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Biomedical subjects

M Steinbuch

Publications and source records attributed to M Steinbuch.

At least 37 records · Page 2Linked to original sources
PubMed1996

Malignant neoplasms following bone marrow transplantation.

We undertook an analysis of 2,150 recipients of bone marrow transplant (BMT) at the University of Minnesota to determine the incidence of post-BMT malignant neoplasms (MNs). Fifty-one patients developed 53 MNs, compared with 4.3 expected from general population rates (standardized incidence ratio [SIR], 11.6, 95% confidence interval [CI], 8.2-14.5). These included 22 occurrences of B-cell lymphoproliferative disorder (BLPD), 17 solid nonhematopoietic tumors, 10 myelodysplastic syndromes (MDS), 1 acute myelogenous leukemia (AML), 2 non-Hodgkin's lymphoma (NHL), and 1 Hodgkin's disease (HD). The estimated actuarial incidence of any post-BMT malignancy was 9.9% +/- 2.3% at 13 years posttransplant. The cumulative probability of BLPD plateaued at 1.6% +/- 0.3% by 4 years from transplant and factors independently associated with increased risk included in vitro T-cell depletion of marrow (relative risk (RR) = 11.9, P < .001), HLA mismatch (RR = 8.9, P < .001), use of antithymocyte globulin (ATG) for graft versus host disease (GVHD) prophylaxis (RR = 5.9, P < .001) or in the preparative regimen (RR = 3.1, P = .03) and primary immunodeficiency (RR = 2.5, P = .06). The cumulative probability of developing solid malignancy was 5.6% +/- 2.2% at 13 years from BMT. Malignant melanomas were the most common (SIR, 10.3, 95% CI 1.9 to 25.4). The actuarial incidence of MDS/AML plateaued at 2.1% +/- 0.8% at 9 years and was seen most often in older patients receiving autologous peripheral blood stem cells for HD or NHL. These data document that BMT recipients are at an increased risk of later malignancy, which may add significant morbidity and mortality to the transplant process. Methods for screening and identification of individuals at increased risk need to be addressed in future studies.

Adolescent↗
PubMed1996

Liquid pasteurization of an immunoglobulin preparation without stabilizer: effects on its biological and biochemical properties.

Intravenous immunoglobulins (IVIg) purified by cold ethanol fractionation have a very good safety record with regard to the transmission of many viruses. However, a few cases of non-A-non-B hepatitis have been described after intravenous injection of some immunoglobulin preparations. To ensure even higher safety for our IVIg, an additional virus inactivation step, based on pasteurization, was developed. The heating of aqueous IVIg was performed without stabilizer, and at a very low salt concentration (< 1 mM) at acidic pH. No generation of polymer was detected after pasteurization and a significant decrease in the proportion of dimers was observed. Analysis of the secondary structure by circular dichroism showed a very slight change in the secondary structure. The biological properties of the Fc region as well as the Fab region were not affected by the pasteurization. Our method has several advantages: (1) improvement of viral safety; (2) there is no need to add stabilizer which may stabilize viral particles, and (3) the absence of any hypotensive effect and low anticomplementary activity indicates a good clinical tolerance of IgG preparation.

Animals↗
PubMed1996

Outcome of second bone marrow transplantation following a uniform conditioning regimen as therapy for malignant relapse.

Twenty-three second bone marrow transplants (BMT) were performed between October 1987 and January 1994 for patients with malignant relapse following initial BMT. For first BMT, twenty-one of 23 (91%) were conditioned with cyclophosphamide plus total body irradiation. For second BMT, a uniform conditioning regimen consisting of busulfan and cyclophosphamide was used. Eleven patients had chronic myelogenous leukemia, seven acute leukemia, four lymphoma, and one myelodysplastic syndrome. Median patient age at second BMT was 32 years, the median time between first BMT and relapse was 22 months, and the median time to second BMT after relapse was 5 months. The second BMT marrow source included: autologous marrow (1), unrelated donors (4), new matched sibling donors (5) and same matched sibling donors as the first BMT (13). The Kaplan-Meier disease-free survival and survival rates at 3 years were 38 and 43%, respectively (median follow-up of survivors was 45 and 48 months, respectively), and five patients survive disease-free at 4-6 years. Nine of the 13 deaths occurred within 100 days after second BMT; eight had relapsed within 1 year of the first BMT. We conclude that: (1) second BMT can offer durable long-term survival in certain patients, especially those who relapse late after first transplant; (2) busulfan and cyclophosphamide is a suitable conditioning regimen for second BMT.

Adolescent↗
PubMed1995

Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease.

