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Biomedical subjects

M Freund

Publications and source records attributed to M Freund.

At least 235 records · Page 13Linked to original sources
PubMed1991

Treatment of anti-recombinant interferon-alpha 2 antibody positive CML patients with natural interferon-alpha.

Of 38 patients with a Philadelphia-chromosome positive chronic myeloid leukaemia treated with recombinant interferon alpha (rIFN-alpha) 2a or 2b and monitored for emergence of IFN-antibodies in their sera 11 patients developed rIFN-alpha 2 binding and 10 rIFN-alpha 2 neutralizing antibodies. rIFN-alpha neutralizing antibody positive patients experienced significantly (P less than 0.025) more clinical relapses (6/10) than IFN-antibody negative patients (6/28) during continuous IFN-therapy. Furthermore, IFN-antibody-positive patients with titre above 400 INU/ml were more likely to relapse under rIFN-alpha-therapy than IFN-antibody-negative patients with titre below 400 INU/ml (P less than 0.05). Seven rIFN-antibody-positive patients experiencing a clinical relapse or a primary non-responsiveness were treated with two- to three-fold increased doses of rIFN-alpha 2. Only one of these seven patients developed a partial haematological remission upon intensification of the rIFN-alpha 2 therapy. Consecutively, the six patients failing high dose rIFN-alpha treatment were switched to a natural IFN-alpha preparation (3 x 9 x 10(6) I.U. weekly s.c.). Under such treatment two of the six patients achieved a long-lasting complete, one a partial haematological remission. In high-titred IFN-antibody positive patients significantly altered serum-IFN-titre and minimal IFN-inducible Mx-homologue concentrations were measured; in contrast, nIFN-alpha induced normal IFN-titre and dose-equivalent Mx-homologue amounts in these patients. The data prove that high-titred rIFN-alpha neutralizing antibodies abrogate the biological action of rIFN-alpha, but not of nIFN-alpha in vivo and explains why nIFN-alpha can be effective in the anti rIFN-alpha 2 positive patients.

Antibodies, Neoplasm↗
PubMed1991

Diagnosis of paroxysmal nocturnal haemoglobinuria using immunophenotyping of peripheral blood cells.

Paroxysmal nocturnal haemoglobinuria (PNH) is now generally accepted as a disease in which bone marrow derived cells are deficient in phosphatidylinositolglycan (PIG)-anchored surface molecules. A series of new monoclonal antibodies detecting PIG-anchored surface structures on human leucocytes (CD48, CD55, CD59) has recently been described. In the present study 12 patients with the diagnosis PNH and a positive Ham test were examined for PIG-anchored surface antigen expression on various cell lineages using immunofluorescence. In all patients deficient cells were detected in erythrocyte, granulocyte and monocyte analysis. A deficient lymphocyte subset was also observed in all but one of these patients. Using two-colour analysis, all lymphocyte subpopulations such as T, B and NK cells were found to be affected. In addition, peripheral blood cells of 22 patients with severe aplastic anaemia (SAA) were tested for the PIG-anchoring defect. In five of these patients the defect was detected, and in four of the five the lack of PIG-anchored molecules was confined to the granulocyte and monocyte lineages apparently without affecting the erythrocytes. The results of these studies demonstrate that cytofluorographic testing of peripheral blood cells provides a simple and reliable method for establishing the diagnosis of PNH. Furthermore, especially in the case of aplastic anaemia patients, the sensitivity of immunophenotyping might be superior to conventional laboratory tests.

Anemia, Aplastic↗
PubMed1991

[Arterioarterial shunt coated with collagen. A model of acute arterial thrombosis for testing antithrombotic agents in rats].

We developed a new thrombosis model in Wistar rats. It consists of a shunt of which the central part is coated with collagen, a thrombogenic protein, implanted between the two carotid arteries of the rat. The occlusion time of the shunt is measured by a thermic method. The composition of the thrombus is analyzed by double isotope labeling of platelets and fibrinogen. Four antithrombotic drugs were studied: two antiplatelet agents, aspirin and clopidogrel; two anticoagulants, heparin and recombinant hirudin. The results show that aspirin alone does not increase the occlusion time of the shunt. Clopidogrel, heparin and hirudin at doses of 50 mg/kg, 500 IU/kg and 5 mg/kg significantly increase the thrombosis time but the composition of the thrombus varies according to the nature of the drug: antiplatelet (clopidogrel) or anticoagulant (heparin, hirudin). This model enables a plurifactorial analysis of acute arterial thrombosis and should be of value to discriminate the effects of antithrombotic and thrombolytic agents.

