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Biomedical subjects

M A Moore

Publications and source records attributed to M A Moore.

At least 271 records · Page 15Linked to original sources
PubMed1988

Down regulation of myelopoiesis by mediators inhibiting the production of macrophage-derived granulomonopoietic enhancing activity (GM-EA).

Monocyte-derived lipid-containing macrophages (MDLMs) constitutively synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates the function of granulocyte-macrophage colony-stimulating activity (GM-CSA). In the study reported, we show that GM-EA is distinct from interleukin-1 (IL-1) in biochemical and functional properties and that its production is negatively regulated by several mediators. Thus, MDLM cultures pretreated with interferon-gamma (IFN-gamma, 3 to 900 U/mL), prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF, 10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated controls. The relative potency of inhibition was in the order of IFN-gamma greater than or equal to PGE2 greater than LF. The extent of the inhibitory effects was proportional to dosage and the duration of treatment and could be observed following only a brief exposure (two hours) of the MDLMS to physiologic doses of the mediators. Under optimal conditions, IFN-gamma (300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours) could totally abrogate the ability of the MDLMs to produce GM-EA. However, the drug-inhibited MDLMs could be reactivated to produce GM-EA by treatment with zymosan (60 micrograms/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-gamma, PGE2, and LF may involve the inhibition of GM-EA production. Furthermore, this negative feedback control is reversible and can be overridden when a proper stimulatory signal is given.

Cells, Cultured↗
PubMed1988

Differential expression of class II MHC antigens in subpopulations of human hematopoietic progenitor cells.

Expression of major histocompatibility complex class II Ags HLA-DR, HLA-DP, and HLA-DQ on human BM granulocyte-erythroid-macrophage-megakaryocyte CFU (CFU-GEMM), BFU-E, and CFU-GM was examined by indirect immunofluorescence, cell sorting, and complement-mediated cytotoxicity. BM, highly enriched for progenitor cells by depletion of mature hematopoietic elements, was further separated by sterile sorting into HLA-DR (-), low, intermediate, and high intensity HLA-DR (+), as well as HLA-DP (+) and HLA-DP (-) cell fractions and assayed for progenitor cell content. In addition, in the case of HLA-DR, CFU-GM response to inhibition by prostaglandin E was determined. Cell sorting and cytotoxicity data confirm that approximately 95% of assayable erythroid, myeloid, and multipotential progenitor cells expressed HLA-DR, whereas HLA-DQ Ags were undetectable. HLA-DR and HLA-DP Ags were co-expressed on 61% of these progenitor cells, predominantly those expressing HLA-DR at high intensity. Day 7 and 14 CFU-GM showed a trend toward segregation to the high HLA-DR (+) cell fractions, especially when recombinant human G-CSF was used to stimulate clone formation. Both day 7 and day 14 CFU-GMs were found predominantly in the HLA-DP (+) cell fraction. In contrast, BFU-E and CFU-GEMM were found in the low intensity HLA-DR cell fraction and predominantly in the HLA-DP (-) fraction. Both eosinophil CFU and cells giving rise to basophil/mast cells in suspension culture were found in the low and intermediate intensity HLA-DR fractions, but could be segregated into HLA-DP (+) and HLA-DP (-) cell fractions, respectively. Functional analysis of day 7 CFU-GM segregated, based upon HLA-DR intensity, indicated a positive correlation between increasing HLA-DR intensity and responsiveness to inhibition by prostaglandin E. Furthermore, only those CFU-GM expressing HLA-DR at high intensity could be removed by cytolytic treatment using a mAb anti-HLA-DR previously shown to be selective for CFU-GM responsive to PGE and in S phase of the cell cycle.

Adult↗
PubMed1988

Improving compliance with antihypertensive therapy.

Optimal control of hypertension may be impeded by poor patient-physician communication, excessive dietary sodium, cost of antihypertensive medications and laboratory studies, and drugs that antagonize antihypertensive agents. The physician is responsible for removing as many of these obstacles as possible. Prescribing an effective, inexpensive, once-daily medication with minimal side effects will improve patient compliance considerably.

Antihypertensive Agents↗
PubMed1988

Rapid quantitative apolipoprotein analysis by gradient ultracentrifugation and reversed-phase high performance liquid chromatography.

