PubMed Health⌕ Search

Biomedical subjects

A J MacDonald

Publications and source records attributed to A J MacDonald.

17 recordsLinked to original sources
PubMed1990

Effects of inhaled PAF in humans on circulating and bronchoalveolar lavage fluid neutrophils. Relationship to bronchoconstriction and changes in airway responsiveness.

We have compared the effect of inhaled platelet activating factor (PAF) on circulating neutrophils with its ability to induce bronchoconstriction and bronchial hyperresponsiveness in humans. Human volunteers inhaled PAF, given as six successive inhalations 15 min apart, followed by bronchoalveolar lavage (BAL) 4 h later. The mean density and volume of circulating neutrophils were measured by metrizamide gradients and flow cytometry, respectively. PAF caused a decrease in Vp20 of 38.2 +/- 4.5% at 5 min after the first inhalation (p less than 0.001). This was associated with a fall in the peripheral blood neutrophil count from 3.15 +/- 0.3 to 1.1 +/- 0.3 x 10(6) per ml (p less than 0.001), followed by a rebound neutrophilia (p less than 0.01). The mean density of peripheral blood neutrophils fell significantly at 15 min (p less than 0.02), with a return to baseline values despite further PAF inhalations; this was associated with an increase in neutrophil volume (n = 4; p less than 0.05). The numbers of neutrophils (x 10(5] in BAL fluid after PAF were significantly greater than after inhalation of lyso-PAF: 7.1 +/- 1.4 (n = 7) versus 1.3 +/- 0.3 (n = 5, p less than 0.01); eosinophil counts did not change significantly. The PC40 (the concentration of methacholine needed to cause a fall in Vp30) decreased from 17.1 (GSEM 1.40) to 8.7 (1.44) mg/ml (n = 12, p less than 0.02) 3 days after PAF. Inhaled lyso-PAF was inactive in all these respects.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

The effect of platelet-activating factor on IgE binding to, and IgE-dependent biological properties of, human eosinophils.

This study investigated the effect of platelet-activating factor (PAF), leukotriene B4 (LTB4) histamine and formyl-methionyl-leucyl-phenylalanine (FMLP) on immunoglobulin E (IgE) binding and IgE-dependent cytotoxicity of human normal density eosinophils. The binding of a native myeloma IgE to normal human eosinophils was measured by flow cytometry using a fluorescein-conjugated polyclonal anti-IgE antibody. Preincubation with PAF (optimal at 10(-7)M), but not lyso-PAF or FMLP, gave dose-dependent increases in IgE binding. PAF and LTB4 gave significant increases in IgE binding after 5 min preincubation (P less than 0.05); the effect was further enhanced at 30 min (P less than 0.01). This was further confirmed using the rosette assay where PAF and LTB4, but not lyso-PAF or FMLP, gave dose- and time-dependent increases in IgE eosinophil rosettes. Eosinophil cytotoxicity for schistosomula of Schistosoma mansoni, incubated with immune serum, was also significantly enhanced (P less than 0.01) by PAF in a dose-dependent fashion (optimal at 10(-8) M). Schistosomula coated with FPLC-purified IgE fractions were susceptible to killing by normal density eosinophils, and this was enhanced with PAF (10(-8)M), LTB4 (10(-7)M) and histamine (10(-5)M) but not with FMLP (10(-7)M) or lyso-PAF. IgE-dependent cytotoxicity was confirmed by the removal of contaminating IgG from IgE-rich fractions, and by the abolishment of IgE-dependent cytotoxicity after IgE adsorption. These results suggest that PAF (and to a lesser extent LTB4 and histamine) increase IgE binding, IgE-dependent adherence and cytotoxicity of normal human eosinophils. Although IgE receptors have not been identified, the data support current concepts that certain biological properties of eosinophils may be IgE associated.

Cells, Cultured↗
PubMed1989

IgE-mediated release of rat mast cell protease II, beta-hexosaminidase and leukotriene C4 from cultured bone marrow-derived rat mast cells.

Functional characteristics of cultured bone marrow-derived rat mast cells (BMMC) were studied. BMMC were shown to release in a time- and dose-dependent fashion the mucosal mast cell (MMC)-specific enzyme, rat mast cell protease II (RMCPII), following IgE-mediated activation in vitro. RMCPII release was temporally associated with that of the mast cell granule-derived enzyme, beta-hexosaminidase (beta-hex). Release of the pre-formed granule constituents, RMCPII and beta-hex, was associated with the generation of the membrane-derived lipid mediator, leukotriene C4 (LTC4) and, in older cultures, substantial amounts were generated (25.2 ng/10(6) BMMC). Absolute amounts of RMCPII, beta-hex and LTC4 released were dependent upon the age of the BMMC. These results extend our previous observations on the staining properties and protease content of rat BMMC and provide evidence that these cells are functionally, as well as histochemically, analogous to the MMC subset, which is so prominent during intestinal nematode infections in rats.

