Biomedical subjects

J A Hamilton

Publications and source records attributed to J A Hamilton.

At least 235 records · Page 13Linked to original sources

PubMed1989

Activation and proliferation signals in murine macrophages: relationships among c-fos and c-myc expression, phosphoinositide hydrolysis, superoxide formation, and DNA synthesis.

Murine bone marrow-derived macrophages (BMM) undergo DNA synthesis in response to growth factors such as colony stimulating factor-1 (CSF-1) and granulocyte-macrophage CSF (GM-CSF). These macrophages can also be "activated," but without subsequent DNA synthesis, by a number of other agents, including lipopolysaccharide (LPS), concanavalin A, zymosan, formyl-methionyl-leucyl-phenylalanine (FMLP), and the Ca2+ ionophore, A23187. When BMM are treated with a range of stimuli, there is some, although not perfect, correlation between transient elevations in both c-myc mRNA and c-fos mRNA levels and increases in DNA synthesis. However, enhanced DNA synthesis and oncogene expression are readily dissociated from rises in inositol phosphates and, by implication, phospholipase C-mediated hydrolysis of phosphatidyl inositol 4,5-bisphosphate. Superoxide formation in BMM can also be dissociated from the other responses and does not necessarily depend on protein kinase C activation.

Animals↗

PubMed1989

Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2.

Stimulated human monocytes/macrophages are a source of mediators such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), and prostaglandin E2 (PGE2), which can modulate inflammatory and immune reactions. Therefore, the ability to control the production of such mediators by monocytes/macrophages may have therapeutic benefits, and it has been proposed that glucocorticoids may act in this way. Purified human monocytes, when stimulated in vitro with lipopolysaccharide (LPS) or with LPS and gamma interferon (IFN-gamma), produce TNF-alpha, IL-1, and PGE2. Cotreatment of stimulated cells with the purified human lymphokine, interleukin 4 (IL-4 greater than or equal to 0.1-0.5 unit/ml; 12-60 pM) dramatically blocked the increased levels of these three mediators; for TNF-alpha and IL-1, the inhibition was manifest at the level of mRNA. Thus, IL-4 can suppress some parameters of monocyte activation and, as for B cells, have opposite effects to IFN-gamma. The effects of IL-4 on human monocytes are similar to those obtained with the glucocorticoid dexamethasone (0.1 microM).

Cell Survival↗

PubMed1989

Medium-chain fatty acid binding to albumin and transfer to phospholipid bilayers.

Temperature-dependent (5-42 degrees C) 13C NMR spectra of albumin complexes with 90% isotopically substituted [1-13C]decanoic acids (3 mol of fatty acid per mol of albumin) showed a single peak at greater than 30 degrees C but three peaks at lower temperatures. The chemical-shift differences result from different ionic and/or hydrogen-bonding interactions between amino acid side chains and the fatty acid carboxyl carbon. Rapid exchange of fatty acid among binding sites obscures these sites at temperatures greater than 30 degrees C. Rate constants for exchange at 33 degrees C were 350 sec-1 for octanoate and 20 sec-1 for decanoate, corresponding to lifetimes in a binding site of 2.8 msec (octanoate) and 50 msec (decanoate). Temperature-dependent data for octanoate showed an activation energy of 2 kcal/mol for exchange. Spectra of albumin complexes with the 12-carbon saturated fatty acid, lauric acid, had several narrow laurate carboxyl peaks at 35 degrees C, indicating longer lifetimes (tau much greater than 66 msec) in the different binding sites. Fatty acid exchange between albumin and model membranes (phosphatidylcholine bilayers) occurred on a time scale comparable to that for exchange among albumin binding sites, following the order octanoate greater than decanoate greater than laurate. The equilibrium distribution of fatty acid between lipid bilayers and protein was measured directly from NMR spectra. Decreasing pH (8.0 to 5.5) increased the relative affinity of fatty acid for the lipid bilayer. The results predict that the relative affinity of octanoic acid for albumin and membranes will be similar to that of long-chain fatty acids (e.g., oleic acid), but the rate of equilibration will be approximately 10(4) faster for octanoic acid.

Fatty Acids↗

PubMed1989

Evidence for a menstrual-linked artifact in determining rates of depression.

