Relationship between surface area and volume of the mastoid air cell system in adult humans.

INTRODUCTION: The geometry of the adult human mastoid air cell system has not previously been described over a large range of mastoid air cell volumes. METHODS: Twenty subjects with a wide range of mastoid air cell pneumatised areas, as determined by X-ray, underwent computed tomography scanning of the middle ear. Mastoid air cell surface areas and volumes were then reconstructed from serial imaging sections, using Image J software. RESULTS: Mastoid air cell volumes varied from 0.7 to 21.4 ml, and were linearly related to the pneumatised area. Right and left mastoid air cell volumes and surface areas were highly correlated. The mastoid air cell surface area was a linear function of volume. CONCLUSION: The relationship between mastoid air cell surface area and volume is similar over a wide range of volumes. Given that the rate of gas exchange across the mastoid air cell mucosa is related to the mastoid air cell surface area, that rate will thus also be a direct linear function of the mastoid air cell volume.

Urinary histamine metabolite elevations during experimental influenza infection.

BACKGROUND: Although histamine is hypothesized to mediate symptoms induced by viral upper respiratory infections, elevations of this mediator have not been observed in nasal lavage fluids recovered from patients with viral upper respiratory infections. OBJECTIVE: The purpose of this study was to use a novel method to determine whether histamine is released during experimental influenza A infection. METHODS: Healthy adults (n = 15) were cloistered and inoculated intranasally with influenza A virus, and monitored for infection and illness. Daily morning void urines were collected and assayed for histamine and its metabolites by gas chromatography-mass spectrometry. Total histamine was calculated for each urine specimen by summing the assayed values of histamine and its metabolites. RESULTS: All subjects were infected and developed illness. ANOVA documented a significant effect of study day (viral infection) on urinary levels of total histamine (P < 0.02). Pairwise analysis showed a significant elevation 2 days after inoculation. CONCLUSIONS: These results provide the first direct evidence that histamine is released in vivo during infection with a virus that causes cold/flu symptoms.

Effect of intranasal challenge with interleukin-6 on upper airway symptomatology and physiology in allergic and nonallergic patients.

BACKGROUND: Interleukin-6 (IL-6) is a potent regulator of airway inflammation and an important component of biologic homeostasis. Previously, a temporal relationship between the local elaboration of IL-6 and the development of upper airway symptoms and pathophysiologic findings was reported for patients experimentally infected with influenza A virus or rhinovirus. OBJECTIVE: The objective of this study was to determine the provocative effects of direct, intranasal administration of IL-6 on those symptoms, signs, and pathophysiologic findings that accompany viral upper respiratory infection. METHODS: In this double-blind, placebo-controlled, crossover trial, 10 symptomatic allergic, 10 asymptomatic allergic, and 10 nonallergic adult patients were pretreated with intranasal histamine and, after 15 minutes, were challenged with repeated doses of placebo (saline) or with increasing doses (0, 0.01, 0.1, and 1 microg/mL) of recombinant IL-6 at 20-minute intervals, during randomized paired sessions. Symptom scores, sneeze and cough counts, nasal secretion weights, nasal conductance (rhinomanometry), middle ear pressure (tympanometry), Eustachian tube function (sonotubometry), and pulmonary function (spirometry) were evaluated before and after the histamine challenge, after each dose of IL-6 or placebo, and then at 90 minutes and 2, 3, 4, 6, and 24 hours. RESULTS: At the doses used, intranasal challenge with IL-6 was well tolerated. At the 90-minute postchallenge endpoint, a significant effect of challenge substance and group assignment was documented for nasal secretion weight. Paired comparisons showed that the effect was greater for the allergic patients when compared with the nonallergic patients. There were no differences between placebo and IL-6 challenge for any of the other measured parameters. CONCLUSIONS: These results show that local IL-6 at relatively low doses can provoke increased nasal secretions in patients with allergic rhinitis.

Effect of experimental influenza A infection on systemic immune and inflammatory parameters in allergic and nonallergic adult subjects.

BACKGROUND: The economic impact and medical complication rate of viral upper respiratory infections are well documented, but many of the physiologic, inflammatory, and immune responses to respiratory viruses have only recently been investigated. A previous study demonstrated differential systemic immune and inflammatory responses in allergic rhinitis (AR) and nonallergic rhinitis (NAR) subjects during experimental infection with rhinovirus-39. OBJECTIVE: The purpose of this study was to compare selected systemic immune and inflammatory responses to experimental influenza A virus (FLU) challenge in seronegative AR and NAR subjects. METHODS: Peripheral blood was obtained at baseline (study day 0) and 3, 6, 18, and 31 days after intranasal FLU challenge and assayed for leukocyte histamine release, serum immunoglobulins, and plasma histamine. RESULTS: All subjects were infected, as manifested by viral shedding in nasal secretions and/or seroconversion. FLU infection induced decreases in spontaneous leukocyte histamine release and increases in anti-immunoglobulin E-induced leukocyte histamine release, which were evident at least 1 month after infection, but caused no significant changes in serum immunoglobulins or plasma histamine. There were no differences between AR and NAR subjects for any of the study parameters. CONCLUSIONS: The results show that intranasal challenge with FLU induces changes in leukocyte histamine release, but not other systemic immune and inflammatory responses.

