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Biomedical subjects

M Koehler

Publications and source records attributed to M Koehler.

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

Possible role of adenosine deaminase in vaso-occlusive diseases.

OBJECTIVE: To describe several emerging concepts regarding the biosynthesis, metabolism and biological roles of adenosine and to illustrate the possible significance of these ideas to vascular biology by proposing a hypothesis pertaining to the role of erythrocyte-derived adenosine deaminase in vaso-occlusive diseases associated with damaged erythrocytes. MULTIPLE PATHWAYS FOR ADENOSINE FORMATION: Three pathways of adenosine biosynthesis have been well established: the intracellular ATP pathway, the extracellular ATP pathway and the transmethylation pathway. A fourth pathway that has received relatively little attention, but could be particularly important in vascular smooth muscle, is the cyclic AMP-adenosine pathway. This pathway involves the extracellular or intracellular metabolism, or both, of cyclic AMP to AMP and hence to adenosine. Our recent experiments in cultured vascular smooth muscle cells, isolated vascular beds and intact animals support the existence of the cyclic AMP-adenosine pathway. Together these four pathways of adenosine formation should assure pharmacologically active levels of vascular adenosine. ANTIVASO-OCCLUSIVE ACTIONS OF ADENOSINE: The overall pharmacologic profile of adenosine suggests that this nucleoside functions to protect vascular beds from vaso-occlusive events. In this regard, some well known effects of adenosine include vasodilation, release of nitric oxide from vascular endothelial cells and inhibition of platelet aggregation, platelet adhesion, neutrophil-endothelial interactions, renin release and noradrenergic neurotransmission. Moreover, studies indicate that adenosine also releases nitric oxide from cultured vascular smooth muscle cells and inhibits vascular smooth muscle cell growth. Thus, any condition that reduces the levels of adenosine in the blood vessel wall or blood vessel-blood interface might predispose toward vaso-occlusive events. DAMAGE TO ERYTHROCYTES REDUCES ADENOSINE LEVELS: Adenosine deaminase rapidly metabolizes adenosine to inosine, which lacks antivaso-occlusive properties. Because erythrocytes are generously endowed with adenosine deaminase, any condition that damages erythrocytes will cause leakage of adenosine deaminase from erythrocytes directly onto the blood vessel wall, thus diminishing local vascular levels of adenosine. Experiments using dimethyl sulfoxide-induced hemolysis have confirmed the hypothesis that erythrocyte-derived adenosine deaminase can reduce adenosine levels in vivo. HYPOTHESIS: THE ROLE OF ERYTHROCYTE-DERIVED ADENOSINE DEAMINASE IN VASO-OCCLUSIVE DISEASES: Because multiple biosynthetic pathways maintain pharmacologically active levels of adenosine within the blood vessel wall and adenosine exerts a number of antivaso-occlusive effects, release of adenosine deaminase from erythrocytes may increase the risk for vaso-occlusive events.

Adenosine Deaminase↗
PubMed1994

XomaZyme-CD5 immunotoxin in conjunction with partial T cell depletion for prevention of graft rejection and graft-versus-host disease after bone marrow transplantation from matched unrelated donors.

Patients who receive bone marrow transplants from unrelated donors have a high incidence of graft-versus-host disease (GVHD). If the donor marrow is first T cell-depleted, the everity of GVHD declines but the risk of rejection rises. In an attempt to prevent both graft rejection and GVHD, we included an anti-T cell antibody-toxin conjugate (CD-5-Ricin; XomaZyme H65) in the transplant conditioning regimen. After receiving a partially T cell-depleted marrow, patients then received a second course of immunotoxin as additional GVHD prophylaxis. Eight recipients of unrelated donor marrow transplants were studied. All engrafted (ANC > 500 x 10(6)/l by day 15, range 13-20 days). One patient had grade II skin GVHD and one developed grade IV disease but the other six patients had no acute GVHD. However, there was high morbidity and mortality from virus infections associated with a sluggish return of CD4 and CD8 T cells into the normal range. Four patients died from virus disease (CMV, n = 2; EBV, n = 1; adenovirus, n = 1) and the remaining patients had frequent documented viral illnesses during the first year. We conclude that improvement in the outcome of unrelated donor marrow transplantation will require strategies which prevent rejection and GVHD coupled with attempts to accelerate immune reconstitution.

