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Biomedical subjects

A M Fischer

Publications and source records attributed to A M Fischer.

At least 55 records · Page 3Linked to original sources
PubMed1992

Behçet syndrome associated with protein S deficiency.

Behçet syndrome is a multisystem disorder characterized by ocular, mucocutaneous, articular, gastrointestinal and neurologic abnormalities. We report here an unusual case of Behçet syndrome, characterized by the importance of the thrombotic events (7 phlebitis of both legs and resection of two toes). Additional manifestations of the Behçet syndrome occurred only 10 years after the first thrombotic episode. The oldest daughter of the propositus and his brother suffered also from thrombophlebitis; this familial history of thrombosis led to the performance of a haemostatic study. A congenital protein S deficiency was found in the propositus and in three of his children. Normal protein S levels were found in nine unrelated patients with Behçet syndrome. Thus this observation suggests that, when thrombotic manifestations are the first and major symptom of Behçet syndrome, an additional cause of thrombosis has to be investigated.

Adult↗
PubMed1992

Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis.

Hereditary protein C (PC) deficiency is usually associated with a high risk of thrombosis. We report the results of a study undertaken to screen for molecular defects in families with hereditary quantitative PC deficiency. Using a strategy combining polymerase chain reaction amplification of selected gene fragments, denaturing gradient gel electrophoresis of the amplification products, and direct sequencing of fragments with altered melting behavior, we studied the PC gene exons and exon/intron junctions of subjects with hereditary type I PC deficiency. Computer simulation of DNA melting was used to design several sets of primers, each containing a GC-clamp, permitting the complete analysis of each amplified exon sequence. Using this procedure, we identified two previously undescribed mutations located in exon VII: a C-to-T substitution generating a nonsense codon in place of Arg 157 in the mature PC and a G-to-A substitution converting Arg 178 to GIn. The two mutations were detected in, respectively, 3 and 2 apparently independent families. This strategy is therefore a valuable tool for screening patients, and the results emphasize its advantages over plasma assays in individuals with a family history of thrombosis.

Adult↗
PubMed1992

The prevalence of selective IgA deficiency in type 1 diabetes mellitus.

A significant increase in the prevalence of selective IgA deficiency has been observed in patients with autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease and susceptibility to both IDDM and IgA deficiency is associated with HLA DQB1 alleles encoding non-Asp amino acids at position 57. In order to assess whether the prevalence of selective IgA deficiency is increased in IDDM, we have screened a homogeneous series of adult patients with IDDM for selective IgA deficiency. One patient (1:261) was found to have a selective IgA deficiency. The prevalence of selective IgA deficiency among adult French blood donors is 1:1400. Thus, although IDDM and selective IgA deficiency are both associated with the presence of non-Asp amino acids at position 57 of the HLA DQ beta chain, the frequency of this immunodeficiency in adult IDDM patients is not significantly increased.

Autoimmune Diseases↗
PubMed1992

Control of human B cell tumor growth in severe combined immunodeficiency mice by monoclonal anti-B cell antibodies.

Severe combined immunodeficiency (scid) mice develop EBV (+)B cell tumors after infusion of EBV(+)B cells or of B cells and EBV. In this study, scid mice were infused with B cell lines derived from three patients who developed a B lymphocyte proliferative disorder after bone marrow or organ transplantation. Intraperitoneal injection of 5 x 10(6) B cells induced tumor growth in all mice, leading to death within 60 d. Human B cells were identified in spleen and bone marrow by means of immunofluorescence or EBV genome amplification, and human IgM was detected in serum. Infusion of murine monoclonal antibodies specific for human B cell membrane antigens CD21, CD24, and CD23 was effective in 80% of animals, against two of the three cell lines preventing tumor development or inducing remission according to the time of treatment. The effect was antibody dose dependent and was optimal with four intravenous infusions of at least 0.1 mg 4 d apart. Human IgM in serum and human B cells in spleen and bone marrow became undetectable when peritoneal tumors regressed completely. Infusions of IgG1 isotype-matched anti-CD4 antibody or anti-CD3 antibody had no effect. Tumors developed or recurred in 50% of these animals injected with one of the B cell line 3 mo after treatment was stopped. The same anti-CD21 and anti-CD24 antibodies had been used to treat the three patients, and shown similar degrees of effectiveness as in the scid mouse model. These results indicate that scid mice may be suitable for assessing therapeutic approaches to human B cell proliferation.

