Biomedical subjects
Publications and source records attributed to W Hinterberger.
Hexobendine (Ustimon) given i.v. increases the arterial blood flow in the musculus tibialis anterior ninefold and improves the peripheral circulation for a limited time. Also the better arterial perfusion caused by adenosine and similar substances is intensified by hexobendine given i.v. These results are discussed with the already known effects of other coronary vasodilators.
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Blood granulocyte-macrophage colony stimulating activity (GM CSF) was measured in 6 normal individuals challenged with low-dose endotoxin and in 63 unselected patients with nonhaematological disorders. 5/63 patients were febrile and 5 other patients whoed detectable endotoxin levels, as measured by the Limulus assay. CSA levels showed a rapid increase in normal individuals following endotoxin administration, but were in the normal range in patients with chronic endotoxinemia or in those with febrile disorders. Thus, unlike acute endotoxinemia, chronic endotoxinemia is not associated with elevated activity that promotes growth of myeloid commited stem cells. In addition, fever per se did not coincide with elevated blood CSA levels.
The response to artificial endotoxinemia was studied in adult dogs. Granulocyte-macrophage colony stimulating activity (CSA) in lung tissue and blood was measured along with the number of circulating granulocytes and myeloid committed stem cells (colony forming units, CFUc). Acute endotoxinemia induced a measurable CSA increase in lung tissue before being detectable in blood. Granulocytes, rapidly removed from the circulation, showed no release of CSA during sequestration. These experiments demonstrate that the process of endotoxin recognition and subsequent transition into a myelopoietic stimulus is medicated by cells belonging to tissue; mature granulocytes, involved in the defence against bacterial infection, do not release activity that promotes growth of immature myeloid cells.
Low doses of endotoxin were administered to normal and acute anc chronic myeloid leukaemic subjects. Temperature, leucocyte count, blood colony stimulating activity and the number of circulating colony forming units were monitored. All subjects acquired fever while the leucocyte count remained unaltered. Blood CSA rose sharply in 6 normal individuals, but failed to increase in 4 acute leukaemic patients and in 2 patients with CML in blast crisis. 2 patients with CML in the chronic stage increased their blood CSA comparable to normal individuals. The number of circulating colony forming units rose following endotoxin with a peak at 30 min and declined subsequently. 4 patients with acute leukaemia showed no increase of circulating colony formers.
Human mononuclear leucocytes release colony stimulating factors. Monocytes and thymocytes release different colony stimulating factors as determined by estimation of molecular weights. Blasts from patients with acute leukaemia do not release substantial activity, while blasts from patients with chronic myeloid leukaemia in blast crises may show production of colony stimulating factors.
Cells from the monocyte-macrophage pathway release colony-stimulating factors. The release of colony-stimulating activity is increased upon endotoxin activation in the presence of fresh serum. Heat-inactivation of serum (56 degrees C, 30 minutes) abolishes the endotoxin-mediated activation of macrophages. Decomplementation with zymosan, iodipamide and the use of commercially serum deficient in C3 provide indirect evidence for a complement dependence of the endotoxin-macrophage interaction, which leads to release of colony-stimulating activity.
Medium conditioned by human lung tissue was found to contain colony stimulating activity (CSA). This material was tested against mouse and human bone marrow as target system. Colony forming units (CFUc) from both species responded and gave rise to clonal growth in agar cultures. This colony formation was dose dependent and the relationship was a sigmoid one. Experiments to determine the molecular weight of human lung derived colony stimulating Factors brought evidence for four active molecular weight fractions with approximately 79000, 40000, 23000 and 2000 daltons. The 23000 dalton fraction activated human cells only, whereas the other fractions were active on both human and mouse bone marrow cells.
PHA-activated lymphocytes release colony-stimulating activity (CSA) for macrophage-granulocyte precursor cells (colony forming units, CFUc) in the culture medium. Somatostatin, known to interfer with ribosomal protein synthesis, was demonstrated to reduce the release of CSA from PHA-treated mouse spleen lymphocytes.
Granulocytic Chalone (GCh) has been highly purified from culture medium conditioned by human peripheral leukocytes. Purification was performed by column chromatography on Sephadex G-25 and G-10, rechromatography on G-10, preparative paper chromatography and thin-layer-chromatography. The inhibitory activity and specificity of GCh was monitored by agar colony formation and 3H-thymidine incorporation into bone marrow and thymic cells. The gelchromatographic behavior of GCh is discussed in detail with regard to its molecular weight. The results obtained indicate that GCh may be a small (MW 500--600), acidic and highly polar peptide containing aspartic and glutamic acid among others. The N-terminal aminogroup seems to be blocked.