Adolescent↗
PubMed1993

Complications of bacteremia due to Stomatococcus mucilaginosus in neutropenic children.

Stomatococcus mucilaginosus, a normal inhabitant of the human oral cavity and upper respiratory tract, can cause fatal sepsis and meningitis in neutropenic patients. We identified eight cases of bacteremia due to S. mucilaginosus in children with cancer, of whom five developed complications despite receiving appropriate antibiotics. At the time cultures were positive, seven patients had profound neutropenia (< 100 neutrophils and band forms/mm3) and four had mucositis; five had central venous catheters. In two cases, there was unequivocal evidence of catheter-related sepsis. Bacteremia was eradicated in all patients within 48 hours after initiation of antibiotics. Despite prompt instigation of effective antibiotic therapy, the complication rates in this series were high: septic shock (50%), pneumonia (50%), dermatologic manifestations (38%), altered neurological status (25%), meningitis (13%), and adult respiratory distress syndrome (13%). No fatalities were attributable to S. mucilaginosus infection. These cases illustrate the virulence of S. mucilaginosus organisms in neutropenic children and suggest a substantial risk of sequelae even when adequate antibiotic therapy is given.

Adolescent↗
PubMed1993

Expression of a novel form of Tec kinase in hematopoietic cells and mapping of the gene to chromosome 5 near Kit.

The Tec kinase was initially identified as a novel cytoplasmic protein tyrosine kinase that is preferentially expressed in the liver and is highly homologous to the Drosophila Dsrc28C src-related tyrosine kinase. In screening of interleukin 3 (IL-3)-dependent myeloid leukemia cells for protein tyrosine kinases, we observed that all cell lines examined expressed high levels of Tec transcripts. However, characterization of Tec cDNAs indicated that they differed significantly from the published sequence. Most strikingly, an insertion of 41 bp in the 5' region affects the initiation codon and results in replacing the published 13 amino acid amino-terminal sequences with 94 amino acids. Using polymerase chain reaction (PCR) analysis, only the form containing the insertion was detected in hematopoietic cells. In addition, we found an in-frame insertion of 66 bp that introduces an additional 22 amino acids into the SH3 domain. This insertion restores conserved SH3 sequences that are found in the src gene family and in the Dsrc28C gene. By PCR analysis, approximately equal levels of Tec transcripts containing the intact SH3 domain and containing the 22 amino acid deletion were found in hematopoietic cells. Lastly, by interspecies backcross analysis, we show that the Tec gene is tightly linked to the c-Kit gene on mouse chromosome 5.

Amino Acid Sequence↗
PubMed1993

Transitional pre-B-cell acute lymphoblastic leukemia of childhood is associated with favorable prognostic clinical features and an excellent outcome: a Pediatric Oncology Group study.

The presenting characteristics and survival of children with the newly recognized transitional cell pre-B immunophenotype of acute lymphoblastic leukemia (ALL) are compared with those of children with pre-B ALL to determine the clinical significance of the new phenotype. Patients with transitional pre-B ALL (n = 17), defined by lymphoblasts expressing cytoplasmic and surface mu heavy chains without kappa or lambda light chains, have lower initial leukocyte counts (p = 0.02) and a higher frequency of DNA indexes > 1.16 (p < 0.001) than patients with pre-B ALL (n = 501), whether or not cases with the unfavorable prognostic (1;19) translocation are included in the analysis. Patients with transitional pre-B ALL lack FAB L3 morphology, bulky extramedullary disease, surface kappa or lambda chains, and the (8;14), (8;22), and (2;8) translocations, features that characterize the syndrome of B-cell ALL. The 4-year relapse-free survival result for children with transitional pre-B ALL appears better than that for children with pre-B ALL (93.3 +/- 17% versus 72.9% +/- 4.6%), but this difference is not statistically significant. We conclude that patients with transitional pre-B ALL have a very favorable prognosis in the context of the therapy used in this study.

Adolescent↗
PubMed1993

Expression of activation antigens CD38 and CD71 is not clinically important in childhood acute lymphoblastic leukemia.

