Biomedical subjects
Publications and source records attributed to M J Bargetzi.
Patients with myelodysplasia are susceptible to infections due to their compromised immunity. If presenting with a cervical lymphadenopathy patients must, in addition to other causes, be evaluated for tuberculosis, especially if they show a concurrent erythema nodosum.
Paraneoplastic pemphigus is a severe mucocutaneous disease associated in most cases with B-cell lymphoproliferative disorders. Independent of the course of the underlying malignancy, this autoimmune skin disease is resistant to any treatment in most cases and may lead to death by infectious complications. We observed a patient with recovery of paraneoplastic pemphigus associated with follicular non-Hodgkin's-lymphoma after therapy with rituximab. In addition, we reviewed the literature and analyzed the few cases with comparable outcome with other treatment modalities.
A 66-year-old Caucasian woman presented with a Philadelphia chromosome positive common B-cell acute lymphoblastic leukemia and a dic(9;12) involving the der(9)t(9;22), a rearrangement so far not observed in acute lymphoblastic leukemia. The patient was treated for the acute lymphoblastic leukemia, but showed refractory disease and died 6 months after initial diagnosis. This case suggests that, in the combination of t(9;22) and dic(9;12), the known poor prognostic feature of t(9;22) in acute lymphoblastic leukemia may outweigh the favorable outcome reported in patients with dic(9;12).
Explore the source record for details and available documents.
We observed the occurrence of celiac disease following allogeneic bone marrow transplantation in a patient transplanted for acute leukemia. The marrow donor was his HLA-identical sister, who had suffered from celiac disease since birth. The post-transplant period was characterized by recurrent episodes of diarrhea. Detailed workup showed atrophic intestinal mucosa on histology and anti-gliadin and anti-endomysium antibodies in the serum, features that were not present before transplantation. GVHD was absent at that time. The patient remains free of symptoms on gluten-free diet and slight immunosuppression. This case suggests transmission of celiac disease by bone marrow transplantation and supports the T cell concept in celiac disease.
In acute promyelocytic leukemia (APL), disseminated intravascular coagulation is frequently observed. Massive alveolar bleeding can lead to respiratory insufficiency, requiring tracheal intubation and mechanical ventilation. Today all-transretinoic acid (ATRA) is part of induction chemotherapy in acute promyelocytic leukemia. The administration of ATRA is oral. No intravenously administered form is available. ATRA can be administered to intubated patients in the following manner: the daily amount of ATRA is placed in a sterile 50 ml tube. After addition of about 20 ml of sterile water the tube is heated in a waterbath to a temperature of 37 degrees C until the capsules melt and the suspension is completely liquid. The resulting oily fluid is then administered via nasogastric tube. We have treated 2 patients with acute promyelocytic leukemia intubated due to massive alveolar bleeding in this manner, and have observed a differentiation of promyelocytes to granulocytes and complete remission in both patients, indicating that the ATRA administered had been resorbed intestinally.
Optimum treatment of severe neutropenia, a major factor for morbidity and mortality in T-large granular lymphocyte (LGL) leukemia, is undefined. We observed a rapid improvement of the neutrophil count in a patient with T-LGL leukemia and severe neutropenia after the combined administration of antilymphocyte-globulin (ALG), cyclosporin A, prednisone, and granulocyte colony-stimulating factor (G-CSF). Although G-CSF treatment was terminated after 7 days, the neutrophil count has persisted above 1.0 x 10(9)/1 for up to 6 months now. Oral methotrexate is given continuously as treatment for T-LGL leukemia. The response to this immunosuppressive regimen suggests a T-cell-mediated mechanism as the underlying cause for neutropenia in T-LGL leukemia.
Hydroxyurea is used in the treatment of sickle cell anemia and beta-thalassemia major to increase the content of hemoglobin F (HbF) and presumably ameliorate clinical symptoms. Under therapy with hydroxyurea an increase of the mean corpuscular volume (MCV) of the erythrocytes can be observed. To evaluate a possible estimation of the content of HbF using the increase of MCV under treatment with hydroxyurea, we measured MCV and HbF during therapy with hydroxyurea. The median MCV before therapy was 87.8 fl (range 74.3-95.7) and under hydroxyurea 104.1 fl (81.0-139.5), and the median HbF 1.8% (0.1-5.4). Although both MCV and HbF increased under treatment with hydroxyurea, a linear correlation between these two parameters was not detectable. Therefore, MCV cannot replace the measurement of HbF.
