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Biomedical subjects

M P Carroll

Publications and source records attributed to M P Carroll.

16 recordsLinked to original sources
PubMed1995

Efficacy of radioprotective agents in preventing small and large bowel radiation injury.

PURPOSE: A variety of adjuvant treatments and cytoprotective agents have been proposed to lessen the toxicity of radiation therapy. The following study was designed to evaluate the benefit of six agents or combinations using anastomotic bursting strength as a measure of transmural radiation injury. METHODS: The 40-Gy study consisted of the following. Seventy-two male Sprague-Dawley rats were divided into eight equal groups: nonradiated control, radiated untreated control, and six radiated treated groups. The radioprotective treatments included ribose-cysteine (Rib-Cys), WR-2721, glutamine, vitamin E, MgCl2/adenosine triphosphate, and RibCys/glutamine in combination. Radiated animals received 40 Gy to the abdomen. Two weeks after radiation, all animals underwent small bowel and colonic resection with primary anastomosis. Animals were sacrificed one week postoperatively, at which time anastomoses were evaluated and bursting strengths determined. The 70-Gy study consisted of the following. The same protocol was repeated for five groups of nine rats divided into nonradiated, radiated untreated, and three radiated treated groups receiving RibCys (8 mmol/kg), RibCys (20 mmol/kg), and WR-2721. All radiated animals received 70-Gy doses. RESULTS: In the 40-Gy group, there were 10 radiation-related deaths and 6 anastomotic leaks among 70 rats studied. None of the differences between groups were significant. Nonradiated control group small bowel and large bowel anastomotic bursting pressures were significantly elevated compared with all radiated groups. Compared with radiated controls, there were significant improvements in small bowel bursting strength in the RibCys, WR-2721, RibCys-glutamine, and vitamin E groups and significant improvement in colonic bursting strength in MgCl2/adenosine triphosphate, WR-2721, and RibCys groups. In the 70-Gy group, all nine nonradiated control rats survived. All eight untreated radiated control rats died, four of eight WR-2721 animals died (P = 0.03), all RibCys (8 mmol/kg) animals died (P = 0.03), and three of nine treated with RibCys (20 mmol/kg) survived (P = 0.08). CONCLUSIONS: WR-2721 and RibCys gave consistent protection against large and small bowel radiation injury. The lower incidence of treatment-related toxicity and potentially equal or greater radioprotective effects may make RibCys more clinically useful than WR-2721.

Adenosine Triphosphate↗
PubMed1995

Early identification of interleukin-16 (lymphocyte chemoattractant factor) and macrophage inflammatory protein 1 alpha (MIP1 alpha) in bronchoalveolar lavage fluid of antigen-challenged asthmatics.

Accumulation of CD4+ interleukin (IL)-2R+ lymphocytes in the airways of asthmatics is generally attributed to the presence of chemoattractant cytokines. The precise mechanism for the initiation of the earliest CD4+ lymphocyte infiltration and activation is unknown. In this study, we describe for the first time the presence of lymphocyte chemoattractant activity in the bronchoalveolar lavage (BAL) fluid obtained from asthmatics 6 h after antigen challenge. The majority of the chemoattractant activity at this early time point is represented by IL-16 (lymphocyte chemoattractant factor), a CD4+ cell-specific chemoattractant and growth factor. In addition to IL-16, macrophage inflammatory protein 1 alpha (MIP1 alpha) chemotactic bioactivity was detected in significant levels. While IL-16, MIP1 alpha, and IL-8 were all identified by enzyme-linked immunosorbent assay, the great majority of the lymphocyte chemoattractant activity in the BAL fluid after antigen challenge is attributable to IL-16 and MIP1 alpha. There were no detectable levels of IL-16 nor MIP1 alpha in BAL fluid of antigen-challenged normal subjects nor atopic nonasthmatics nor in saline-challenged lobes from the asthmatics. The identification of multiple lymphocyte chemoattractants early after antigen challenge suggests a complex cellular, as well as chemoattractant cytokine, profile in initiating the CD4+ T cell-mediated inflammatory process that is specific for the atopic asthmatic phenotype.

Adult↗
PubMed1994

Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways.

We have examined the mucosal changes occurring in bronchial biopsies from six atopic asthmatics 5-6 h after local endobronchial allergen challenge and compared them with biopsies from saline-challenged segments from the same subjects at the same time point. All the subjects developed localized bronchoconstriction in the allergen-challenged segment and had a decrease in forced expiratory volume in 1 s (FEV1) (P < 0.01) and a decrease in their methacholine provocative concentration of agonist required to reduce FEV1 from baseline by 20% (P < 0.05) 24 h postchallenge. At 6 h we observed an increase in neutrophils (P = 0.03), eosinophils (P = 0.025), mast cells (P = 0.03), and CD3+ lymphocytes (P = 0.025), but not in CD4+ or CD8+ lymphocyte counts. We also detected an increase in endothelial intercellular adhesion molecule type 1 (P < 0.05) and E-selectin (P < 0.005), but not vascular cell adhesion molecule type 1 expression with a correlative increase in submucosal and epithelial LFA+ leucocytes (P < 0.01). Thus, in sensitized asthmatics, local endobronchial allergen instillation leads to an increased inflammatory cell infiltrate of the airway mucosa that involves upregulation of specific adhesion molecules expressed on the microvasculature.