Animals↗
PubMed1987

Disodium cromoglycate inhibits activation of human inflammatory cells in vitro.

Recent clinical studies indicate that disodium cromoglycate (DSCG) may have a direct effect on inflammatory cells because the drug reversed various changes in leukocyte function, such as increased membrane-receptor expression and enhanced cytotoxic capacity observed in peripheral white blood cells from subjects with asthma undergoing allergen-inhalation challenge. In the present study, we have demonstrated that DSCG, at low concentrations (a concentration of drug required to produce 50% inhibition, approximately 10(-8) mol/L) and in a time-dependent fashion, directly inhibited the activation in vitro of human neutrophils, eosinophils, and monocytes. Peripheral blood leukocytes were incubated with the synthetic chemoattractant, formyl-methionyl-leucyl-phenylalanine (at an optimal concentration of 10(-8) mol/L), and activation was assessed by measuring increases in the percentages of complement and IgG (Fc) rosettes as well as the enhanced capacity of these cells to kill target organisms (schistosomula of Schistosoma mansoni). DSCG at a concentration of 10(-7) mol/L totally inhibited both the formyl-methionyl-leucyl-phenylalanine-induced enhancement of complement and IgG rosettes, as well as increased schistosomular killing. These observations indicate that DSCG directly inhibits the secretory properties of inflammatory cells and that in turn might have important implications in modulating mechanisms contributing to the inflammatory component of asthma and allergic disease. It may also help to explain why compounds with considerably greater mast cell stabilizing properties than DSCG have been so disappointing when they are evaluated clinically.

Cromolyn Sodium↗
PubMed1987

Chemotactic factor-induced low density neutrophils express enhanced complement (CR1 and CR3) receptors and increased complement-dependent cytotoxicity.

We have studied chemotactic factor-induced 'complement receptor enhancement' to determine whether changes in receptor expression and complement-dependent cytotoxicity were associated with alterations in cell density. Ficoll-Paque separated normal human neutrophils (greater than 90%), when further fractionated on discontinuous metrizamide (MTZ) gradients (18, 19, 20, 21, 22, 23% MTZ), consistently gave two major bands at the 20/21% and 21/22% interfaces. Incubation with the synthetic chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP (10(-8) M)), converted virtually all neutrophils to low density cells sedimenting on MTZ at the 18/19% and 19/20% interfaces. There was a time-dependent change of density after fMLP-stimulation which was maximal at 30 min, with cells reverting towards normal density by 60 min. Control unstimulated cells did not alter their density at any of the time points examined. Activated, low density neutrophils had increased expression of CR1 and CR3 (as shown by flow cytometry and the uptake of 125I-F(ab')2 monoclonal anti-CR1 antibody (E11)). These cells also showed enhanced cytotoxic capacity in vitro for helminthic targets (schistosomula of Schistosoma mansoni) opsonized with autologous complement. There were highly significant correlations between cell density and anti-CR1 uptake (P less than 0.001), and between schistosomular killing and change in density (P less than 0.001). Increased CR1 expression also correlated with enhanced helminthicidal capacity of neutrophils (P less than 0.001). Complement dependent cytotoxicity was partially reduced after treatment of cells with anti-human CR1 and/or CR3 antibodies, but only in the presence of a second antibody. These findings indicate that chemotactic factor-induced complement receptor enhancement of human neutrophils is associated with a decrease in cell density and increased complement-dependent cytotoxicity (CTX).

Animals↗
PubMed1987

Release of leukotrienes during rapid expulsion of Trichinella spiralis from immune rats.

