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Biomedical subjects

D G Wright

Publications and source records attributed to D G Wright.

At least 91 records · Page 5Linked to original sources
PubMed1985

Direct analysis of differentiation proteins in normal and leukemic human granulocytes by high-performance liquid chromatography.

The feasibility of the use of reverse-phase high-performance liquid chromatography (RP-HPLC) for detecting differences in the protein phenotypes of highly purified fractions of normal and chronic myelogenous leukemic (CML) mature granulocytes isolated from peripheral blood was determined. At least 21 protein peaks were consistently and reproducibly detected in the RP-HPLC profiles of acetonitrile-trifluoroacetic acid extracts of normal granulocytes. This assay takes only 60 minutes to perform and can be done on 4 X 10(6) granulocytes (approximately the number of granulocytes in 1 ml normal blood). Furthermore, sodium dodecyl sulfate-gel electrophoresis of the RP-HPLC fractions provides a second dimension to the analysis of the polypeptide pattern of these cell lysates. Analyses of subcellular fractions by these methods revealed that most of the major peaks in the RP-HPLC profiles of intact granulocytes originate mainly from the granule and membrane fractions. Although the protein phenotypes of mature granulocytes were remarkably uniform among normal individuals, those of mature granulocytes obtained from the blood of CML patients were consistently abnormal and varied considerably among individual patients. The results indicate that the approach used here could have useful application in the study of abnormal granulocyte differentiation in leukemia.

Acetonitriles↗
PubMed1985

Death at high altitude in the hypobaric chamber.

A small number of accidental and suicidal deaths have occurred in the hypobaric, or high altitude, chamber. A case of an unusual suicide in a hypobaric chamber is presented. The changes that resulted from decompression and hypoxia are discussed.

Adult↗
PubMed1984

Maturation of human promyelocytic leukemia cells induced by nicotinamide: evidence of a regulatory role for ADP-ribosylation of chromosomal proteins.

We have studied the role of ADP-ribosylation of chromosomal proteins in the regulation of myeloid cell maturation using the HL-60 cell line as a model. Nuclei isolated from this human promyelocytic leukemia cell line contained (ADP-ribose)n synthetase activity, whereas little or no enzymatic activity was detectable in normal human blood neutrophils. Furthermore, the activity of (ADP-ribose)n synthetase was decreased in HL-60 cells when they were induced to mature with retinoic acid (RA). To determine whether reduced (ADP-ribose)n synthetase activity is simply a result of induced maturation or whether it is a necessary precedent event for the maturation process, we evaluated the effects of nicotinamide (NAm) and its methyl derivative, N'-methylnicotinamide (N'-Met-NAm), agents which decrease ADP-ribosylation. Treatment of HL-60 cells with these drugs caused the cells to undergo maturation and to acquire certain of the morphologic, functional, and biochemical characteristics of normal neutrophils. N'-Met-NAm was more potent than NAm in inducing maturation; at a concentration of 0.8 mM, it caused greater than 80% of the cells to mature, whereas a tenfold greater concentration of NAm was required to induce a similar degree of maturation. NAm and N'-Met-NAm also potentiated the maturation of HL-60 cells induced by RA. Exposure of cells to noninducing concentrations of these compounds caused a leftward shift in the dose-response curve for RA; maturation was observed at 10(-11) M RA in the presence of either 2 mM NAm or 0.2 mM N'-Met-NAm while 10(-9) M RA was required to induce maturation in their absence. A leftward shift in the dose response curve for maturation in the presence of low doses of NAm or N'-Met-NAm did not occur with another inducer, dimethyl formamide (DMF). Two enzymes, NAD glycohydrolase and tissue transglutaminase, that are abundant in macrophages, were induced by RA but not by NAm. N'-Met-NAm decreased by about 75% the amount of endogenous (ADP-ribose)n in a selected fraction of chromosomal proteins which included histone H1 and the nonhistone high mobility group proteins. The results of this study support the concept that ADP-ribosylation of chromosomal proteins influences the regulation of human myeloid cell maturation.

Acyltransferases↗
PubMed1984

Symposium on infectious complications of neoplastic disease (Part II). Leukocyte transfusions: thinking twice.