Animals↗
PubMed1990

Allogeneic bone marrow transplantation for Langerhans' cell histiocytosis.

A group of proliferative diseases of the epidermal Langerhans' cells are commonly referred to as Langerhans' cell histiocytosis (LCH). A small number of the patients with this disease face an unfavorable disease course despite chemotherapy and radiation therapy. In LCH patients with a poor prognosis, allogeneic bone marrow transplantation (BMT) could be the appropriate treatment with proven antiproliferative effects and may be able to repopulate the recipient with stem cell-derived Langerhans' cells from the donor or correct the presumed underlying immunodeficiency. An LCH was diagnosed in a 15-year-old boy with multiple osteolytic lesions, anemia, and diabetes insipidus centralis. Repeated flare-ups of the disease had necessitated several courses of conventional chemotherapy including cyclophosphamide (CY), prednisolone (P), 6-mercaptopurine (6-MP), vincristine (VCR), and additional local irradiation without stable remission. Three years after first being diagnosed with LCH the patient underwent high-dose chemotherapy-radiation therapy followed by allogeneic BMT from his human lymphocyte antigen (HLA)-identical brother. Currently, he is alive and well and has been disease-free for more than 41 months after BMT.

Adolescent↗
PubMed1990

Inhibition by recombinant hirudins of experimental venous thrombosis and disseminated intravascular coagulation induced by tissue factor in rats.

Antithrombotic potency of recombinant hirudins rHV2, rHV2-Lys47 and rHV2-Arg47 was studied in a model of experimental thrombosis induced by tissue factor in the rat. Venous thrombosis was induced by i.v. injection of 25 mg/kg tissue factor followed by stasis of the inferior vena cava. In this model natural recombinant hirudins, rHV2 and rHV2-Lys47 injected 5 min before thrombo-plastin totally inhibited thrombosis in the same micrograms range as heparin or natural hirudin extracted from leeches. However, the mutant variant rHV2-Arg47 gave a maximal 60% inhibition of thrombosis. Variants rHV2-Lys47 (30 micrograms/kg) and rHV2-Arg47 (157 micrograms/kg) injected 5 min before thromboplastin prevented by 90 to 100% the drop in platelet count observed during the disseminated intravascular coagulation induced by thromboplastin injection. Recombinant hirudins were less anticoagulant than heparin as measured by an APTT on rat plasma. After rat tail transection, rHV2-Lys47 caused a 2-fold smaller prolongation of the bleeding time than an equivalent antithrombotic dose of heparin. Plasmatic elimination of rHV2-Lys47 from rat plasma after i.v. injection had a fast distribution phase with a half-life of 3 min during which 90% of injected rHV2-Lys47 was lost and was followed by a slower elimination phase. Thus recombinant hirudin rHV2-Lys47 appears as a promising potent antithrombotic agent for the prevention of thrombin-dependent venous thrombosis and disseminated intravascular coagulation.

Animals↗
PubMed1990

Mitoxantrone, cytosine arabinoside, and VP-16 in 36 patients with relapsed and refractory acute myeloid leukemia.

Mitoxantrone in combination with VP-16 proved to be effective in refractory and relapsed acute myeloid leukemia (AML), with 42% of patients achieving complete remission (CR). The aim of this study was to assess whether the addition of cytosine arabinoside increased the response rate at a tolerable toxicity. The regimen consisted of mitoxantrone (M) 10 mg/m2 i.v. days 4-8, cytosine arabinoside (A) 100 mg/m2 continuous infusion days 1-8, and etoposide (VP-16) (V) 100-120 mg/m2 i.v. days 4-8 (MAV protocol) for relapsed and refractory AML. Thirty-six patients were treated, with a median age of 51 (20-73) years. For induction therapy one to two MAV cycles and for consolidation therapy two courses were scheduled. Twenty-one (58.3%) patients attained a complete remission (CR), with a median duration of 4.5 (1-12+) months. The median survival of all patients was 5.5 (0.5-15.5+) months. Four patients died in CR from chronic infections or after consolidation therapy with MAV. In evaluable patients, times to greater than 500 granulocytes/microliters and greater than 25,000 platelets/microliters were 23 (7-46) and 23 (6-44) days, respectively. In 54 evaluable MAV courses the following toxicity was observed (WHO grades 3/4): 26%, nausea and vomiting: 9%, hemorrhage; 6%, bilirubinemia; 11%, diarrhea; 22%, mucositis; 6%, local infection; 20%, septicemia; 13%, fever of unknown origin; 2%, cardiac arrhythmia; 7%, congestive heart failure. We conclude that MAV therapy is a highly active antileukemic combination with acceptable toxicity, which is recommended for further clinical trials in untreated AML.

