Search PubMed⌕ Search

Biomedical subjects

K Lechner

Publications and source records attributed to K Lechner.

At least 289 records · Page 16Linked to original sources
PubMed1989

Identification of the target platelet glycoprotein in autoimmune thrombocytopenia occurring after allogeneic bone marrow transplantation.

We report the case of a patient who developed autoimmune thrombocytopenia after allogeneic bone marrow transplantation from her HLA-identical sister. An IgG autoantibody was detected that bound to the platelet glycoprotein IIb/IIIa and to the HLA class I proteins. Immunoprecipitation studies with radiolabeled platelets revealed additional antibody binding sites on proteins of 214 kDa molecular weight under nonreduced conditions and 65 and 56 kDa molecular weight under reduced conditions.

Adult↗
PubMed1989

Organization and nucleotide sequence of a transcriptional unit of Methanococcus vannielii comprising genes for protein synthesis elongation factors and ribosomal proteins.

By a chromosome walking strategy the DNA region from Methanococcus vannielii flanking the genes for protein synthesis elongation factor (EF) 1 alpha and EF-2 was cloned and sequenced. A gene organization of 5' - beta' - open reading frame (ORF) 1 - ORF2 - S12 - S7 - EF-2 - EF-1 alpha - S10 - ORF3 - ORF4 - 3' was found where beta', S12, S7, S10, EF-2, and EF-1 alpha represent gene products with sequences similar to the beta' subunit of RNA polymerase, ribosomal proteins S12, S7, and S10, and EF-G and EF-Tu from Escherichia coli, respectively. ORF1-4 represent gene products with no known eubacterial counterparts. Northern blot analysis of transcripts and nuclease S1 mapping showed that transcription initiates between beta' and ORF1 and terminates at the 3' side of the S10 gene and that the genes from ORF1 to S10 are cotranscribed. Apart from the presence of two additional ORFs, ORF1 and ORF2, and of the gene for S10, this organization is identical to that of the eubacterial "streptomycin operon." ORF1 displays sequence similarity to rat liver ribosomal protein L30 and may represent one of the "additional" ribosomal proteins of Methanococcus. The sequenced part of the beta' gene and the EF-2 and EF-1 alpha gene products from Methanococcus are more similar to their eukaryotic than to their eubacterial counterparts. It appears, therefore, that the genetic organization of the translational components resembles the situation in eubacteria, whereas their primary structures are more eukaryotic in nature.

Amino Acid Sequence↗
PubMed1989

Interleukin 3 activates human blood basophils via high-affinity binding sites.

Pure populations of human basophilic granulocytes were obtained from chronic myeloid leukemia (CML) blood by negative selection using a mixture of monoclonal antibodies and complement. 125I-radiolabeled recombinant human interleukin 3 (rhIL-3) bound to purified basophils in a specific manner. Quantitative binding studies and Scatchard plot analyses performed on samples from two donors revealed the presence of a single class of high-affinity IL-3 binding sites (500 and 2100 sites per cell; dissociation constant at equilibrium, 230 and 160 pmol/liter, respectively). Purified CML basophils maintained in suspension in the presence of rhIL-3 (100 units/ml) incorporated up to 12 times more [3H]thymidine than basophils in control cultures. Furthermore, after preincubation in vitro with rhIL-3 (100 units/ml) for 30 min, normal blood basophils released 2- to 3-fold more histamine than basophils pretreated with control medium when exposed to various concentrations of an anti-IgE antibody. Together, these results show that rhIL-3 binds to a specific receptor on blood basophils and is a regulator of basophil function.

Antibodies, Monoclonal↗
PubMed1989

Immune thrombocytopenia more than a year after allogeneic marrow transplantation due to antibodies against donor platelets with anti-PlA1 specificity: evidence for a host-derived immune reaction.