A case of refractory anaemia with medullary myeloblastosis (RAMM) is described. RAMM is a very rare disease and its relationship to aplastic anaemia and smouldering leukaemia is not clearly established. The diagnosis is confirmed by evaluation of the bone-marrow aspirate and ferrokinetic studies which demonstrate ineffective erythropoiesis. The disease is combined with leucopenia, thrombocytopenia and a hyperplastic bone-marrow. Our patient was monitored for 18 months, during which time her haematological findings remained stable. Since transformation into acute leukaemia occurs in about 25% of the cases, a bone-marrow culture study was performed in order to determine such a leukaemic transformation which is not detectable on examination by the light microscope. Culture studies are discussed along with some prognostic, therapeutic and pathophysiological problems of RAMM.
Leukamic blasts from 8 patients with different forms of acute leukaemia were investigated for their capability to produce colony stimulating factor. A second point of investigation was to detect inhibitory activity from the same blasts. The agar technique in its double layer modification was used with bone marrow from C57 Bl mice as target cell population. No single pattern of colony growth was observed. CSF production was absent or very low, when compared with CSF from normal mononuclear cells. However, blasts from 4 patients disclosed inhibition of colony growth. No certain relationship existed between the cytochemic type of leukaemia and the production of either activator or inhibitor of in vitro colony formation.
Chalones specifically inhibit cell rpoliferation not only in their respective normal cell system, but also in the malignant descendants of these cells. Consequently, a number of hypotheses have been put forward as to how chalones could be used in cancer treatment or related areas. As chalones are not cytotoxic themselves, but merely inhibit proliferation, the regression of tumors which have been observed in some cases must have been caused by other mechanisms, not directly related to the increased chalone level. Some of the potential advantages and drawbacks of this direct approach will be discussed. Some models in which chalones serve as adjuncts to other forms of therapy will be discussed. The experimental testing of these procedures and hypothesis is hampered severly by the unavailability of satisfactory chalone preparations. A possible approach to overcome this by using synthetic granulocytic (and possibly other) chalone(s) is discussed in detail.
The experiments described in this paper were performed in order to elucidate a possible regulatory role of acute and chronic myeloid leukemic leucocytes. The influence of these cells on either activated or non-activated mouse bone marrow cells was measured, and the results were compared with the action of the two major leucocyte fractions, mononuclear cells and granulocytes. It was demonstrated that acute leukemic blasts were almost completely unable to activate myeloid committed stem cells (Colony Forming Units, CFUC). In contrast, blasts from patients with chronic myeloid leukemia (CML) in blastic crisis disclosed a variable pattern of activation, in that two out of three cases exerted normal stimulatory capacity. A possible inhibitory action of leukemic cells was the subject of further experiments. Acute leukemic blasts in some cases disclosed inhibitory activity, a few cases appeared to be without influence on normal proliferating CFUC. Granulocytes from patients with CML in the chronic phase showed inhibitory capacity when compared with granulocytes from normal individuals. It is apparent from these experiments that leukemic cells themselves may contribute to the regulatory derangements of leukemias.
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Sixty-seven patients undergoing allogenic bone marrow transplantation (BMT) were examined before and at regular intervals for up to 87 months (1-87 months, mean 18) after transplantation. Within a period of 1-39 months, 14 of these patients died (11 male, 3 female; age at BMT 16-46y). Five of these patients died within the first 100 days. They showed no eye involvement; three patients had intraretinal hemorrhage, in one case of squamous blepharitis and filiform keratitis developed during chronic graft-versus-host disease (GVHD). In contrast, 22 of 53 (41.5%) surviving patients (30 male, 23 female; age at BMT 1-47y) were found to have ocular involvement. Before BMT only two cases of retinal hemorrhage and central chorioretinal scars each were detected. During the stage of acute GVHD (up to day 100), nine patients were free of ocular manifestations. However, 16 of the 20 patients with chronic GVHD showed ocular involvement; 14 (70%) had reduced tearflow, ten had severe keratoconjunctivitis sicca, four suffered from sterile corneal ulcerations. Bilateral cataracts were detected in 11 patients, nine of whom only had minimal posterior subcapsular opacification, possibly resulting from highdose steroid medication. One additional case presented with bilateral multifocal recurrent chorioretinitis and panuveitis. The fundus lesions appeared some months after BMT (before cyclosporin-A treatment started) and recurred during systemic treatment. All patients undergoing allogenic BMT, especially when treated for severe chronic GVHD, require regular ocular observation to avoid complications such as keratoconjunctivitis sicca at an early stage, as late complications are often severe and hardly amenable to conservative or surgical treatment.
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