Biomedical subjects

W J Doyle

Publications and source records attributed to W J Doyle.

At least 55 records · Page 3Linked to original sources

PubMed1997

Magnetic resonance imaging of the development of otitis media with effusion caused by functional obstruction of the eustachian tube.

In this study, magnetic resonance imaging (MRI) was used to define in vivo the effect of experimental functional obstruction of the eustachian tube (ET) on vascular permeability and the development of middle ear (ME) effusion. After collection of baseline data for ME pressure and MRI, the right tensor veli palatini muscle of 10 cynomolgus monkeys was injected with botulinum toxin A to induce ET obstruction. The left tensor veli palatini muscle was injected with saline in 4 monkeys. Right and left ME pressures and compliances were measured twice daily over a follow-up period of 36 days, and MRI scanning sessions including administration of a contrast agent, gadopentetate dimeglumine, were repeated on days 3, 6, 11, 15, 21, 29, and 36 in 6 animals and on days 15, 21, 29, and 36 in 4 animals. Two right ears did not develop underpressures, 5 developed persistent underpressures, and 3 developed underpressures that resolved. No changes in MRI parameters were noted for the ears that did not develop underpressures, but a progressive brightening of the ME on T2-weighted images, indicative of the development of inflammation and effusion, was noted for the others. Also, an increasing rate of transfer of the contrast agent between the vascular and ME compartments, indicative of increasing vascular permeability, was observed to track the temporal changes in ME pressure. These results support a causal relationship between ET dysfunction, ME underpressures, increased vascular permeability, and otitis media with effusion

Acoustic Impedance Tests↗

PubMed1997

Increases in middle ear pressure resulting from counter-diffusion of oxygen and carbon dioxide into the middle ear of monkeys.

The mechanism of middle ear (ME) pressure regulation is incompletely understood. Previously, Hergels and Magnuson reported an unexpected increase in ME pressure for human subjects who partially evacuated their relative positive ME pressures by swallowing. They suggested that a novel, but unknown mechanism for the generation of gas was responsible for the pressure increase. In this experiment, the MEs of rhesus monkeys were inflated with N2 via the eustachian tube and post inflation ME pressures were recorded for up to three hours. Eleven of 20 experiments showed an initial increase in ME pressure caused by the inflation followed by stable pressures for the remainder of the followup period. In 9 of the experiments, a rapid and temporally discrete decrease in ME pressure was observed during the course of followup. Following the observed pressure decrease which was interpreted as a transient eustachian tube opening, ME pressures showed a progressive increase characterized by a kinetic pattern similar to that of the human experiment. To understand the mechanism responsible for this effect, the monkey experiment was simulated using a mathematical model of ME pressure regulation. Free parameters of the model were taken from experimental data for monkeys. The model accurately predicted the time course of pressure change documented in the monkey experiments. The effect is driven by a decrease in the preexisting ME partial pressures of CO2, O2 and H2O consequent to tubal openings at relative positive pressures, with the subsequent counter diffusion of those gases from blood to ME causing the observed increase in total ME pressure. The results reported by Hergels and Magnuson can also be explained by this mechanism.

Animals↗

PubMed1996

Suppression of in vivo cell-mediated immunity during experimental influenza A virus infection of adults.

A variety of recent evidence documents that otitis media is a frequent complication of upper respiratory tract viral infections. This relationship has been attributed to the interaction of a number of virus-provoked host responses, including eustachian tube dysfunction, changes in nasopharyngeal bacterial flora and suppressed immune function. The present study examined the effect of experimental influenza A virus infection on immune function as assessed by delayed skin test reactivity to candida, tetanus, and diphtheria/tetanus antigens in healthy adults with (n = 12) and without (n = 15) allergic rhinitis. All subjects became infected with the challenge virus as evidenced by viral shedding into nasal secretions and/or a four-fold rise in convalescent serum antibody titers compared to baseline. Intradermal skin tests were placed at baseline and 2, 4, 17, and 24 days after intranasal influenza A inoculation, the reactions were imaged and recorded 48 h after placement, and response areas were calculated by computerized digitization. The average combined areas for the three antigens (+/- S.T.D.) on each of the 5 study days were 1.4 +/- 1.4, 0.7 +/- 0.7, 0.6 +/- 0.6, 1.4 +/- 1.4, and 1.2 +/- 1.2 cm2, respectively. The responses to candida, but not tetanus and diphtheria/tetanus, returned to baseline levels by day 17. Repeated measures ANOVA documented significant effects of study day and antigen, but not allergy status. These results show that experimental influenza A infection suppressed delayed hypersensitivity skin tests in both allergic and non-allergic subjects, and suggest that alterations in immune function may contribute to otitis media.