We report on a male patient transplanted from his HLA-matched sister for Ph1-chromosome positive chronic myelogenous leukaemia who developed immune thrombocytopenia more than 1 year after transplantation. The platelet antibody reacted with the platelet specific antigen PlA1 on donor platelets, and also on recipient platelets after engraftment. A presumed host-versus-donor induced thrombocytopenia was supported by Southern blot analysis using a Y-chromosome specific probe demonstrating residual host-origin cells in the patient's excised spleen.

Adult↗
PubMed1989

Oral cyclosporin-A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure.

16 patients with transfusion-dependent, life-threatening bone marrow failure (14 with severe aplastic anaemia, 1 with systemic lupus erythematosus and 1 with pure red cell aplasia) were treated with cyclosporin-A (Cy-A) after either lack of response to conventional immunosuppression with antithymocyte-globulin/high-dose methylprednisolone for 95 to 1190 days (median 186.5) (group I, 8 patients) or as a primary treatment due to ineligibility for conventional immunosuppression (group II, 8 pat.). Cyclosporin-A was given orally to maintain trough levels of 200 to 300 ng/ml (RIA). In group I, 6 out of 8 patients responded 30 to 480 d (median 53) and are currently alive 627 to 1482 d (median 731) after initiation of Cy-A, respectively. In 3 of the responders Cy-A has been withdrawn, without relapse. In group II, 5 of 8 patients responded 26 to 170 d (median 63) and are currently alive 142 to 697 (median 420) d following initiation of Cy-A, respectively. These data indicate a place for cyclosporin-A in the management of patients with life-threatening bone marrow failure in whom a) immunosuppressive therapy with antithymocyte-globulin and high-dose methylprednisolone had failed and b) who are not candidates for vigorous immunosuppression or bone marrow transplantation, for medical or other reasons.

Administration, Oral↗
PubMed1989

Gene organization and structure of two transcriptional units from Methanococcus coding for ribosomal proteins and elongation factors.

Two transcriptional units coding for ribosomal proteins and protein synthesis elongation factors in Methanococcus vannielii have been cloned and analysed in detail. They correspond to the "streptomycin operon" and "spectinomycin operon" of the Escherichia coli chromosome. The following general conclusions can be drawn from comparison of the nucleotide and the derived amino acid sequences of ribosomal proteins from Methanococcus with those from eubacteria and eukaryotes. (i) Ribosomal protein and elongation factor genes in Methanococcus are clustered in transcriptional units corresponding closely to E. coli ribosomal protein operons with respect to both gene composition and organization. (ii) These transcriptional units contain, in addition, a few open reading frames whose putative gene products share sequence similarity with eukaryotic 80S but not with eubacterial, ribosomal proteins. They may correspond to "additional" ribosomal proteins of the Methanococcus ribosome, there being no functional homologues in the eubacterial ribosome. (iii) Methanococcus ribosomal proteins and elongation factors almost exclusively exhibit a higher sequence similarity to eukaryotic 80S ribosomal proteins than to those of eubacteria. (iv) Many Methanococcus ribosomal proteins have a size intermediate between those of their eukaryotic and eubacterial homologues. These results are discussed in terms of a hypothesis which implies that the recent eubacterial ribosome developed by a "minimization" process from a more complex organelle and that the archaebacterial ribosome has maintained features of this ancestor.

Amino Acid Sequence↗
PubMed1989

Lymphokine overproduction in severe aplastic anemia is not related to blood transfusions.

The production of interferons (IFNs), IFN-gamma, tumor necrosis factors (TNFs) and TNF-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMNCs) of untransfused and transfused, but otherwise untreated patients with severe aplastic anemia (SAA) was determined using bioassays and immunoassays. In untransfused and pretransfused SAA patients, spontaneous and lectin-induced production of these cytokines by PBMNCs was strongly enhanced. Cytokine production in untransfused SAA patients did not differ from that in pretransfused patients. Similar relative frequencies of activated (HLA-DR+) lymphocyte subpopulations present in the PBMNCs demonstrated cytokine overproduction per cells. Cytokine production was studied in three SAA patients before and after blood cell transfusions. Spontaneous and lectin-induced production of these cytokines was abnormally high and unaffected by blood transfusions. In another patient exhibiting abnormal cytokine production, the hematopoietic response to cyclosporin-A in vivo was accompanied by normalization of cytokine production in vitro. We conclude that overproduction of IFN-gamma and TNF-alpha by lectin-stimulated PBMNCs is an intrinsic abnormality of SAA unrelated to blood transfusions. Normalization of production of IFN-gamma and TNF-alpha accompanying a clinical response to cyclosporin-A may cautiously be taken as further evidence suggesting a pathogenetic role of cytokine overproduction in SAA.