In a prospective open-labelled phase I/II trial we tested efficacy and tolerability of recombinant human interleukin-3 (rhIL-3) alone in patients with refractory severe aplastic anaemia (SAA). 15 patients with idiopathic (12 patients) or secondary (one post-hepatitic, one drug induced, one dyskeratosis congenita) SAA, refractory or relapsing after one to three courses of antilymphocyte globulin were included. 14 patients were transfusion dependent (RBC 14, platelet 12). RhIL-3 was planned for three patients each at five escalating dose levels of 1, 2, 4, 8 and 16 micrograms/kg, given daily as 24 h continuous infusion for 21 d. RhIL-3 was prematurely withdrawn at days 10 and 11 for adverse events in two patients. 9/15 patients showed an increase in WBC; 2/6 at the 1-2 micrograms/kg and 7/9 at the 4-16 micrograms/kg level, but no sustained effects were seen. No patient showed a response in platelet counts. Additionally, platelet and RBC transfusion requirements were unchanged pre and post study. All patients experienced one or more adverse event, mainly fever (15 patients), bleeding (nine patients), and headache (six patients). Occurrence of adverse events was dose related and the maximum tolerated dose was reached with 8 micrograms/kg. Five patients suffered serious adverse events. RhIL-3 as single growth factor and used alone is of minimal benefit in severe aplastic anaemia.
Sustained release or high levels of interleukin-1 (IL-1) and/or tumor necrosis factor (TNF), as observed after endotoxin challenge, can produce a variety of toxicities. Naturally occurring inhibitors to IL-1 and TNF, IL-1 receptor antagonist (IL-1ra) and soluble TNF receptor forms, have been detected. These proteins may function to buffer or limit the effects of these cytokines as part of a regulatory network. As part of a clinical trial of recombinant human interleukin-1 beta (rhIL-1 beta), serial plasma samples were obtained from 6 patients with metastatic melanoma treated with 30-min infusions of rhIL-1 beta for 5 consecutive days. The presence of circulating IL-1 receptor antagonist and soluble TNF binding proteins (TNF-R55-BP and TNF-R75-BP) were assessed. A maximum 86-fold increase for IL-1ra, a 7-8-fold increase for TNF-R55-BP, and a 2-3-fold increase for TNF-R75-BP were seen 2-4 h, 1 h, and 4 h, respectively, after rhIL-1 beta infusion. On each day of the treatment, the secretion of IL-1ra and release of TNF-R55-BP was observed, but there was no accumulation above baseline value for IL-1ra before each of the 5 daily infusions. Although there was a steady decrease of the 6-h postinfusion plasma levels for IL-1ra and TNF-R55-BP over the 5 treatment days, no increase of clinical side effects was noted. Two patients had measurable levels of TNF-alpha, but no correlation to TNF-binding proteins was observed. Our data show that early after rhIL-1 beta infusion the induction of IL-1ra secretion, as well as TNF-binding protein release, is observed.
The effect of N-acetyl-L-cysteine on the cytotoxicity of tumor necrosis factor-alpha was investigated in cultured bovine pulmonary artery endothelial cells and L929 mouse tumor cells. In endothelial cells, a 72-h incubation with tumor necrosis factor-alpha (100 ng/ml) reduced the number of viable cells to 27% of control. Simultaneous incubation with N-acetyl-L-cysteine (0.5-5 mmol/l) protected endothelial cells from tumor necrosis factor-alpha-mediated cytotoxicity and increased viability in a concentration-dependent fashion to 69% of control. Under the same conditions, a 72-h incubation with tumor necrosis factor-alpha (100 ng/ml) reduced the number of viable L929 tumor cells to 31% of control. However, this cytotoxic response remained unaltered in the presence of N-acetyl-L-cysteine (0.5-5 mmol/l). Similar results were obtained when using a lower concentration of tumor necrosis factor-alpha (50 ng/ml). These findings demonstrate protection from tumor necrosis factor-alpha-mediated toxicity by N-acetyl-L-cysteine in endothelial cells but not in a tumor cell line. It is concluded that N-acetyl-L-cysteine might serve as a therapeutic agent to limit the vascular toxicity of tumor necrosis factor-alpha without affecting its antineoplastic activity.