A new methodology for the analysis of lipoprotein composition using a combination of gradient ultracentrifugation and high performance liquid chromatography was used to determine the differences in lipoprotein composition between non-hyperlipidemic men and women. Lipoproteins from each subject were separated into six subfractions: VLDL, IDL, LDL, and three subfractions of HDL by a single gradient ultracentrifugation spin of less than 5 hr. The HDL subfractions were designated HDL-L (the lightest density subfraction, rich in apoCs and poor in apoA-II), HDL-M (the middle subfraction, rich in apoA-II), and HDL-D (the most dense, relatively poor in both the apoCs and apoA-II). The concentrations of the water-soluble apolipoproteins in each subfraction were determined using reversed-phase HPLC. The concentrations of apoB and the lipid components of the lipoproteins were determined by chemical and enzymatic methods. This methodology proved to be highly reproducible when performed on fresh plasma samples and we were able to identify many sex-associated differences in lipoprotein composition. This methodology is the only nonimmunological technique available for analyzing lipoprotein composition that offers such a combination of accuracy, speed, and completeness.

Adult↗
PubMed1988

1,25-Dihydroxyvitamin D3 transcriptionally regulates tumour necrosis factor mRNA during HL-60 cell differentiation.

We investigated TNF-alpha gene expression in HL-60 cells under the influence of 1,25(OH)2D3. Our results show that TNF-alpha gene expression is transcriptionally activated by 1,25(OH)2D3. Despite the increase of TNF-alpha mRNA, very little TNF protein is found in either supernatants or cell lysates of HL-60 cells cultured in the presence of the vitamin. Therefore 1,25(OH)2D3 is regulating the transcription of the TNF-alpha gene in HL-60 cells without affecting translation. Our data suggest that an additional signal is necessary under physiological conditions to control post-transcriptionally TNF-alpha protein synthesis and secretion.

Calcitriol↗
PubMed1987

Characterization of a factor produced by human T cell clones exhibiting eosinophil-activating and burst-promoting activities.

It has long been suggested that eosinophil response observed in certain immunological reactions depends on the release of soluble products from sensitized lymphocytes when exposed to the challenging antigen. We were able to show that alloreactive T cell clones (ATLC) obtained from human rejected kidney produced, when stimulated with specific antigen (kidney donor-B lymphoblastoid cell line) and interleukin 2, a factor triggering the proliferation of a subline (DA-2) of the interleukin 3 sensitive DA-1 murine cell line. The biochemical features of this factor called HILDA (human interleukin DA) and the DA-2 nonresponsiveness to several human T cell lymphokines and cytokines lead us to the conclusion that this 41,000 m.w. glycoprotein could not be likened to already known T cell lymphokines. Highly purified HILDA turned out to be a potent chemoattractant and activator of, respectively, mouse and human eosinophils. It also displayed burst-promoting activity on human marrow.

Animals↗
PubMed1987

Recombinant human granulocyte colony-stimulating factor. Effects on hematopoiesis in normal and cyclophosphamide-treated primates.

We examined the in vivo effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in primates (cynomolgus monkeys) treated with subcutaneous doses of rhG-CSF for 14-28 d. A dose-dependent increase in the peripheral white blood cells (WBC) was seen, reaching a plateau after 1 wk of rhG-CSF treatment. The elevation of WBC was due to an increase in the absolute neutrophil count. These results demonstrate that rhG-CSF is a potent granulopoietic growth and differentiation factor in vivo. In cyclophosphamide (CY)-induced myelosuppression, rhG-CSF was able to shorten the time period of WBC recovery in two treated monkeys to 1 wk, as compared to more than 4 wk for the control monkey. Its ability to significantly shorten the period of chemotherapy-induced bone marrow hypoplasia may allow clinicians to increase the frequency or dosage of chemotherapeutic agents. In addition, the increase in absolute numbers of functionally active neutrophils may have a profound effect in the rate and severity of neutropenia-related sepsis. Furthermore, the activities reported here indicate a potential role for rhG-CSF in the treatment of patients with myelodysplastic syndrome, congenital agranulocytosis, radiation-induced myelosuppression, and bone marrow transplantation.

Animals↗
PubMed1987

Evidence for an alternative mechanism of human platelet secretion involving peripheralization of secretory granules and formation of membrane-associated multivesicular structures.

Stimulated platelets release the content of their granules to the environment by a process known as platelet secretion. The precise mechanism of platelet secretion is poorly understood. The most widely-held theory suggests that, during platelet activation, secretory granules centralize and their content is released into the surface-connected canalicular system. Using fixation techniques directed at preserving membrane structures, morphological evidence is provided that human platelet activation is associated with secretory granules migrating to the periphery of platelets, where they undergo transition to participate in the formation of membrane-associated multivesicular structures. These multivesicular structures then undergo dissolution resulting in granule content secretion to the environment. The formation of the membrane-associated multivesicular structures occurs in platelets in which some of the secretory granules have also become centralized. This suggests that during the activation of human platelets, membrane-associated multivesicular structure release may occur concurrently with other mechanisms of secretory granule content release. The present observations are consistent, however, with the hypothesis that during human platelet activation the formation of membrane-associated multivesicular structures by platelet secretory granules contributes importantly to the mechanism of platelet secretion.