Anemia, Aplastic↗
PubMed1988

Evidence for an increased generation of prostacyclin in the microvasculature and an impairment of the platelet alpha-granule release in chronic renal failure.

The formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the alpha-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is--at least partially--due to an acquired defect of the platelet alpha-granule release and an increased generation of PGI2 in the microvasculature.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Functional asplenia after bone marrow transplantation. A late complication related to extensive chronic graft-versus-host disease.

STUDY OBJECTIVE: To evaluate splenic function in bone marrow transplant recipients, with relation to chronic graft-versus-host disease and infections. DESIGN: Survey, outpatients geographically accessible for voluntary participation. SETTING: Bone marrow transplantation referral center. PATIENTS: Fifteen bone marrow graft recipients (13 allogeneic, 2 autologous), out of a total of 33 patients who received transplants at the center and survived more than 6 months after grafting. MEASUREMENTS AND MAIN RESULTS: In 6 of 15 patients impaired splenic function (functional asplenia) was indicated by the presence of Howell-Jolly bodies in peripheral blood smears, reduced spleen size (P less than 0.001), higher platelet counts (P less than 0.01), higher indium-111 labeled autologous platelet recovery (P less than 0.005), reduced splenic blood flow (P less than 0.001), and reduced accumulation of radioactivity at the splenic site (P less than 0.001). All patients with functional asplenia but only 2 patients without functional asplenia had extensive chronic graft-versus-host disease. The incidence of bacterial infections was four times higher in patients with impaired splenic function. CONCLUSIONS: Functional asplenia is a late complication after allogeneic bone marrow transplantation and contributes to the high susceptibility to bacterial infections in patients with extensive chronic graft-versus-host disease.

Adolescent↗
PubMed1988

Gene for the diphtheria toxin-susceptible elongation factor 2 from Methanococcus vannielii.

Protein synthesis elongation factor 2 (EF-2) from all archaebacteria so far analysed, is susceptible to inactivation by diphtheria toxin, a property which it shares with EF-2 from the eukaryotic 8OS translation system. To resolve the structural basis of diphtheria toxin susceptibility, the structural gene for the EF-2 from an archaebacterium, Methanococcus vannielii, was cloned and its nucleotide sequence determined. It was found that (i) this gene is closely linked to that coding for elongation factor 1 alpha-(EF-1 alpha), (ii) the size of the gene product, as derived from the nucleotide sequence, lies between those for EF-2 from eukaryotes and eubacteria, (iii) it displays a higher sequence similarity to eukaryotic EF-2 than to eubacterial homologues, and (iv) the histidine residue which is modified to diphthamide and then ADP-ribosylated by diphtheria toxin is present in a sequence context similar to that of eukaryotic EF-2 but it is not conserved in eubacterial EF-G. The EF-2 gene from Methanococcus is expressed in transformed Saccharomyces cerevisiae but is not ADP-ribosylated by diphtheria toxin. This indicates that the Saccharomyces enzyme system is unable to post-translationally convert the respective histidine residue from the Methanococcus EF-2 into diphthamide.

Adenosine Diphosphate Ribose↗
PubMed1988

[Interferon therapy in hematologic neoplasms].