Adolescent↗

PubMed1996

Effect of influenza A virus infection on natural and adaptive cellular immunity.

Influenza A virus (FLU) is an important pathogen in humans. Although many features of the antiviral immune response have been elucidated in murine and human models of disease, little is known about the role of NK cells, which provide natural, innate immunity. The effects of experimental intranasal FLU (H1N1) inoculation on NK cells and other immune parameters were studied in 18 healthy, adult volunteers during the acute and convalescent phases of infection. Peripheral blood mononuclear cells (PBMNC) were assayed at baseline and on Postinoculation Days 1, 3, 4, 6, 7, 23, and 44. FLU infection and pathophysiologic upper airway responses were documented in all subjects, and there was no mortality. During both the acute (Days 1-3) and the convalescent (Days 23 and 44) stages of the FLU infection, significant increases in NK activity and decreases in the number of activated NK cells were observed. Reductions in the absolute number of T lymphocytes and in PBMNC proliferation to FLU virus antigen and mitogen were also observed. The current investigation extended those findings to include reductions in the number of CD4+ and CD8+ T lymphocytes and increases in the number of activated T lymphocytes. These results document that FLU infection was accompanied by enhancement of natural immunity and, as expected, suppression of most of the other measured parameters of cellular immunity. The normal response to FLU infection in humans may involve sequential modulation of the different components of the cellular immune system.

Adult↗

PubMed1996

Effects of middle ear oxygen and carbon dioxide tensions on eustachian tube ventilatory function.

The objective of this study was to determine the effect of middle ear (ME) gas composition on eustachian tube ventilatory function (ETVF). ETVF was evaluated by using forced-response and inflation-de-flation tests in four alert cynomolgus monkeys during test sessions with different gas compositions. The ME was flushed with one of the four gas mixtures: 1. air; 2. 12% oxygen, 88% nitrogen; 3. 100% oxygen; and 4. 5% carbon dioxide, 21% oxygen, and 74% nitrogen before and during testing. The results documented lower opening, steady-state, and closing pressures, lower passive and active resistance, and greater dilatory efficiency following ME flushes with the hypercarbic and hypoxic gas mixtures when compared to the others. Also, for applied ME overpressure, the maximum pressure change during a swallow, the average pressure drop for all swallows, and the percentage of the applied pressure equalized were greater under hypoxic and hypercarbic conditions. These results show that ME gas composition affects ETVF and support feedback modulation of ME pressure regulation.

Animals↗

PubMed1996

Prechallenge antibodies: moderators of infection rate, signs, and symptoms in adults experimentally challenged with rhinovirus type 39.

This study determined the influence of serum neutralizing antibody titers on infection rate, symptom manifestations, and provoked signs and pathophysiologies in adults experimentally exposed to rhinovirus type 39 (RV-39). Antibody status was determined for 151 healthy volunteers who were then cloistered in a hotel for 6 days. At the end of the first cloister day, the volunteers were challenged with RV-39 in a median tissue culture infective dose of 100. On each of the 6 days, a nasal examination was performed, symptoms were scored, and objective tests of nasal mucociliary function, nasal airway patency, secretion production, and middle ear pressures were completed. Both subjects and investigators were blinded to the prechallenge serum homotypic antibody titers of the subjects. Four subjects presented with a wild virus and were excluded from the analysis. Of the 147 included subjects, prechallenge serum antibody titers to RV-39 were low (under 2) in 56 subjects, intermediate (2 to 8) in 51 subjects, and high (above 16) in 40 subjects. The high-titer group was significantly different from the low-titer group with respect to viral shedding, symptom load, subjective extent of illness, and secretion production, as well as in the frequency of subjects with abnormal nasal mucociliary clearance and positive middle ear pressures. The study results document that for experimental RV-39 exposure, high levels of homotypic serum neutralizing antibody titers are associated with protection from infection and a lessened degree of disease expression, but not with a reduction of otologic complications.