Blood Platelets↗
PubMed1987

Immunohistochemically demonstrated increase in glutathione S-transferase species in propylnitrosamine-induced focal proliferative and neoplastic Syrian hamster pancreatic lesions.

Immunohistochemical investigation of focal proliferative and neoplastic Syrian hamster pancreatic lesions induced by propylnitrosamine administration revealed a distinct pattern of expression of different molecular forms of glutathione S-transferase (GST) during neoplastic development. Initial increase in levels of GST placental (P) and B forms in early ductal/ductular proliferations and atypical (dysplastic) lesions was followed by a drop in the latter during transition to carcinoma. Unequivocal acinar cells observed within so-called 'pseudoductules' did not share the altered phenotype evident in ductular elements, suggesting their non-involvement in the generation of early lesions. However, the fact that component cells were occasionally of abnormal morphology did not allow the exclusion of acinar cell participation in histogenesis. Elevation of GST-A and C forms was limited to stromal elements surrounding the epithelial lesions and since they were associated with benign, cystic as well as atypical lesions and a similar increase was observed after common duct ligation, they appeared to be non-specific. The results indicated independent control of expression of individual GST forms and suggest that biochemical similarities exist between early, putative preneoplastic lesions induced by propylnitrosamines in the hamster lung, liver (both hepatocellular and intrahepatic bile duct) and pancreas.

Animals↗
PubMed1987

Altered enzyme expression in propylnitrosamine-induced Syrian hamster lung lesions.

Focal proliferative and neoplastic lung lesions induced in Syrian hamsters by dihydroxy-di-n-propylnitrosamine (DHPN) were investigated using a combined histochemical, autoradiographic and electron microscopic approach. Expression of elevated glucose-6-phosphate dehydrogenase (G6PD) and gammaglutamyl-transpeptidase (GGT) activities and levels of immunohistochemically demonstrable glutathione S-transferase placental form (GST-P) were evident in epithelial cells of focal proliferative populations and bronchioloalveolar neoplasms. Binding for the GST-C form, normally only weak, became very pronounced in the stromal elements of DHPN-induced lesions. Increased labelling with tritiated thymidine was associated with increase in morphological atypia within the tumours. Although the enzyme phenotype findings were equivocal the presence of lamellar bodies in some cells of focal proliferative and neoplastic lesions suggested an origin from alveolar type II cells. The present results regarding changed enzyme phenotype in lung lesions suggest important similarities at the biochemical level for the process of neoplasia in the different target organs of DHPN in the hamster and indicate that GST-P may be a useful 'marker' for lung neoplasia.

Adenocarcinoma↗
PubMed1987

Level of Opisthorchis infestation and carcinogen dose-dependence of cholangiocarcinoma induction in Syrian golden hamsters.

The relationship between different levels of liver fluke, Opisthorchis viverrini infestation and dimethylnitrosamine (DMN) dosage in the induction of cholangiocarcinomas was investigated in Syrian golden hamsters. Two hundred and eighty male, weanling animals were divided into 4 groups: Group 1 served as untreated controls; group 2 received O. viverrini metacercariae only at levels of 100, 50, 25 or 12 per animal; group 3 received DMN only at doses of 12.5, 6.25 or 3.125 ppm; group 4 received various combinations of metacercariae and DMN. Only 2 of 17 animals (12%) in group 3 receiving 12.5 ppm had detectable tumours and no neoplastic lesions were seen in the 6.25 and 3.125 ppm DMN subgroups or in parasite alone or untreated control hamsters. In contrast, high carcinogen and parasite dose-dependent yields of cholangiocarcinomas (incidences up to 93%) and putative preneoplastic cholangiofibrotic lesions were observed in group 4. Thus the results indicate clear dose-dependent synergistic effects for the two agents and reveal the crucial importance of the presence of parasite, even at levels as low as 12 metacercariae, for DMN induction of bile duct carcinogenesis.

Adenoma, Bile Duct↗
PubMed1987

Inhibition of spontaneous proliferation of human leukemic B cells from patients with chronic lymphocytic leukemia by anti-mu antibodies.

