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Biomedical subjects

W J Doyle

Publications and source records attributed to W J Doyle.

At least 73 records · Page 4Linked to original sources
PubMed1995

In vivo observation with magnetic resonance imaging of middle ear effusion in response to experimental underpressures.

In this study, magnetic resonance imaging (MRI) was used to define, in vivo, the effect of acute middle ear (ME) underpressures on vascular permeability and the development of effusion. The MEs of four cynomolgus monkeys were unilaterally inflated with oxygen and carbon dioxide on different occasions and followed for a period of approximately 4 hours by tympanometry and MRI scanning. Carbon dioxide inflations caused the rapid development of ME underpressures of less than -600 mm H2O by 10 minutes. The MRI scans showed a progressive brightening of the ME and all associated air cells, indicative of the accumulation of effusion in three of the four experiments. An MRI contrast agent was administered to the vascular compartment during the course of the experiment and was rapidly transferred to the ME space, indicating vascular permeability to the agent. The contralateral, control side did not develop significant underpressures, effusion, or increased vascular permeability. Inflation with oxygen caused lesser underpressures and no accompanying changes in the MRI scans. These data support the hydrops ex vacuo theory and confirm the usefulness of MRI for in vivo documentation of the development of ME effusions and changes in vascular permeability of the mucosa in the experimental setting.

Animals↗
PubMed1995

Otologic and systemic manifestations of experimental influenza A virus infection in the ferret.

In an effort to further validate an animal model and to better define the mechanisms relating viral upper respiratory tract infections and acute otitis media, we infected 10 ferrets intranasally with influenza A virus. Infection was monitored by cultures and antibody titers, illness was monitored by signs and temperatures, and otologic complications were monitored by otoscopy, tympanometry, and eustachian tube function testing. All animals became infected. Forced-response test results showed progressive increases in the passive function variables after inoculation. Inflation-deflation test results documented progressive impairment of active tubal function, which was accompanied by the development of middle ear underpressures. No otitis media was seen. The results suggest that influenza A virus infection results in progressive, subtotal occlusion of the eustachian tube lumen, which compromises the ventilatory function of the tube, thereby promoting the development of middle ear underpressures. These findings support the hypothesized pathophysiologic relationship between viral upper respiratory tract infections, eustachian tube dysfunction, middle ear underpressures, and acute otitis media. Given these pathophysiologic changes and previously documented physiologic similarities to the eustachian tube-middle ear system of human beings, we conclude that the ferret represents an appropriate animal model for studying the pathogenic processes related to viral upper respiratory tract infections, eustachian tube dysfunction, and otitis media and for testing of potential prophylactic and therapeutic regimens.

Animals↗
PubMed1995

Effects of dopamine, dobutamine and phentolamine on middle ear pressure and blood flow in cynomolgus monkeys.

To test the hypothesis that changes in mucosal perfusion could influence gas exchange and thus, middle ear pressure, the effects of systemically administered drugs showing alpha adrenergic effects on mucosal perfusion and middle ear pressure were evaluated in 4 cynomolgus monkeys. Two drugs with well characterized sympathomimetic effects, dopamine and dobutamine, were studied, and dopamine was combined with an antagonist, phentolamine. For each experiment, the monkeys were anesthetized with pentobarbital and followed for a 90 min baseline period. Then, the drug was administered for 60 min with follow-up extending through that period and for an additional 60 min. Data consisted of repeated measurements of rectal temperature, heart rate, blood pressure, left middle ear pressure and right mucosal blood velocity, volume and flow. The results documented an increase in middle ear pressure after intravenous infusion of either dopamine or dobutamine and an attenuation of the response by concurrent administration of phentolamine. Laser Doppler measurements documented a variable, non-directional change in blood volume, velocity and flow. The changes in the middle ear pressure observed following systemic administration of autonomic drugs are consistent with the rapid establishment of a transmucosal pressure gradient secondary to changes in the supply and/or metabolism of gases.

Animals↗
PubMed1995

Effects of intranasal challenge with histamine, bradykinin and prostaglandin on middle ear pressure and blood flow in cynomolgus monkeys.