Adolescent↗

PubMed1996

Efficacy of clarithromycin treatment of acute otitis media caused by infection with penicillin-susceptible, -intermediate, and -resistant Streptococcus pneumoniae in the chinchilla.

Because of the increasing frequencies of recovery of penicillin-resistant Streptococcus pneumoniae from the middle ears of children with acute otitis media, non-beta-lactam antibiotics are being explored as treatment alternatives to amoxicillin. In this study, the efficacy of a 10-day course of clarithromycin was evaluated with chinchillas. After the pharmacokinetic profiles for clarithromycin were established, 180 animals were assigned to one of three susceptibility groups (n = 60/group; penicillin-susceptible, -intermediate, and -resistant S. pneumoniae), and the right middle ear was infected with the appropriate strain of S. pneumoniae. Equal numbers of animals in each group were treated orally beginning on day 2 with a 10-day course of clarithromycin (15 mg/kg of body weight; given twice a day) or amoxicillin as a control (20 mg/kg twice a day). On days 4, 9, and 13, otomicroscopy and tympanometry were performed, and on day 13, the middle ears were cultured for bacteria. The results showed 100% eradication of the challenge organism in both treatment groups for the susceptible strains of S. pneumoniae. Cultures were negative in 87 and 74% (P > 0.05) of the animals challenged with the intermediate resistant strains and in 100 and 56% (P < 0.05) of the animals challenged with the resistant strains and treated with clarithromycin and amoxicillin, respectively. There were no differences between treatments in the diagnosis of effusion for any group. These results support the use of the chinchilla to evaluate drug efficacy in the treatment of acute otitis media and show clarithromycin to be effective in sterilizing the middle ears of animals challenged with penicillin-susceptible, -intermediate, and -resistant strains of S. pneumoniae.

Amoxicillin↗

PubMed1996

Lower airway responses to influenza A virus in healthy allergic and nonallergic subjects.

Acute asthma is considered a complication of respiratory viral infections. This investigation assessed the effects of influenza A virus infection on both the patency and responsiveness of the lower airways. Subjects with allergic rhinitis (AR; n = 21) and without AR (non-AR; n = 25) were intranasally inoculated with influenza A virus and monitored for 8 d in a cloistered environment for changes in symptoms, signs, and airway physiology (pulmonary function, bronchial methacholine provocation). All subjects were infected after inoculation. Significant increases in nasal symptoms and secretion weights were observed, with peak effects on Days 3 and 4. Cough was a relatively minor symptom, and none of the subjects developed wheezing. Likewise, there were no significant changes in the measured functions of the lower airways. No effects on allergy status were observed. Under these experimental conditions, influenza A virus infection did not produce detectable alterations in lower airway function in health AR and non-AR subjects.

Adult↗

PubMed1996

Lower airway responses to rhinovirus 39 in healthy allergic and nonallergic subjects.

Acute asthma is considered to be a complication of respiratory viral infections. This investigation assessed the effects of rhinovirus 39 (RV-39) infection both on the patency and responsiveness of the lower airways. Subjects with allergic rhinitis (AR; n = 50) and without AR (non-AR; n = 46) were intranasally inoculated with RV-39, and monitored for 8 days in an enclosed environment for changes in symptoms, signs, and airway physiology (pulmonary function, bronchial methacholine provocation). All subjects were infected postinoculation. Significant increases in nasal symptoms and secretion weights were observed, with peak effects on days 2-3. Cough was a relatively minor symptom and none of the subjects developed wheezing. Likewise, there were no significant changes in the measured functions of the lower airways. No allergy status effects were observed. Under these experimental conditions, rhinovirus 39 infection did not produce detectable alterations in lower airway function in healthy subjects with and without allergic rhinitis.