In a monoclonal system, F(ab')2 fragments of rabbit anti-mu antibody (anti-mu) were found to inhibit the proliferation and differentiation of highly purified E-rosette-negative largely leukemic B cells from two patients with chronic lymphocytic leukemia (CLL). Leukemic B cells from these two patients, in contrast with the majority of patients with CLL, exhibited high spontaneous proliferation in culture medium alone. This spontaneous proliferation was significantly inhibited by moderate concentrations of anti-mu (10-50 micrograms/ml). In contrast, lower concentrations of anti-mu (0.6-1.2 micrograms/ml) induced proliferation of leukemic B cells. Conditioned media (CM), derived by stimulation of human peripheral blood mononuclear leukocytes with phytohemagglutinin, induced significant proliferation of these leukemic B cells. This induced proliferation at optimal CM concentrations was inhibited by anti-mu. However, at high CM concentrations, which did not cause significant proliferation, synergism between CM and anti-mu in inducing proliferation was observed. Stimulation of spontaneously proliferating leukemic B cells with CM resulted in differentiation into cells synthesizing and secreting immunoglobulin M (IgM) but not IgG. This IgM production was also inhibited by anti-mu.

Antibodies, Anti-Idiotypic↗
PubMed1987

Synergy of interleukin 1 and granulocyte colony-stimulating factor: in vivo stimulation of stem-cell recovery and hematopoietic regeneration following 5-fluorouracil treatment of mice.

The human bladder carcinoma cell line 5637 produces hematopoietic growth factors [granulocyte and granulocyte/macrophage colony-stimulating factors (G-CSF and GM-CSF)] and hemopoietin 1, which synergizes with CSFs to stimulate colony formation by primitive hematopoietic stem cells in 5-fluorouracil-treated mouse bone marrow. Molecular and functional properties of hemopoietin 1 identified it as identical to interleukin 1 alpha (IL-1 alpha). When bone marrow cells from 5-fluorouracil-treated mice were cultured in suspension for 7 days with recombinant human IL-1 alpha and/or G-CSF, it was found that the two factors synergized to enhance recovery of myelopoietic cells and colony-forming cells of both high and low proliferative potential. G-CSF alone did not sustain these populations, but the combination had greater-than-additive stimulating capacity. In vivo, 5-fluorouracil (150 mg/kg) produced profound myelosuppression and delayed neutrophil regeneration for up to 2 weeks in C3H/HeJ mice. Daily administration of recombinant human G-CSF or recombinant human IL-1 alpha accelerated recovery of stem cells, progenitor cells, and blood neutrophils by up to 4 days in 5-fluorouracil-treated C3H/HeJ and B6D2F1 mice. The combination of IL-1 alpha and G-CSF acted synergistically, reducing neutropenia and accelerating recovery of normal neutrophil numbers by up to 7 days. This was accompanied by accelerated regeneration of spleen colony-forming units and erythroid, myeloid, and megakaryocytic progenitor cells in marrow and spleen, with enhanced erythroid and granulocytic differentiation. These results indicate the possible therapeutic potential of combination therapy with IL-1 and hematopoietic growth factors such as G-CSF in the treatment of chemotherapy- or radiation-induced myelosuppression.

Animals↗
PubMed1987

Single GST-P positive liver cells--putative initiated hepatocytes.

Immunohistochemical investigation of liver tissue 48 h after single doses of the hepatocarcinogens diethylnitrosamine (DEN), dimethylnitrosamine, aflatoxin B1 and methylazoxymethanol acetate revealed the generation of a population of single glutathione S-transferase placental form (GST-P) positive hepatocytes. Yield was carcinogen dose dependent. Although the mixed function enzyme inducers sodium phenobarbital (PB), methylcholanthrene (Mech), polychlorinated biphenyls (PCB) and isosafrole (IS) did not in themselves induce comparable single cell lesions, their application prior to DEN caused significant alteration in the resultant numbers of GST-P positive hepatocytes observed. While PB and IS were associated with decreased yield, Mech and PCB, in contrast, brought about an increase. The results gained from investigation of the effects of 3-aminobenzamide administration and partial hepatectomy carried out at different times after carcinogen treatment also pointed to an 'initiated' character for the lesions and suggest that GST-P may be a useful marker for analyzing factors relevant to the initiation stage of hepatocarcinogenesis. Thus the interplay between carcinogen metabolism, DNA adduct formation and repair, toxicity and proliferation may be assessable in terms of numbers of enzyme-altered solitary hepatocytes.

Animals↗