Animals↗
PubMed1992

The frequency of selective IgA deficiency in myasthenia gravis.

The frequency of selective IgA deficiency is unknown in myasthenia gravis. We screened a series of 333 consecutive adult myasthenic patients for selective IgA deficiency and found only one patient with a selective IgA deficiency, which is not significantly different from the normal population. Organ-specific autoimmune diseases may differ from systemic autoimmune diseases concerning their frequency of association with selective IgA deficiency.

Adult↗
PubMed1991

Anticoagulant properties of a fucoïdan fraction.

Fucoïdans are a family of high molecular weight sulphated polysaccharides in the Mr range 8 x 10(5) -10(6), widely dispersed in brown seaweed cell wall. When extracted from several brown algae, they exhibit anticoagulant properties. The chemical degradation of a crude extract, from Pelvetia canaliculata, was undertaken to obtain a low molecular weight polysaccharide (Mr 20,000 +/- 5,000) with the purpose of a possible clinical use. Its anticoagulant potency was investigated through the inhibition of factor IIa and factor Xa in the presence of antithrombin III or heparin cofactor II. The degraded fucoïdan revealed a potent antithrombin activity: studied in an antithrombin III depleted plasma or in the presence of purified heparin cofactor II, the fucoïdan was as efficient as heparin and dermatan sulphate on heparin cofactor II potentiation, at the same concentration by weight. In whole plasma or in the presence of the purified inhibitor, an anti-factor IIa activity mediated by antithrombin III was detected (30 times less potent than for heparin, on a weight to weight basis). In contrast, no anti-factor Xa activity was detected in the presence of the degraded fucoïdan, under the same experimental conditions. These fucoïdans, by-products of alginates preparation in the food and cosmetologic industries, are obtained easily. Thus, they may represent a cheap and easy source of a new type of anticoagulants.

Anticoagulants↗
PubMed1991

Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation.

BACKGROUND: The B-cell lymphoproliferative syndrome is an infrequent life-threatening complication of marrow or organ transplantation that is the consequence of profound immunosuppression. The results of treatment have been disappointing, although a small number of patients have been cured by chemoradiotherapy or antiviral agents after a reduction in the dosage of immunosuppressive therapy. We report here the results of treating this disorder with anti-B-cell antibodies. METHODS: Twenty-six patients in whom aggressive B-cell lymphoproliferative syndrome developed after bone marrow (n = 14) or organ (n = 12) transplantation received 0.2 mg of CD21-specific and of CD24-specific antibodies per kilogram of body weight for 10 consecutive days in an open, prospective, multicenter trial. RESULTS: The treatment was well tolerated. All patients had transient neutropenia, apparently because the CD24 molecule is also expressed on granulocytes. The treatment was ineffective in seven patients with monoclonal B-cell proliferation. In contrast, 16 patients with oligoclonal B-cell proliferation had complete remission. Systemic remission also occurred in two other patients with oligoclonal proliferation who had central nervous system involvement, although they subsequently died because of progression of the central nervous system disease. In one patient who died early, clonality was not determined. Of the 16 patients who had complete remission, 2 with persistent immunodeficiency due to graft (marrow) rejection or acute graft-versus-host disease had a relapse, and the 1 with graft-versus-host disease subsequently died. Eleven patients were alive and disease-free after a median follow-up of 35 months (5 of 14 marrow recipients and 6 of 12 organ recipients). Four other patients in complete remission died of unrelated causes 4 to 12 months after treatment. CONCLUSIONS: Intravenous administration of anti-B-cell antibodies may be effective in controlling diffuse, severe, oligoclonal B-cell proliferation not involving the central nervous system.

Adolescent↗
PubMed1991

Immobilization of dermatan sulphate on a silica matrix and its possible use as an affinity chromatography support for heparin cofactor II purification.