Previous studies documented a significant increase in middle ear pressure following intranasal challenges with ascaris antigen or histamine in sensitized cynomolgus monkeys. To confirm that effects and investigate the mechanism, 4 monkeys were intranasally challenged at separate sessions with histamine (10 mg), bradykinin (1, 10 mg) and prostaglandin D2 (PgD2, 0.5, 1.0 mg) and followed for 90 min. Before and after challenge, middle ear pressure, mucosal blood flow, heart rate, blood pressure, body temperature and the partial pressures of O2 and CO2 in the venous blood were measured. The results showed that while bradykinin challenge had no effect on these measures, PgD2 provoked increased middle ear pressure, and histamine resulted in a biphasic pattern of increasing pressures followed by decreasing pressures. The pattern of change in middle ear pressure after histamine challenge was explicable by a mechanism involving transmucosal gas exchange, while that for PgD2 was related to increased mucosal inflammation. These results document the development of positive middle ear pressures during provoked nasal inflammation and may have relevance to similar observations in the clinical setting.

Administration, Intranasal↗
PubMed1995

Reproducibility of the effects of intranasal ragweed challenges in allergic subjects.

BACKGROUND: Intranasal allergen challenges have been used to study the pathogenesis of disease expression, to evaluate the efficacy of therapies and to make diagnosis of allergic status. Few data, however, are available regarding the reproducibility of the responses to such provocative challenges. OBJECTIVE: The purpose of this study was to evaluate the reproducibility of selected responses of allergic subjects to intranasal pollen challenge. METHODS: Eighteen adults with ragweed allergy completed three dose-response challenge sessions at a minimum interval of 1 week. Sessions were single blinded and randomized to include two intranasal ragweed challenges (doses 10, 100, and 1000 PNU) and one placebo challenge conducted out of the ragweed season. Additionally, 12 of these subjects completed a third ragweed challenge session conducted during the ragweed season. Following administration of each dose, symptoms were scored, sneezes counted, and nasal patency measured by active posterior rhinomanometry. Total nasal secretion weight for each session was measured. RESULTS: For all measures, average dose response curves were identical for the two extra-seasonal ragweed challenges and these were significantly different from those of the placebo challenge session. Intra-individual responses to the two ragweed challenges were highly correlated between sneeze count and secretion weight, and were moderately correlated for objective and subjective measures of rhinorrhea and congestion. No significant increases in these responses were observed for the intra-seasonal ragweed challenge session. CONCLUSIONS: These results document a reproducible symptomatic and physiologic response to intranasal ragweed challenge.

Adult↗
PubMed1994

Effect of experimental rhinovirus 39 infection on the nasal response to histamine and cold air challenges in allergic and nonallergic subjects.

To determine whether a viral upper respiratory tract infection can alter the responsiveness of the nasal mucosa, paired intranasal histamine and cold air challenge sessions were performed before and after (8 to 13 days) experimental rhinovirus infection in 18 nonallergic subjects and 20 subjects with seasonal allergic rhinitis. The nasal response to the challenges was measured as symptom scores for rhinorrhea and congestion, counts for sneezing, weight for expelled secretions, and inspiratory conductance for nasal patency. For both sessions, a greater response was observed in allergic subjects for sneezing, symptoms of rhinorrhea and congestion, secretion weights provoked by histamine challenge, and secretion weights provoked by cold air challenge when compared with the nonallergic subjects. A comparison of the responses to the paired challenge sessions showed greater responses for sneezing, secretion weight and rhinorrhea to histamine and for secretion weight to cold air challenges performed after rhinovirus infection. No differences were observed between allergic and nonallergic subjects with respect to the degree of enhanced responsiveness secondary to viral infection. These results document an increased responsiveness of the nose to these stimuli during the postsymptomatic period of a rhinovirus infection in both allergic and nonallergic subjects.

Adolescent↗
PubMed1994

An experimental study of cefixime in the treatment of Streptococcus pneumoniae otitis media.

Previous studies using the chinchilla animal model demonstrated that the third generation cephalosporin cefixime (Suprax) with split dosing was as effective as ampicillin in sterilizing the middle ear cleft when infected with S. pneumoniae. In this investigator-blinded, randomized trial, a single daily dose of cefixime (8 mg/kg per day) performed as well as split dosing of cefixime (8 mg/kg every 8 h) and ampicillin (150 mg/kg every 8 h) in the time to sterilization of the middle ear cleft. No statistically significant differences were noted between groups in otoscopy or tympanometry. All antibiotic regimens performed better than saline control (P < 0.0001) with regard to time to sterilization of the middle ear cleft. The results of this study support the daily administration of cefixime as an effective agent for the treatment of otitis media due to its extended half-life and broad antibiotic spectrum.