There is convincing evidence that leukocyte transfusions have a definite, albeit restricted, role in managing profoundly neutropenic patients and certain rare patients with qualitative disorders of neutrophil function. Nonetheless, leukocyte transfusion techniques have yet to meet a number of important conceptual challenges of neutrophil replacement. Even with pharmacologic manipulation of leukocyte donors, current methods of leukapheresis cannot provide neutrophils in numbers that match the body's normal use and turn-over of these cells. Neutrophils have also proved to be fragile cells in the blood bank, readily losing normal function with certain collection procedures and during short periods of storage. Moreover, transfused neutrophils that are unable to function and circulate normally in recipients can produce serious toxic reactions. In light of the marginal demonstrable benefits of leukocyte transfusions, potential toxicity is necessarily an important consideration in decisions to use this form of hematologic support. The fact that leukocyte recipients are usually extremely ill does not alter the physician's responsibility to avoid bringing harm to the patient without benefit.

Adult↗
PubMed1983

Induced maturation of the human promyelocytic leukemia cell line, HL-60, by 2-beta-D-ribofuranosylselenazole-4-carboxamide.

The new synthetic nucleoside analogue, 2-beta-D-ribofuranosylselenazole-4-carboxamide, was evaluated for its effects upon the growth and maturation of the human promyelocytic leukemia cell line, HL-60. At a concentration of greater than or equal to 1 nm, this agent was found both to decrease HL-60 cell proliferation and to cause the cells to acquire an ability to phagocytose opsonized yeast and to reduce nitroblue tetrazolium dye, functions characteristic of mature myeloid cells. In addition, this agent at similar concentrations caused a marked depression of intracellular guanosine nucleotide pools and a reduction in the incorporation of [14C] hypoxanthine into guanylates. These results suggested that the selenazole nucleoside caused an inhibition of inosinate monophosphate dehydrogenase, a key enzyme of guanylate biosynthesis. We therefore measured the activity of this enzyme indirectly by simultaneous-UV-radioactivity HPLC as well as by a direct radiometric method and demonstrated markedly reduced enzyme activities by both assays in drug treated cells. Dose response studies indicated that concentrations of drug which caused greater than 30% inhibition of IMP dehydrogenase activity induced greater than 50% maturation of the cells. These observations with this new nucleoside analogue provide further support for the concept that production of guanosine nucleotides and the activity of IMP dehydrogenase have a role in regulating the terminal maturation of myeloid cells.

Carbon Radioisotopes↗
PubMed1983

Purine metabolism in myeloid precursor cells during maturation. Studies with the HL-60 cell line.

In studies with the human promyelocytic leukemia cell line HL-60, we defined changes in intermediary purine metabolism that appear to contribute to the regulation of terminal maturation in myeloid cells. When HL-60 cells were exposed to compounds that induce maturation, consistent alterations in purine metabolism were found to occur within 24 h of culture. Perturbation of guanosine nucleotide synthesis and decreases of up to 50% in intracellular guanylate pool sizes were associated with the induced maturation of these cells in response to diverse inducing agents. While immature HL-60 cells were observed to synthesize purine nucleotides by both de novo and salvage pathways, the activity of both pathways decreased in cells induced to mature, although the relative contribution of purine salvage increased. Moreover, incorporation of the salvage pathway precursor, [14C]hypoxanthine from the intermediate, inosine monophosphate (IMP), into guanylates was reduced by approximately 65% in induced HL-60 cells, reflecting decreased activity of both hypoxanthine phosphoribosyltransferase and IMP dehydrogenase. When various inhibitors of IMP dehydrogenase (mycophenolic acid, 3-deazaguanosine, and 2-beta-D-ribofuranosylthiazole-4-carboxamide) were evaluated for their effects upon HL-60 cells, each agent was found to induce the cells to mature morphologically and functionally. Like other inducers, these agents decreased HL-60 cell proliferation and caused the cells to acquire an ability to phagocytose opsonized yeast and reduce nitroblue tetrazolium. Each agent reduced intracellular guanosine nucleotide pool sizes and induced HL-60 cell maturation at micromolar concentrations. These observations suggest that the size of intracellular guanosine nucleotide pools, the biosynthesis of guanosine nucleotides, and the activity of IMP dehydrogenase may be central to the regulation of terminal maturation in myeloid cells.

