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Biomedical subjects

M A Moore

Publications and source records attributed to M A Moore.

At least 361 records · Page 20Linked to original sources
PubMed1983

Hormonal responses to acute volume changes in anephric subjects.

The response of plasma aldosterone and cortisol concentrations to acute volume depletion was studied in 18 chronically anephric subjects and four recently nephrectomized subjects. Volume-depleting hemodialysis and hemodialysis without volume depletion produced insignificant changes in plasma aldosterone concentrations in chronically anephric subjects. Failure of volume depletion to increase plasma aldosterone concentrations in these subjects could not be attributed to reductions in plasma potassium concentrations and was in marked contrast to the effect on plasma cortisol concentrations, which increased significantly during volume depletion. Changes in plasma cortisol concentrations exhibited a negative correlation with changes in diastolic blood pressure (r = -0.712, P less than 0.001) and were shown to correspond to similar changes in plasma ACTH concentrations. Comparable increases in plasma cortisol and ACTH concentrations were also demonstrated in the studies on recently nephrectomized subjects, who, in contrast to chronically anephric subjects, exhibited increases in plasma aldosterone concentrations which were concordant with the changes in plasma cortisol and ACTH concentrations. These findings suggest that plasma aldosterone concentrations are regulated by a volume-sensitive mechanism in recently nephrectomized subjects but not in chronically anephric subjects. We interpret these data as evidence of aldosterone responsiveness to ACTH that persists for a limited time only after removal of the stimulus provided by the renin-angiotensin system. Volume-related changes in plasma cortisol and ACTH concentrations occur in the absence of stimulation by a functioning renin-angiotensin system.

Adolescent↗
PubMed1983

Early lesions during pancreatic carcinogenesis induced in Syrian hamster by DHPN or DOPN. I. Histologic, histochemical and radioautographic findings.

The early lesions which arise in the Syrian hamster pancreas prior to the appearance of carcinomas induced by treatment with the related carcinogens di-hydroxy-di-n-propyl nitrosamine or di-oxo-di-n-propyl nitrosamine were investigated in order to assess their roles in tumourigenesis. A sequence of events is proposed leading from ductal or ductular proliferations through regions of epithelial atypia (so-called dysplastic lesions) to carcinomas. This sequence appears distinct from that leading from ductular proliferations to benign multilocular cysts or cystadenomas. Radioautographic and histochemical evidence is presented supporting this proposal linking atypical proliferations but not cystic lesions with the induced carcinomas. Increase in the activity of glucose-6-phosphate dehydrogenase was established as being a good histochemical marker for early atypical proliferations during pancreatic carcinogenesis whereas gamma-glutamyl transpeptidase was found lacking in this respect. In addition, alteration in polysaccharide metabolism was observed during the development of the carcinomas.

Animals↗
PubMed1983

Early lesions during pancreatic carcinogenesis induced in the Syrian hamster by DHPN or DOPN. II. Ultrastructural findings.

The ultrastructure of multi-locular cystic lesions and atypical epithelial proliferations arising in the Syrian hamster pancreas prior to the appearance of carcinomas during treatment with the related carcinogens di-hydroxy-di-n-propyl nitrosamine and di-oxo-di-n-propyl nitrosamine was compared in order to assess the role these lesions play in tumourigenesis in this model. Whereas the cells of low cuboidal ductular morphology forming multi-locular cystic lesions demonstrated basic fine structural similarities to normal ductular epithelium the columnar cells prevalent in atypical epithelial proliferations exhibited marked alterations reminiscent of ultrastructural features present in many cells of carcinomas. Most conspicuous amongst these changes were production of mucous granules and occurrence of goblet type cells, glycogen accumulation, nuclear abnormalities and thickening and interruption of the basement membrane. The ultrastructural findings support the view that the atypical proliferations showing alteration in carbohydrate metabolism are precursors for pancreatic carcinomas in the Syrian hamster.

Animals↗
PubMed1983

Enhancement of NNM-induced carcinogenesis in the rat liver by phenobarbital: a combined morphological and enzyme histochemical approach.