Adult↗
PubMed1992

Domiciliary nocturnal nasal intermittent positive pressure ventilation in hypercapnic respiratory failure due to chronic obstructive lung disease: effects on sleep and quality of life.

BACKGROUND: Domiciliary assisted ventilation, using negative or positive pressure devices, is an effective treatment for respiratory failure due to chest wall deformity and neuromuscular disease. Negative pressure ventilators have been used with some success in patients with chronic obstructive lung disease in hospital, but attempts to continue treatment at home have been disappointing. This study evaluates the practicalities of nasal intermittent positive pressure ventilation at home in patients with chronic obstructive lung disease and the effect on sleep and quality of life. METHODS AND RESULTS: Twelve patients with chronic obstructive lung disease and hypercapnic respiratory failure received nasal intermittent positive pressure ventilation at home during sleep. At six months eight were continuing with the ventilation. One patient had died and three had withdrawn because they were unable to sleep with the equipment. Full polysomnography performed during ventilation in patients continuing treatment at six months showed an increase in mean PaO2 of 11% (+2% to +23%) and lower mean transcutaneous carbon dioxide tensions (by -2.7 (-1.3 to -5.1) kPa) overnight compared with spontaneous breathing before the start of nasal intermittent positive pressure ventilation. Total sleep time and sleep efficiency changed during ventilation by +72.5 (+21 to +204) minutes and +5% (-3% to +30%) respectively; sleep architecture and the number of arousals were unchanged. Quality of life did not change but was no worse during ventilation. At one year seven patients were still using the ventilator and PaCO2 and bicarbonate ion concentration during the day had improved further by comparison with the values at six months (change from baseline -1.7 (-2.1 to -0.6) kPa, p less than 0.05, and -6.3 (-11.9 to -4) mmol/l, p less than 0.05). CONCLUSIONS: Nasal intermittent positive pressure ventilation can be used effectively at home during sleep in selected patients with chronic obstructive lung disease. Its future place in management can be established only by formal comparison with long term oxygen therapy.

Female↗
PubMed1992

Four interleukin-2 surface binding proteins detected in rat spleen cells.

Four specific interleukin-2 (IL-2) surface binding proteins can be detected by covalent cross-linking of [125I]IL-2 to rat spleen cells that have been activated with various stimuli including concanavalin A (Con A), phytohaemagglutinin (PHA), calcium ionophore, and phorbol dibutyrate (PDB) with or without calcium ionophore. These four cross-linked proteins could not be demonstrated in either unstimulated T cells or in activated T cells when binding was performed in the presence of a 20-100-fold excess of unlabelled IL-2. The molecular weights of the four cross-linked proteins, after subtraction of the molecular weight contribution of IL-2 are: 53,000, 70,000, 90,000 and 118,000. The 53,000 MW protein was identified as the rat IL-2 receptor (IL-2R) alpha-chain by immune precipitation. Additionally, results suggest that the rat IL-2R alpha-chain is tightly complexed to both the 118,000 and 90,000 MW IL-2 binding proteins. Purification of surface labelled proteins from activated cells using IL-2 affinity chromatography yields four proteins with similar molecular weight to those identified by cross-linking plus an additional non-ligand cross-linked protein of 46,000 MW. The 46,000 MW band may be a non-binding associated protein since it was not seen following [125I]IL-2 binding cross-linking. Tryptic digests and two-dimensional separation of the affinity-isolated proteins indicate that unique peptide maps are generated for the 46,000, 53,000 and 70,000 MW proteins and excludes the possibility that the bands identified by cross-linking represents cross-linking of multiple ligands to the 53,000 MW subunit. However, the 90,000 and 118,000 MW bands yield peptide maps that closely resemble each other suggesting that these binding proteins may be related. These results suggest that at least four IL-2 surface binding proteins may constitute the rat IL-2R system.

Animals↗
PubMed1991

Erythropoietin induces Raf-1 activation and Raf-1 is required for erythropoietin-mediated proliferation.

Erythropoietin mediates the rapid phosphorylation of Raf-1 in the murine cell lines HCD-57 and FDC-P1/ER, which proliferate in response to this cytokine. Phosphorylation occurs at both serine and tyrosine residues and as such is similar to the Raf-1 phosphorylation seen after interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and interleukin-2 stimulation in other murine cell lines. Such data suggest that these growth factors may share a common mechanism(s) of Raf-1 phosphorylation. Furthermore, in association with Raf-1 phosphorylation, erythropoietin induces a 2-3-fold increase in Raf-1 kinase activity as measured in immune complex kinase assays in vitro. Finally, a c-raf antisense oligodeoxyribonucleotide, which specifically decreases intracellular Raf-1 levels, also substantially inhibits both erythropoietin and IL-3-directed DNA synthesis. Together, these results provide evidence that activated Raf-1 is a necessary component of erythropoietin and IL-3 growth signaling pathways.