This is the first empirical report suggesting a menstrual-linked artifact in determining rates of depression. We investigated the effects of perceived menstrual cycle phase, and premenstrual and postmenstrual timing in the cycle, on scores for a self-report measure of depression that is widely used in epidemiological studies, the Center for Epidemiologic Studies Depression Scale (CES-D). The first study used a cross-sectional design and the second used a follow-up design with repeated measures across the menstrual cycle. Both studies assessed a community-based sample of regularly menstruating women. In the second study, testing was also done at 2-week intervals in men for comparison purposes. Both studies supported the hypothesis of a significant menstrual cycle-related effect on CES-D scores. The menstrual-linked effect is greater than the test-retest variability observed in men, such that women more often tend to meet the cut-off criteria for depression on the CES-D premenstrually, as compared with postmenstrually. Thus it is possible that cyclic variations in ratings on the CES-D may elevate epidemiological estimates of depression, as defined by RDC criteria, for menstruating women. Further longitudinal assessment in randomly selected samples will be needed in order to clarify whether a menstrual-linked effect is substantial and specific enough to require correction, or documentation of cycle phase, in epidemiological studies of depression.

Adult↗

PubMed1989

Control by IFN-gamma and PGE2 of TNF alpha and IL-1 production by human monocytes.

There have been suggestions that the production of pro-inflammatory mediators by human monocytes in response to interferon-gamma (IFN-gamma) may be controlled by changes in prostaglandins. Therefore we investigated tumour necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) activities and prostaglandin E2 (PGE2) levels in the supernatants of highly purified human monocytes cultured for 18 hr with recombinant human IFN-gamma. IFN-gamma (100 U/ml) did not stimulate monocytes isolated by counter-current centrifugal elutriation for detectable TNF alpha or IL-1 activities, or PGE2 production. However, IFN-gamma synergistically enhanced lipopolysaccharide (LPS)-induced TNF alpha and IL-1 activities. In contrast, there was no consistent change in PGE2 levels upon addition of IFN-gamma to LPS-treated monocyte cultures. The TNF alpha and IL-1 activities induced by LPS and by LPS with IFN-gamma were reduced by PGE2, and stimulated by indomethacin. As reported previously for IL-1 activities, the regulation by cyclo-oxygenase products of TNF alpha activities reflected predominantly a control of the production of immunoreactive TNF alpha, rather than the measurement of TNF alpha bio-activity. However, the addition of indomethacin or PGE2 to monocyte cultures did not change the extent of IFN-gamma synergy with LPS for increased TNF alpha and IL-1 activities. The results of this study suggest that, despite control by cyclo-oxygenase products of TNF alpha and IL-1 production in human monocytes, IFN-gamma may enhance TNF alpha and IL-1 activities independently of this regulatory mechanism. These findings are contrary to those suggested for the regulation by prostanoids of IL-1 production by murine macrophages.

Cells, Cultured↗

PubMed1989

Interleukin-4 stimulates human monocytes to produce tissue-type plasminogen activator.

Tissue-type plasminogen activator (t-PA) is involved in the lysis of blood clots (fibrinolysis) and is used clinically for this purpose. Endothelial cells are one source of the t-PA present in blood. We report here that interleukin-4 (IL-4) (0.1 to 0.25 U/mL; 1 to 3 x 10(-11) mol/L), but not interferon-gamma (IFN-gamma), elevates t-PA messenger (m)RNA expression and secretion of t-PA activity by human monocytes, with the maximum response at 2.5 U/mL. Supernatant t-PA activity was detected within three hours of exposure to IL-4 and maximum activity within six hours. Thus, IL-4 may control fibrin deposition at sites of inflammation during cell-mediated immune responses, as well as having a therapeutic role in thrombolysis.

Cell-Free System↗

PubMed1989

Emotional consequences of victimization and discrimination in "special populations" of women.

The emotional consequences of victimization are believed to be mediated in part by the social context in which the abuse experience occurs. For selected "special populations" of women, subgroup membership is examined as a risk factor for victimization and as a contextual determinant of outcome. Membership in a disadvantaged subgroup can complicate recovery from abuse experiences in several ways. As examples, discrimination and revictimization can impede recovery from victimization.

Adaptation, Psychological↗

PubMed1989

Postpartum psychiatric syndromes.

Psychiatric symptoms after childbearing tend to arrange themselves into well-defined patterns or syndromes. When these syndromes are examined, each is found to have unique qualities and unique hazards. Confusion occurs in all syndromes. Many postpartum symptoms, and the timing of their development, lead to the hypothesis that critical etiologic mechanisms may be related to postpartum hormonal changes. Explorations of preventive and specific therapeutic measures provide support for this position.