Interferons are new and effective agents in the treatment of various haematological neoplasias. Alpha-interferon (natural or recombinant) has a high efficacy (90% response rate) in hairy cell leukaemia. Complete remissions are, however, rare and definite cure of the disease is unlikely. Alpha-interferon induces haematological remissions in about two thirds of patients with chronic myeloid leukaemia and leads to a reduction in Philadelphia chromosome in about 40% of patients. It is uncertain, however, whether this treatment will actually prolong the life of these patients as compared with conventional treatment. Alpha-interferon has a beneficial effect in some patients with low malignant non-Hodgkin lymphomas (in particular follicular lymphomas). The response rate in myeloma is rather small (20%). Gamma-interferon is not effective in hairy cell leukaemia, non-Hodgkin lymphoma and myeloma. It is, however, of some efficacy in chronic myeloid leukaemia (the response rate in lower than with alpha-interferon) and possibly has some effect in patients with acute myeloid leukaemia and myelodysplastic syndromes. The toxicity of interferons (alpha and gamma) consists of an influenza-like syndrome during the first days of treatment. Low doses of alpha-interferon show virtually no long-term toxicity. However, bone and muscular pain is sometimes dose-limiting with intermediate doses (5 to 15 million units) of alpha-interferon.

Hematologic Diseases↗
PubMed1988

Recombinant alpha-interferon (alpha-IFN) for progressive hairy-cell leukemia (HCL): a study in previously untreated nonsplenectomized patients.

Ten nonsplenectomized patients (5 males, 5 females) with hairy-cell leukemia were treated with recombinant alpha-IFN. The median age of patients was 54 years (32-76 years). The time between diagnosis and onset of treatment ranged from 1-120 months. Initially the patients received 5 x 10(6) I.U. daily by intramuscular or subcutaneous injections for 10 weeks. Thereafter the dose of IFN was reduced to 5 x 10(6) I.U. 3 x weekly and after 6 months to 5 x 10(6) I.U. 2 x weekly for at least 6 months. The median time of patient follow-up is 23 months (4-28 months). Three complete remissions were achieved after 3-24 months and five partial remissions after 4-18 months. One patient showed improvement after 3 months, and one patient died from cerebral hemorrhage after 5 weeks. In eight of ten patients peripheral blood cell counts normalized after a median of 7 months (1.5-11 months). A marked reduction in spleen size was observed in all seven patients who had splenomegaly at study entry. Two of three patients who interrupted therapy have relapsed after 2 and 6 months. We conclude that alpha-interferon is an effective method of first-line treatment in patients with HCL.

Adult↗
PubMed1988

Deficiency of pluripotent hemopoietic progenitor cells in myelodysplastic syndromes.

Pluripotent (CFU-MIX), erythroid (BFU-E) and granulocyte/macrophage (CFU-GM) progenitor cells were examined in bone marrow (BM) from 23 patients with myelodysplastic syndromes (MDS). Patients were grouped according to the FAB classification: Refractory anemia (RA), n = 3; RA with ring sideroblasts (RARS), n = 3; RA with excess of blasts (RAEB), n = 8; RA with excess of blasts in transformation (RAEBt), n = 7; chronic myelomonocytic leukemia (CMML), n = 2. In FAB groups RA, RARS, RAEB and RAEBt CFU-GM concentrations were normal or decreased but both CMML-patients had increased CFU-GM values. Abnormal cluster growth was observed in 9 of 23 MDS-patients. BFU-E colony formation was subnormal in all cases. Mixed-colony assay values were at the lower limit of controls in one patient and decreased in the remaining 22 MDS-patients. A similar growth pattern of hemopoietic progenitor cells was observed in 19 patients with acute nonlymphocytic leukemia (ANLL), who were studied for comparison. These data suggest a quantitative or qualitative/functional defect of the pluripotent progenitor cell compartment as the major cause for the cytopenia in MDS-patients.

Aged↗
PubMed1988

Colony growth characteristics in chronic myelomonocytic leukemia.