The influence of sodium phenobarbital (PB) treatment on the sequence of N-nitrosomorpholine (NNM) induced focal preneoplastic lesions in the rat liver was investigated using a combined morphological and enzyme histochemical approach. Quantitative assessment of the different types of foci of altered hepatocytes visible in H&E sections after carcinogen application, namely the clear and acidophilic cell glycogen storage foci and mixed cell foci comprising glycogen storing cells and also more basophilic hepatocytes showing reduction in glycogen reserves, revealed a shift towards mixed cell character and greater size in PB-treated livers in comparison to those receiving NNM alone. Within the three dose levels of PB investigated (0.75, 0.075 or 0.0075 g/l drinking water) a clear dose dependence in appearance of mixed cell foci was apparent. Assessment of alterations in the activities of marker enzymes observed within preneoplastic foci was carried out by comparison of PAS preparations with sections reacted for glucose-6-phosphate dehydrogenase (G6PDH), gamma-glutamyl transpeptidase, glucose-6-phosphatase and adenosine triphosphatase. G6PDH proved the most consistent enzyme marker for small glycogen storage foci whereas larger foci of that type and mixed cell foci were associated with change in activity of all enzymes studied. The results are discussed in relation to the sequence of events occurring during hepatocarcinogenesis and the influence of PB on altered cellular populations. The applicability of enzyme markers is further considered in view of the question of heterogeneity within populations of preneoplastic foci.

Acyltransferases↗
PubMed1983

Phenotypic instability in focal and nodular lesions induced in a short term system in the rat liver.

A comparative morphologic, morphometric and enzyme histochemical investigation of lesions induced by short-term application of N-nitrosomorpholine (NNM) and subsequent so-called 'selection pressure' was carried out in order to assess the characteristics of the numbers of induced putative preneoplastic populations and to cast light on reversibility associated with this model. The glycogen storage foci, mixed cell foci and neoplastic nodules observed after 'selection pressure' were in principle similar to those seen after stop experiments, although alterations in morphology and enzyme phenotype of individual cells were usually far more pronounced after short-term induction. It was established that 75% of the lesions were no longer visible 11 weeks after withdrawal of induction stimuli and that a large proportion of these remaining demonstrated heterogeneity in morphological and histochemical markers indicative of reversion to normal phenotype. After a further 10 weeks a slight increase in number of foci associated with decrease in size and enhanced homogeneity in phenotypic markers was established. The behaviour of foci and nodules undergoing reversion was considered with respect to changes in basophilia and glycogen storage and activity of the enzymes glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, glyceraldehyde 3-phosphate dehydrogenase, glycogen phosphorylase and synthase, acid phosphatase and gamma-glutamyl transpeptidase and correlated with location of altered cellular populations within the liver functional acinus.

Animals↗
PubMed1983

Influence of phenobarbital on glycogen metabolism of rat liver pretreated with N-nitrosomorpholine.

Sprague-Dawley rats were treated with N-nitrosomorpholine (NNM) alone (7 weeks, 120 mg/l in drinking water), with NNM followed by phenobarbital (PB) (750 mg/l for 6 weeks) or PB alone. The livers from these animals were investigated for glycogen content and activities of glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, glycogen phosphorylase and glycogen synthetase. The following parameters proved to be significantly altered in the livers of rats treated with either NNM or PB or both compared with untreated controls: glycogen content was increased and the activities of glucose-6-phosphatase and glycogen synthetase were decreased. Although these data show some similarities in changes of glycogen metabolism of livers treated with NNM or PB, earlier histochemical investigations revealed important differences in the distribution of these alterations within the liver parenchyma.

Animals↗
PubMed1983

Marrow cytogenetic and cell-culture analyses of the myelodysplastic syndromes: insights to pathophysiology and prognosis.

Marrow cytogenetic and granulocyte-macrophage colony formation (CFU-GM) studies were performed on 34 previously untreated patients with documented myelodysplastic syndromes seen between January 1978 and June 1982. All patients were managed without chemotherapy until progression to acute leukemia was observed. All 10 patients with exclusively abnormal marrow metaphases developed acute leukemia (100%) while only one (7%) of 14 patients with solely normal marrow metaphases subsequently developed leukemia (p less than 0.001). Three (42%) of the seven patients with both normal and abnormal marrow metaphases developed acute leukemia. Fifteen (86%) of the 19 patients with either large cluster or no growth patterns developed acute leukemia while only two (13%) of 15 patients with either small cluster or colony forming growth patterns developed acute leukemia (p less than 0.001). Abnormal marrow cytogenetic status correlated with abnormal marrow CFU-GM growth pattern (p less than 0.05). Analysis of CFU-GM sensitivity to inhibition by prostaglandin E was performed in 12 patients. Nine patients showed CFU-GM refractoriness to inhibition by prostaglandin E. Seven of these patients eventually developed leukemia. Three patients had CFU-GMs which were initially sensitive to prostaglandin E inhibition. In these three patients, a loss of CFU-GM sensitivity to prostaglandin E was observed prior to their progression to morphologically identifiable acute leukemia.