Acoustic Impedance Tests↗
PubMed1994

Nasal and otologic effects of experimental influenza A virus infection.

Past studies showed that experimental rhinovirus colds in adults resulted in eustachian tube dysfunction and abnormal middle ear pressures. In the present study, the symptoms and pathophysiologic findings accompanying experimental influenza viral infection were documented. A total of 33 healthy adult volunteers were intranasally challenged with an influenza A/Kawasaki/86 (H1N1) virus and cloistered over a 9-day postchallenge period to monitor for evidence of infection, signs and symptoms of illness, and the extent and frequency of pathophysiologic responses of the nose, eustachian tube, and middle ear. Results showed a protective effect of high (> or = 16) prechallenge specific hemagglutination-inhibition antibody titer on the rate of infection and the magnitude and extent of provoked symptoms and pathophysiologic findings. Infected subjects with low (< 16) prechallenge serum antibody titers (n = 21) developed significant respiratory illness. These subjects also had objectively measurable increases in nasal secretion production, and decreased nasal patency and mucociliary clearance rates. More than 80% of the infected subjects developed eustachian tube dysfunction, and approximately 80% had middle ear underpressures of less than -100 mm H2O on study days 4 and 5. Five of 21 infected subjects with low prechallenge antibody titers had otoscopic evidence of otitis media with effusion. These results support a causal role for viral upper respiratory tract infection in the pathogenesis of otitis media, possibly mediated by the early development of eustachian tube dysfunction and abnormal middle ear pressure.

Adult↗
PubMed1994

Middle ear gas exchange in rhesus monkeys.

The mechanism of gas exchange between the middle ear and tissue is fundamental to understanding middle ear physiology and pathophysiology. In this study, the middle ears of six rhesus monkeys were inflated on separate occasions with nitrogen (N2), carbon dioxide (CO2), and oxygen (O2), and middle ear pressures were recorded at defined times postinflation for up to 4 hours. From these data, rate constants governing the exchange of these gases were estimated and compared to those predicted under both diffusion and perfusion limitations. The results show that the rate constants for middle ear to tissue exchange of O2 and CO2 are consistent with a diffusion-limited process. In contrast, middle ear pressure did not decrease over the study period following introduction of N2 into the middle ear. This is interpretable as a much slower rate of N2 exchange than that predicted by either perfusion or diffusion-limited models calibrated to the O2 and CO2 rate constants. These results have significant implications for middle ear gas exchange and suggest that for relatively short observation periods, the behavior of middle ear pressure is controlled by experimentally established O2 and CO2 gradients.

Animals↗
PubMed1994

Role of IgE-mediated hypersensitivity in otitis media with effusion: pathophysiologic considerations.

A pathophysiologic model of otitis media with effusion secondary to IgE-mediated hypersensitivity is described. Specific mediators of inflammation are released by mucosal mast cells in the nasal mucosa following the interaction of antigen and specific IgE antibody. These mediators increase vascular permeability, mucosal blood flow, and, most important, mucus production. Furthermore, accessory cell types are recruited by colony-stimulating factors that in turn provide an autocrine-positive feedback for the influx of further inflammatory cells. The eustachian tube is then effectively obstructed by both intrinsic venous engorgement and extrinsic mucus plugs, isolating the middle ear space from the ambient environment. The net result is the increased exchange of nitrogen into the middle ear mucosa from the middle ear cavity. This causes the development of a significant middle ear underpressure that disrupts tight junctions and allows for transudation of fluids into the middle ear space. The prolonged obstruction of the eustachian tube with mucus results in middle ear inflammation, mucosal metaplasia, and increased glandular activities, all of which are hallmarks of chronic otitis media with effusion.

Basophils↗
PubMed1994

Sensorineural hearing loss from quinolinic acid: a neurotoxin in middle ear effusions.

Quinolinic acid (QUIN) is an endogenous metabolite that exerts a neurotoxic effect by binding to specific neuronal receptors. Studies involving a broad spectrum of infectious and inflammatory central nervous system diseases have suggested a role for QUIN in causing neuronal injury. Since there is evidence for presence of the QUIN receptor in mammalian cochleas, QUIN was measured in middle ear effusions (MEEs). Gas chromatography/mass spectrometry detected QUIN in each of 65 diluted human MEEs, with a mean of 482 +/- 75 (SEM) nmol/L and a range from 15 to 2667 nmol/L. QUIN was also detected in each of 197 chinchilla MEEs from five different models of otitis media, with a mean of 10.6 +/- 1.3 (SEM) mumol/L and a range from 0.23 to 146.0 mumol/L (corrected for dilution). To determine whether QUIN causes sensorineural hearing loss (SNHL), QUIN solutions were placed on round window membranes (RWM) for 20 to 240 minutes, in 20 chinchillas. SNHL was detected by electrocochleography in QUIN-exposed animals, but not in saline controls. We conclude that QUIN is present in MEEs and that QUIN in the middle ear has the potential to cross the RWM and cause sensorineural hearing loss, possibly by binding to specific neuronal receptors in mammalian cochleas.