Dermatan sulphate (DS) is a glycosaminoglycan which catalyses specifically thrombin inhibition by a plasmatic inhibitor, Heparin cofactor II (HCII). DS was insolubilized on a silica matrix to study its interaction with HCII. The immobilization of DS was performed with a good yield on a silica previously coated with polysaccharides in order to neutralize the negatively charged silanol groups. The value of the affinity constant of insolubilized DS for HCII, measured by the adsorption isotherm, is consistent with the value obtained for soluble DS. The DS bound to the silica matrix was also tested as a chromatographic support for the purification of HCII from human plasma; the optimum conditions for HCII adsorption and desorption were determined. The eluted HCII was obtained with a good yield (21%) and with no contamination by antithrombin III, the other main plasmatic inhibitor of thrombin.

Chromatography, Affinity↗
PubMed1991

[Prevention of vascular thromboses after renal transplantation using low molecular weight heparin].

Vascular thrombosis is one of the main causes of early transplant failure in pediatric patients. This paper reports the results of an open trial of the low molecular weight heparin (Enoxaparine) used to prevent renal graft thrombosis in pediatric recipients with risk factors including donor or recipient age under 5 years, multiple arteries supplying the transplant, and positive history for recurrent thrombosis. During 1989, 42 of 67 children given a renal transplant were prophylactically treated with Enoxaparin. Only one transplant was lost to thrombosis among treated patients (1.5%), versus 9 transplants among 73 (12%) children who received their kidney in 1988 without prophylactic Enoxaparin. Risk factors were comparable in both groups of recipients. Enoxaparine therapy was associated with an increased rate of bleeding (12/42) without severe consequences. In conclusion, Enoxaparin is effective in preventing renal graft thrombosis. Availability of this prophylactic therapy makes it possible to use transplants removed from the youngest donors considered as inadequate by some groups.

Age Factors↗
PubMed1990

Influence of the oversulfation method and the degree of sulfation on the anticoagulant properties of dermatan sulfate derivatives.

Six oversulfated dermatan sulfate (DS) derivatives, differing in their tissue origin (porcine skin, bovine and porcine intestinal mucosa), and the oversulfation method of preparation, have been tested for their anticoagulant properties. In the first method, the SO3-trimethylamine complex is added to a DS sodium salt dissolved in formamide while it is added to a DS-benzethonium salt dissolved in dimethyl formamide in the second method. The rate of sulfation of these compounds ranged from 7.8 to 11.5 percent of sulfur on a weight basis, whereas it is 6% and 12% for natural DS and for heparin respectively. The anticoagulant potency was assessed by determining the catalytic effect of each glycosaminoglycan on the inhibition of thrombin added to (i) plasma (ii) purified heparin cofactor II(HC II) or (iii) purified antithrombin III(AT III). The catalytic effect on Factor Xa inhibition in the presence of AT III has also been investigated. The increased sulfation is found to enhance the antithrombin activity of the native dermatan sulfate whatever the method used, while the Factor Xa inhibition by AT III could be catalysed only by the most sulfated derivative obtained by the second method. The two derivatives which were less oversulfated, by the first oversulfation method, exhibit equal or even higher catalytic effects on thrombin inhibition when compared to the four other derivatives. The use of the first oversulfation method provides slightly oversulfated derivatives which exhibit strong anticoagulant properties and may constitute effective antithrombotic drugs with no bleeding tendency, a side effect perhaps related to a high rate of sulfation.

Animals↗
PubMed1990

Plasmatic antiproteinase activity enhancement by insoluble functionalized polystyrene surfaces.

Antithrombogenic functional polymer surfaces have been obtained by grafting heparin or by substituting insoluble polystyrene with sulphonate and/or amino acid sulphamide groups. Their heparin-like properties have been related to their catalytic effects on the antithrombin III - thrombin complex formation. Amongst these antithrombogenic surfaces, this study demonstrates that some insoluble amino acid sulphamide derivatives of polystyrene strongly potentiate heparin cofactor II, in addition to antithrombin III. In contrast, an insoluble polystyrene sulphonate and, to a lesser extent, an insoluble heparin copolymer, are better catalysts of antithrombin III. It is hypothesized that such different behaviours result from different conformations of the species adsorbed onto the surfaces. The conclusions support the possible use of such amino acid sulphamide groups to prepare antithrombogenic surfaces in contact with blood.