Adult↗
PubMed1990

Treatment of relapsed acute lymphocytic leukemia in adults.

Thirty-three patients with ALL/AUL in first relapse were treated with an induction of prednisone, vindesine, daunorubicin, Erwinia asparaginase, i.t. MTX (phase I), high-dose cytarabine, and etoposide (phase II). Twenty-one (64%) achieved a complete remission, one a partial remission. Side effects of induction-phase I were predominantly hematological with subsequent infections and gastrointestinal toxicity. In phase II some patients had additional cutaneous, ocular, and hepatic toxicity. The treatment efficiently induced remissions with tolerable toxicity in relapsed ALL. The disease-free survival, however, needs to be improved.

Adolescent↗
PubMed1990

Selective advantage of fra (X) heterozygotes.

The high incidence of the fra (X) syndrome (about 1:2000 male newborns) requires an explanation in view of the low fitness of mentally retarded hemizygous males and heterozygous females. In the past, it has been proposed that the mutation rate may be unusually high, and that mutations occur exclusively in male germ cells. According to an alternative hypothesis, a moderately high mutation rate might combine with a selective advantage of clinically unaffected heterozygotes. In earlier studies, such a combined hypothesis was shown to lead to plausible implications regarding mutation rate and fitness. Moreover, a mutation rate in male germ cells of the magnitude required by the exclusive mutation hypothesis was excluded by studies on comprehensive pedigree data. In this third study in the series, an increased fitness of heterozygous females is demonstrated directly by a comparison of the reproductive performance of heterozygotes with that of adequate controls (mothers and grandparents of Down's syndrome patients). Since, average numbers of children have decreased during recent decades in populations of industrialized countries, heterozygotes (mothers of affected probands and their female relatives in their own generation) were subdivided into those born before and after 1940. Moreover, sibship sizes of probands' mothers and fathers were analyzed separately for family branches in which the fra (X) trait segregated (mostly the maternal branch), or did not segregate (in most instances the paternal branch). In all four categories reproductive performance in heterozygotes was found to be higher than in the controls. This difference was significant statistically for two of the four groups; it was small and nonsignificant only for the parental family branch in which the fra (X) mutant did not segregate and for mothers born after 1940. Fitness estimates ranged between 1.11 and 1.36. A higher incidence of dizygotic twinning suggests a biological component for this increased fertility. On the other hand, fra (X) families have a significantly lower social status than the controls. This suggests a socio-psychological component of their higher fertility. Apparently, both components contribute to their fertility; at present, their relative importance cannot be assessed.

Birth Rate↗
PubMed1990

Effects of cytokines on in vitro colony formation of primary human tumour specimens.

Although under study to alleviate chemotherapy-induced bone marrow toxicity, cytokines can stimulate in vitro growth of solid human tumour cell lines. The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) on in vitro colony formation of primary human tumours was studied in a capillary soft-agar cloning system. Of 108 tumour specimens from 100 patients, 85 specimens were tested against all three factors at concentrations ranging from 0.1 to 1000 ng/ml. 44 of 100 tumours showed adequate growth in controls. 8 out of 43 (19%) specimens were significantly stimulated by GM-CSF, 6 of 40 (15%) by G-CSF and 10 of 44 (23%) by IL-3. Sensitivity to all three cytokines was observed in 4 of 44 (9%) specimens. By light microscopy the appearance of colonies from stimulated specimens was identical to that of controls. Sensitivity to cytokines was independent from sensitivity to epidermal growth factor, transferrin or insulin. Sensitivity to GM-CSF, G-CSF and IL-3 may be aberrantly expressed in a subgroup of solid human tumours.

Biopsy↗
PubMed1990

Enzymatic hydrolysis of (di)methacrylates and their polymers.

