Biomedical subjects
Publications and source records attributed to H O Nieweg.
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On the basis of previously obtained evidence that Gram-negative bacteria may influence the activity of leukaemia, a study of the composition of the flora, the immune stimulation by the Gram-negative bacteria and the endotoxin concentration in faeces was conducted in patients with low-grade malignant B-cell lymphoma as well as in patients with acute leukaemia. In these patients it was investigated whether the number of facultative anaerobic Gram-negative bacteria in the faeces correlated with endotoxin concentration. In addition, IgA coating of Gram-negative bacteria in the faeces was determined and the titre of circulating antibodies to endogenous Enterobacteriaceae species from the faeces of the corresponding patient was studied. No clear difference was found to exist in the percentage of IgA-coated Gram-negative bacteria in the faeces and in the circulating antibody titres to endogenous Enterobacteriaceae between healthy control persons, lymphoma patients and patients with acute leukaemia. Antimicrobial treatment to establish selective decontamination (SD) of Enterobacteriaceae species from the digestive tract did cause a significant decrease in the faecal endotoxin concentration in a subset of patients treated for SD with polymyxin.
A therapeutic trial of plasma exchange was conducted in an 82-year-old woman with severe cold agglutinin hemolytic anemia, who was unresponsive to conventional treatment. In spite of considerable improvement of pertinent parameters (total IgM, cold agglutinin titer and thermal amplitude) this treatment failed to induce a clinical remission. This failure may be the result of the ability of the cold agglutinin to fix complement to the red cell membrane at temperatures much higher than the thermal amplitude. A simple laboratory test to detect this dissociation between complement fixing ability and agglutination activity is described.
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A patient from the Caribbean area with active T-cell lymphoma-leukaemia was primarily treated with deoxycoformycin (DCF), 5 mg/m2 i.v. on 3 consecutive days, followed by 5 mg/m2 i.v. weekly. A complete remission was attained and maintained during several weeks with DCF. A single consolidation course with other cytostatics was then given. The patient continues in complete remission without further therapy, 24 months after diagnosis, 17 months after the last cytostatic drugs. T-cell lymphoma-leukaemia has a bad prognosis with conventional anti-lymphoma therapy but was exquisitely sensitive to DCF in this patient.
Fibrinolytic factors were assessed during L-asparaginase administration, to study whether their changes may predispose to a haemorrhagic or thrombotic diathesis. The total level of alpha 2-antiplasmin declined, as well as the ratio of the plasminogen-binding form of alpha 2-antiplasmin to the non-plasminogen-binding form. After cessation of L-asparaginase administration, the ratio increased to 1.6 times that of the pretreatment value. These data indicate that the plasminogen-binding form of alpha 2-antiplasmin is the form primarily synthesized in vivo. L-Asparaginase therapy reduced plasma levels of plasminogen and histidine-rich glycoprotein ( HRG ) and influenced the equilibrium between HRG , plasminogen and HRG -plasminogen complex, with a more pronounced decrease of plasminogen (62% +/- 8) and HRG (76% +/- 11) in comparison to the free-plasminogen levels (51% +/- 6). alpha 2-Macroglobulin was only slightly influenced by L-asparaginase and may consequently play a more pronounced role in inhibition. This is suggested by moderate declines in functional tests of plasmin, urokinase and tissue activator inhibition by patients plasma, and by the ratio of inhibition of these enzymes over alpha 2-antiplasmin. Thus the bleeding tendency described during L-asparaginase therapy can be ascribed not only to a temporary deficiency of coagulation factors but also to temporary alpha 2-antiplasmin deficiency.
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The level of the aminoterminal propeptide Col 1-3 of type III procollagen (PC-III) was determined in patients with paroxysmal nocturnal haemoglobinuria (PNH) and primary myelofibrosis (PMF), to study whether PC-III can be used as a parameter for the rate and/or degree of bone marrow replacement with collagen. Normal PC-III levels were found in PNH (6.6 +/- 1.1 micrograms/l; N: 8.6 +/- 1.8 micrograms/l), while significantly increased levels were found in PMF (24.8 +/- 2.2 micrograms/l). During a follow-up of 1 year, a slight increase of 2 micrograms/l occurred in three patients with a stable fibrosis, while one patient with more active disease demonstrated an increase of 25 micrograms/l. Treatment with acetylsalicylic acid led to a decline of PC-III as well as beta-thromboglobulin level, although normalization did not occur. It was demonstrated by means of gel filtration that the antigens related to the PC-III peptide were heterogenous, and that in PMF at least two main peaks were present, with molecular masses equal to and smaller than PC-III peptide. These data demonstrate that the radioimmunoassay cannot be used for the quantitative determination of PC-III; nevertheless it gives some insight in the process of bone marrow fibrosis.
