Preleukemic state preceding adult acute lymphoblastic leukemia.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
R Hoffman
Publications and source records attributed to R Hoffman.
Inosine monophosphate dehydrogenase inhibitors. Probes for investigations of the functions of guanine nucleotide binding proteins in intact cells.
Taken together, the above reports indicate that the IMP dehydrogenase inhibitors are valuable probes for investigation of the biological functions of guanine nucleotides in intact cells. While these agents have minor effects on levels of other nucleotides and enzymes, non-specific effects can be monitored by addition of guanine or guanosine to provide substrates for the salvage pathway of guanine nucleotide synthesis. The most important question yet to be resolved in employing these agents is why incomplete depletion of intracellular guanine nucleotides results in such dramatic effects on G-protein function. Since the level of GTP in resting cells is approximately 0.5 mM, even a 90% reduction in GTP levels should leave enough nucleotide to adequately activate most known G-proteins, as the latter display high binding affinities for guanine nucleotides in cell free systems. Several explanations have been proposed to account for this disparity. Much of the intracellular guanine nucleotide may be bound or compartmentalized and therefore unable to interact with certain G-proteins. Possibly, G-proteins in the intracellular environment possess a much lower affinity for GTP that they do in cell free system. It may be to the cells' advantage that relatively minor fluctuations in levels of GTP result in pronounced alterations in the biological function of G-proteins as this effect may provide a physiologically important mechanism for the regulation of G-proteins in vivo. Further studies are necessary to clarify the mechanisms involved in the regulation of the biological function of G-proteins and oncogene products by guanine nucleotides in intact cells.
Animals↗
Diaphragmatic flutter resulting in failure to wean from mechanical ventilator support after coronary artery bypass surgery.
Diaphragmatic dysfunction, most commonly elevation of the left hemidiaphragm and/or phrenic nerve paralysis, are well-known complications of coronary artery bypass grafting (CABG). Diaphragmatic flutter (DF) is an easily overlooked breathing pattern characterized by rapid (greater than 40 times/min) involuntary contractions of the diaphragm, at times superimposed on a more normal breathing pattern (dirhythmic breathing). Using respiratory inductive plethysmography, we were able to record this unusual ventilatory pattern in four patients after CABG. All procedures were performed via median sternotomy with topical hypothermia. Sternal complications were present in three cases (instability, dehiscence, infection). DF could not be suppressed by mechanical hyperventilation or patient volition. Weaning was unsuccessful until after DF abated. Diaphragmatic flutter may occur after CABG and should be considered as a cause of failure to wean from mechanical ventilator support in this setting.
Aged↗
Serum lipoprotein profile in children with celiac disease.
Jejunal mucosa is responsible for the absorption of triglycerides and the production of lipoproteins [chylomicrons, very-low-density lipoprotein (VLDL), high-density lipoprotein (HDL)] and apolipoproteins (B-48, A-I, A-II, A-IV, C-II). Mucosal damage is known to cause fat malabsorption and probably also affects the serum lipid profile. To determine lipoprotein production in states of enterocyte dysfunction, we compared the serum lipid profiles in a group of 12 children with untreated celiac disease (flat jejunal mucosa) with the profiles in a control group of 10 children suffering from other intestinal diseases. Statistically significant differences were found in the following parameters (celiac versus control): plasma levels of triglycerides (70 versus 119 mg/dl), cholesterol content in LDL (107 versus 67.7 mg/dl), protein content in VLDL (6 versus 10 mg/dl), and level of apoprotein A-I (112 versus 140 mg/dl). No significant differences were found between the two groups in the serum levels of total cholesterol, the cholesterol content in VLDL and HDL, the protein content in LDL and HDL, and the level of apoprotein B. Following institution of a gluten-free diet, the lipoprotein profile reverted to normal. These data suggest that the changes in the serum lipoprotein profile in celiac disease are secondary to alterations in enterocyte function and not only a reflection of fat malabsorption.
Celiac Disease↗
Cytokine-dependent long-term culture of highly enriched precursors of hematopoietic progenitor cells from human bone marrow.