Acute Disease↗
PubMed1983

Association of cell cycle expression of Ia-like antigenic determinations on normal human multipotential (CFU-GEMM) and erythroid (BFU-E) progenitor cells with regulation in vitro by acidic isoferritins.

An association has been established between human Ia-like antigenic determinants, expression during DNA synthesis on multipotential (CFU-GEMM) and erythroid (BFU-E) progenitor cells, and the regulatory action of acidic isoferritins in vitro. Treatment of human bone marrow cells with monoclonal anti-Ia (NE1-011) plus complement inhibited colony formation of CFU-GEMM) and BFU-E by 50%-70%. Reduction of colonies was similar whether bone marrow cells were exposed to anti-Ia plus complement, high specific tritiated thymidine (3HTdr), or acidic isoferritins. No further decrease was apparent with 3HTdr or acidic isoferritins after Ia-antigen+ CFU-GEMM or BFU-E were removed, or with anti-Ia plus complement or acidic isoferritins after S-phase CFU-GEMM or BFU-E were removed. Anti-Ia, in the absence of complement, had no effect on colony formation but blocked the inhibition of CFU-GEMM and BFU-E by acidic isoferritins. Demonstration of Ia-antigens on BFU-E and inhibition of BFU-E by acidic isoferritins appeared to require the presence of phytohemmagglutinin leukocyte conditioned medium (PHA-LCM) in the culture medium during the 14-day incubation period. these results implicate Ia-antigen+ cells, acidic isoferritins, and PHA-LCM in the regulation of multipotential and erythroid progenitor cells in vitro.

Antibodies, Monoclonal↗
PubMed1983

Lymphokine inducing "terminal differentiation" of the human monoblast leukemia line U937: a role for gamma interferon.

The human monoblast leukemia line, U937, is growth-inhibited and induced to develop markers of mature monocytes by lymphokine preparations. Lymphokine is cytostatic and induces expression of Fc receptors in U937 and in myelomonocytic leukemic lines RC-2A and KG-1, but does not have these effects on T- and B-lymphocytic lines. In addition to previously described properties, including complement receptors, phagocytosis, and antibody-dependent cellular cytotoxicity (ADCC), Mac-1 and Mac-3 surface antigens defined by monoclonal antibodies are induced on U937 cells by lymphokine and phorbol ester. The Mac-1 surface component appears to have a regulatory role in differentiation of the monocyte lineage line, since antibodies to this antigen block the induction of Mac-3 antigen. The lymphokine activity was concentrated by salt precipitation and characterized by ion-exchange and size chromatography. Fractions of about 40,000 daltons were responsible for growth inhibition and induction of Fc receptors and Mac-1 antigen in U937 cells. However, ADCC was not induced in U937 by individual fractions of lymphokine, suggesting that this cytotoxic capacity may be regulated by a lymphokine of a different size, which is only effective after initial maturation steps. Since gamma-interferon is present on the 40K size range of lymphokine, the possibility that interferon is a differentiation modulator for the monoblast cells was investigated. Highly purified gamma-interferon (10(7) U/mg protein) at 10-300 U/ml inhibited growth and induced Fc receptors in U937 similar to the effect of lymphokine. The Fc-receptor-inducing activity of lymphokine was inhibited by a neutralizing monoclonal antibody to gamma-interferon, suggesting that this differentiation factor in lymphokine is gamma-interferon.

Animals↗
PubMed1983

Phase I clinical trial of 13-cis-retinoic acid in myelodysplastic syndromes.