In six patients with paroxysmal nocturnal haemoglobinuria (PNH) lymphocyte studies were performed to investigate whether the observed immunological dysfunction could be ascribed to a defect in lymphocytes as result of the PNH characteristics, or to an imbalance between T-cell subsets. The PNH characteristics were studied by means of the effect of serum and acidified serum on Indium111-oxine labelled lymphocytes. No increase in release of Indium111-oxine was found when lymphocytes were exposed to acidified sera. Thus a complement mediated lymphocyte lysis in PNH could not be demonstrated. T-cells were defined by monoclonal antibodies, directed at total T-cells (OKT3), helper T cells (OKT4) and suppressor/cytotoxic T-cells (OKT8). In two of the six patients a decreased proportion of OKT3 cells was found, while a significantly depressed ratio of OKT4/OKT8 cells was present in the whole group. No obvious correlation was found between a functional assay - the concanavalin-A suppressor cell activity - and the ratio of OKT4/OKT8 positive cells. It is concluded that the PNH characteristics could not be demonstrated in the lymphocytes; and that the immunological dysregulation in PNH may be ascribed to an imbalance of T-cell subsets, while a decreased number of monocytes, defined by the monoclonal antibody OKM1, may contribute to this defect.
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Eighteen patients with melphalan refractory myeloma were treated with vindesine and prednisone. Plasma spermidine concentrations were measured by radioimmunoassay before and after a single vindesine injection. Seven patients showed a significant rise of plasma spermidine after vindesine and five of these showed a clinical response on further evaluation. Of the 11 patients who did not show raised spermidine concentrations, 10 did not respond to the therapy. The correlation between clinical response/rise of spermidine and between non-response/no rise of spermidine was statistically significant (p less than 0.05). Pretreatment spermidine concentrations did not distinguish those who responded to treatment nor did they differ in patients and controls.
Monoclonal immunoglobulins with affinity for platelets were detected in the blood of seven patients. Two of these had thrombocytopenia and non-Hodgkin's lymphoma (NHL). One patient had thrombocytopenia and possibly incipient NHL. The other four patients had pseudothrombocytopenia at the time of diagnosis but one of them developed NHL six years later. It is suggested that these monoclonal immunoglobulins may in some cases be associated with malignant lymphoma and that subjects presenting with these immunoglobulins should have a long term follow-up in order to elucidate the question whether or not lymphoma will develop.
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There was evidence of impaired cellular immunity in 10 patients with myelofibrosis. In-vitro lymphocyte transformation with phytohaemagglutin, concanavalin A, and dinitrochlorobenzene skin reaction were diminished. Signs of impaired humoral activity were also found, the primary response to alpha-Helix pomatia haemocyanin being impaired, particularly in the immunoglobulin-A class. Moreover three patients had a benign paraproteinaemia. Immunecomplexes (IC) could be demonstrated with various test systems. The indirect granulocyte phagocytosis test was positive in 50%, the C1q-binding in 70% and the polyethylene glycol precipitation test in 50%. In most patients complement levels were normal, although the patient with the most advanced disease had low C3A, C3 and C4 levels accompanied by high levels of IC. No correlation could be shown between impaired immune response or levels of IC when they were related to spleen diameter or degree of anaemia. Some relation however existed between disturbed immune response and IC when they were related to time elapsed since diagnosis. It is suggested that the impaired immune response is the result of primary bone marrow disease and that the presence of IC may reflect the extent of fibrosis.
In 43 patients with aplastic anaemia we assessed the accuracy of different prognostic systems. Patients dying within 6 months after diagnosis were correctly predicted in 60% of cases with the Lynch-index with a sensitivity of 82%. With the Najean-index 40% of these patients are correctly predicted, this index has a sensitivity of 100%. More accurate are the prognostic criteria proposed by Camitta et al [5]. With these criteria, this rapidly fatal group is correctly predicted in 85% of the patients, indicating that 15% of the patients are incorrectly predicted to have a limited survival. The sensitivity, however, is 100%. The Lohrmann-index, based on reticulocyte count predicts 64% of this group with severe aplasia. None of these prognostic systems do accurately predict long survival. We suggest that the best differentiation between patients with a long-term prognosis (more than 5 years) and patients who die from aplastic anaemia within 5 years, is made by re-evaluating the leucocyte and platelet count 3 months after the initial diagnosis. Decrease in blood counts (over 10%) predicts death from aplastic anaemia within 5 years correctly in all patients; stable or increased blood counts predict long survival in 75% of the patients.
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