Human marrow cells positive for the CD34 antigen but not expressing HLA-DR, CD15, or CD71 antigens were isolated. In a liquid culture system supplemented with 48-hourly additions of recombinant interleukins IL-1 alpha, IL-3, IL-6, or granulocyte/macrophage colony-stimulating factor (GM-CSF), these cells were capable of sustaining in vitro hematopoiesis for up to eight weeks. The establishment of an adherent cell layer was never observed. Cultures containing no exogenous cytokine produced clonogenic cells for only 1 wk. IL-1 alpha and IL-6 were alone able to support hematopoiesis for 2 or 3 wk. Cells maintained with GM-CSF proliferated and contained assayable colony-forming cells for 3 or 4 wk, while maximal cellular expansion and generation of assayable progenitor cells occurred in the presence of IL-3 for 4-5 wk. When IL-3 was combined with IL-1 alpha or IL-6, hematopoiesis was sustained for 8 wks. Basophil numbers were markedly increased in the presence of IL-3. These studies indicate that marrow subpopulations can sustain hematopoiesis in vitro in the presence of repeated additions of cytokines. We conclude that a major function of marrow adherent cells in long-term cultures is that of providing cytokines which promote the proliferation and differentiation of primitive hematopoietic cells.
Antigens, CD↗
Improvement in speech perception and production abilities in children using a multichannel cochlear implant.
Nine children received the Nucleus multichannel cochlear prosthesis. The preoperative evaluation consisted of assessments of auditory function, speech recognition, linguistic skills, and speech production. There were no surgical complications, and recovery in all patients was uneventful. The device was programmed 4 to 5 weeks following surgery, and all children were conditioned to the task. Postoperative training began immediately following device stimulation and is ongoing. Auditory skills and speech production scales were devised to monitor each child's progress. All children have shown varying degrees of improvement in auditory skills and speech production using the implant alone.
Auditory Perception↗
Cheyne-Stokes respiration in patients recovering from acute cardiogenic pulmonary edema.
Cheyne-Stokes respiration is characterized by crescendo-decrescendo fluctuations in tidal volume and respiratory rate interrupted by central apneas. It has long been associated with cardiac disease and has often been cited as a poor prognostic indicator, yet the incidence and immediate significance of CSR in the setting of acute cardiogenic PE is not well defined. Therefore, we studied 95 patients who required MVS because of PE. Breathing patterns were monitored by continuous respiratory inductive plethysmography for a minimum of 12 hours of spontaneous respiration after recovery from PE; CSR was noted in 42 patients (44 percent). There were no significant differences between patients with PE and CSR and those with only PE in regard to LVEF (mean +/- SD, 36 +/- 18 percent vs 33 +/- 16 percent; p = 0.55), reinstitution of MVS within 48 hours (4.8 percent vs 17.0 percent; p = 0.065), or in-hospital mortality (16.7 percent vs 26.4 percent; p = 0.255). We conclude that CSR is a relatively common breathing pattern in patients who required MVS because of cardiogenic PE and does not portend a poor immediate prognosis in this population.
Aged↗
[Perioperative prevention of thromboembolism with low molecular weight heparin and postoperative bleeding complications].
In three studies the effect and secondary effect of low molecular weight heparin (LMWH) were examined. Study 1: LMWH (Embolex-LM, n = 464) versus standard heparin (Liquemin, n = 452); Study 2: LMWH (Sandoparin, n = 298) versus standard heparin (n = 296). In the 3rd study controls of LMWH were performed in the clinic of visceral surgery, and the clinic of traumatology both. During these three studies all excluded patients who did not receive a thromboembolic prophylaxis were also examined. The first two studies showed no significant differences in the frequency of thromboembolic and bleeding complications. The bleeding complication was the same (3-6%) in the group of excluded patients. This is valid for study 3 too. In all studies the surgeon had an important influence on the frequency of bleeding complications.
Dihydroergotamine↗
Human megakaryocyte production: cell biology and clinical considerations.
Advances in the methodologic study of megakaryocytopoiesis are discussed, and their effect on the understanding of the production of platelets is included. This knowledge has led to a better understanding of disorders of megakaryocytopoiesis and platelet production. Specific diseases discussed are congenital megakaryocyte hypoplasia, acquired amegakaryocytic thrombocytopenic purpura, myeloproliferative disorders, reactive thrombocytosis, megakaryoblastic leukemia, and megakaryocyte and marrow fibrosis.
Animals↗
Cytokine control of human megakaryocytopoiesis.
Explore the source record for details and available documents.
Animals↗
Characterization of human hematopoietic stem cells.