13-cis-Retinoic acid (13-cRA) induces maturation and differentiation of neoplastic myeloid cell lines in vitro. We conducted a phase I clinical trial of 13-cRA in patients with myelodysplastic syndromes (MDS), using a single daily oral dose schedule. Seventeen patients with MDS and one each with acute nonlymphoblastic leukemia and chronic myelogenous leukemia in blast crisis were treated with 13-cRA at doses ranging from 20 to 125 mg/m2/day. Hepatotoxicity was dose-limiting and was manifested by hyperbilirubinemia and increased SGOT levels. This effect was seen only at the highest dose level of 125 mg/m2/day and was completely reversible upon cessation of the drug. Other toxic effects were mild, and included cheilosis, hyperkeratosis, stomatitis, and elevation of serum triglyceride levels. Fifteen patients with MDS were evaluable for therapeutic response. Five patients showed improvement in hematologic parameters. These responses included normalization of bone marrow blast count and increases in leukocyte count, platelet count, and/or hemoglobin concentration. Responses were generally not seen until at least 3 weeks of therapy were completed. We conclude that further study of 13-cRA in myelodysplastic syndromes is warranted and recommend that future studies utilize a starting dose of 100 mg/m2.

Administration, Oral↗
PubMed1983

Production and regulation of interleukin-2 in human lymphoblastic leukemias studied with T-cell monoclonal antibodies.

Human leukemias are illnesses of hemopoietic stem cells that go through processes of self-replication and partial differentiation under the control of as yet largely unknown growth and differentiation factors. IL-2 is a powerful factor controlling proliferation of normal T cells. We report that acute lymphoblastic leukemias of T and non-B, non-T phenotypes produce a growth factor after mitogen stimulation. This factor is able to support the proliferation of human and murine IL-2-dependent cytotoxic cells, has a mol wt of 26,000 daltons by gel filtration, an isoelectric point of 6.6, and its biologic activity is inhibited by an anti IL-2 monoclonal antibody. This factor is, therefore, by all parameters studied very similar to IL-2 produced by normal lymphocytes. A recently developed monoclonal antibody, Pan T2, binds to normal T cells, renders T cells responsive to IL-2, and induces the release of IL-2, which in turn provides the second signal for T-cell proliferation. Mononuclear cells from acute lymphoblastic leukemia do not respond to the addition of this monoclonal antibody unless cocultured with irradiated Daudi cells. Since normal T cells do not require Daudi to produce IL-2 and since Daudi cells do not produce IL-2 under any conditions, we conclude that the cell responsible for IL-2 production in acute lymphatic leukemia is a leukemic T cell with an altered mechanism of IL-2 production at the level of the Pan T2 binding site.

Antibodies, Monoclonal↗
PubMed1983

Sodium azide enhancement of interleukin-2 production.

The production of large quantities of Interleukin-2 (IL-2) from normal human lymphocytes has been limited by the short production and release period, as well as its absorption by the responsive cell population. We report the utilization of sodium azide (NaN3, 0.01% final concentration) to allow continued production of IL-2 as long as 72-96 hr and thereby increase the yield significantly. Cell cycle analysis performed by flow cytometry indicates that NaN3 blocks cells at the G0-G1 transition and the G1-S transition, depending on the time of addition of NaN3 to the cultures.

Animals↗
PubMed1983

Characterization of mast cell precursors by physical means: dissociation from T cells and T cell precursors.

Murine bone marrow precursors (MCP) differentiate into mast cells and proliferate in response to mast cell growth factor (MCGF). An assay system based on the incorporation of [3']thymidine by proliferating mast cells in response to substantially purified MCGF was used to titrate MCP. Murine bone marrow was separated into fractions by Percoll density gradient centrifugation or velocity sedimentation at unit gravity. Individual fractions were analyzed to determine the relative concentrations of MCP. To determine if mast cells were derived from precursors different from those for T lymphocytes and granulocytes and macrophages, separated cells were also analyzed for responsiveness to interleukin 2 (IL 2) in standard [3H] thymidine incorporation assays and to granulocyte-macrophage colony stimulating factors (CSF) in agar cloning (CFU-GM) assays. Cultured marrow cells from Dexter type long-term marrow cultures (LMC) were included as a source of marrow cells devoid of mature T cells, so as to dissociate MCP from pre-T cells. MCP were readily dissociable from T cells and/or pre-T cells present in fresh, as well as cultured, marrow cells by either density or velocity of sedimentation separation techniques. MCP were, however, not readily separable from CFU-GM. Nevertheless, MCP appeared not to share a common precursor with pure macrophage type colony-forming cells (CFU-M phi). The implications of the findings on the lineage origin of mast cells were discussed.