Depressive Disorder↗

PubMed1988

Recombinant human interleukin-1 stimulates human articular cartilage to undergo resorption and human chondrocytes to produce both tissue- and urokinase-type plasminogen activator.

Cytokines capable of stimulating cartilage resorption have frequently been identified as 'interleukin-1 (IL-1)-like' peptides. In this study for the first time we have employed homogeneous recombinant IL-1 alpha and IL-1 beta in an all-human culture system to define the effects of IL-1 on articular cartilage and chondrocytes in culture. Recombinant IL-1 (10-100 U/ml) could stimulate cartilage resorption, although the maximum degree of tissue breakdown rarely reached the levels obtained when cartilage was treated with crude mononuclear-cell conditioned medium or all-trans retinoic acid (1 microM) over a similar time course. Levels of plasminogen activator (PA) activity, a neutral proteinase which may contribute to cartilage destruction in arthritis, increased markedly in the cartilage/chondrocyte culture supernatants and in the chondrocyte cell layers in response to the stimulation of cultures with recombinant IL-1 (1-100 U/ml). Elevated levels of PA activity were detectable after 4-8 h stimulation of the chondrocytes with IL-1 while characterization of the PA activities indicated that both types of PA activity were expressed, viz. urokinase-type PA (u-PA) and tissue-type PA (t-PA). Both IL-1 alpha and IL-1 beta could elicit these responses and their effects were comparable for a given dose. These studies show definitively that pure IL-1, free from contaminating cytokines, is capable of inducing human cartilage resorption and stimulating the expression of two types of PA activity by chondrocytes. In contrast to IL-1, retinoic acid increased the detectable levels of only u-PA in the chondrocyte cell layers. Chondrocyte u-PA may have an important role in cartilage degradative processes since it is one of the few neutral proteinases now known to be increased in activity in retinoid-stimulated cartilage.

Adult↗

PubMed1988

Synergistic activation of human monocytes by granulocyte-macrophage colony-stimulating factor and IFN-gamma. Increased TNF-alpha but not IL-1 activity.

TNF-alpha and IL-1 activities and PGE2 levels were investigated in the supernatants of highly purified human monocytes cultured for 18 h with recombinant human granulocyte-macrophage CSF (GM-CSF). GM-CSF alone did not stimulate IL-1 or TNF-alpha activities or the production of PGE2. GM-CSF with IFN-gamma, but not with LPS, consistently activated the monocytes for TNF-alpha activity. In contrast, for increased IL-1 activity, GM-CSF synergized weakly and irregularly with LPS, but not at all with IFN-gamma. For the third monocyte product investigated, GM-CSF was a weak and inconsistent inducer of PGE2 and only in the co-presence of IFN-gamma. Thus, GM-CSF can elicit different responses in human monocytes depending both on the co-stimulus as well as the monocyte product being investigated.

Colony-Stimulating Factors↗

PubMed1988

Ionization and phase behavior of fatty acids in water: application of the Gibbs phase rule.

The phase behavior of several medium-chain (10- and 12-carbon) and long-chain (18-carbon) fatty acids in water was examined as a function of the ionization state of the carboxyl group. Equilibrium titration curves were generated above and below fatty acid and acid-soap chain melting temperatures and critical micelle concentrations, and the phases formed were characterized by X-ray diffraction, 13C NMR spectroscopy, and phase-contrast and polarized light microscopy. The resulting titration curves were divided into five regions: (i) at pH values less than 7, a two-phase region containing oil or fatty acid crystals and an aqueous phase; (ii) at pH approximately 7, a three-phase region containing oil, lamellar, and aqueous (or fatty acid crystals, 1:1 acid-soap crystals, and aqueous) phases; (iii) between pH 7 and 9, a two-phase region containing a lamellar fatty acid/soap (or crystalline 1:1 acid-soap) phase in an aqueous phase; (iv) at pH approximately 9, a three-phase region containing lamellar fatty acid-soap (or crystalline 1:1 acid-soap), micellar, and aqueous phases; and (v) at pH values greater than 9, a two-phase region containing micellar and aqueous phases. Interpretation of the results using the Gibbs phase rule indicated that, for oleic acid/potassium oleate, the composition of the lamellar fatty acid/soap phase varied from approximately 1:1 to 1:3 un-ionized to ionized fatty acid species. In addition, constant pH regions observed in titration curves were a result of thermodynamic invariance (zero degrees of freedom) rather than buffering capacity. The results provide insights into the physical states of fatty acids in biological systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty Acids, Nonesterified↗

PubMed1988

Interactions of oleic acid with liver fatty acid binding protein: a carbon-13 NMR study.