Adult↗

PubMed1996

Pattern of nasal secretions during experimental influenza virus infection.

To define the pattern of secretion production during influenza virus infection, 28 adult subjects were inoculated with influenza-A virus (H1N1) and cloistered for a period of 8 days. On each day, symptoms associated with virus infection were scored, nasal secretions were collected and nasal lavages were performed. Recovered lavage fluids were submitted for virus culture and assayed for proteins, histamine, and bradykinin. Twenty-one subjects were infected with influenza-A virus and had significant increases in daily secretion weights and symptom scores extending from day 2 to 7, post-inoculation. Plasma-derived proteins in the nasal lavage fluids showed an early increase to peak at day 4 and then decreased. Glandular proteins showed a later increase to peak at day 5. Bradykinin but not histamine was significantly elevated and tracked the changes in the glandular proteins. In contrast, a shallow increase in symptoms confined to day 2 post-inoculation, but no increase in daily secretion weights was documented in the seven uninfected subjects. There, an increase in plasma proteins was observed on days 1 and 2, but no change in glandular proteins was obvious. These results support a biphasic secretory response during influenza-virus infection with transudation dominating the early period and glandular secretions contributing later.

Adult↗

PubMed1995

Cytokines, immunoglobulins, and bacterial pathogens in middle ear effusions.

OBJECTIVE: To elucidate the role of cytokines, immunoglobulins, and bacterial pathogens in the middle ear effusions (MEEs) of children with otitis media (OM). DESIGN: Paired MEEs and serum samples collected from consecutive patients were assayed for immunoglobulins. Middle ear effusions were cultured for bacterial pathogens and assayed for interleukin-1 beta, interleukin-6, tumor necrosis factor alpha, and interferon gamma. The medical charts of the patients were retrospectively reviewed to define the history of OM. SUBJECTS: Seventy-five patients with a history of recurrent acute OM, persistent OM with effusion, or both. Exclusion criteria included the presence of a major coexisting condition, or an unclear or atypical history of OM. SETTING: A private practice at a tertiary care children's hospital. INTERVENTIONS: At the time of tympanostomy tube placement, with the patient under general anesthesia, one MEE and a serum sample were collected. RESULTS: Interleukin-1 beta was detected in 58% (44/75) MEEs; interleukin-6, 83% (60/72); tumor necrosis factor alpha, 37% (28/75) [corrected]; and interferon gamma, 61% (45/74). Concentrations of interleukin-1 beta, interleukin-6 and tumor necrosis factor alpha in MEEs were highly correlated with each other (P < .01 for each association) suggesting increased local production and the expected effects of cytokines stimulating their own production during OM. High concentrations of tumor necrosis factor alpha in MEEs were also associated with a history of multiple placements of tympanostomy tubes (r = .63). CONCLUSIONS: These data suggest a regulatory role for cytokines in inflammation during OM, and suggest that high concentrations of tumor necrosis factor alpha in MEEs may be a marker for OM chronicity.

Adolescent↗

PubMed1995

Gas exchange across the middle ear mucosa in monkeys. Estimation of exchange rate.

OBJECTIVE: To estimate the rate of exchange of selected gases across the middle ear (ME) mucosa and define the exchange limitations. DESIGN: At separate sessions, the ME was inflated via the eustachian tube with a bolus of pure nitrogen, carbon dioxide, oxygen, or nitrous oxide, and ME pressures were recorded by tympanometry at selected intervals for up to 4 hours. The slope of the function relating pressure change to pressure was calculated by least squares regression and used as an estimate of the rate constant for exchange of that gas (experiment 1). Because of the slow rate of nitrogen exchange, a second experiment was performed in which the tensor veli palatini muscle was unilaterally paralyzed. The ME was inflated with nitrogen, and the slope of the rate-pressure function for measurements at 24-hour intervals was used to estimate the rate constant. SUBJECTS: Ten juvenile cynomolgus monkeys, six for experiment 1 and four for experiment 2. RESULTS: The relative, average rate constants for carbon dioxide, nitrous oxide, oxygen, and nitrogen were 1, 10.7, 18.6, and greater than 700, respectively. Comparisons of these rates with those predicted by theory show that oxygen and carbon dioxide exchange is diffusion limited, and nitrous oxide and nitrogen is perfusion limited. CONCLUSIONS: The perfusion limitation for nitrogen suggests that its exchange rate is notably increased by inflammation from increased mucosal blood flow. Targeting inflammation for therapy of persistent ME effusions may decrease the rate of nitrogen exchange and reestablish normal ME pressure regulation.