Using cell culture studies specific in-vitro characteristics have been reported for Philadelphia chromosome positive myelogenous leukemia (Ph+ CML) and for juvenile chronic myelogenous leukemia (JCML) previously. We performed cell culture studies in four patients with chronic myelomonocytic leukemia (CMML) and demonstrated the following in-vitro features: excessively increased circulating CFU-C, while BFU-E and CFU-mix were either moderately increased or not detectable; CFU-C colony formation from CMML mononuclear cells (MNC) without addition of exogenous colony stimulating activity (CSA), even after depletion from adherent cells; failing inhibition of CMML MNC on normal BFU-E colony formation. These in-vitro characteristics point to CMML as a distinct entity. In two CMML-patients investigated CFU-C proliferation appeared to some extent inhibited by the addition of IFN-alpha, IFN-gamma and TNF-alpha to cell cultures.

Aged↗
PubMed1988

IIB von Willebrand's disease: pathogenetic and therapeutic studies.

Infusion of 1-deamino-(8-D-arginine)-vasopressin (DDAVP) into patients with IIB von Willebrand's disease (vWD) has been reported to induce thrombocytopenia. In some families with this disorder thrombocytopenia is present even in the resting state. We have investigated the basis of this chronic thrombocytopenia in one such patient by performing platelet recovery and survival studies. Increased platelet consumption was suggested by a decrease in platelet recovery (40.5%, normal 45%) and mean platelet survival (112 h, normal range 144-224 h). In addition, we have administered test infusions of DDAVP and observed the effect on bleeding time and platelet count. DDAVP caused a decrease in the median platelet count from 86 x 10(9)/l (range 30-221) to 60 x 10(9)/l (range 5-144), the individual decline in the nine subjects ranging from 12% to 84% compared to the pretreatment values. Formation of platelet aggregates was observed in all patients following DDAVP. The bleeding time was prolonged before DDAVP in all patients and lengthened further in two after the infusion. However, partial correction of the bleeding time was seen in three and normalization in one patient following DDAVP infusion. Two IIB vWD patients were treated with virus-inactivated cryoprecipitate (Ristofact). Infusion of cryoprecipitate was followed by rapid appearance of all but the largest vWF multimers in plasma and did not affect the platelet count. The bleeding time was normalized in one patient but remained prolonged in the other. In conclusion, in IIB vWD patients virus-inactivated cryoprecipitate is the treatment of choice in the case of bleeding. Infusion of DDAVP might be effective in a subset of IIB vWD patients that has yet to be characterized.

Bleeding Time↗
PubMed1988

Immunoblot analysis shows changes in factor VIII inhibitor chain specificity in factor VIII inhibitor patients over time.

We have used immunoblotting of purified factor VIII (FVIII) to determine whether or not changes in FVIII chain specificity occur during the course of an inhibitor. Serial plasma samples from 15 inhibitor patients (13 hemophilic and two spontaneous) were analyzed. Nine of the 15 antibodies, all with epitopes on the 44-kilodalton (Kd) thrombin fragment of the 92-Kd FVIII heavy chain and/or the 72-Kd thrombin fragment of the 80-Kd FVIII light chain, showed no change in FVIII chain specificity. However, six of the inhibitors analyzed showed changes in FVIII fragment specificity. Four inhibitors (three hemophilic and one spontaneous) reactive with 72-Kd thrombin fragment also became reactive with the 44-Kd thrombin fragment after an anamnestic response to FVIII infusion. Another inhibitor with epitopes on both the 54-Kd and 44-Kd thrombin fragments lost most of its reactivity with the 44-Kd fragment but retained its reactivity with the 54-Kd fragment following a FVIII infusion. The inhibitor later regained its 44-Kd-fragment reactivity but lost its 54-Kd-fragment reactivity following treatment with FEIBA, FVIII inhibitor bypassing activity. The last inhibitor studied had an antibody to either the 44-Kd fragment or to both the 44-Kd and 72-Kd fragments during anamnestic responses to FVIII. These data indicate that a FVIII inhibitor patient can potentially produce antibody to multiple areas on the FVIII molecule and that this must be taken into account in the design of specific therapeutic products.

Epitopes↗