Administration of interleukin-1 beta (IL-1 beta) to humans initiates a cascade of metabolic, hematologic, and cardiovascular events. To investigate the role of the sympathetic nervous system in the early cardiovascular response to IL-1 beta in humans, we recorded the heart rate, blood pressure, and changes in hand vein compliance in five patients with malignant melanoma treated with a 30-min infusion of 10,000-20,000 U/kg of human recombinant IL-1 beta. All patients developed fever, chills, and marked hemodynamic changes. During or shortly after the infusion, a dramatic decrease in hand vein compliance occurred (vasoconstriction). At the time of maximum venoconstriction (35 min after the start of the IL-1 beta infusion), the mean heart rate and systolic blood pressure were significantly increased by 30 mm Hg and 31 beats/min, respectively. Venoconstriction always preceded the onset of chills by several minutes (mean of 7 min), was closely correlated with the heart rate, and could be reversed by local administration of the alpha-antagonist phentolamine, indicating involvement of catecholamines. Our study shows that cardiovascular responses that occur early after IL-1 beta administration in humans are most likely the result of adrenergic stimulation possibly through its effect on the central nervous system.
Intrapulmonary sequestration is a rare disorder which should be considered when an intrathoracic mass is found in the lower part of the lungs. The clinical symptoms range, as in our two patients, from an asymptomatic mass in the chest X-ray film to frequent pulmonary infections. A definite diagnosis is possible only by visualization of the aberrant artery by arteriography, which is also helpful to the surgeon at lobectomy.
Explore the source record for details and available documents.
Flecainide acetate, a class Ic antiarrhythmic agent, is eliminated to a larger extent by renal excretion and to a minor extent by the liver. In patients with impaired renal function or with elevated urinary pH, however, its elimination is dominated by hepatic metabolism. Recent evidence suggests that the in vivo metabolism of flecainide is controlled by the genetic polymorphism of the debrisoquin/sparteine type; i.e., it is a substrate of cytochrome P450IID6. We investigated the inhibitory effect of flecainide on bufuralol 1'-hydroxylation in human liver microsomes in vitro and on the metabolic dextromethorphan urinary ratio in eight healthy male volunteers. Both bufuralol and dextromethorphan are well-known substrates of cytochrome P450IID6. Microsomal bufuralol 1-hydroxylation was competitively inhibited by flecainide with an apparent Ki of 0.954 mumol/L. Moreover, a statistically significant increase in the urinary metabolic ratio (MR) of dextromethorphan/dextrorphan after 1 week of administration of oral flecainide was observed (p = 0.013) in all subjects. One individual increased the urinary MR to a value consistent with the poor metabolizer phenotype. We conclude that flecainide is a potent inhibitor of cytochrome P450IID6 in vitro and in vivo and that careful drug monitoring is required with respect to renal function, debrisoquine phenotype, and concomitant drug administration.
A new nitrocellulose-based ELISA technique, the line immunobinding assay (LIBA), permits the quantitative detection of multiple antigen-antibody reactions in one single assay. The antigen solutions are sprayed in thin lines onto a nitrocellulose sheet which is then cut into several strips before incubation in a multi-channel tray with serially diluted serum. The reacting antibodies are visualized by a peroxidase system. Comparison with other techniques routinely used for the detection of antibodies against measles, mumps and rubella, suggest that the LIBA offers specificity with sensitivity and may have a broad range of applications.
Explore the source record for details and available documents.
The metabolism of lidocaine to its major metabolite monoethylglycinexylidide (MEGX) was studied in human liver microsomes of 13 kidney transplant donors and of one patient with liver cirrhosis. Interindividual variation in metabolite formation was considerable. Biphasic kinetics indicated the involvement of at least two distinct enzymatic activities. With use of a series of antisera that recognize different human cytochrome P450 isozymes, we were able to identify an enzyme of the P450III gene family as one of two enzymes. By expressing human P450IIIA4 complementary deoxyribonucleic acid (cDNA) in HepG2 cells, we directly demonstrated lidocaine-deethylase activity for this P450 isozyme. These data suggest that P450IIIA4 is at least in part responsible for microsomal MEGX formation.