Cell activation antigen expression, because it is related to cell proliferation, may offer useful information about tumor characteristics and treatment outcome. To assess the clinical utility of assays for the plasmocyte activation antigen CD38 (T10) and the thymocyte activation antigen CD71 (transferrin receptor; T9) in childhood acute lymphoblastic leukemia (ALL), we reviewed the presenting features and clinical outcomes of 325 ALL patients treated on a single protocol at St Jude Children's Research Hospital. T-cell ALL cases were more likely than B-lineage ALL cases to express CD38 (100% versus 90.5%, p < 0.01) and CD71 (92% versus 32%, p < 0.01). However, expression of these antigens was not related to any clinical or biologic feature within the immunophenotypic subgroups. More importantly, event-free survival did not differ significantly between CD38+ and CD38- cases or between CD71+ and CD71- cases in the study group as a whole or in immunophenotypic subgroups. Studies of CD38 and CD71 expression in childhood ALL provide no clinically useful information beyond that obtained from standard immunophenotyping studies.

ADP-ribosyl Cyclase↗
PubMed1992

Fibrinolytic effects of pro-urokinase combined with low-dose urokinase compared to high-dose urokinase in patients with acute myocardial infarction.

20 patients (6 females, 14 males) aged between 47 and and 75 years (mean: 62.6 yrs.) with acute myocardial infarction (onset of symptoms within 6 hours) were treated intravenously with either 200,000 U urokinase (UK) and 4.5 million U pro-urokinase (pro-UK) within 60 min (group I, N = 10), or 2.5 million U UK within 5 min (group II, N = 10). Blood samples for haemostatic and fibrinolytic function tests were taken prior to and repeatedly during the 24 hours following treatment. Peak fibrinolytic activity measured by fibrin plates was equivalent in both regimens. Average decreases, with lowest levels within 60 to 120 min following thrombolytic therapy, were observed of 27% and 70% for plasminogen, of 71% and 91% for alpha-2-antiplasmin, and of 20% and 74% for fibrinogen in group I and II, respectively. The reptilase time reached maximum values of 1.5- and 4.5-fold within 60 to 180 min. Peak levels of D-dimers and thrombin-antithrombin III complexes in group II were 2.6 and 3.2 times those of group I. After 24 hours, in contrast to group I, all these parameters still remained significantly different from pretreatment values in group II. These data indicate that, contrary to high-dose UK, pro-UK in combination with low-dose UK causes minor systemic fibrinolytic effects and is, therefore, assumed to be largely clot-specific, although the fibrinolytic potential is equivalent for both regimens.

Aged↗
PubMed1992

A monoclonal antibody to a novel surface antigen, MKW, blocks the antiproliferative and differentiation effects of granulocyte-macrophagecolony-stimulating factor and vitamin D3.

A monoclonal antibody (MoAb) recognizes a novel 52-Kd cell protein (MKW) that is expressed on cells of the normal myelocytic and monocytic lineage, a subset of B cells, and the U937 cell line. Using the U937 cell line as a model, the MoAb (anti-MKW) was examined for its ability to inhibit the effects of differentiation-inducing factors. In the U937 cell line, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) inhibits cell proliferation, 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits proliferation and induces the early differentiation antigen CD11b, and vitamin D3 inhibits proliferation and induces both CD11b and the late differentiation antigen CD14. The antiproliferative and differentiation effects of rhGM-CSF and vitamin D3 on U937 cells were inhibited by the anti-MKW MoAb. Similar effects were seen when anti-MKW antibody was added 30 minutes before or 2 hours after rhGM-CSF or vitamin D3, suggesting that its effects are not mediated by blocking or binding to the receptors for these growth factors. The anti-MKW MoAb had no effect on TPA-induced differentiation in U937 cells, indicating that TPA exerts its effects through a pathway different from rhGM-CSF and vitamin D3. These results suggest that the MKW antigen is important in controlling the proliferation and differentiation of monocytic cells.

Antibodies, Monoclonal↗
PubMed1992

Childhood acute lymphoblastic leukemia immunophenotypes and their prognostic significance: experience of the IGCI-study in 389 children. International Society for Chemo-immunotherapy (IGCI-Vienna) Cooperative Group.

