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The effect on marrow myeloblast colony formation in blood from nine patients with acute myeloid leukemia was studied by using three recombinant-DNA-derived human leukocyte interferons (IFN alpha 2, IFN alpha-A, and IFN alpha-C). In preliminary experiments, a brief exposure of leukemic marrow cells to IFN alpha resulted in a sharp increase in the IFN-induced enzyme 2-5A synthetase, indicating the expression of IFN cell receptors as well as the ability of leukemia cells to respond metabolically. Dose-response studies showed a dose-dependent suppression of myeloblast colony formation in all experiments using concentrations of 10(2)-10(5) U/ml of the three IFN subtypes. In self-renewal assays derived from the primary cultures that initially contained IFN alpha 2, a "carryover" antiproliferative effect was observed with a dose-dependent decline in secondary growth. In comparison studies of IFN alpha-A and IFN alpha-C, the suppressive effect on primary myeloblast growth was much more pronounced with IFN alpha-C at concentrations of 10(3) U/ml and higher; in self-renewal assays, the antiproliferative effect of IFN alpha-C on secondary growth was no longer observed, whereas that of IFN alpha-A persisted. These three subtypes of gene-cloned IFN have antileukemic properties in vitro, with differences in degree of suppression of primary myeloblast growth and of self-renewal.

As deferoxamine (DFO) appeared to have certain toxic effects on the sensory pathways in some of our patients on nightly subcutaneous deferoxamine (DFO) for transfusion-dependent anemia, treatment was stopped in all of these patients to obtain a comprehensive baseline assessment of sensory function. Visual evoked potentials (VEPs) were studied in all patients; the 77 described in this report all had normal ophthalmological examinations. Abnormally prolonged VEP latencies were found in 21%. The patients remained off DFO for 2-6 months, and most of those with abnormal VEPs who were retested showed improvement in their VEPs over this period with the VEPs returning to within normal range in half the cases; two showed no change. Since restarting DFO, VEP latencies in 10 of these patients have increased again beyond normal limits, as have the VEPs in 7 who had previously normal VEPs. Although most of the 77 patients have VEPs that are currently normal and stable while on DFO, a significant sub-group have abnormal VEPs that appear sensitive to the administration of DFO and may reflect a vulnerability to DFO neurotoxicity. These data suggest that the VEPs can detect subclinical toxic effects of DFO on the visual system and should be considered as a monitor for patients receiving chronic DFO therapy.

The anemia of chronic renal failure was studied by assessing the inhibitory effect of uremic serum on the proliferation of normal human marrow erythroid progenitor cells (CFU-E and BFU-E) using an in vitro colony assay. Of 10 uremic patients studied, sera from 9 inhibited CFU-E colony growth by 29-100%, sera from 8 inhibited BFU-E colony growth by 23-94%, and sera from all inhibited either CFU-E or BFU-E. The sera were fractionated by Sephacryl gel filtration and the fractions were added to the marrow cultures. Almost all the suppressive activity against erythroid colony growth was detected in fractions with mol. wts of from 47,000 to greater than 150,000 daltons and this indicates the presence of several high mol. wt inhibitors. Serum fractionation by Sephacryl gel was useful in confirming the presence of uremic inhibitors of erythropoiesis, and in concentrating them to a degree that will allow detailed characterisation studies.

The influence of products derived from the arachidonic acid 5-lipoxygenase (5-LO) pathway on normal human marrow haematopoiesis was studied using clonogenic assays. The leucotrienes (LT) B4 and C4 caused a reduction in granulocyte-macrophage (CFU-GM) as well as erythroid (CFU-E and BFU-E) colony numbers in a dose-dependent manner. Conversely, nordihydroguaiaretic acid (NDGA), a LT synthesis inhibitor, promoted proliferation of these colonies. The inhibitory effect of LTC4 but not that of LTB4 was abolished by FPL-55712, a LT antagonist; the enhanced colony growth induced by NDGA was reversed by both LTB4 and LTC4. LTD4 had no significant effect on colony growth despite its structural similarity to LTC4, which implies that the haematopoietic suppression by LTB4 and LTC4 is specific for these compounds. Depletion of marrow T-cells or removal of adherent cells, or both, did not alter the response to LTB4 and LTC4, suggesting that LT action is exerted directly on progenitor cells and probably is not mediated by other cell populations. Our studies show that the 5-LO pathway is functional in these culture systems and yields products with inhibitory properties. The 5-LO pathway may have an important regulatory function in normal marrow haematopoiesis.

Characterization studies were performed on the malignant peripheral blood cells from three patients with juvenile chronic myelogenous leukemia (JCML) by allowing the cells to increase numerically in liquid cultures. JCML cells proliferated rapidly and excessively in the absence of an added humoral growth factor, whereas control peripheral blood cells declined in number when cultured under identical conditions. Clonality of JCML cells was proven by cytogenetic analysis of the proliferating population. JCML cells were exclusively of monocytic lineage as determined by morphology, staining characteristics, and monoclonal antibody identification of cell-specific surface antigens, but cytochemical and functional studies identified aberrant properties indicating defective differentiation. Striking differences from control cells in ultrastructure and topography were also observed by transmission and scanning electron microscopy. These data provide new information on the cellular origin of JCML and form the basis for further study of leukemic cell biology in this disease.

Since decompression from depth is known to produce a fall in platelet count, the effect of altitude decompression and high-altitude exposure on platelets was investigated. Sixteen subjects decompressed without hypoxia to 20,000 ft simulated altitude for two hours showed a significant (P less than 0.01) drop in circulating platelet count of approximately 10% for three days following decompression. Four of five subjects similarly exposed had a shortened autologous platelet survival compared to that prior to exposure. Subjects exposed to 9,800 ft and then 17,600 ft in a mountain environment showed a significant mean decrease in platelet count on day 2 of 7% and 25% respectively, which had returned to control by day 5. Nonhypoxic and hypoxic decompressed rabbits which received homologous chromium-51-labeled platelets had an increase in lung radioactivity compared with sea-level controls. It is postulated that altitude decompression produces platelet reductions similar to these seen after decompression from depth, and that platelets sequester in the pulmonary vascular bed.

During the course of investigation of two infants with seizure disorders it was discovered that both had been given large amounts of a preparation of borax and honey which resulted in chronic borate intoxication. In one child a profound anemia developed as well. The symptoms of chronic borate intoxication are different from those of the acute poisoning with which we are more familiar. The borax and honey preparations are highly dangerous and should no longer be manufactured or distributed for sale.