Animals↗
PubMed1991

Sniff esophageal and nasopharyngeal pressures and maximal relaxation rates in patients with respiratory dysfunction.

Sniff esophageal pressure (Pes) and maximal relaxation rate (MRR, percent pressure loss/10 ms) are useful measurements of inspiratory muscle performance, but they require the passage of an esophageal balloon. We have examined the relationship between sniff esophageal and nasopharyngeal pressures (sniff Pes, sniff Pnp) and maximal relaxation rates (Pes MRR, Pnp MRR) in 13 patients with chronic obstructive pulmonary disease (COPD), five with intrapulmonary fibrosis (IPF), and seven with the "shrinking lung syndrome" of systemic lupus erythematosus (SLE). The ratio sniff Pnp/Pes (mean +/- SD) was 0.65 +/- 0.15 in COPD, 0.76 +/- 0.18 in IPF, and 0.91 +/- 0.03 in SLE. The ratio Pnp/Pes MRR was 1.20 +/- 0.2 in COPD, 1.14 +/- 0.12 in IPF, and 1.07 +/- 0.13 in SLE. We confirm that the transmission of pleural pressure to the upper airways during brief dynamic maneuvers is impaired in the presence of airway obstruction and lung fibrosis. We conclude that measurements of sniff Pnp and Pnp MRR are of limited value in patients with abnormal lung mechanics.

Adult↗
PubMed1990

Interleukin-3 and granulocyte-macrophage colony-stimulating factor mediate rapid phosphorylation and activation of cytosolic c-raf.

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor induce the rapid phosphorylation of the c-raf protein in the growth factor-dependent FDC-P1 and DA-3 murine myeloid cell lines. Furthermore, immunoprecipitates of c-raf isolated from growth factor-stimulated cells demonstrate a marked increase in intrinsic protein kinase activity as measured in vitro. IL-3 and granulocyte-macrophage colony-stimulating factor induce phosphorylation of c-raf at both serine and tyrosine residues. Antiphosphotyrosine immunoprecipitates from IL-3-stimulated cells demonstrate the rapid and coordinate phosphorylation of both c-raf and a protein co-migrating with the 140-kDa putative IL-3 receptor component. Collectively, the findings of rapid and coordinate ligand-induced phosphorylation of a potential IL-3 growth factor receptor component and cytoplasmic c-raf with concomitant c-raf activation provide a cogent sequential molecular model for linking external growth stimuli to intracellular signal transduction events.

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↗
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↗
PubMed1985

Activation of neutrophils and monocytes after allergen- and histamine-induced bronchoconstriction.

To determine whether neutrophils and monocytes are activated after allergen-induced asthma, changes in the expression of complement (C3b) receptors were measured by use of the rosette technique. There was a time-dependent increase in the percentages of neutrophil and monocyte rosettes in 13 asthmatic patients for up to 60 min after allergen-inhalation challenge. This was preceded by elevations in the concentrations of serum neutrophil chemotactic activity and reductions in the FEV1. These changes were not observed in seven asthmatic patients who had histamine-induced bronchoconstriction. The present findings support the view that inflammatory cells are activated after allergen-induced asthma and that this may be the result of the release of mast cell-associated mediators rather than the consequence of bronchoconstriction per se.

Adult↗
PubMed1984

Receptor associated defects of cultured monocytes in bronchial carcinoma.

Using peripheral blood monocytes from individuals with bronchial carcinoma (BC) we have measured changes, over an 8 day culture period, in monocyte/macrophage complement (C3b) and IgG (Fc) rosettes, chemotactic factor (CF)-induced enhancement of C3b and IgG (Fc) rosettes, and the phagocytic index (PI) for yeast particles. The same measurements were made on monocyte/macrophages from individuals with non-malignant respiratory diseases (NMRD) and healthy controls (HC). Following 8 days of culture there was a significant increase in C3b rosettes, IgG (Fc) rosettes and the PI in NMRD and HC. In contrast there was no significant increase in C3b rosettes in BC. The PI increased in BC, but on day 8 was still significantly less than control monocytes/macrophages. IgG (Fc) rosettes increased in BC following culture to a similar degree as that observed with NMRD and HC. In addition, there were no differences between BC and HC in CF-induced enhancement of IgG (Fc) rosettes at either day 0 or day 8 of culture whereas complement receptor enhancement in BC was impaired both at the beginning and end of the 8 day culture period. These results indicate that in advanced BC there is an abnormality in the expression of monocyte/macrophage complement receptors (which is not readily demonstrable for IgG [Fc]receptors) and that the defect persists following an 8 day culture period.

Adult↗