Animals↗
PubMed1994

Otologic manifestations of experimental rhinovirus infection.

Episodes of acute otitis media are commonly associated with viral upper respiratory tract infections. Rhinoviruses account for approximately 40% of these infections, and were previously shown to alter eustachian tube function and middle ear pressures. However, progression to otitis media has not been prospectively documented. In the present study, changes in tympanometric pressures and otoscopic findings resulting from experimental intranasal rhinovirus type-39 inoculation were documented in 60 adult volunteers. Fifty-seven (95%) subjects became infected and 34 (60%) of these had a clinical cold. Prior to viral inoculation, 3 (5%) subjects had middle ear pressures of less than -100 mm H2O and two of these subjects developed middle ear effusions following infection. In all, 22 (39%) subjects developed middle ear pressures of less than -100 mm H2O. No subject with normal middle ear pressures prior to infection developed evidence of effusion. This study extends the otologic manifestations of rhinovirus infection to include otitis media. Furthermore, these results support the hypothesized relationship between upper respiratory tract infections, eustachian tube dysfunction, and otitis media.

Acoustic Impedance Tests↗
PubMed1993

Analysis of nasal secretions during experimental rhinovirus upper respiratory infections.

BACKGROUND: To determine the underlying mechanisms for rhinovirus-induced nasal secretions, nasal lavage fluids were analyzed during experimental rhinovirus infections. METHODS: Twenty patients with allergic rhinitis and 18 nonallergic control subjects were inoculated with rhinovirus type 39. Nasal lavage was performed before and on days 2 through 7 after viral inoculation, and the lavage fluids were assayed for proteins and mast cell mediators. RESULTS: The secretion of total protein and both plasma proteins (albumin and IgG) and glandular proteins (lactoferrin, lysozyme, and secretory IgA) increased after rhinovirus inoculation. Analysis of the specific protein constituents revealed that nasal secretions during the initial response to the rhinovirus infection were predominantly due to increased vascular permeability. Allergic subjects tended to have fewer symptoms and more vascular permeability than control subjects, and increased histamine secretion after rhinovirus inoculation was more frequently seen in the allergy group. CONCLUSION: Nasal secretions found early in the course of a viral upper respiratory infection are due to increased vascular permeability, whereas glandular secretions predominate later in the infection.

Adolescent↗
PubMed1993

Effect of rhinovirus 39 infection on cellular immune parameters in allergic and nonallergic subjects.

Patients with allergic rhinitis (AR), compared with nonallergic persons, have been reported to respond differently to a variety of stimuli, some of which are immunologic in nature. This study compared the systemic cellular immune responses to experimental rhinovirus (RV) 39 challenge in RV-39-seronegative AR (n = 20) and nonallergic (n = 18) subjects. Peripheral blood was obtained before, 4 or 7 days after, and 23 days after RV-39 intranasal challenge and assayed for the number and function of various white blood cells. All subjects were infected, as manifested by viral shedding in nasal secretions or seroconversion. RV-39 induced marked changes from baseline values in both immune cell number and functions. Compared with nonallergic subjects, AR subjects manifested different responses for the following parameters: (1) numbers of total white blood cells and lymphocytes (smaller increases on day 4), (2) helper/suppressor T cell ratio (absence of an increase on day 7 and presence of an increase on day 23), (3) number of IL-2 receptor-positive suppressor T cells (presence of a decrease on day 7), (4) natural killer (NK) cell numbers (absence of an increase on day 4 and presence of increases on days 7 and 23), (5) NK/T cell ratio (absence of an increase on day 4 and a decrease on day 7), (6) NK cell activity (a blunted decrease on day 7 and absence of a decrease on day 23), and (7) RV-39-induced lymphocyte proliferation (exaggerated increase on day 4). The results show that intranasal challenge with RV-39 induced RV-39-specific and nonspecific systemic cellular immune responses and a unique immunologic response pattern in AR subjects.

