PubMed Health⌕ Search

Biomedical subjects

C G Irvin

Publications and source records attributed to C G Irvin.

At least 91 records · Page 5Linked to original sources

Hard-rock mining exposures affect smokers and nonsmokers differently. Results of a community prevalence study.

The physiologic consequences of occupational dust exposure, their relation to smoking, and their reversibility with cessation of exposure remain controversial. To address these questions, we studied a random sample of male residents of Leadville, Colorado when the major employer, a hard-rock mine, had been closed for 5 to 11 months. Subjects were interviewed for respiratory symptoms and occupational history, underwent plethysmographic measurements of lung volume and airflow, and performed a single breath diffusing capacity procedure. Dyspnea was the only respiratory symptom exacerbated by mining exposures. Cumulative dust exposure, estimated with historic respirable dust measurements for mining job titles and weighted by time at the job, was associated with decreases in maximal expiratory flow rates when controlled for smoking, age, and height. However, determinations of plethysmographic lung volume that allowed calculation of flow rates at equivalent absolute lung volume indicated that dust effects differed in never-smokers and smokers. In never-smokers, dust exposure was associated with decreased lung volume, increased flow rates, and increased DLCO/VA. In smokers, dust exposure was associated with increased lung volume, lower flow rates, and lower DLCO/VA than that accounted for by smoking. We suggest that hard-rock mining exposures result in irreversible pulmonary function changes of airflow limitation in smokers and of a restrictive nature in never-smokers.

Adult↗

Preclinical studies of a perfluorochemical emulsion as an adjunct to radiotherapy.

Tumor growth and tumor cell survival endpoints were used to examine the effects of a perfluorochemical emulsion, Fluosol-DA, 20%, and carbogen (95% O2/5% CO2) on EMT6 mouse mammary tumors in BALB/c mice. These studies defined the effects of the Fluosol dose on the hematocrit and fluorocrit of the mice and on the radiation response of the tumors. The effect of varying the duration of carbogen breathing before irradiation was examined; times of 5-60 min gave similar enhancements of tumor radiosensitivity. Potentiating effects were not observed when the tumors were irradiated 1-3 days after Fluosol injection, probably reflecting the observed clearance of the perfluorochemicals from the circulating blood. Fluosol injected 30 min-2 days before irradiation did not alter the radiation response of tumors in air-breathing or N2-asphyxiated mice. Together, these studies provided additional support for the hypothesis that the potentiation of tumor radiation response observed after treatment with Fluosol plus carbogen results from changes in O2 delivery to the hypoxic tumor cells by oxygenated perfluorochemical particles. This confirms the conclusion drawn on the basis of the observed changes in the tumor cell survival curve. Studies of tumor cell survival, tumor cell yield, tumor growth, and artificial lung metastasis formation revealed no effects of Fluosol treatment (without irradiation) on tumor progression or metastasis. Studies examining the effects of Fluosol plus carbogen on the growth of tumors irradiated with 5 Gy showed that the changes in tumor radiosensitivity observed using cell survival endpoints also occurred in tumors left in situ after irradiation with a radiation dose similar to those used in some clinical trials.

Animals↗

Effects of the mode of administration of mitomycin on tumor and marrow response and on the therapeutic ratio.

The antineoplastic and toxic effects of mitomycin (MC) administered as a single pulse injection were compared with the effects of MC given as infusions over 2, 5, or 24 hours and with the effects of the drug administered in fractionated regimens incorporating 2-20 injections. The antineoplastic effects of MC were assessed using EMT6 mouse mammary tumors implanted in BALB/c mice; tumor response was assessed using both cell survival and tumor growth assays. The host toxicity of MC was assessed by measuring the survival of bone marrow stem cells (CFU-S) and by determining LD50/30's (which reflect primarily marrow injury). The survival curve for cells from tumors treated with varying doses of MC was exponential, with no shoulder which might suggest accumulation of sublethal lesions. No evidence was found that the tumor cells repaired MC damage when left in situ for up to 24 hours after treatment (repair of potentially lethal damage) or that the tumor repaired sublethal damage during times of up to 24 hours between drug treatments or during drug infusions. The responses of tumors treated with single injections of MC, with infusions over 2, 5, and 24 hours, with two injections separated by 5 or 24 hours, and with five daily injections were all similar. The survival curve for CFU-S from mice treated with varying doses of MC was exponential, with no shoulder which might suggest accumulation of sublethal lesions. LD50/30's were the same whether MC was administered as single injections, as infusions over 2, 5 or 24 hours, or as five daily fractions. Longer fractionated regimens, in which mice received daily injections, 5 days per week, for up to 4 weeks, produced less host toxicity but also less antineoplastic effect; the therapeutic ratio for the most protracted regimen tested was lower than that for single injections. The therapeutic ratios achieved with infusions and fractionated regimens were never greater than that obtained with a large single dose, confirming clinical impressions that infrequent, large doses of MC are an optimal method of treatment with this drug.