These data clearly indicate that suitable systems are presently available to isolate the human hematopoietic stem cell. The CFU-B1 and cells responsible for initiating long term hematopoiesis in vitro are likely identical since they share the same phenotype, CD34+DR-CD33-CD15-C71-. The suspension culture system as indicated above has several advantages over an adherent cell based long term marrow culture system. Use of this suspension culture system with 48 hourly feeding with recombinant cytokines will facilitate definition of the cytokine requirements for the human CFU-S.
Antigens, Surface↗
Regulation of human megakaryocytopoiesis by interacting cytokines.
Explore the source record for details and available documents.
Animals↗
Involvement of guanine nucleotides in superoxide release by fluoride-treated neutrophils. Implications for a role of a guanine nucleotide regulatory protein.
Previous studies demonstrating hydrolysis of phosphatidylinositol bisphosphate (PIP2) and generation of inositol phosphates in neutrophils exposed to 20.0 mM NaF provide indirect evidence that activation of phospholipase-associated guanine nucleotide regulatory protein, a guanine nucleotide binding protein which regulates the activation of a membrane inositol-specific phospholipase C, is an early event in the neutrophil stimulus-response pathway triggered by fluoride. Consistent with this hypothesis, exposure of a plasma membrane rich preparation isolated from 32P labeled neutrophils to 20.0 mM NaF resulted in hydrolysis of labeled PIP2. Levels of other phospholipids were not affected. Inositol bisphosphate and inositol trisphosphate were detected in extracts of neutrophil plasma membranes exposed to fluoride. To further explore the involvement of guanine nucleotides in functional responses of intact neutrophils triggered by fluoride, we preincubated cells with 2-beta-D-ribofuranosylthiazole-4-carboxamide (tiazofurin), a selective inhibitor of inosine monophosphate dehydrogenase, to diminish guanine nucleotide synthesis and then compared superoxide generation induced by FMLP, PMA, digitonin, and 20.0 mM NaF to intracellular levels of guanine nucleotides. Preincubation of neutrophils for 2.5 h at 37 degrees C with tiazofurin resulted in dose-dependent depletion of GTP and GDP. Maximal depletion of guanine nucleotides required relatively high levels of tiazofurin (200 to 400 microM) and resulted in a 55 to 60% reduction of GTP and GDP. The effects of tiazofurin on guanine nucleotides levels were not observed when neutrophils were preincubated at 4 degrees C. AT 37 degrees C, tiazofurin also decreased intracellular ATP and ADP levels but adenine nucleotide depletion was less pronounced than guanine nucleotide depletion for each concentration of tiazofurin used. When tiazofurin was removed by washing cells after incubation, adenine nucleotide quickly returned to preincubation values but guanine nucleotide levels remained depressed. Addition of exogenous guanosine (200 microM) prevented tiazofurin-dependent depletion of guanine nucleotides but had no influence on adenine nucleotide depletion. Superoxide released triggered by FMLP and F- was inhibited to an extent similar to that of guanine nucleotide depletion under different conditions of preincubation. Inhibition of superoxide release was not observed if cells were preincubated at 4 degrees C, was not rapidly reversible, and was not observed when guanosine was added with tiazofurin.(ABSTRACT TRUNCATED AT 400 WORDS)
Adenine Nucleotides↗
Acquired cyclic amegakaryocytic thrombocytopenia associated with an immunoglobulin blocking the action of granulocyte-macrophage colony-stimulating factor.
Explore the source record for details and available documents.
Adult↗
Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), a selective inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, provided in end stage leukemic patients a rapid decrease of IMP dehydrogenase activity and GTP concentration in the blast cells and a subsequent decline in blast cell count. Sixteen consecutive patients with end stage acute nonlymphocytic leukemia or myeloid blast crisis of chronic granulocytic leukemia were treated with tiazofurin. Allopurinol was also given to inhibit xanthine oxidase activity to decrease uric acid excretion and to elevate the serum concentration of hypoxanthine, which should competitively inhibit the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the salvage enzyme of guanylate synthesis. Assays of IMP dehydrogenase activity and GTP concentration in leukemic cells provided a method to monitor the impact of tiazofurin and allopurinol and to adjust the drug doses. In this group of patients with poor prognosis, five attained a complete hematological remission and one showed a hematological improvement. A marked antileukemic effect was seen in two other patients. All five evaluable patients with myeloid blast crisis of chronic granulocytic leukemia reentered the chronic phase of their disease. Five patients with acute nonlymphocytic leukemia were refractory to tiazofurin and three were unevaluable for hematological effect because of early severe complications. Responses with intermittent 5- to 15-day courses of tiazofurin lasted 3-10 months. Tiazofurin had a clear antiproliferative effect, but the pattern of hematological response indicated that it appeared to induce differentiation of leukemic cells. In spite of toxicity with severe or life-threatening complications in 11 of 16 patients, tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational, biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy.