Adult↗
PubMed1993

Evaluation of mixtures of purified Haemophilus influenzae outer membrane proteins in protection against challenge with nontypeable H. influenzae in the chinchilla otitis media model.

Nontypeable Haemophilus influenzae (NTHi) is one of the leading causative agents of bacterial otitis media, and no vaccine has been shown to be effective against it. Three outer membrane lipoproteins of NTHi have been investigated extensively and are leading candidates for inclusion in a vaccine against this organism. Hi-PAL (P6), recombinant PCP (rPCP), and e (P4) proteins are antigenically conserved among NTHi strains and elicit bactericidal and protective antibodies. A genetic fusion of the rPCP and Hi-PAL proteins has also been reported. Mixtures of these proteins were used for active immunization experiments in the chinchilla model of otitis media. Chinchillas were immunized either with a mixture of all three lipoproteins or with the mixture of rPCP-PAL hybrid plus e protein. When these animals were challenged with a NTHi strain injected directly into the middle ears, no protection from infection or disease, as measured by otoscopy, was observed in either group. However, effusion and inflammation measured by tympanometry were significantly reduced in animals immunized with the three lipoproteins. Animals that had been immunized with either whole NTHi cells or total outer membranes and then challenged with the homologous strain were significantly protected from both infection and disease, as determined by tympanometry and otoscopy. Unlike other animals antisera, chinchilla antisera against the purified proteins had no bactericidal activity against NTHi but did fix complement on the cell surface. Thus, the chinchilla immune responses to mixtures of these lipoproteins differ from the immune responses observed in other animal species. Further evaluation of these proteins for their vaccine potential remains to be done.

Animals↗
PubMed1993

Efficacy of ceftibuten for acute otitis media caused by Hemophilus influenzae: an animal study.

Ceftibuten is a new oral cephalosporin with an unusual stability to beta-lactamases that can hydrolyze other extended-spectrum cephalosporins. Using the chinchilla animal model, we compared the efficacy of ceftibuten (n = 33) with that of saline (n = 34), ampicillin (n = 32), and cefixime (n = 31) for the treatment of acute otitis media caused by beta-lactamase-producing nontypeable Hemophilus influenzae. Ceftibuten was superior to ampicillin regarding the time necessary to sterilize the middle ear (p < .001) and eliminate effusion (p < .001). The mean days of therapy required for bacteriologic cure were 2.57 for ceftibuten, 2.95 for cefixime, 7.95 for ampicillin, and 8.16 for saline. At the conclusion of therapy, chinchillas treated with ceftibuten had a significantly lower prevalence of positive cultures and middle ear effusion than did animals treated with ampicillin. No significant differences were observed between ceftibuten and cefixime. The results of this randomized, investigator-blinded experiment warrant further consideration of ceftibuten as a second-line agent for acute otitis media caused by ampicillin-resistant H influenzae.

Acute Disease↗
PubMed1993

Therapeutic effects of an anticholinergic-sympathomimetic combination in induced rhinovirus colds.

This study's objective was to determine if the combination of pseudoephedrine hydrochloride and atropine sulfate attenuates the symptomatic and pathophysiologic response of individuals to experimental rhinovirus infection when given after illness begins. Forty-three susceptible adult volunteers were challenged with rhinovirus type 39 and randomly assigned to 1 of 2 treatment groups. Twenty-one subjects were treated with the active medication (0.3 mg atropine sulfate and 60 mg pseudoephedrine) and 22 subjects were treated with inert capsules identical in appearance. Treatments were administered 4 times daily beginning approximately 24 hours after rhinovirus challenge and extending for 5 days. Before challenge and on each of 5 treatment days, all volunteers were asked to rate symptom severity and were evaluated for secretion production (weighted tissues), nasal patency (active posterior rhinomanometry), nasal clearance (dyed saccharin technique), eustachian tube function (9-step test), and middle ear status (tympanometry). Twenty subjects in each group were infected with rhinovirus type 39 and were included in the efficacy analysis. Between-group comparisons showed no significant differences in total symptom scores, combined nasal symptom score, secretion production, or the frequencies of persons with eustachian tube obstruction or abnormal middle ear pressures. However, an objective measure of nasal congestion was significantly lower in the active treatment group. The nasal mucociliary clearance rate was significantly more impaired in that group. Side effects consistent with anticholinergic activity were reported more frequently in the active treatment group.

Administration, Oral↗