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Biomedical subjects

D G Frazer

Publications and source records attributed to D G Frazer.

At least 19 recordsLinked to original sources
PubMed1996

Effect of temperature on pressure-volume hysteresis of excised lungs.

The objective of this study was to determine if the effect of temperature on excised lung pressure-volume (P-V) hysteresis during various P-V maneuvers would be consistent with predicted effects based on the recruitment-derecruitment (R-D) model of lung P-V hysteresis. Three sets of P-V curves were recorded for excised rat lungs at (1) 24 degrees C, (2) either 42 degrees or 45 degrees C, and (3) 24 degrees C. After full inflation of the lung, deflation-inflation (D-I) cycles were performed between total lung capacity (30 cmH2O) and successively decreasing end-expiratory pressures (EEPs). Normalized hysteresis (K) was plotted vs EEP. K remained relatively constant at EEPs > or = +5 cmH2O at 24 degrees C and 42 degrees C and > +5 cmH2O at 45 degrees C. Large increases in K occurred as the EEP was further reduced, with the relationship of K vs EEP being shifted to the right at 42 degrees C and 45 degrees C relative to 24 degrees C, with the greater shift occurring at 45 degrees C. Previous work has shown that the R-D of lung units contributes to P-V hysteresis and is EEP-dependent, increasing at EEPs < or = +4 +/- 1 cmH2O at room temperature (Cheng et al., 1995). This study suggests that at increased temperatures, R-D of lung units is initiated at higher EEPs and is more extensive than at room temperature.

Animals↗
PubMed1996

Pulmonary reactions to organic dust exposures: development of an animal model.

Acute inhalation of organic dusts such as cotton, hay, silage, grain, animal confinement, or compost dust can result in illness characterized by fever, pulmonary inflammation, chest tightness, and airway obstruction. These agricultural materials are complex mixtures of plant, bacterial, and fungal products. Elucidation of the time course of disease onset, the mechanisms of disease progression, and the identity of etiologic agents is essential for effective prevention and treatment. Toward this end, animal models for acute organic dust-induced reactions have been developed and characterized. Information concerning the applicability of various animal models to humans and progress toward elucidation of causative agents and mechanisms of action is presented.

Animals↗
PubMed1995

Properties of lavage material from excised lungs ventilated at different temperatures.

We studied the phospholipid (PL) and protein contents, the PL composition, and some of the surface properties of lavage materials obtained from freshly excised rat lungs and excised lungs which had been ventilated at different temperatures (22, 37, and 42 degrees C). Ventilation (60 breaths/min) was carried out at constant tidal volume with periodic sighs for one hour. Although there is slightly more lavageable PL and protein in lungs ventilated at 22 degrees C than in freshly excised lungs, there is no difference in the PL composition or surface properties of lavage materials from these lungs. However, as the temperature at which lungs are ventilated is increased to 37 degrees and 42 degrees C, there is(are): 1) a reduction in lavage fluid PL, 2) a reduction in the relative amounts of total phosphatidylcholines (PC) and disaturated PC (DSPC), the major surface active component of pulmonary surfactant, 3) an increase in unsaturated PC, and 4) increases in total protein and nonsedimentable protein (100,000 g; 2 hr) in the lavage materials. There are also differences in the surface properties of the lavage materials from lungs ventilated at higher temperatures when compared with freshly excised lungs or lungs ventilated at 22 degrees C, probably as a result of the changes in composition. Maximal surface tension is greater for lavage materials from lungs ventilated at 37 degrees C. For lungs ventilated at 42 degrees C, maximal and minimal surface tension values are increased. These results demonstrate that there are differences in the composition and surface properties of alveolar lavage materials from excised lungs ventilated at different temperatures.

Animals↗
PubMed1995

Contribution of opening and closing of lung units to lung hysteresis.

