Behçet's disease in whom cardiac arrhythmia became the main clinical symptom. This observation and a review of the literature led us to the conclusion that arrhythmia could represent the clinical manifestation of an underlying myocarditis due to Behçet's disease and can be regarded as a feature of cardiac involvement of the disease.     

Expression of protectin (CD59) in human melanoma and its functional role in cell- and complement-mediated cytotoxicity

Immunohistochemical and/or indirect immunofluorescence analysis with monoclonal antibody (MAb) H19 demonstrated the expression of protectin (CD59) in 54 surgically removed metastatic melanoma lesions and on 8 out of 12 melanoma cell lines. CD59 expression had a low degree of intra- and intertumor heterogeneity. SDS-PAGE analysis showed that the molecular weight of CD59 expressed on melanoma cells is about 20 kDa. Treatment of melanoma cells with 5 U/ml of phosphatidylinositol-specific phospholipase C completely abolished cell-surface expression of CD59. Interferon-γ and/or tumor necrosis factor-α or phorbol 12-myristate 13-acetate neither modulated the expression of CD59 by melanoma cells nor influenced the amounts of CD59-specific mRNA. F(ab')₂ fragments of anti-CD59 MAb YTH53.1 did not inhibit the lysis of melanoma cells by allogeneic natural killer (NK) cells or lymphokine-activated killer (LAK) cells. In contrast, the whole lg molecule of MAb H19 or YTH53. I significantly (p < 0.05) enhanced NK-cell-mediated lysis of melanoma cells, suggesting the induction of antibody-dependent cell-mediated cytotoxicity. Lastly, masking of CD59 by MAb YTH53. I or its F(ab')₂ fragments significantly (p < 0.05) enhanced, in a dose-dependent fashion, the lysis of anti-GD3-sensitized melanoma cells by homologous complement. These data demonstrate that CD59 expressed by human melanoma cells might regulate host-tumor interaction by protecting neoplastic cells from complement-mediated lysis. © 1995 Wiley-Liss, Inc.     

Promoter methylation controls the expression of MAGE2, 3 and 4 genes in human cutaneous melanoma

Cancer-testis antigens expressed by different-histotype transformed cells are suitable targets for tumor immunotherapy. However, their heterogeneous expression in neoplastic lesions limits the eligibility of patients for cancer-testis antigen-directed vaccination, and low levels of cancer-testis antigens' expression may impair immune recognition of malignant cells. Because of the primary clinical relevance of cancer-testis antigens' expression in neoplastic tissues, 68 unrelated or sequential metastatic lesions from 56 patients were used to characterize the molecular mechanisms regulating the presence and levels of expression of different cancer-testis antigens of the MAGE family (i.e., MAGE2, 3 and 4) in cutaneous melanoma. Polymerase chain reaction-based methylation analyses showed that methylation status of specific cytosine-guanine dinucleotides in the promoters of investigated cancer-testis antigens correlated with their heterogeneous expression within unrelated metastatic melanoma lesions, and with their homogeneous expression among sequential metastases from three patients with melanoma. Unlike methylated promoters, unmethylated promoters of MAGE2, 3 and 4 genes drove the expression of reporter gene-enhanced green fluorescent protein after transient transfection of cancer-testis antigen-positive Mel 142 melanoma cells. Furthermore, de novo expression of MAGE3 gene induced by the treatment of Mel 195 melanoma cells with the DNA hypomethylating agent 5-aza-2'-deoxycytidine was associated with a 6%-12% demethylation of selected cytosine-guanine dinucleotides in its promoter. Finally, 5-aza-2'-deoxycytidine induced a 16-fold increase of MAGE3 expression in Mel 313 melanoma cells expressing constitutively low levels of the antigen, but did not affect that of Mel 275 melanoma cells expressing high baseline levels of MAGE3. Overall, these findings identify promoter methylation as a shared mechanism directly regulating the expression of therapeutic cancer-testis antigens in metastatic melanomas, and foresee the clinical use of 5-aza-2'-deoxycytidine to design new chemoimmunotherapeutic strategies in patients with melanoma.     