Allogeneic bone marrow transplantation is limited by the availability of suitable marrow donors and risk of graft-versus-host disease (GVHD) and opportunistic infection. In an attempt to ameliorate these limitations, umbilical cord blood has been postulated as an alternative source of allogeneic haemopoietic stem cells for transplantation. From September, 1994, umbilical cord blood from sibling donors has been used to reconstitute haemapoiesis in 44 children with acquired or congenital lympho-haemapoietic disorders, neuroblastoma, or metabolic diseases. Patients who had HLA-identical and HLA-1 antigen disparate grafts, had a probability of engraftment at 50 days after transplantation of 85%. No patient had late graft failure. The probability of grade II-IV GVHD at 100 days was 3% and the probability of chronic GVHD at one year was 6%. With a median follow-up of 1.6 years, the probability of survival for recipients of HLA-identical or HLA-1 antigen disparate grafts is 72%. We conclude that umbilical cord blood is a sufficient source of transplantable haemopoietic stem cells for children with HLA-identical or HLA-1 antigen disparate sibling donors with very low risk of acute or extensive chronic GVHD. The feasibility of umbilical-cord-blood transplantation with HLA-2 and HLA-3 antigen disparate sibling donors remains to be determined.

Acute Disease↗
PubMed1994

Properties of a new fibrin glue stable in liquid state.

A pasteurized preparation of fibrin glue composed of two separate stable, liquid components: highly purified human thrombin and fibrinogen concentrate is described. The components are mixed extemporaneously during application. Thrombin was prepared using a prothrombin complex concentrate as starting material which was activated by calcification and then heated in solution during 10 hours at 60 degrees C in the presence of stabilizers. The isolation of thrombin was carried out using a column of benzamidine-Sepharose 6B. The eluate contained thrombin with a high degree of purity (more than 95% assessed by SDS-PAGE) with a specific activity > 2,500 IU/mg protein. The purified liquid thrombin preparation remained stable for at least 6 months. The fibrinogen concentrate was prepared from cryoprecipitate after removal of factor VIII and then virally inactivated by pasteurization in the presence of glucose and sorbitol. After purification the concentrate containing a high level of fibrinogen was formulated with urea 0.5 M or arginine 5% before conditioning. Both components of the fibrin glue kept its biological properties for more than 6 months at +4 degrees C.

Adhesiveness↗
PubMed1994

Immunoregulatory abnormalities in patients with Epstein-Barr virus-associated B cell lymphoproliferative disorders.

EBVirus-associated B cell lymphoproliferative disorder (BLPD) is a recognized complication of primary immunodeficiency and organ as well as bone marrow transplantation. Although the nature of the immune defects that predispose to the development of BLPD are unknown, it is postulated that aberrant T cell responses are involved. It is our hypothesis that unbalanced lymphokine production is a major contributory factor to abnormal B cell growth in response to EBV, resulting in BLPD. Since IFN-alpha and IL-4 are important regulators of B cell proliferation and also regulate the synthesis of IgE, we determined serum levels of IFN-alpha, IL-4, and IgE in 8 patients with newly diagnosed BLPD. Comparison was made to healthy recipients of organ transplants on immunosuppressive therapy without BLPD, and normal EBV seropositive controls. Levels of serum IL-4 were significantly elevated in both patients with BLPD as well as in healthy immunosuppressed organ transplant recipients as compared with normal healthy individuals. Patients with BLPD exhibited a combination of significantly lower levels of serum IFN-alpha, and significantly higher levels of serum IgE than either healthy EBV seropositive individuals or healthy recipients of organ transplants on immunosuppressive therapy. These results suggest that imbalance in the proportions of circulating cytokines favoring B cell proliferation may be contributing to the development of EBV-associated BLPD. The potential significance of the finding of low IFN-alpha in patients who develop BLPD is exemplified by our recent success in the treatment of BLPD with IFN-alpha and intravenous IgG.

Adolescent↗
PubMed1993

Aprotinin is a competitive inhibitor of the factor VIIa-tissue factor complex.

A highly purified preparation of human plasma factor VIIa was submitted to chromogenic assays with S-2288 factors IXa, Xa, activated protein C and thrombin being absent. Factor VIIa alone or in the presence of calcium, kept its activity even in the presence of high concentrations of aprotinin, inhibition appeared only in the presence of a factor VIIa-tissue factor complex. A two-stage amidolytic assay using activation of purified factor X and hydrolysis of S-2765 chromogenic substrate by the generated Xa was used to show a competitive inhibition with a Ki value of 30 microM. Aprotinin had no effect on factor Xa amidolytic activity per se. The factor VIIa-tissue factor complex could be adsorbed to immobilized aprotinin and removed by a chaotropic ion like KSCN 3 M. The assays with the DFP inactivated VIIa-tissue factor complex proved that the interaction involved the active site of factor VIIa. The inhibition of the VIIa-tissue factor complex was demonstrated in a clotting assay using aprotinin enriched normal or factor VIII deficient plasma.

Aprotinin↗
PubMed1990

Inhibition of activated protein C by aprotinin and the use of the insolubilized inhibitor for its purification.

The study of the interaction between activated protein C (APC) and non-plasmatic inhibitors allowed us to demonstrate that aprotinin is a potent competitive inhibitor of APC with a Ki of 1.35 mumol/L. It was possible to adsorb immunopurified protein C (PC) activated by venom activator to insolubilized aprotinin and to recover the active enzyme after elution by HCl 0.1 N or by a chaotropic ion, for example KSCN 3 mol/L. The interaction involved the active-site of the enzyme since PC and DIP-APC did not bind to the matrix. Thus, APC could be purified, after activation, in a one-stage procedure out of a mixture of protein such as a prothrombin complex concentrate.