The recruitment and derecruitment of lung units is one explanation of the hysteresis observed in an excised lung during inflation and deflation. A simplified model has been proposed in which the recruitment-derecruitment process is a function of end-expiratory pressure (Frazer, D.G., K.C. Weber and G.N. Franz, Respir. Physiol. 61: 277-288, 1985). The object of this study was to test this model with three experimental procedures. During the first set of experiments, progressively larger pressure-volume (PL-VL) loops were recorded with end-expiratory pressure held at either -5 cmH2O, where all lung units are assumed to be closed, or +5 cmH2O, where all recruited lung units are assumed to be open. In the first case hysteresis is maximal, in the second, minimal. The difference in hysteresis is presumed to arise from the recruitment-derecruitment process. In the second set of experiments, excised lungs are slowly inflated and then deflated at a constant rate while constant-amplitude sinusoidal volume oscillations are superimposed. The end-expiratory pressure of the superimposed loops gradually rose as the lung was inflated and fell as the lung was deflated. Hysteresis was minimal when end-expiratory pressure was above 4 +/- 1 cmH2O even as peak-to-peak loop pressure greatly varied. This supports the notion of an end-expiratory pressure dependent mechanism of recruitment/derecruitment. During the third set of experiments lungs were inflated to either 50%, 75%, or 100% TLC. Volumes of air were then withdrawn and replaced so that the initial volume was restored in sinusoidal fashion as the amplitude of the volume excursions increased. For PL-VL loops with end-expiratory pressures between +4 and -2 cmH2O, pressure amplitudes rose and the hysteresis index (loop area/tidal volume) increased, regardless of the initial lung volume. These results are consistent with the previously described model of Frazer et al. (1985) which assumed that PL-VL curves can be divided into an 'opening' region, an 'open' region and a 'closing' region and that the demarcation of these regions depends on transpulmonary pressure, specifically end-expiratory pressure, and to a much lesser degree on lung volume.

Animals↗
PubMed1995

Nitric oxide synthase inhibitor and lipopolysaccharide effects on reactivity of guinea pig airways.

The in vivo and in vitro effects of nitric oxide (NO) synthase inhibitors and lipopolysaccharide (LPS) on reactivity of guinea pig airways were examined. In isolated, perfused tracheas from untreated animals, the NO synthase inhibitors, N omega-nitro-L-arginine methyl ester (L-NAME; 10(-4)M), NG-methyl-L-arginine (L-NMMA; 10(-4) M) and aminoguanidine (10(-4) M) had no effect or inhibited reactivity to extraluminally (EL) or intraluminally (IL) applied methacholine and histamine. L-NMMA (10(-4) M) did not appreciably contract resting or metacholine-contracted preparations (+/- 3 x 10(-4) M L-arginine) and L-arginine only weakly relaxed contracted tracheas (+/- L-NMMA). Sodium nitroprusside and S-nitroso-N-penicillamine elicited relaxant responses and were more potent extraluminally than intraluminally. Methylene blue (10(-5) M) antagonized relaxation to sodium nitroprusside. Incubation with Escherichia coli LPS (10 micrograms/ml; 30 min incubation) alone in the EL and IL baths depressed methacholine and histamine concentration-response curves. In the presence of LPS, L-NAME potentiated responses to intraluminally applied methacholine but did not affect responses to extraluminally added methacholine. Four days after i.p. injection of animals with LPS (4 mg/kg), L-NAME potentiated responses to IL methacholine, and L-arginine acquired greater relaxant activity. LPS injection increased sensitivity to intraluminally added but not extraluminally added isoproterenol. LPS given by i.p. injection or by inhalation did not affect basal specific airway resistance of conscious animals or reactivity to methacholine aerosol during a postexposure period of 6 to 72 h. NO seems to have little role in regulating reactivity of guinea pig airways to bronchoconstrictor agonists, except after in vitro or in vivo exposure to LPS. After LPS injection the in vitro changes suggestive of NO synthase induction are not associated with altered airway reactivity to inhaled methacholine.

Airway Resistance↗
PubMed1994

Polarized effects of amiloride and 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid on ATP-induced contraction of trachea.

Polarity in the effects of amiloride and 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS) in the guinea-pig isolated, perfused trachea was investigated to evaluate the roles of epithelial and airway smooth muscle Na+ and Cl- channels in the development of contractile responses to ATP. The blockers were applied to the mucosal (intraluminal) perfusing solution or to the serosal (extraluminal) bath before the second of two challenges with ATP (10(-4) M), which was added to the same bath as the blocker, or to the abluminal bath. In epithelium-intact tracheas, amiloride (10(-4) M) added to the extraluminal or intraluminal bath rapidly (1 min) and extensively inhibited contractions to extraluminally applied ATP (10(-4) M). In contrast, contractions to intraluminally applied ATP (10(-4) M) were relatively resistant to extraluminal and intraluminal amiloride (10(-4) M), in terms of the degree and onset of the inhibition. DIDS (10(-4) M) present in the extraluminal or intraluminal baths caused a slowly developing elevation of baseline tone. After a 30 min incubation, extraluminal DIDS potentiated responses to extraluminally added ATP, but intraluminal DIDS inhibited contractions to ATP added to the extraluminal and intraluminal baths. In contrast to the intact tracheas where there was no difference, the second response of epithelium-denuded preparations to intraluminally administered ATP was diminished. In rubbed tracheas the response to intraluminally added ATP was inhibited further by intraluminal amiloride but was potentiated by intraluminal DIDS. The results suggest that the effects of amiloride and DIDS were polarized across the tracheal wall and involved epithelial and smooth muscle ion channels.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Organic dust exposure from compost handling: response of an animal model.