Endoglin (CD105): a target for anti-angiogenetic cancer therapy

Targeting of tumor vasculature is a promising strategy for cancer treatment. Among endothelial cell markers, Endoglin, a cell membrane glycoprotein, is emerging as an attractive therapeutic target on angiogenetic blood vessels, and it currently represents a powerful marker to quantify tumor angiogenesis. In normal human tissues, Endoglin is weakly expressed on erytroid precursors, stromal cells and activated monocytes, whereas it is strongly expressed on proliferating endothelial cells. In human neoplasias of different histotype, Endoglin is mainly present on endothelial cells of both peri- and intra-tumoral blood vessels, while it is weakly expressed or absent on neoplastic cells. Endoglin is an accessory component of the receptor complex of Transforming Growth Factor (TGF)-beta, a pleiotropic cytokine that modulates angiogenesis by the regulation of different cellular functions including proliferation, differentiation and migration. Interestingly, the over-expression of Endoglin antagonizes several cellular responses to TGF-beta1, while its down-regulation potentiates cellular responses to TGF-beta1. In animal models, administration of radiolabeled anti-Endoglin monoclonal antibodies (mAb) efficiently images primary tumors, and naked or conjugated anti-Endoglin mAb suppress angiogenesis and tumor growth. In this review we will summarize the complex of experimental evidences pointing to Endoglin as a vascular target to design innovative bioimmunotherapeutic strategies in human neoplasias.     

Emerging role of endoglin (CD105) as a marker of angiogenesis with clinical potential in human malignancies

Angiogenesis is crucial for tumor development and progression, and antiangiogenetic therapy represents a promising approach for cancer treatment. Thus, the in-depth understanding of the molecular mechanism(s) regulating angiogenesis, together with the characterization of molecules expressed by endothelial cells and involved in distinct steps of the angiogenetic process, will greatly improve the design of new and more effective therapeutic strategies in human malignancies. Endoglin (CD105), a cell membrane glycoprotein predominantly expressed on cellular lineages within the vascular system, and over-expressed on proliferating endothelial cells, is involved in blood vessels development and represents a powerful marker of neovascularization. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, a pleiotropic cytokine that regulates different cellular functions including proliferation, differentiation and migration. In human malignancies of different histotype, CD105 is highly expressed on endothelial cells of both peri- and intra-tumoral blood vessels, while it is weakly expressed or absent on neoplastic cells. This unique tissue distribution strongly suggests for a prognostic, diagnostic and therapeutic potential of CD105 in neoplastic diseases. In this review we will summarize the structural and functional features of CD105, as well as its tissue distribution in normal and neoplastic tissues. Furthermore, the practical implications of CD105 in human malignancies will also be discussed.     

Immune modulation in autologous bone marrow transplantation: cyclosporine and gamma-interferon trial.

From March 1994 to November 1994, 16 patients with high risk hematological malignancies were entered in a phase I clinical trial, designed to confirm the toxicity of cyclosporine and gamma interferon given to induce autologous graft-versus-host disease (GVHD) after autologous bone marrow transplantation (ABMT). This trial was based on the results in a rodent model, in which cyclosporine given after ABMT induces an autoimmune syndrome (autologous GVHD) identical to allogeneic GVHD. Further, this autologous GVHD is associated with a graft-versus-tumor effect augmented by interferon that upregulates MHC class II expression on normal and tumor cells, the target of the cytolytic T cells in autologous GVHD. In this trial, cyclosporine 1 mg/kg/day was given from the day of bone marrow reinfusion until the completion of the interferon and gamma-interferon. Gamma-interferon at 0.025 mg/m2 every other day was started when the total white cell count was >200 cells/ml for 2 consecutive days and continued for a total of 10 doses after ABMT. The preparative regimens were busulfan and cyclophosphamide, or cyclophosphamide with total body irradiation. All patients received 4HC-purged marrow grafts. Median age was 45 years (range 19-68). The diagnoses included chemo-resistant non-Hodgkin's lymphoma (10), acute lymphoblastic leukemia (two), chemo-resistant Hodgkin's disease (two), acute myeloid leukemia (one), and multiple myeloma (one). Median absolute neutrophil count recovery was 25.5 days (range 19-46 days). Median platelet count recovery was 40.5 days (range 28-279 days). There were nine deaths, two were related to transplant toxicity (infection), while the other seven were due to relapse. Event-free survival with a median of 964 days (range 19-1441 days of follow-up was 44%. In conclusion, treatment with cyclosporine, and gamma-interferon after ABMT was well tolerated and did not impair engraftment. Further studies with a larger number of patients are required to document any beneficial anti-tumor effect of autologous GVHD induction after ABMT.     