Animals↗
PubMed1983

Therapeutic implications of serum factors inhibiting proliferation and inducing differentiation of myeloid leukemic cells.

Murine post-endotoxin sera contain high levels of myeloid colony-stimulating factor(s) (GM-CSF) and factors capable of inducing terminal granulocyte and macrophage differentiation of the murine myelomonocytic leukemic cell line WEHI-3. The combination of C. parvum and endotoxin induced a serum activity capable of inducing tumor necrosis and inhibiting leukemic colony formation in vitro. This factor (TNF) could be separated from the differentiation-inducing factor (GM-DF) and from CSF. In conjunction with a Phase I trial of highly purified endotoxin in patients with advanced malignancy, we monitored human post-endotoxin sera for CSF and GM-DF. Induction of GM-DF occurred maximally at 2-6 h and was associated with increased serum levels of CSF active against the patient's own bone marrow. Following repeated injections of escalating doses of endotoxin, persistent levels of GM-DF were detected both pre-endotoxin and 24 h post-endotoxin treatment. The ability to induce repeatedly a serum protein with potent capacity to promote terminal differentiation of myelomonocytic leukemic cells suggests a possible therapeutic role in human myeloid leukemias.

Animals↗
PubMed1983

OKT8 antibody inhibits OKT3-induced IL 2 production and proliferation in OKT8+ cells.

We studied IL 2 production and proliferation induced by OKT3 mitogenic monoclonal antibody in the OKT8+ T cell subset. OKT3 antibody induced IL 2 production and proliferation in OKT8+ cells in a typical time-dependent manner: maximal IL 2 levels were found in 24 hr culture supernatants; maximal proliferation was found on day 3. OKT3 antibody was mitogenic over a wide range of concentrations (0.125 to 500 ng/ml). The presence of OKT8 antibody (greater than or equal to 100 ng/ml) in these cultures resulted in almost complete inhibition of IL 2 production and proliferation. Kinetic studies demonstrate that OKT8 antibody suppresses both IL 2 production and response to exogenous IL 2 in OKT8+ cells when added within the first 2 hr of culture. After 14 to 20 hr of culture, addition of OKT8 only blocks IL 2 production but not the IL 2 response of activated OKT8+ cells. The specificity of inhibition by OKT8 antibody of OKT3 mitogenicity on OKT8+ cells was confirmed by the failure of Leu-I and OKT4 antibody to produce the same effect and by the lack of inhibition by OKT8 antibody of OKT3-induced IL 2 production and proliferation in OKT4+ cells.

Antibodies, Monoclonal↗
PubMed1982

Purification of human interleukin 2 to apparent homogeneity and its molecular heterogeneity.

Interleukin 2 (IL-2), produced with and without co-stimulation by the Burkitt's lymphoma line Daudi, was purified 37,000-fold to apparent homogeneity from lymphocyte conditioned medium by (NH4)2SO4 precipitation, DEAE-cellulose ion-exchange chromatography, gel filtration, and chromatography on blue agarose and on Procion-red agarose. The purified IL-2 showed a 10(6) U/mg protein sp act. IL-2 produced in the absence of Daudi cells had a mol wt of 26,000 as measured by gel filtration and an isoelectric point of 6.7. This IL-2 showed a 16,000 and 17,000 mol wt in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). IL-2, produced in the presence of Daudi cells (10(6)/ml), showed a mol wt of approximately 14,000, as measured by both gel filtration and SDS-PAGE, and an isoelectric point of 8.1. The purified IL-2 lacked detectable interferon (alpha and gamma), granulocyte-macrophage colony-stimulating factor, B cell growth factor, T cell-replacing factor, and thymocyte-differentiating activity and was free of any contaminating proteins as judged by silver staining in SDS-PAGE. All three molecular forms of IL-2 were biologically active at concentrations of 10(-11) - 10(-10) M, supporting the growth of human and murine cytotoxic T cell lines.

Animals↗