13C NMR spectroscopy was used to probe the structural interactions between carboxyl-13C-enriched oleic acid (18:1) and rat liver fatty acid binding protein (FABP) and the partitioning of 18:1 between FABP and unilamellar phosphatidylcholine (PC) vesicles. Spectra of systems containing 2-8 mol of 18:1/mol of FABP (but no PC) exhibited one carboxyl resonance (182.2 ppm) corresponding to FABP-bound 18:1. At pH values less than 8.0, an additional carboxyl resonance, corresponding to unbound 18:1 in a lamellar phase, was observed. Both resonances exhibited ionization shifts with estimated apparent pKa values of less than 5 (bound 18:1) and greater than 7 (unbound 18:1). The intensity of the resonance corresponding to FABP-bound 18:1 increased with increasing 18:1/FABP mole ratio and at 8/1 mole ratio indicated that at least 2 and 6 mol of 18:1/mol of FABP were FABP-bound at pH 7.4 and 8.6, respectively. NMR spectra of systems containing equal concentrations (w/v) of FABP and PC and from 1 to 4 mol of total fatty acid (FA)/mol of FABP exhibited two 18:1 carboxyl resonances (182.2 and 178.5 ppm, pH 7.4). The downfield resonance corresponded to FABP-bound 18:1 and the upfield resonance to PC vesicle bound 18:1. At 1/1 mole ratio (FA/FABP), the intensities of both resonances were approximately equal, but at 4/1 mole ratio the resonance for PC vesicle bound 18:1 was 3-fold more intense than that for FABP-bound 18:1. The following conclusions are reached: (i) The carboxyl groups of 18:1 bound to liver FABP experience only one type of binding environment (the aqueous milieu adjacent to the protein surface).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

The ionization and distribution behavior of oleic acid in chylomicrons and chylomicron-like emulsion particles and the influence of serum albumin.

A reproducible, fairly narrow-sized population of rat lymph chylomicrons, approximately 100 nm, was isolated by centrifugation and combined with low levels of [1-13C]oleic acid for NMR studies. The carboxyl chemical shift was monitored as a function of aqueous pH to characterize the ionization behavior of the fatty acid in these particles. The titration curves were very similar to those for oleic acid in equivalent-sized emulsion particles composed of egg phosphatidylcholine and triolein. A simple partition-ionization model was fitted to the data to derive values for apparent ionization constant, expressed as pKapp, of 7.4-7.5 and the "true" surface to core partition coefficient of approximately 7 for oleic acid in chylomicrons. The fatty acid in chylomicrons thus appeared to be largely associated with the surface regions of these particles. Addition of bovine serum albumin to the samples showed that near physiologic pH much of the fatty acid was bound to the albumin at fatty acid to albumin-binding stoichiometries as high as 5.1 and with mass ratios of greater than 2 in favor of the lipid or lipoprotein particles. Lowering the pH of the medium shifted the distribution of fatty acid away from albumin so that at pH 5 with the emulsion, virtually all the fatty acid was associated with the lipid. The behavior observed under physiologic conditions is consistent with the rapid clearance and redistribution of fatty acid generated in these particles by lipolytic processes. However, under conditions of severe acidosis, hyperlipidemia, and hypoalbuminemia a significant portion of fatty acids might be retained in triglyceride-rich lipoproteins and their remnants and affect subsequent metabolism.

Algorithms↗

PubMed1988

Modulation of urokinase-type plasminogen activator messenger RNA levels in human synovial fibroblasts by interleukin-1, retinoic acid, and a glucocorticoid.

Previous studies have shown that mononuclear cell-conditioned medium (MCCM), interleukin-1 (IL-1), and all-trans-retinoic acid rapidly stimulate, while glucocorticoids lower, the urokinase-type plasminogen activator (u-PA) activity of human synovial fibroblast-like cells. It is now reported that MCCM, recombinant human IL-1 alpha (rHuIL-1 alpha), rHuIL-1 beta, and all-trans-retinoic acid elevate the u-PA messenger RNA (mRNA) levels to a steady-state value within 2 hours, while dexamethasone (10(-7)M) inhibits this increase. For both situations, when the u-PA activity is either stimulated or reduced, the changes in the u-PA mRNA levels parallel the changes in the u-PA activity, and it is suggested that modulation of gene transcription plays an important role.