Reversibility of acute cyclosporin nephrotoxicity by dopamine. Micropuncture study in the rat

The ability of dopamine to neutralise the effects acutely induced by cyclosporin (CsA) on glomerular dynamics was evaluated in four groups of female Munich-Wistar rats, prepared for micropuncture: group I (n = 9), normal rats receiving saline as placebo; group II (n = 10), rats treated with CsA (20 mg/kg b.w. in 1 h); group III (n = 8) rats treated with CsA, as in group II, and then with vasodilating doses of dopamine (1.2-2.0 micrograms/100 g b.w./min in continuous intravenous infusion); group IV (n = 7), rats administered Cremophore EL, the vehicle of CsA, in corresponding doses. Single nephron GFR (SNGFR), glomerular plasma flow (GPF), afferent and efferent arteriole resistances (Ra and Re, respectively), SN filtration fraction (SNFF), ultrafiltration coefficient (Kf) were measured. Body weight, blood pressure and haematocrit were similar in the four groups. GFR was significantly reduced in group II (0.83 +/- 0.08 ml/min vs 1.29 +/- 0.01 in group I, 1.46 +/- 0.25 in group III, and 1.40 +/- 0.09 in group IV, P less than 0.05 vs all the groups), while no statistical difference was detected in urinary volume. SNGFR was significantly reduced in group II vs group I (18.7 +/- 1.8 nl/min vs 30.6 +/- 1.3, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cross-reactivity and tolerability of imipenem in patients with delayed-type, cell-mediated hypersensitivity to β-lactams

Background:  Administration of imipenem-cilastatin to patients with IgE-mediated hypersensitivity to β-lactams has always been considered potentially harmful. Recent studies have demonstrated the tolerability of carbapenems (imipenem-cilastatin and meropenem) in patients with IgE-mediated hypersensitivity to β-lactams; there are no studies on this topic regarding patients with cell-mediated allergy to β-lactams. The aim of this study is to assess cross-reactivity and tolerability of imipenem in patients with cell-mediated allergy to β-lactams.
Methods:  From our database we selected 73 patients with cell-mediated allergy to β-lactams, diagnosed by means of immediate-type skin tests, delayed reading intradermal tests, patch tests and detection of specific IgE. Patients with negative patch tests with imipenem-cilastatin underwent an intramuscular test dosing.
Results:  Our patients had a total of 94 nonimmediate reactions to penicillins. All patients had positive patch tests and/or delayed reading intradermal tests for at least one of the penicillin reagent tested and negative immediate-type skin tests and specific IgE. Four patients out of 73 had a positive patch tests to at least one penicillin reagent and imipenem-cilastatin showing cross-reactivity. Sixty-four patients underwent the imipenem-cilastatin intramuscular test dosing and none of them had a clinical reaction.
Conclusions:  Our rate of cross-reactivity between imipenem-cilastatin and other β-lactams was 5.5%. This result is different from previous findings and this may be explained by the fact that we investigated patients with cell-mediated allergy to β-lactams. Patients with cell-mediated allergy to β-lactams should undergo patch tests and a tolerance challenge test before treatment with imipenem-cilastatin.     

Non pharmacological treatments in fibromyalgia

Fibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and with substantial financial costs. Once the diagnosis is made, providers should aim to increase patients' function and minimize pain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction with and the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present, pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptom control and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjective pain with greater success than monotherapy. Physical therapies, rehabilitation and alternative therapies are generally perceived to be more "natural," to have fewer adverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitive behavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.