Rapid expulsion of the nematode Trichinella spiralis from immune rats is associated with an increase in volume of intestinal exudate and the presence of large numbers of tissue mucosal mast cells (MMC) and eosinophils. We have measured the concentrations of leukotrienes (LT) C4 (LTC4) and B4 (LTB4) in gut perfusates and mucosal homogenates at 30 min, 1, 3, 6 and 20 hr after challenge with larvae. Leukotrienes were identified by radioimmunoassay (RIA) combined with reverse-phase high-pressure liquid chromatography (RP-HPLC). There were significant elevations at 30 min and 1 hr in the concentrations of LTC4 in the perfusates from the gut of challenged immune rats compared to controls (infected unchallenged and uninfected naive rats). Similar increases in immunoreactive LTC4 and LTB4 were observed in mucosal homogenates from the gut of immune challenged animals. A second peak of LTB4 was also observed at 20 hr in both immune and naive challenged rats. There were also elevations in serum concentration of the MMC-associated specific serine protease, rat mast cell protease II (RMCPII). Since LTC4 causes smooth muscle contraction, increased vascular permeability and stimulation of mucus hypersecretion, and LTB4 recruits and activates inflammatory cells, leukotrienes may participate in the process of rapid expulsion of T. spiralis.

Animals↗
PubMed1986

Enteral and systemic release of leukotrienes during anaphylaxis of Nippostrongylus brasiliensis-primed rats.

Rats with acquired immunity to the intestinal nematode Nippostrongylus brasiliensis develop anaphylaxis after i.v. challenge with an extract of worm antigen, with the small intestine being the primary shock organ. In the present study we have shown that these events were associated with significant elevations in intestinal and plasma concentrations of leukotrienes LTB4 and LTC4. The changes were observed in immune rats over 10-, 30-, and 60-min intervals after antigen challenge but were absent in control animals. These lipid mediators were identified both in the perfusate of the gut lumen, which contained large quantities of mucus, and in homogenates of intestinal tissue. In addition, significant elevations in the concentrations of plasma LTB4 and LTC4 were detected in immune challenged rats but not in controls. Leukotrienes were identified by radioimmunoassay and validated by reverse-phase high-performance liquid chromatography (RP-HPLC). RP-HPLC analysis of SRS-A leukotrienes in immune challenged rats indicated that LTC4 was the predominant sulfidopeptide leukotriene at 10 min, with almost complete biodegradation to LTD4 and LTE4 within 30 min. Infected rats also had significant increases in the numbers of intestinal mucosal mast cells (MMC) and eosinophils. Evidence of MMC activation during anaphylaxis was obtained by showing significant elevations of intestinal and systemic concentrations of their exclusive serine enzyme, rat mast cell proteinase II (RMCPII). Thus, the release of substantial amounts of leukotrienes in the gut and plasma of N. brasiliensis-primed rats after interaction with worm antigens suggests that these potent mediators may play an important role in allergic-type hypersensitivity known to occur during immune reactions against parasitic helminths.

Anaphylaxis↗
PubMed1986

Do general practitioners "miss" depression in elderly patients?

In a study of the prevalence of depression in 235 elderly patients who attended general practice surgeries less than 12% of the disagreement between the research assessment of depression and the general practitioner's assessment was due to "missed" depression. There were, however, low rates of referral and of treatment with antidepressant drugs. If these findings are confirmed the study of the management and outcome of depression in such patients may be more rewarding than attempts to improve the recognition of depression.

Adult↗
PubMed1986

Enhancement of leukocyte cytotoxicity after exercise-induced asthma.

We have previously shown that there were elevations of neutrophil chemotactic activity (NCA) and increases in the percentages of neutrophil and monocyte complement rosettes after exercise-induced asthma (EIA). These observations suggested that leukocyte activation may occur after EIA, possibly as a result of the release of mast-cell-associated mediators. In the present study, we have attempted to establish whether neutrophils and monocytes are functionally altered after EIA as assessed by changes in their cytotoxic capacity. Cytotoxicity was assessed by a direct visual killing assay using opsonized (complement-coated) schistosomula of Schistosoma mansoni as target organisms. Neutrophils and mononuclear cells obtained from 8 patients after exercise-induced asthma (EIA+ve) had increased cytotoxicity for opsonized schistosomula for as long as 60 min after exercise. These changes were preceded by elevations in the concentrations of serum high molecular weight NCA (which were maximal at 10 min after exercise). In asthmatic patients who did not develop exercise-induced asthma (EIA-ve), no significant increases in neutrophil or mononuclear cell killing of schistosomula, or serum NCA concentrations, were observed. There was a highly significant correlation (p less than 0.001) between the reduction in FEV1 and the increases in neutrophil cytotoxicity. In 5 EIA+ve patients, administration of disodium cromoglycate (cromolyn) prior to the exercise task inhibited both the enhancement in neutrophil and mononuclear cell cytotoxicity, as well as the elevations in circulating NCA and the reductions in FEV1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Enhanced granulocyte cytotoxicity by mediators derived from anti-IgE-stimulated human leucocytes.