The prognostic significance of immunophenotype and other features including sex, age, anaemia, WBC, FAB type, and PAS staining were analysed in a group of 389 children newly diagnosed as acute lymphoblastic leukemia (ALL) and treated according to the BFM 1981/1983 protocol. The CR rate was higher (82-94%) in immunophenotypic subgroups defined as 'non-B' compared with B-ALL (54%). The probability of being in CCR at the end of follow up was 0.68 (median. observation, 3 years). Using the stepwise Cox regression analysis the following independent factors predictive of duration of CCR were selected (relative risk in brackets): 1. WBC (> 25G/1:< 25G/1 = 2.0, P = 0.0008), 2. age (> 10y:2-10y = 1.3, P = 0.04), 3. CALLA positivity (neg.:posit. = 2.4, P = 0.04), 4. CALLA within B-cell progenitor ALL (pre;preB,Calla-:Calla+ = 1.7, P = 0.007). T-ALL appeared to have a worse prognosis than U-ALL and B-progenitor derived ALL but it did not retain independent prognostic significance in multivariate analysis.

Adolescent↗
PubMed1992

MKW, a novel hematopoietic antigen.

A novel hematopoietic antigen was identified using a murine monoclonal antibody raised against KG-1 cells. This antigen, termed MKW, was also detected on the surface of the monocytic cell line U937, but not on the K562, ML1, or HL-60 cell lines. On normal hematopoietic cells, the antigen is expressed on the surface of monocytic and myelocytic cells and on a subpopulation of B-cells. During normal hematopoiesis, the surface expression of MKW is greatest and occurs very early on monocytic cells. Alternatively, in myeloid cells, surface expression occurs later and cell maturation is correlated with increased surface expression. When U937 cells are induced to differentiate, surface expression is transiently up-regulated. Surface expression of MKW, however, does not appear to be an activation antigen since activation of purified T- or B-cells failed to increase MKW on the cell surface. Leukemic blasts from 22 of 80 children (27%) with acute myeloblastic leukemia and from 29 of 225 children (13%) with acute lymphoblastic leukemia expressed MKW on the cell surface. Although surface expression of MKW was absent on T-cell lines, peripheral T-cells, and most B-cells, the antigen was identified in the cytoplasm of some B-cells, T-cells, and cell lines. Immunoprecipitation studies showed that MKW is a 52-kDa protein whether expressed on the cell surface or in the cytoplasm, and it appears to be nonglycosylated. Furthermore, studies with phosphatidylinositol-phospholipase C suggested that MKW is not attached to a glycolipid anchor. The biochemical characterization of MKW and its pattern of expression are distinct from any of the previously identified CD groups or published antigens. Since this unique antigen has prognostic significance in leukemia and appears to be associated with cell differentiation, its exact role in hematopoiesis should be investigated.

Antibodies, Monoclonal↗
PubMed1992

[Comparison of clinical usefulness of immunophenotyping of leukemia using the immunofluorescence and immunoenzyme APAAP methods].

The clinical utility of the indirect immunofluorescence (IF) and the alkaline phosphatase-anti-alkaline phosphatase (APAAP) techniques was compared in 103 newly diagnosed acute leukaemia patients immunophenotyped using a panel of 19 monoclonal antibodies (MoAb). In spite of slight variations in the percentages of cells reacting with particular MoAbs when comparing the two methods we found no discrepancies in the final classification of each case. In ANLL (n = 73) the best correlation between the two methods was found for CDw65 which is a good screening marker, and for CD15 having a prognostic significance. In ALL (n = 30) the best correlation was observed for CD19 and CD10, both of great diagnostic importance. The following antigens present both in membrane and in cytoplasm displayed higher positivity with the APAAP than in IF HLA-Dr, CD71 and CD11b in ANLL, CD22 and HLA-Dr in nonT-ALL and CD3 in T-ALL. The important advantages of the APAAP technique are: 1) its use with routinely performed bone marrow or peripheral blood films, which can be stored before staining, 2) the possibility of correlating morphology with immunological characterization and documentation of the results.

Alkaline Phosphatase↗