Acoustic Impedance Tests↗

PubMed1995

Treatment of experimental acute otitis media with ibuprofen and ampicillin.

The efficacy of concurrent treatment of experimental acute otitis media with ibuprofen and ampicillin was evaluated in chinchillas with respect to clearance of the effusion and resolution of mucosal inflammation. Sixty-four chinchillas were infected with Streptococcus pneumoniae and randomly assigned to treatment with either IM ampicillin (control) or ampicillin plus ibuprofen (experimental) beginning on day 2 post inoculation. On days 3, 6, 9 and 12, 8 animals from each group were killed, effusions recovered for biochemical assay and the right middle ears prepared for histological study. Between group differences in the number of ears with effusion and effusion volume were not statistically significant. Mucosal thickness and the frequencies of ears with histopathological signs of inflammation were significantly less in the experimental group when compared to the control group. Differences in the effusion concentrations of total protease, 3 of 4 hydrolytic enzymes and free fatty acids favoring the experimental group were observed at the 6, 9 and 12 day endpoints. Also, at those times the levels of the 3 measured products of the cyclooxygenase pathway were less in the experimental group. These results suggest that the addition of ibuprofen to ampicillin for the treatment of acute otitis media decreases production of select eicosonoids, reduces mucosal inflammation and alters the course of the disease in this model of bacterial infection.

Acute Disease↗

PubMed1995

Effect of ibuprofen treatment during experimental acute otitis media.

In this study, the efficacy of concurrent treatment of experimental acute otitis media with ibuprofen and ampicillin was evaluated in chinchillas with respect to clearance of the effusion, presence of mucosal inflammation, and modulation of biochemical markers. Forty chinchillas were infected with non-typable Haemophilus influenzae and randomly assigned to treatment with either IM ampicillin (control) or ampicillin plus ibuprofen beginning on day 2 post inoculation. On days 5 and 10, animals from each group were killed, effusions recovered for biochemical assay, and the middle ears prepared for histological study. Differences in outcome measures favoring the control group were observed at the 5 day endpoint. However, at the 10 day endpoint, mucosal thickness was significantly less, the number of effusion free ears greater, and the concentrations of free fatty acids and thromboxane less in the animals treated with the combined therapy when compared to the control group. These results suggest that the addition of ibuprofen to ampicillin for the treatment of acute otitis media alters disease pathogenesis in this infectious model.

Acute Disease↗

PubMed1995

State and trait negative affect as predictors of objective and subjective symptoms of respiratory viral infections.

State and trait negative affect (NA) were measured in healthy people immediately before an illness was induced through exposure to a respiratory virus. State NA, disease-specific health complaints (e.g., runny nose, congestion, and sneezing), and an associated objective marker of disease severity (mucus secretion weights) were assessed daily during the illness. Baseline trait and state NA were both associated with increased numbers of subsequent complaints. Although greater numbers of complaints among people high in state NA were explicable in terms of greater disease severity, the association of trait NA and symptoms was independent of objective disease. The trait NA complaint association was also independent of state NA and hence not attributable to trait-elicited state affect. Greater trait NA was associated with biases in complaining during but not before illness. This suggested failure to discriminate between symptoms rather than increased sensitivity or hypochondriacal response.

Adolescent↗

PubMed1995

Influenza A virus--induced acute otitis media.