Animals↗

Reactions of tumors and normal tissues in mice to irradiation in the presence and absence of a perfluorochemical emulsion.

The effect of pre-treatment with the perfluorochemical emulsion, Fluosol-DA, on the radiation response of normal tissues and EMT6 mammary tumors in BALB/c mice was examined. Pre-treating tumor-bearing mice with .015 ml/g of Fluosol and 30 min of carbogen (95% O2/5% CO2) increased the number of tumor cells killed by irradiation with doses of 2.5-20 Gy; the change in the radiation dose-response curve was consistent with a reduction in the hypoxic fraction. Fluosol did not alter the response of tumors in air-breathing or N2-asphyxiated mice and carbogen alone did not alter the radiation response of this tumor significantly. Carbogen treatments 5-60 min in duration produced similar enhancements of tumor radiosensitivity in Fluosol-treated animals. Pre-treatment with Fluosol plus carbogen also increased the number of tumor cells killed by a fractionated regimen of four 2.5 Gy fractions given over 2 days. Pre-treatment with Fluosol-DA plus carbogen, therefore, increased the antineoplastic effects of radiotherapy in both single-dose and multi-fraction radiation regimens. In contrast, Fluosol did not increase the effect of radiation on the partially committed (CFU-GM) or pluripotent (CFU-S) stem cells of the bone marrow or on the CFU-GM of the spleen. The radiation response of the skin was only slightly enhanced by pre-treatment with Fluosol plus carbogen. These data show that treatment of mice with perfluorochemical emulsions plus carbogen can produce therapeutic gain by improving the radiation response of solid tumors, without producing an equivalent increase in the radiation response of potentially dose-limiting normal tissues. These findings encourage further evaluations of these agents as adjuncts to clinical radiotherapy.

Animals↗

The requirement for polymorphonuclear leukocytes in the late asthmatic response and heightened airways reactivity in an animal model.

The antigen-induced late asthmatic response (LAR) and subsequent heightened airways reactivity after this response have been associated with increased airways inflammation. Employing an animal model of the LAR in rabbits previously developed in our laboratory, 3 phases of experiments were performed to investigate the role of polymorphonuclear leukocytes (PML) in the LAR and heightened reactivity. In all 3 phases, airways reactivity to histamine and bronchoalveolar lavage analysis were performed 3 days before and 3 days after bronchial challenge with ragweed extract. In Phase 1, 2 groups of rabbits receiving nitrogen mustard were studied: an immune group received immune serum containing antiragweed IgE, and a control group received nonimmune serum. In Phase II, nitrogen mustard was administered to immune rabbits during aortic occlusion to allow the lungs to be exposed to nitrogen mustard while limiting exposure of the bone marrow to this drug, preventing depletion of PML. In Phase III, both an immune and a nonimmune group of rabbits received nitrogen mustard as in Phase I; however, prior to antigen challenge, they were repleted with a neutrophil-rich population of PML. In all experiments, no group of control (nonimmune) rabbits, whether depleted or repleted of PML, developed an immediate asthmatic response (IAR) or a LAR. In addition, no significant increases in lavage cells or airways reactivity occurred after ragweed challenge. In contrast, those animals receiving immune serum and nitrogen mustard developed an IAR; however, no LAR occurred, and no significant change in airways reactivity was observed. Rabbits receiving immune serum and nitrogen mustard with aortic occlusion developed an IAR and LAR, and airways reactivity increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Airways hyperreactivity and inflammation produced by aerosolization of human C5A des arg.