Antimetabolites, Antineoplastic↗
Cyclic thrombocytopenia of apparent autoimmune etiology.
Serial studies were performed in two patients with cyclic thrombocytopenia to investigate the pathogenesis of this disorder. Mean life span of autologous platelets when platelet levels were declining was subnormal (2.4 and 0.8 days), and megakaryocytes were abundant in the bone marrow during thrombocytopenia. Megakaryocyte colony-stimulating activity could not be detected in the serum of either patient at any point of their cycles. In each patient, total platelet-associated IgG varied inversely with platelet levels. Surface platelet-associated IgG was measured only in patient 2 and was significantly elevated (greater than 1,280 IgG molecules per platelet) at all stages of the cycle, even during thrombocytosis. However, the highest values were observed during thrombocytopenia. Platelet-bindable IgG in plasma declined to normal immediately before platelet levels began to rise. IgG eluted from the platelets of this patient reacted strongly with autologous and homologous platelets in contrast to a "mock eluate" prepared from platelets of a normal subject. The eluate from the patient's platelets reacted strongly with immobilized autologous and homologous glycoprotein IIb/IIIa complex and weakly with GPIb but not with isolated GPIIIa alone. In each patient the decline in platelet levels was significantly delayed following administration of intravenous gamma globulin 0.4 g/kg body weight for five days. These findings suggest that platelet-reactive autoantibodies are of pathogenic significance in some patients with cyclic thrombocytopenia.
Adult↗
Interacting cytokines regulate in vitro human megakaryocytopoiesis.
The effects of hematopoietic growth factors on in vitro human megakaryocytopoiesis were studied using a serum-depleted culture system. Both recombinant interleukin-3 (r-IL-3) and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) increased megakaryocyte (MK) colony formation (P less than .01) above that observed in baseline cultures. Recombinant interleukin-4 (rIL-4) and interleukin 1 alpha (rIL-1 alpha) failed either to promote MK colony formation alone or to increase rIL-3 or rGM-CSF promoted colony formation. Recombinant erythropoietin (rEpo) and purified thrombocytopoiesis-stimulating factor (TSF) did not increase (P greater than .05) MK colony formation when added alone but synergized with rIL-1 alpha, leading to a twofold increase in MK colony formation. Such a synergistic relationship was not observed between rIL-4 and rEpo. In addition, TSF enhanced the ability of rIL-3 but not rGM-CSF to promote MK colony formation. Addition of rEpo to optimal or suboptimal concentrations of rGM-CSF or suboptimal concentrations of rIL-3 resulted in a significant increase (P less than .05) in the total number of MK-containing colonies, due to the appearance of multilineage colonies containing MKs. The addition of rEpo to optimal concentrations of rIL-3 resulted in increased numbers of multilineage colonies containing MKs; however, the number of total MK-containing colonies was not significantly increased when compared to assays containing rIL-3 alone. By contrast, transforming growth factor-beta (TGF-beta) inhibited both rIL-3, and rGM-CSF promoted MK colony formation, with optimal inhibition resulting in a 35%-45% reduction of MK colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Factors↗
A phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a new dihydrofolate reductase inhibitor.
A total of 68 patients were treated in a phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a novel lipophilic dihydrofolate reductase (DHFR) antagonist. The dose was increased from 5.4 mg/m2 to 460 mg/m2 given as a 1-h infusion, with 460 mg/m2, 600 mg/m2 and 800 mg/m2 given as a 24-h infusion. The dose-limiting toxicity was nausea and vomiting, which was marked at doses above 360 mg/m2 by 1-h infusion and 600 mg/m2 by 24-h infusion. Above 250 mg/m2 patients also described subjective neurological symptoms, although no objective signs were apparent. Myelosuppression was not consistent at any dose level. No objective responses were seen. In view of the lack of anti-folate activity at toxic levels, no phase II trials are currently proposed; toxicological and in vitro studies will continue.
Antineoplastic Agents↗