Amides↗
PubMed1989

A human factor VIIa concentrate and its effects in the hemophilic A dog.

Properties of a new concentrate of FVII/FVIIa, obtained by adsorption onto an inorganic adsorbent followed by a chromatographic step onto Q-Sepharose using a by-product of routine fractionation as starting material, are described. This fraction contains only small amounts of the other components of the prothrombin complex but it is enriched in Proteins C and S. This preparation is essentially free of FVIIICag. It has been submitted to animal experiments including those carried out on normal and hemophilic A dogs. A normalization of the buccal bleeding time was seen after injection of a minimal dose of 4 uFVIIa/kg. No adverse reaction was observed at any dose employed. This concentrate might thus be indicated for the treatment of Haemophilia A patients with inhibitors. Its viral inactivation has been achieved.

Animals↗
PubMed1987

Appraisal of the protein composition of prothrombin complex concentrates of different origins.

The protein composition of 12 different prothrombin complex concentrates, including 2 purified factor IX concentrates and 2 activated fractions, was evaluated. There is a clear difference between ion exchanger-prepared fractions and those obtained by adsorption onto calcium phosphate. The former contain high molecular weight kininogen and complement components, the latter only trace amounts of these proteins but relatively high quantities of the pro- and even partially activated enzymes of the contact phase. Calcium phosphate adsorbed preparations contain less VIII:CAg than the DEAE-Sephadex-prepared fractions. The inorganic adsorbent showed higher affinity for IgG than the ion exchangers.

Adsorption↗
PubMed1986

Risk of hepatitis B in hospital personnel.

Between Jan 1, 1981, and Aug 31, 1983, 1,323 Ohio State University Hospital employees were screened for hepatitis B. There were 105 employees (cases) with present or past evidence of hepatitis B virus infection, and 210 randomly selected employees (controls) with no evidence of hepatitis B virus infection. Using logistic regression analyses to develop a risk index, the best predictive model indicated that nonwhites, males, discontinuity of employment, and frequency of contact with blood products constituted the most important risk factors in acquiring hepatitis B virus infections. Those with no blood product contact were at higher risk than those exposed to blood products. Thus, although there was a gradient of risk among those exposed to blood products, the findings suggest other factors may contribute more substantially to the risk than the exposure variables tested.

Blood↗
PubMed1985

Reaction of human ceruloplasmin and anion treated ceruloplasmin with diethyldithiocarbamate.

The reaction of human ceruloplasmin and anion treated ceruloplasmin with diethyldithiocarbamate was studied at pH 5.5. The analysis of optical and EPR spectra at 9 GHz showed that ceruloplasmin contains five paramagnetic copper ions, two of which, X and Y, not involved in enzymatic activity, are chelated by diethyldithiocarbamate; the complex thus formed is easily removed by high-speed centrifugation. However, the enzyme depleted of these two X and Y copper ions is able to compete with the Cu(II)-diethyldithiocarbamate complex, as time elapses, recovering both Cu(II) atoms. In addition diethyldithiocarbamate acts as a reducing agent for the two type-I copper atoms when added in large excess to the enzyme or the anion treated enzyme.

Anions↗
PubMed1984

Studies on prothrombin complex concentrates contact factors, complement components and proteinase inhibitors.

The behaviour of contact factors, complement components and antiproteases during the preparation of prothrombin complex concentrates by adsorption of the clotting components on DEAE-Sephadex has been studied. The pro-enzymes: factors XII, XI and prekallikrein were removed by pre-elution in function of the salt concentration. In contrast, high molecular weight kininogen was considerably enriched in PCC preparations. C4 of the complement system displayed an analogous behaviour. C1s reached a 4-5 fold plasma concentration but C3 only 30% of the normal plasma level. The prothrombin complex concentrate contained no antithrombin III nor alpha 2M nor alpha 2 antiplasmin but a three fold plasma concentration of C1-inactivator and a 15 fold increase of inter-alpha-trypsin inhibitor. NAPTT (Non Activated Partial Thromboplastin Time) ratios did not seem to be in accordance with either the presence or the absence of contact enzymes. Moreover 0.20 M NaCl appeared as the minimal pre-elution molarity necessary to ensure a NAPTT ratio above thrombogenic values. Molecular alteration of high molecular weight kininogen and C4 was observed and its significance discussed. Complex formation between C1-inactivator and proteases was shown to be another sign of undesirable proteolytic events.

Blood Coagulation Factors↗
PubMed1984

Interaction of alpha 2-macroglobulin-bound thrombin with hirudin.

The human thrombin bound to alpha 2-macroglobulin (alpha 2 M) in a 1:1 stoichiometry is still able to interact with one of its specific inhibitors, hirudin. The dissociation constant of the complex hirudin--alpha 2M-bound thrombin is 1 X 10(-7) M, whatever the mode of thrombin binding, covalent or non-covalent.

Chromatography, Gel↗