Cells, Cultured↗

PubMed1988

Stimulation of the hyaluronic acid levels of human synovial fibroblasts by recombinant human tumor necrosis factor alpha, tumor necrosis factor beta (lymphotoxin), interleukin-1 alpha, and interleukin-1 beta.

Monocyte/macrophage polypeptides (monokines) alter the properties of synovial cells. This interaction could explain some of the properties of the inflamed synovium in rheumatic disease. Only recently has it been possible to test the action of purified monokines on the target synovial cells. We report here that recombinant human tumor necrosis factor alpha, tumor necrosis factor beta (lymphotoxin), interleukin-1 alpha, and interleukin-1 beta stimulate the hyaluronic acid (HA) levels of human synovial fibroblast-like cells. The effect of monokines was generally inhibited by indomethacin, suggesting the involvement of an endogenous cyclooxygenase product in the stimulation, and by the glucocorticoid, dexamethasone. In contrast, all-trans-retinoic acid stimulated synovial cell plasminogen activator activity but did not increase the HA levels. These findings could help to explain the raised HA levels found in the joint fluids and in the circulation of patients with rheumatic disease.

Dexamethasone↗

PubMed1988

Activation and proliferation signals in murine macrophages: stimulation of Na+,K+-ATPase activity by hemopoietic growth factors and other agents.

Purified colony stimulating factor (CSF-1) stimulates the Na+,K+-ATPase activity of murine bone marrow-derived macrophages (BMM) and resident peritoneal macrophages (RPM) measured as ouabain-sensitive 86Rb+ uptake. Similar concentrations of CSF-1 stimulate the Na+,K+-ATPase activity and DNA synthesis in BMM whilst ouabain, a specific inhibitor of the Na+,K+-ATPase, also inhibits this CSF-1-mediated DNA synthesis. Other purified hemopoietic growth factors, granulocyte-macrophage CSF (GM-CSF) and interleukin-3 (IL-3), and the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), even though differing in their mitogenic capabilities, are also stimulators of the Na+,K+-ATPase activity in BMM and RPM. The non-mitogenic agents, lipopolysaccharide (LPS) and Concanavalin A (Con A), are also active. CSF-1 stimulation of the Na+,K+-ATPase was shown to be dependent on elevation of intracellular Na+ via an amiloride sensitive Na+-channel, most likely representing Na+/H+ exchange activity. Such stimulation of Na+,K+-ATPase activity via activation of the Na+/H+ exchange appears to be a necessary but insufficient early macrophage response for subsequent DNA synthesis.

Animals↗

PubMed1988

Activation and proliferation signals in murine macrophages: stimulation of glucose uptake by hemopoietic growth factors and other agents.

Purified colony-stimulating factor (CSF-1) (or macrophage colony stimulating factor [M-CSF]) stimulated the glucose uptake of murine bone marrow-derived macrophages (BMM) and resident peritoneal macrophages (RPM) as measured by 3H-2-deoxyglucose (2-DOG) uptake. Similar concentrations of CSF-1 stimulated the 2-DOG uptake and DNA synthesis in BMM. Other purified hemopoietic growth factors, granulocyte-macrophage CSF (GM-CSF) and interleukin-3 (IL-3) (or multi-CSF), and the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), even though differing in their mitogenic capabilities on BMM, were also stimulators of 2-DOG uptake in BMM and RPM. The nonmitogenic agents, lipopolysaccharide (LPS) and concanavalin A (Con A), were also active. The inhibition by cytochalasin B and by high concentrations of D-glucose suggest that the basal and stimulated 2-DOG uptake occurred via a carrier-facilitated D-glucose transport system. The responses of the two macrophage populations to the hemopoietic growth factors and to the other agents were quite similar, suggesting that events that are important for the induction of DNA synthesis are not tightly coupled to the earlier rise in glucose uptake. For the BMM, the ability of a particular agent to stimulate glucose uptake did not parallel its ability to promote cell survival. However, stimulation of glucose uptake could still be a necessary but insufficient early macrophage response for cell survival and subsequent DNA synthesis.

Animals↗

PubMed1988

Secondary and tertiary structure of apolipoproteins.

The advent of these and other high-powered techniques for the detailed study of apoLP organization will allow us to obtain a high resolution picture of apoLP conformation both in solution and on native lipoprotein particles.

Apolipoproteins↗