The premise of this study was that complement fragments would lead to granulocyte infiltration and to associated changes in airways reactivity. Inflammation was induced in large airways (greater than 1.0 mm) by aerosolization of the complement chemotactic factor, C5a des arg, which was isolated from activated human serum. Pulmonary function (resistance, compliance, and lung volume) and histamine reactivity were assessed at 4 and at 48 h after C5a des arg or a saline sham aerosol. Four hours after exposure to C5a des arg, the animals exhibited evidence of significant bronchoconstriction and hyperinflation. In addition, an increased responsiveness to histamine was demonstrated, which was not correlated with the degree of bronchospasm. By 48 h, these alterations were partially or completely resolved. Histologic examination and quantitation demonstrated significant accumulation of neutrophils, which was limited to airways 0.5 mm in or larger. Saline-treated animals also demonstrated a neutrophil infiltration, but significantly less than those treated with C5a des arg. However, these animals did not demonstrate hyperreactivity to histamine, and there was little change in baseline mechanical function. The mild inflammation associated in the saline control animals was demonstrated to be a result of intubation of the airways. Granulocyte dependence of the effects of C5a des arg was partially established by abrogation of these effects when the animals were rendered granulocytopenic with nitrogen mustard. We conclude that the physiologic responses of the airways to C5a des arg were largely granulocyte dependent. However, since granulocyte accumulation could occur without airways dysfunction, it is suggested that cell activation is an important step in producing neutrophil-associated airways hyperresponsiveness.

Aerosols↗

Inflammation and the late phase reaction in asthma: the effect of polymorphonuclear leukocyte depletion on airways obstruction and bronchial hyperreactivity in an animal model.

Increases in airway reactivity noted after antigen exposure in which a late asthmatic response (LAR) develops may be related to pulmonary inflammation. Employing an animal model of the LAR developed in our laboratory, we conducted experiments to determine if depletion of polymorphonuclear leukocytes (PMLs) would ablate the LAR and inhibit subsequent increases in airways reactivity. Four groups of ten animals each were studied. The first group was given immune sera (I) containing anti-ragweed IgE. The second group received non-immune sera (NI). A third group of animals received immune sera plus nitrogen mustard (I + NM), while a fourth group received non-immune sera plus nitrogen mustard (NI + NM). Airways reactivity to histamine and the evaluation of different cell types in bronchoalveolar lavage fluid (BALF) were determined three days before and three days after bronchial challenge with ragweed extract (RWE). No control rabbit (NI or NI + NM) developed either an immediate asthmatic response (IAR) or an LAR, and no significant increases occurred in their airways reactivity or cells in lavage fluid after bronchial challenge with RWE. In contrast, the sensitised rabbits not given nitrogen mustard developed an LAR and airways reactivity increased markedly three days later. Those animals receiving immune sera and nitrogen mustard developed an IAR; however, no LAR occurred and no significant change in airways reactivity ws observed. BALF analysis seventy-two hours after ragweed challenge in the animals that received immune sera showed a significant increase in PMLs. However, there was no significant increase on BALF PMLs in the animals receiving immune sera and nitrogen mustard.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Obstruction↗

Effect of 1-methyl-5-sulfonamide-4-nitroimidazole and 1-methyl-5-bromide-4-nitroimidazole on the radiosensitivity of EMT6 tumor cells.

The compounds 1-methyl-5-sulfonamide-4-nitroimidazole and 1-methyl-5-bromide-4-nitroimidazole are extremely effective radiosensitizers of hypoxic cells in vitro. Preincubation of hypoxic cells with these and related drugs produces greater sensitization than is obtained with short incubations or is expected from the electron affinities of the compounds. The experiments reported here were undertaken to determine whether these agents were effective in sensitizing the naturally occurring hypoxic cells of solid tumors in mice. Neither of the 4-nitroimidazoles produced significant radiosensitization of the hypoxic cells of EMT6 mouse mammary tumors in vivo with any of the single- or multiple-injection regimens tested.

Animals↗

Increases in airway reactivity to histamine and inflammatory cells in bronchoalveolar lavage after the late asthmatic response in an animal model.