Basophil-containing leucocyte fractions stimulated with an anti-human IgE, F(ab')2, generated histamine and the leukotrienes LTB4 and LTC4 with significant correlations between LTB4 and histamine (P less than 0.01; n = 26) and LTC4 and histamine release (P less than 0.001; n = 29) in the cell-free supernatants (SN). SN from these anti-IgE-treated cells enhanced the cytotoxicity of eosinophils and neutrophils (against complement-coated schistosomula of Schistosoma mansoni) in vitro. When SN were fractionated by reverse phase-high performance liquid chromatography (RP-HPLC), the enhancing activity for neutrophils was almost totally confined to fractions having LTB4 immunoreactivity (co-eluting as a single peak with the synthetic LTB4 marker). In contrast, the LTB4-containing fraction had minimal effects on eosinophil cytotoxicity, whereas synthetic histamine gave comparable enhancement to the unfractionated SN. The generation of LTs (but not histamine), as well as enhanced neutrophil cytotoxicity from basophil-containing leucocytes by anti-IgE treatment, was maximally inhibited by the 5-lipoxygenase inhibitors U-60, 257 and BW755C. Conversely, the cyclooxygenase inhibitor indomethacin did not significantly affect LT release, nor did it affect the subsequent cytotoxicity enhancing activity of SN from such cells. These results indicate that LTB4 and LTC4 are released from basophils, together with histamine, by IgE-dependent mechanisms, LTB4 enhances the cytotoxicity of bystander neutrophils, and histamine (and to a lesser extent, LTB4) augments eosinophil cytotoxicity.

Basophils↗
PubMed1985

Enhancement of human eosinophil- and neutrophil-mediated killing of schistosomula of Schistosoma mansoni by reversed type (IgE-mediated) anaphylaxis, in vitro.

Using human peripheral blood leucocytes we have developed a model for studying the effect of in vitro anaphylaxis on granulocyte-mediated killing of helminthic larvae (schistosomula (Sch) of Schistosoma mansoni). Leucocytes were incubated with either an F(ab')2 rabbit anti-human IgE (alpha E) or a control F(ab')2 prepared from non-specific rabbit IgG (alpha Ec). A time-dependent enhancement of eosinophil- and neutrophil-mediated complement (C) or antibody- (Ab) dependent killing of Sch was observed following incubation with alpha E, but not alpha Ec. Optimal enhancement of granulocyte killing was dependent on the concentration of alpha E, pre-incubation of granulocytes with alpha E prior to addition to C coated Sch, as well as the granulocyte: Sch ratio. Baseline killing of Ab and/or C coated Sch by eosinophil rich cells was significantly greater than neutrophil rich suspensions and both were proportionally increased following incubation with alpha E. Enhanced eosinophil and neutrophil killing by alpha E required the presence of mononuclear cells containing basophils, whereas there was no difference in the killing of C or Ab coated Sch when eosinophils or neutrophils alone were incubated with alpha E or alpha Ec. This IgE and leucocyte-dependent model might facilitate the isolation and identification of the pharmacological mediator(s) of hypersensitivity which enhance eosinophil or neutrophil killing of appropriately opsonized helminthic larvae.

Anaphylaxis↗
PubMed1977

Pharmacokinetic aspects of protriptyline plasma levels.

Plasma levels of protriptyline have been determined in 30 patients undergoing antidepressant therapy. After 3 1/2 weeks treatment at dosage levels of 40 mg/day, protriptyline plasma levels ranged from 430 to 1430 nmol/l. During this period only two-thirds of the subjects had definitely achieved asymptotic concentrations. Single dose studies in 5 volunteers suggest that the volume of distribution of protriptyline shows little intersubject variation. The half life of the drug, however, may vary appreciably from subject to subject, ranging from 54 to 198 h. The effects of two sedatives on mean protriptyline plasma levels have been determined. Mean plasma levels for nitrazepam recipients are indistinguishable from those for patients receiving no night sedation. The mean plasma levels for a group of patients receiving sodium amylobarbitone were significantly reduced. The problems of choice and early adjustment of dosages in order to achieve satisfactory plasma levels is discussed. For practical purposes it is suggested that early values may be of predictive significance in allowing early dosage adjustments to be made.

Administration, Oral↗
PubMedDate not supplied

Review: children and companion animals.

The literature concerning the relationship between the child and companion animal is reviewed including the possible use of companion animals as aids in the psychotherapy of children. The literature pertaining to cruelty to animals is also discussed. It is concluded that the evidence available is sufficient to justify further research into interactions between children and companion animals both in therapy and in the population generally, and some possible approaches are suggested.

Adolescent↗