The objective of this investigation was to elucidate the pulmonary responses of an animal model to dust generated from leaf/wood compost which had caused a severe case of acute respiratory illness in an individual. Guinea pigs were exposed for 4 hr to 30 mg/m3 of aerosolized leaf/wood compost dust. Inhalation resulted in significant cellular activation and changes in pulmonary mechanics. Maximal elevation in breathing rate (increases 36%) was observed 12-18 hr postexposure. Similarly, maximal granulocyte infiltration (increases 1,600%) and activation of alveolar macrophages (increases 65%) occurred 18 hr postexposure. In contrast, maximal airway obstruction (increases 120%) occurred immediately after exposure and returned toward normal (increases 53%) by 18 hr postexposure. In several respects, the airway obstruction and pulmonary inflammation described in the animal model were comparable to the human response to compost dust. Therefore, this animal model may be useful in predicting the potential respiratory hazard associated with exposure to various organic dusts.

Agriculture↗
PubMed1993

Infective endophthalmitis following vitreoretinal surgery.

Eleven cases of endophthalmitis occurring after vitreoretinal surgery are described. At Moorfields Hospital, London, from 1986 to 1990 the incidence of endophthalmitis after explant surgery with or without drain was 0.19% and after vitrectomy was 0.15%. We conclude that the parity may be due to the intraocular instrumentation of most conventional retinal detachment repair procedures. The best indicator of poor prognosis was speed of onset of symptoms, those with rapid evolution having the worst outcome; 2 of these cases were enucleated. Those presenting at 2-3 days had the best outcome, consistent with infection due to a less virulent organism. Delays in diagnosis were in part due to the posterior location of signs of infection. Potential risk factors amenable to prophylactic strategy were identified in 10 of the 11 patients. Supplementary prophylaxis using ciprofloxacin or imipenem is proposed for cases with an identifiable risk factor. After systemic administration these antibiotics achieve vitreous levels that exceed the MIC90 of the commonest causative pathogens.

Drainage↗
PubMed1993

A review of 72 consecutive cases of Acanthamoeba keratitis, 1984-1992.

A review of consecutive cases of Acanthamoeba keratitis presenting since 1984 was undertaken in order to assess prognostic factors, the success of culture procedures and the outcome of medical and surgical management, with reference to current clinical practice. Seventy-two consecutive cases (77 eyes) of Acanthamoeba keratitis have been managed. Sixty-four patients were contact lens wearers, 28 of these wearing disposable lenses. Superficial corneal involvement and perineural infiltrates were common in those diagnosed less than a month after first symptoms, designated 'early' presentation. Ring infiltrates and ulceration with stromal lysis characterised those presenting at 1-2 months ('intermediate') or after 2 months ('late'); these groups also progressed more frequently to hypopyon, scleritis, glaucoma and cataract formation. Positive corneal cultures were obtained in 10 of 14 (71%) intermediate and 17 of 23 (74%) late cases; early cases underwent epithelial biopsy but formal trephine biopsy was not usually justified (1 of 35 cases) and only 19 of 35 (54%) were tissue-positive. Microbial co-isolates were obtained from 20 corneas. Thirty-four penetrating keratoplasties were performed in 23 eyes, 21 whilst inflamed and 13 when quiet. Of 13 failures in inflamed eyes, 9 were due to recurrence of Acanthamoeba infection. Medical cure is known to have been achieved in 64 of 73 (88%) eyes, 4 of the original 77 having been lost to follow-up abroad. Fifty-eight of 73 eyes (79%) achieved a final visual acuity of 6/12, and of the culture-positive cases, 32 of 46 (70%) achieved 6/12.(ABSTRACT TRUNCATED AT 250 WORDS)

Acanthamoeba↗
PubMed1993

Contractile effects of nucleotides in guinea pig isolated, perfused trachea: involvement of respiratory epithelium, prostanoids and Na+ and Cl- channels.