An increase in airway reactivity after the late asthmatic response (LAR) has been noted in humans. Although these alterations in reactivity have been proposed to be associated with inflammation, no clinical study of the LAR has shown both increased airway reactivity and evidence of pulmonary inflammation. Employing an animal model of the LAR in rabbits developed in our laboratory (Am Rev Respir Dis 1982; 126:493-498), we examined changes in airway reactivity and pulmonary inflammation in rabbits having a late asthmatic response. Two groups of rabbits were studied: a control group (n = 10) received nonimmune serum, and a sensitized group (n = 10) received serum containing homocytotropic antibody (IgE) to ragweed extract (RWE) from rabbits previously immunized from birth with ragweed. Airway reactivity to histamine and the evaluation of different cell types in bronchoalveolar lavage fluid were determined 3 days before and 3 days after bronchial challenge with RWE in all rabbits. No control rabbit developed a LAR, and no significant changes occurred in this group's airway reactivity or cells in lavage fluid after bronchial challenge with RWE. In contrast, all sensitized rabbits developed a LAR, and airway reactivity for this group was markedly increased 3 days later. In addition, the total number of cells including both polymorphonuclear and mononuclear cells in lavage fluid increased significantly 3 days after the LAR. Ten days after the LAR in the sensitized group (n = 8), as airway reactivity returned towards baseline, so did the cells in lavage. We conclude that increased airway reactivity to histamine is temporally associated with pulmonary inflammation as defined by cells in lavage after the LAR in this model.

Animals↗

Demand and continuous flow intermittent mandatory ventilation systems.

A mechanical lung was used to evaluate the pressure and flow characteristics of four demand and two continuous flow intermittent mandatory ventilation (IMV) systems. The amount of negative pressure required to initiate inspiratory flow and peak expiratory resistance were measured. The inspiratory pressure required to initiate flow in the demand mode was also compared to pressures generated in the assist mode. In addition, the peak expiratory resistance was measured with four commercially available exhalation valves. Results showed that the ventilator manometer measuring internal machine pressures significantly underestimated the amount of negative pressure required to open the demand valve (p less than 0.01). There are major differences in the flow and pressure characteristics among demand and continuous flow IMV systems. Systems that impose high inspiratory elastic threshold loads and expiratory flow resistive loads may have a deleterious effect on the mechanics of breathing, and thereby limit weaning success and eventually impair the recovery of certain patients in respiratory failure. The basic methodology, especially the simple technique of inserting an aneroid manometer in line next to a patient's ET tube, for measuring proximal negative inspiratory force (NIF test) can be easily applied to any and all ventilators at any practitioner's individual institution.

Acute Disease↗

Enhancement of artificial lung metastases by misonidazole.

The effect of treatment with the hypoxic cell radiosensitizer misonidazole on the formation of artificial lung metastases was examined. Both single treatments with large doses of misonidazole and fractionated treatments with smaller doses of misonidazole were found to increase the number of lung tumors developing after intravenous injection of EMT6 mouse mammary carcinoma cells. The immunologic and physiologic effects of the nitroimidazole were postulated to be responsible for the enhancement of lung tumor formation.

Animals↗

When dreams die.

Explore the source record for details and available documents.

Abortion, Spontaneous↗

Effect of breathing pattern on esophageal pressure gradients in humans.

This study examines the hypothesis that respiratory muscle action alters regional pleural pressures. Seven normal volunteers were studied in the seated posture with three esophageal balloons positioned in the upper, middle, and lower esophagus. The intraesophageal pressure swings were recorded during natural breathing, enhanced rib cage, and enhanced diaphragmatic breathing. The pressures were also recorded at three frequencies ranging from 12 to 60 breaths/min. Data were processed with an ensemble average technique that largely removes cardiogenic artifact. During quiet natural breathing, the pressure swings in the lower esophagus were, on the average, 30% larger than the pressure swings in the upper esophagus but became nearly equal as the frequency increased to 60 breaths/min. Rib cage breathing nearly abolished the intraesophageal dynamic pressure differences, whereas abdominal breathing preserved the observed pressure difference even at 60 breaths/min. We concluded that muscle action can affect intrathoracic pressures in a regional way depending on the groups of muscles that are active. These results are discussed in terms of the topographical distribution of ventilation.

Adult↗

Inhibition of delayed hypersensitivity by metronidazole and misonidazole.

The effect on cell-mediated immunity of two hypoxic cell radiosensitizers, metronidazole and misonidazole, was examined. Immunocompetence was assayed by measuring delayed hypersensitivity reactions in mice sensitized on the abdomen with 2,4-dinitro-1-fluorobenzene (DNFB) and subsequently challenged on the ears with DNFB. Single and fractionated treatments with misonidazole or metronidazole were found to suppress delayed hypersensitivity reactions to DNFB. This finding is in agreement with other data in the literature which show that many imidazoles, including nitroimidazoles, inhibit aspects of the cell-mediated immune response in animals and man. The potential immunosuppressive effects of nitroheterocyclic radiosensitizers should be considered when these agents are evaluated in the laboratory or used in the clinic.