To better understand the significance of viral upper respiratory tract infections in the pathogenesis of acute otitis media (OM), 27 adults underwent intranasal inoculation with influenza A virus. Monitoring consisted of antibody titer determination, tympanometry, and otoscopy. Microbiologic analysis consisted of cultures and polymerase chain reaction (PCR)-based detection for influenza A virus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. All subjects became infected with the challenge virus. By day 4, 16 (59%) developed middle ear pressures of -100 mm H2O or below and 4 (25%) of them developed OM. One subject (4%) developed purulent OM requiring myringotomy for pain relief. Middle ear effusion cultures were negative. PCR analysis of that subject's middle ear effusion and nasal washes were positive for influenza A virus and S. pneumoniae. These findings support a causal role for viral upper respiratory tract infections in the pathogenesis of OM, possibly mediated by middle ear underpressures and viral and bacterial middle ear infection.

Acute Disease↗

PubMed1995

Effect of rhinovirus 39 (RV-39) infection on immune and inflammatory parameters in allergic and non-allergic subjects.

The economic impact and medical complication rate of the common cold are well documented, but many of the physiological, inflammatory, and immune responses to common cold viruses have only recently been investigated. The purpose of this study was to compare selected systemic immune and inflammatory responses to experimental rhinovirus (RV)-39 challenge in seronegative allergic rhinitis and non-allergic rhinitis subjects. Peripheral blood was obtained before (baseline), during (acute), and 23 days after (convalescent) RV-39 intranasal challenge and assayed for leucocyte histamine release, serum immunoglobulins, allergen-specific IgE antibodies, plasma histamine, and platelet aggregation. All subjects were infected, as manifested by viral shedding in nasal secretions or seroconversion. RV-39 infection induced significant acute increases in serum IgE, leucocyte histamine release, and platelet aggregation, but caused no changes in serum IgG, serum IgA, serum IgM, and plasma histamine. The first change was confined to the allergic rhinitis subjects. There was no evidence that the acute rise in total serum IgE was due to an elevation of a pre-existing, pollen-specific serum IgE antibody. The results show that intranasal challenge with RV-39 induced changes in systemic immune and inflammatory parameters with a unique response pattern in allergic rhinitis subjects.

Adolescent↗

PubMed1995

Effect of experimental influenza A virus infection on isolation of Streptococcus pneumoniae and other aerobic bacteria from the oropharynges of allergic and nonallergic adult subjects.

Intranasal challenge with both influenza A virus and Streptococcus pneumoniae promotes otitis media with S. pneumoniae in chinchillas. We investigated whether influenza A virus infection promotes oropharyngeal colonization with S. pneumoniae and other middle ear pathogens by selectively inhibiting commensal bacteria. On study day 0, 12 allergic and 15 nonallergic adult subjects were intranasally inoculated with influenza A/Kawasaki (H1N1) virus. Every subject was infected with the virus as demonstrated by nasal shedding or seroconversion. Average upper respiratory symptom scores and nasal secretion weights from the entire subject group were elevated between days 2 and 6 (acute phase) and were not significantly different between allergic and nonallergic subjects. S. pneumoniae was not isolated from any subject prior to the virus challenge but was isolated in heavy density from 4 (15%) subjects on day 6 (P = 0.055). Staphylococcus aureus was isolated more frequently from the nonallergic subjects than from the allergic subjects on days 2 (80 versus 25%, respectively) 4, (67 versus 17%, respectively), and 6 (73 versus 25%, respectively) (P < 0.05). The isolation rates of other middle ear pathogens were not significantly different before virus challenge and during the acute and resolution phases (days 27 to 30) of the experimental infection for the entire subject group or either the allergic or nonallergic subgroup. Densities and isolation rates of commensal bacteria from the entire subject group were similar throughout the observational period. These results suggest that the virus infection promoted S. pneumoniae colonization of the oropharynx and that nonallergic persons may be more vulnerable to colonization with S. aureus than allergic persons. The altered colonization rates were not attributed to inhibition of commensal bacteria.

Acute Disease↗