Adenine Nucleotides↗
PubMed1983

Lithium is an ineffective therapy for human cyclic hematopoiesis.

Cyclic hematopoiesis is a rare disease in man in which severe neutropenia recurs at 21-day intervals with associated illness. Because lithium carbonate therapy has been shown to eliminate cyclic hematopoiesis in grey collie dogs, we examined the effects of lithium treatment on five patients with this disease. With lithium levels maintained between 0.5 and 1.0 meq/liter, these patients showed no change in the fluctuations of their neutrophil counts. We conclude that lithium carbonate is not a simple cure for human cyclic hematopoiesis.

Enuresis↗
PubMed1982

Evidence for histamine-mediated inhibition of monocyte chemotaxis in atopic dermatitis.

Leukocyte chemotaxis was studied in 11 patients with severe childhood onset atopic dermatitis at a time when their disease was relatively quiescent. Pyoderma had been an important complication of the dermatitis in these patients. The chemotactic responsiveness of patient neutrophils and monocytes was on the average not significantly different from that of healthy control subjects, although three patients were identified who had significantly impaired responses. No correlation between IgE levels and leukocyte chemotaxis was observed. Because excessive amounts of histamine have been recovered from the skin of patients with atopic dermatitis, we evaluated the effects of histamine on the chemotactic responsiveness of leukocytes from these patients. Histamine caused a small dose-related increase in chemotaxis of neutrophils from both patients and control subjects (10(-7)M to 10(-5)M histamine). In contrast, histamine had no effect on the chemotaxis of monocytes from control subjects but inhibited the chemotactic responsiveness of monocytes from atopic dermatitis patients. These findings suggest that an abnormal sensitivity of monocytes to histamine is an intrinsic feature of atopic dermatitis that may be detectable when the disease is quiescent. Furthermore, this abnormality may contribute to the impairment of monocyte chemotaxis that has been previously observed in patients with active atopic dermatitis.

Chemotaxis↗
PubMed1982

Inhibition of bone marrow myeloid precursor cell proliferation by chemotactic oligopeptides.

Three N-formylated oligopeptides with different known activities as chemotactic factors for leukocytes were studied to determined if these mediators affect the in vitro proliferation of myelomonocytic colony-forming cells (CFU-C) recovered from murine bone marrow. All three oligopeptides inhibited CFU-C growth in a dose-dependent fashion that correlated with their relative potencies as chemotactic factors. This inhibition was not altered by growth of CFU-C in the presence of indomethacin, by varying the concentrations of colony-stimulating factor (CSF), or by depleting marrow cell preparations of mature granulocytic elements. These studies indicate that chemotactic factors may mediate myelosuppression through effects on committed myeloid precursor cells in the marrow.

Animals↗
PubMed1981

Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions.

Amphotericin B is used increasingly in high-risk patients with profound neutropenia and suspected sepsis. We have observed serious pulmonary reactions characterized by acute dyspnea, hypoxemia, and interstitial infiltrates on chest films in patients receiving amphotericin B and leukocyte transfusions. We reviewed 6 1/2 years of experience at the National Institutes of Health to determine whether this combination was associated with pulmonary toxicity not characteristic of either therapy alone. Amphotericin was used during 22 of 57 leukocyte-transfusion courses. Acute respiratory deterioration occurred during 14 (64 per cent) of these courses but in only two (6 per cent) of 35 courses without amphotericin (P less than 0.01). In seven cases, respiratory deterioration began during or immediately after amphotericin infusion, and it contributed to death in five patients. Diffuse intraalveolar hemorrhage was found when lung biopsy or autopsy was performed. Acute respiratory deterioration was not observed in comparably neutropenic patients given amphotericin but not leukocyte transfusions during the same period. It was mot common when amphotericin was begun with or after institution of daily leukocyte transfusions. Leukocyte transfusions may cause changes in the lungs that amplify the acute toxicity of amphotericin, thereby permitting severe pulmonary reactions.