ATP and UTP contracted guinea pig isolated, perfused trachea and were more potent when applied to the mucosal (intraluminal, IL) surface than when applied to the serosal (extraluminal, EL) surface. IL ATP and IL UTP were equipotent (ATP approximately UTP); EL ATP was 7-fold more potent than EL UTP (ATP > UTP). beta, gamma-Methylene ATP was nearly devoid of activity. Epithelium (Epi) removal decreased IL ATP potency and EL and IL maximum response magnitude, but elevated the IL UTP maximum response. In the presence of EL and IL indomethacin (3 x 10(-6) M; +/- Epi) to inhibit cyclo-oxygenase, or beta, gamma-methylene ATP (10(-4) M) to desensitize receptors, contractions to ATP were abolished, but those to UTP were not. Cl- channel blockade with 4,4'-diisothiocyano-2,2'-stilbene disulfonate (DIDS; 10(-4) M; +/- Epi) and sodium channel blockade with amiloride (10(-4) M; +/- Epi) antagonized contractions to EL and IL ATP and UTP. DIDS and amiloride did not inhibit contractions to methacholine; IL reactivity to methacholine was potentiated by indomethacin and Epi removal. Our findings indicate that the Epi facilitates contraction to ATP, which involves an atypical P2 purinoceptor, prostanoids, and Na+ and Cl- channels. Contractile responses to UTP involve a different receptor, and are neither facilitated by the Epi nor mediated by prostanoids, but involve these channels.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Relaxant effects of nucleotides in guinea pig isolated, perfused trachea: lack of involvement of prostanoids, Cl- channels and adenosine.

In higher concentrations (> 3 x 10(-4) M) than those causing contractile responses. ATP relaxed the smooth muscle of the guinea pig perfused trachea. Here we examined the relaxant effects of nucleotides. ATP and its nonhydrolyzable congener, beta, gamma-methylene ATP (APPCP), were approximately 4- and approximately 117-fold, respectively, more potent when applied separately to the serosal (extraluminal, EL) surface compared to the mucosal (intraluminal, IL) surface of methacholine (3 x 10(-7) M; EL)-contracted tracheae. APPCP was orders of magnitude more potent than ATP in both EL and IL compartments. EL UTP did not cause relaxation; IL UTP was nearly devoid of activity. The order of EL and IL activity (APPCP >> ATP) was unusual for nucleotide-induced relaxation of smooth muscle. Relaxation to ATP was not inhibited by the Cl- channel blocker 4,4'-diisothiocyano-2,2'-stilbene disulfonate (10(-4) M) or by the cyclo-oxygenase inhibitor indomethacin (3 x 10(-6) M), in contrast to the inhibitory effects of these drugs on contraction to ATP. The adenosine receptor antagonist 8-phenyltheophylline (10(-6) M) had no effect on relaxation to ATP or APPCP. Our findings indicate that Cl- channels, prostaglandins and adenosine are not involved in relaxation to adenine nucleotides.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1993

Alteration in the modulatory role of respiratory epithelium after exposure of guinea pigs to respirable cotton dust.

Chest tightness may occur after inhalation of cotton dust. To understand the origins of this symptom of byssinosis, we exposed guinea pigs to respirable cotton dust and determined whether the resulting pulmonary obstruction was associated with alterations in the in vitro reactivity of the trachea to methacholine. The isolated, perfused trachea preparation was utilized because it allows a comparison of airway smooth muscle responses to drugs after they are applied separately to the mucosal or serosal surfaces. In epithelium-containing control tracheae, mucosally applied methacholine was less potent and elicited smaller maximum contractile responses than those obtained when it was applied to the serosal compartment. After a 6-h inhalation exposure to 30 mg/m3 respirable cotton dust, the mucosal maximum response to methacholine was substantially increased immediately (0 h) after the end of the exposure, but it was decreased 18 h postexposure. A dust level of 10 mg/m3 produced modest increases in the mucosal maximum responses at both postexposure periods, elevating them to the magnitude of the extraluminal maximum response. The potency of serosally applied methacholine was not affected by any cotton dust exposure. Mechanical epithelium removal increased mucosal reactivity to the serosal level in both control and cotton (30 mg/m3)-exposed groups, and abolished the effects of dust on mucosal reactivity to methacholine. Our findings suggest that the modulatory effect of the epithelium may be inhibitory or excitatory. The balance between the two influences may be altered by inhaled cotton dust.

Administration, Inhalation↗
PubMed1992

Risks of keratitis and patterns of use with disposable contact lenses.

Disposable soft contact lenses have been marketed as a safer alternative to conventional soft lenses. We undertook a case-control study of patients attending the casualty unit of an eye hospital to quantify the relative risk of keratitis in disposable lens wear and to establish associated patterns of use. All eligible contact lens users were identified and asked to complete a questionnaire (n=242). Keratitis, microbial or sterile, was the most common complication in disposable lens users, occurring in 16 of 41 subjects. The relative risks for all lens types were estimated by comparison with rigid lenses (the referent). Both extended- and daily-wear disposable lenses were associated with higher risks of keratitis than other lens types including conventional extended-wear lenses. Poor hygiene, disinfectant system failure, and lens type may all account for these statistically significant trends.