Antithrombin III↗
PubMed1990

Prospective study of the occurrence of monoclonal gammapathies following bone marrow transplantation in young children.

We have prospectively studied the occurrence of monoclonal serum immunoglobulins in 38 recipients of BMT. Patients were young children with primary immunodeficiencies (n = 31), other inherited diseases (n = 4), leukemia (n = 2), or aplastic anemia (n = 1). Twenty-nine received an HLA-nonidentical marrow and nine an HLA-identical marrow. Serum monoclonal immunoglobulins were detected by the immunofixation method. Monoclonal immunoglobulins were found in 26 patients. Monoclonal components were more frequently detected in patients with primary severe T cell deficiencies (21/25) rather than in the other patients (6/13). In 7 of 29 recipients of HLA-nonidentical transplants, versus 0 out of 9 recipients of HLA-identical transplants, serum monoclonal immunoglobulins were found associated with a B lymphocyte proliferation syndrome due to an Epstein-Barr virus infection. In this group, monoclonal immunoglobulins were detected early, prior to the onset of the clinical syndrome. The simultaneous occurrence of several monoclonal immunoglobulins was more frequent in these patients, while monoclonal immunoglobulin concentrations increased faster, especially those of IgM isotype. These characteristics may allow in patients at risk (recipients with primary T cell immunodeficiencies and receiving HLA-nonidentical transplantation) an earlier diagnosis of B lymphocyte proliferative syndrome that may eventually lead to early and more efficient therapy.

Bone Marrow Transplantation↗
PubMed1989

A new case of 'type II' inherited protein S deficiency.

Protein S inherited deficiency is associated with high risk of recurrent venous thrombotic disease (Broekmans et al, 1985a, b). Protein S exists as two forms in plasma, either free and functionally active or complexed with C4b-binding protein (C4b BP) and inactive (Dahlbäck & Stenflo, 1981). We report here the case of a 26-year-old woman and her brother, 28 years old, both suffering from recurrent venous thrombosis since the age of 20, diagnosed as severe protein S deficiency according to the following data: free protein S: 2.5-3% by ELISA, undetectable by electroimmunodiffusion (EID); total protein S: 13-16% by ELISA, 21-18% by EID, C4b BP: normal levels. Crossed immunoelectrophoresis using anti-protein S antibodies revealed only traces of protein S associated with C4b BP and no free protein S. All these assays were performed in the absence of any anticoagulant therapy. Among the investigated relatives, less severe protein S deficiency was observed in three children of the propositus: total protein S levels ranging from 41% to 50% (EID), 40-53% (ELISA); free protein S levels ranging from 16% to 18% (EID), 10-12% (ELISA); normal C4b BP levels. Crossed immunoelectrophoresis revealed traces of free protein S but a significant amount of protein S associated with C4b BP. From these results, we consider, according to Comp's classification (Comp et al, 1986a), that the propositus and her brother are the second case of protein S deficiency type II to be reported in the literature while her children belong to the type I category.

Adult↗
PubMed1989

Molecular characterization of antithrombin III (ATIII) variants using polymerase chain reaction. Identification of the ATIII Charleville as an Ala 384 Pro mutation.

The genes of seven structural mutants of antithrombin III (ATIII), presenting either defective serine protease reactivity or abnormal heparin binding, were analyzed. The polymerase chain reaction (PCR) was used to amplify the corresponding gene exon and the mutation was identified by either dot blot analysis using a battery of allele-specific oligonucleotide probes or sequencing. Variants Paris and Paris 2 were identified as Arg 47 Cys mutations, and Clichy, Clichy 2, and Franconville were found to be Pro 41 Leu mutations. All five are heparin binding-site variants. ATIII Avranches is an Arg 393 His mutation and ATIII Charleville is an Ala 384 Pro mutation. These two mutations impair the reactive site of the molecule. ATIII Charleville is a new mutation of the reactive center, as predicted by previous biochemical data. The position of this new mutation, together with the other previously described mutations of the reactive center, sheds light on the molecular function of this site in inhibiting thrombin. Finally, genomic amplification by PCR is a powerful technique for the fast identification of antithrombin III mutations and their homozygous/heterozygous status, and should be useful for predicting thrombotic risk.

Adult↗