Adolescent↗
PubMed1981

Human cyclic neutropenia: clinical review and long-term follow-up of patients.

Human cyclic neutropenia is a distinctive disorder of unknown cause characterized by regularly recurrent episodes of profound neutropenia, which have a periodicity of about 3 weeks. This periodicity remains constant and is remarkably consistent among patients. Although blood elements other than neutrophils are nt depleted, essentially all patients experience a cycling of monocyte counts with monocyte cycles of the same length as but reciprocal to neutrophil cycles. Cycling of platelet and reticulocyte numbers also may occur. Patients experience a clinical syndrome of recurrent illness characterized by malaise, fever, aphthous stomatitis, and cervical adenopathy. Incidental infections may occur with neutropenia but respond readily to antibiotics. The clinical course is benign compared with others conditions in which similar degrees of neutropenia occur. The only life-threatening complication encountered during long-term follow-up of patients was the occurrence of spontaneous peritonitis, segmental bowel necrosis, and septicemia which required surgical intervention. Most patients develop the disease in childhood, but a significant number of patients develop the disease in adulthood as an apparently acquired condition. The disease occurs equally in both sexes and is familial in some. Studies of marrow morphology, myelopoiesis, and neotrophil kinetics have shown that cyclic neutropenia is primarily a disease of abnormally regulated neutrophil production. The judicious use of antibiotics, careful oral and dental care, and patient education are the mainstays of management. Alternate-day corticosteroids have been used successfully to abate the recurrent signs and symptoms, and in one patient the disease was gradually corrected by alternate day prednisolone. Human cyclic neutropenia is of special investigative interest because clarification of this disease may contribute greatly to an understanding of the normal control of myelopoiesis.

Agranulocytosis↗
PubMed1981

Human blood monocytes: characterization of negatively selected human monocytes and their suspension cell culture derivatives.

Normal human monocytes were negatively selected from leucapheresis cell suspensions by countercurrent centrifugation-elutriation in high yield with a mean purity of 93.5%. The combination of the novel methods of negative cell selection and suspension cell culture has provided the opportunity to study serially over several days the morphologic and functional changes of monocytes from a single donor as they matured in culture to typical macrophages. Human monocytes nearly double in size during the first week of culture, experiencing near daily increases in cell volume. This was associated with changes in the ultrastructure of these cells, including the development of numerous small knob-like projections on the cell membrane and the proliferation of microtubules and filamentous structures within the cell cytoplasm during the first 6 days of culture. Peroxidase activity declined during the first 4 days of culture, whereas 5'-nucleotidase activity was acquired during the first 48 h of culture. Lysozyme activity in the cultures increased form day 2 to day 6 of culture. The phagocytic capacity of monocytes for igG-coated erythrocytes increased dramatically during the first week of culture, but the cytotoxic capability of monocytes against similar targets in an antibody-dependent cytotoxicity assay declined to nearly half of base-line levels by day 2 of culture and remained at this diminished level during subsequent days of culture.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1981

Neutrophil-mediated endothelial injury in vitro mechanisms of cell detachment.

Neutrophil-mediated endothelial injury was assessed in vitro using assays of cell lysis and cell detachment. Activation of human peripheral blood neutrophils adherent to human umbilical vein endothelial cell monolayers by serum-treated zymosan produced dose-dependent endothelial cell detachment without concomitant cell lysis. This injury was inhibited by neutral protease inhibitors, but not by catalase or superoxide dismutase. Neutrophils from a patient with chronic granulomatous disease also produced endothelial cell detachment when activated by serum-treated zymosan similar to normal neutrophils. Endothelial detachment was also produced by cell-free postsecretory media from activated neutrophils or by partially purified human neutrophil granule fraction and was inhibitable by tryptic, elastase, and serine protease inhibitors, but not by an acid protease inhibitor. Analysis of iodinated endothelial cell surface proteins that had been exposed to partially purified neutrophil granule fraction showed complete loss of proteins migrating in the region of fibronectin by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. This result was prevented in the presence of neutral protease inhibitors. We conclude that neutrophil-derived neutral proteases mediate endothelial cell detachment in vitro through digestion of endothelial cell surface proteins including fibronectin.

Catalase↗