Acanthamoeba Keratitis↗
PubMed1992

Influence of epithelium on the reactivity of guinea pig isolated, perfused trachea to bronchoactive drugs.

The mechanisms by which the epithelium affects reactivity of guinea pig trachealis to agonists were examined using the isolated, perfused trachea preparation. Contractile agonists (acetylcholine, methacholine, carbachol or histamine) were more potent when applied to the serosal (extraluminal, EL) surface compared to the mucosal (intraluminal, IL) surface, and the IL maximum responses to these agents were smaller. In epithelium-denuded tracheae, IL reactivity to the agonists was increased to the EL level. Physostigmine (10(-7) M) increased the EL and IL potency of acetylcholine to that of carbachol (+/- epithelium), and elevated the IL acetylcholine maximum response (+ epithelium); the relative role of epithelial acetylcholinesterase could not be defined. Indomethacin (3 x 10(-6) M) increased, in an epithelium-dependent manner, the IL acetylcholine, carbachol and histamine maximum responses to the EL level. Phentolamine plus propranolol (both 10(-6) M) potentiated the IL maximum response to methacholine, Isoproterenol also was more potent extraluminally than intraluminally, and the EL and IL maximum responses were similar. IL isoproterenol reactivity was elevated to the EL level in rubbed tracheae. Corticosterone (5 x 10(-5) M) potentiated EL and IL responses to isoproterenol (+/- epithelium); the relative role of epithelial extraneuronal uptake could not be delineated. The epithelium reduces reactivity to mucosally applied drugs by acting as a diffusion barrier. In addition, responses to mucosally administered contractile agonists are inhibited by a physiological antagonism caused by modulatory prostanoids, catecholamines and, possibly, epithelium-derived relaxing factor.

Animals↗
PubMed1991

Inhibition of stimulant-induced activation of phagocytic cells with tetrandrine.

Tetrandrine is an alkaloid obtained from the root of a medicinal herb which is employed in China as a treatment for silicosis. One proposed mechanism for the development of silica-induced fibrosis is lung damage resulting from particle-induced inflammation and secretion of reactive compounds from alveolar phagocytes. Therefore, the objective of the present study was to determine if tetrandrine exhibited the ability to inhibit respiratory burst activity of pulmonary phagocytes. The data indicate that although tetrandrine is not cytotoxic to phagocytic cells, it is a potent inhibitor in vitro of zymosan-stimulated oxygen consumption, superoxide anion release, and hydrogen peroxide secretion by alveolar macrophages. Tetrandrine is also effective in vivo in preventing activation of alveolar macrophages after inhalation or intratracheal instillation of silica. Tetrandrine also inhibits stimulant-induced chemiluminescence by polymorphonuclear leukocytes. Since tetrandrine does not alter stimulant-induced depolarization of phagocytic cells, its inhibitory action is not via interference with receptor-ligand binding but rather must occur elsewhere in the stimulus-secretion coupling scheme.

Alkaloids↗
PubMed1990

Reactivity of guinea-pig isolated trachea to methacholine, histamine and isoproterenol applied serosally versus mucosally.

Guinea-pig tracheas were perfused with recirculating modified Krebs-Henseleit solution while monitoring changes in inflow-outflow pressure difference, which is an index of trachealis muscle tone. The reactivities of the trachealis muscle to methacholine, histamine and isoproterenol applied separately to the mucosal (intraluminal, IL) or serosal (extraluminal, EL) compartments were compared, and evidence for the agonist-induced release of epithelium-derived relaxing factor (EpDRF) was sought. All agents were more potent when added to the EL compartment, but the IL/EL EC50 ratios were different: 100 for methacholine, 41 for histamine and 25 for isoproterenol. Methacholine or histamine added to the IL compartment, after the preparations were pre-contracted with the same concentration of the agonist or 30 mM KCl added EL, did not result in relaxation. Likewise, IL isoproterenol did not evoke contraction. IL KCl evoked relaxation. The results indicate that the epithelium reduces access of bronchoactive agents to the muscle, while an immediate relaxant effect of EpDRF released by agonists could not be demonstrated.

Animals↗
PubMed1987

Ghost cell glaucoma in phakic eyes.

We report 3 cases of ghost cell glaucoma all of which occurred in phakic patients with onset between 18 months and 4 years after vitreous haemorrhage. There appears to have been spontaneous disruption of the anterior hyaloid face in all 3 cases. Control of the glaucoma was achieved by medical treatment in one case and by trabeculectomy in two.

Glaucoma↗