Di- and monomethacrylates hydrolyze to methacrylic acid and the alcohol part at neutral pH catalyzed by an unspecific esterase (hydrolase) and by enzymes in saliva. The rate constants of the enzymatic hydrolysis of various (di)methacrylates increase in the following order: HPMA less than BISGMA less than LAMA less than DECMA less than TEGDMA less than UEDMA less than DEGDMA. Esterase added to aqueous slurries of various powders made of polymerized BISGMA/TEGDMA-mixtures gave rise to liberation of methacrylic acid, presumably deriving from degradation of those of the dimethacrylates only bonded in the matrix by one end of the molecule. It was estimated that a TEGDMA-polymer will be hydrolyzed faster than a BISGMA-polymer. It is proposed that hydrolases in saliva increase the wear rate of composite resin fillings.

Acrylates↗
PubMed1990

Enzymatic degradation of BISGMA/TEGDMA-polymers causing decreased microhardness and greater wear in vitro.

The microhardness of the surfaces of BISGMA/TEGDMA-polymers decreased after treatment with pork liver esterase for 48 h in concentrations greater than or equal to 0.05 U/ml. This softening effect on BISGMA/TEGDMA-polymer surfaces was also shown as an increased wear rate of the polymers in the presence of esterase measured by a laboratory abrasion method. In this method, polymer cylinders were vigorously shaken in an aqueous slurry containing abrasive particles. The shaking was performed for 3 s followed by a rest period of either 100 or 200 s. This was repeated for 24 h. A greater mean loss of weight of the cylinders was measured when esterase was present in the slurry and the loss of weight increased significantly from 6.7% to 23.8% (P less than 0.001) when the rest period was increased from 100 s to 200 s. The results indicate that enzymatic hydrolytic activity in the mouth will contribute to a breakdown of composite resin fillings.

Acrylates↗
PubMed1990

Results and prognosis of acute non-lymphocytic leukemia in adults. A retrospective study of 319 patients between 1977-1987.

Between 1977-87, 319 patients with AML were admitted to Hannover Medical School. At all 41 of these patients were not treated (median duration of survival 0.6 months). Among the 278 treated patients, there was a CR rate of 53.6%, the median duration of remission was 10.1 months and the median duration of survival 7.0 months. The patients with FAB-classification M4-M5 had a worse prognosis than those with M1-M3. Patients under 50 years of age had a significant higher remission rate and survival time than those over 50 years. In the last 10 years, the remission rate rose from 37.3% to 61.0% (p = 0.1776). There was a rise in median duration of survival from 5.9 months (1977-79) to 8.0 months (1984-85) (p less than 0.001). The median remission time decreased from 15.8 months (1977-79) to 12.0 months (1984-85) (p less than 0.001). After the first reinduction therapy, the remission rate (46.6%), duration of remission (5.3 months), and duration of survival (4.1 months) was lower than after primary therapy. After the second reinduction therapy the CR rate was 69.2%, and the remission time 2.9 months. The CR rate after the third reinduction therapy was 22.2%.

Adolescent↗
PubMed1990

[Alpha interferon in therapy of non-Hodgkin's lymphoma].

Interferon alpha is a new therapeutic option in malignant Non-Hodgkin's lymphomas. Favourable results have been achieved in low-grade malignant histologies. Objective responses have been reported in 39% of patients with nodular histology (mostly centrocytic-centroblastic according to the Kiel classification), most of them being partial remissions. Clinical studies suggest a dose-response relationship. Interferon alpha has also been combined with alkylating agents. The toxicity of the combination is subjectively and objectively well tolerable. Though combinations are very active with high response rates, an improvement of survival has not been shown. In other studies interferon alpha has been administered for maintenance after induction chemotherapy. Responses have been noted in only 16% of patients with advanced chronic lymphocytic leukemia. In early stages (mostly Binet stage A) the disease is more sensitive with a response rate of 73%. As the prognosis of these patients is very good, the relevance of the therapeutic response is not clear. The results of interferon alpha in cutaneous T-cell lymphoma and mycosis fungoides are controversial. Based on pooled published data, the overall response rate is 44%. High-grade malignant non-Hodgkin's lymphomas have been treated with high doses of interferon alpha. The overall remission-rate is 14%. In most cases, remissions have been short.

Humans↗