Animals↗

Mechanisms of histamine-induced contraction of canine airway smooth muscle.

We studied the effects of atropine (10(-10) to 10(-6) M), tetrodotoxin (TTX) (10(-6) g/ml), and neostigmine (10(-7) M) on the histamine dose-response curve of canine tracheal smooth muscle (TSM) in vitro. Pretreatment with atropine or TTX reduced base-line tension in some TSM samples, whereas neostigmine invariably caused contraction of TSM. All concentrations of atropine reduced the maximum isometric tension produced by histamine (Tmax). With 10(-6), 10(-8), and 10(-10) M atropine, Tmax was 57, 74, and 88%, respectively, of its value in paired control samples. Atropine, 10(-9) to 10(-6) M, increased the concentration of histamine which produced 20% of Tmax, whereas 10(-6) M also increased the concentration required to produce 50% of Tmax. TTX reduced tension produced by low concentrations of histamine but had no effect at higher concentrations. Neostigmine shifted the histamine dose-response curve and caused greater tension for any given histamine concentration; Tmax increased by 30% (P less than 0.05). Our data are consistent with spontaneous release of acetylcholine from cholinergic nerves in the airway tissue and suggest that histamine either accelerates this release or interacts supra-additively with the acetylcholine at the smooth muscle.

Acetylcholine↗

Nonpurinergic nature and efficacy of nonadrenergic bronchodilation.

The nonadrenergic inhibition of airway smooth muscle was investigated in vivo in the anesthetized cat. We examined 1) the bronchodilatating nature of the selective purinergic agonists [adenosine (AD) and adenosine triphosphate (ATP)], 2) antagonistic nature of aminophylline and quinidine, and 3) the comparative efficacy of nonadrenergic and sympathetic inhibition in reversing bronchoconstriction induced with serotonin. Alterations in smooth muscle tone were studied via electrical stimulation of the vagus nerves and measurements of pulmonary resistance. We found that neither AD nor ATP, aerosolized or injected, altered the tonic bronchoconstriction. Dipyridamole, an AD reuptake inhibitor, did not alter the response to AD, ATP, or electrical stimulation. Both aminophylline and quinidine block nonadrenergic dilatation at high dose levels (69 and 29 mg/kg, respectively); further, both reputed antagonists impair cholinergic excitation. Nonadrenergic inhibition is equipotent to sympathetic inhibition in reversing bronchoconstriction; however, nonadrenergic inhibition is more prolonged (4.0 +/- 1.8 min). We conclude that probably neither ATP nor AD is the neurotransmitter for nonadrenergic bronchodilatation in the cat, and that nonadrenergic inhibition is both potent and long lasting.

Adenosine↗

Bronchodilatation: noncholinergic, nonadrenergic mediation demonstrated in vivo in the cat.

The composite vagus nerve was stimulated during intravenous infusion of 5-hydroxytryptamine in cats subjected to pharmacologic autonomic blockade with atropine, propranolol, and phentolamine. Bronchial caliber, as assessed by changes in pulmonary resistance, demonstrated a marked dilatation, and dilatation could still be demonstrated after preliminary treatment with reserpine. By stimulating the component branches of the vagus nerve, it was determined that the parasympathetic branch is responsible for this phenomenon.

Airway Resistance↗

Human pulmonary resistance: effect of frequency and gas physical properties.

We have investigated a new technique that could be specific for detecting small airway diseases. We measured resistance in nine subjects, evaluating the effect of breathing 80% He-20%O2, air, and 80% SF6-20% O2 at different flow rates (0.25--1.01 l/s) and frequencies (4--12 Hz). To test the sensitivity and specificity of this new technique, we used intravenous histamine infusion to cause peripheral constriction. During histamine infusion six of nine subjects showed the following changes: 1) dynamic compliance decreased; 2) subjects developed frequency dependence of compliance, and 3) there was no significant change in pulmonary resistance or Rrs (respiratory resistance) at 4 Hz. These data suggested a time-constant discrepancy in the periphery due to histamine infusion. These six subjects also developed frequency dependence of resistance (delta Rrs from 4 to 12 Hz), which was significant when breathing air (-22 +/- 6%) and maximal when we used He-O2 (-32 +/- 3%). We conclude that He-O2 can improve the specificity of frequency dependence of Rrs for detecting events occurring in the peripheral airways.

Adult↗