Abnormal middle ear pressures during experimental influenza A virus infection--role of Eustachian tube function.

INTRODUCTION: Experimental infection of adults with influenza A virus, rhinovirus or RSV causes abnormal ME pressure in some, but not all subjects. The hypothesis tested in this study is that the response variability is caused by constitutional differences in the functioning of the Eustachian tube. METHODS: 18 adult subjects were experimentally infected with influenza A virus. On five occasions before virus exposure, middle ear pressure (by tympanometry) and Eustachian tube function (by sonotubometry) were recorded bilaterally. Tests were repeated on days 1 through 8 and 10 after infection. Individual ears were classified with respect to the number of pre-exposure, positive sonotubometric testings and the middle ear pressure response to infection was compared between ears with Eustachian tube openings at all pre-infection test sessions (GR-A) and those with at least one negative test (GR-B). RESULTS: Pre-exposure, 19, six, four, four, one and two ears had tubal openings on five, four, three, two, one and zero sessions, respectively. For that period, GR-A had significantly lesser average intra-ear and intra-group middle ear pressure variances compared to GR-B, but there were no between-group differences in the average middle ear pressure or in the number of observations of abnormal middle ear pressure. After virus exposure, middle ear pressure variances and the number of abnormal observations increased and the average pressure decreased in both groups, but the effects were more pronounced for GR-B ears. CONCLUSIONS: These results support the hypothesis that pre-existing good Eustachian tube function reduces the otological complications of viral upper respiratory tract infection.

Experimental results do not support a gas reserve function for the mastoid.

The mastoid is an aerated extension of the middle ear gas pocket whose state of development was shown to be an indicator of past and future otitis media experience. While the function(s) of the mastoid is not known, a number of hypotheses has been advanced to explain the reported association between mastoid size and middle ear disease. These include the hypotheses that, with respect to the middle ear, the mastoid functions as a pressure buffer, a gas reserve, and/or a pressure regulator. In this paper, a physical model of the mastoid is presented that makes specific predictions against which the validity of the hypothesized gas reserve function could be tested. Data from three published clinical experiments were evaluated for consistency with the predictions of the model, and the hypothesis was rejected. Also, when reinterpreted within the context of the model, the published data do not support a pressure-regulating function for the mastoid.

Mathematical model explaining the sources of error in certain estimates of the gas exchange constants for the middle ear.

Mover-Lev and colleagues reported a carbon dioxide-oxygen time-constant ratio of 3.9 for transmucosal gas exchange in guinea pigs under conditions of a large positive oxygen pressure gradient and a negative carbon dioxide gradient. That ratio is much less than the value of 19 reported previously for monkeys and used in predictive models of middle ear pressure regulation. In this report, the mathematics that underlie models of transmucosal gas exchange are developed and the conditions that allow accurate estimation of time constants are defined. The results demonstrate that the experimental and analytic methods used by Mover-Lev et al do not control for certain confounding effects or concurrently measure all required system parameters. Under the most realistic conditions, their ratio of 3.9 represents a significant underestimation of a true value on the order of 10. Also, their expectation of nonvarying, transmucosal time constant ratios for pairings that include reactive gases is simplistic and true only for identical experimental contexts.

Prevention of otitis media with effusion by repeated air inflation in a monkey model.

OBJECTIVES: To test the following hypotheses that (1) middle ear (ME) air inflation prevents the development of otitis media with effusion in a monkey model of functional eustachian tube obstruction, and (2) ME inflation treatment of otitis media with effusion can cause artifactual clinical improvements due to fluid displacement from the tympanum to the adjacent airspaces. DESIGN: Randomized controlled trial. SUBJECTS: Twelve cynomolgus monkeys. INTERVENTIONS: Eustachian tube dysfunction was induced by botulinum paralysis of the right tensor veli palatini muscle in all monkeys. Before and on study days 9, 15, and 21 after paralysis, the presence or absence, and distribution of ME effusion were documented using magnetic resonance imaging (MRI). Right and left ears were examined twice daily for 21 days using tympanometry, and right ME air inflation (n = 6 ears) or sham inflation (n = 6 ears) was done immediately after those examinations if the ME pressure was -100 mm H2O or less. On 10 of the scheduled MRI evaluations, the MRI was repeated immediately after an inflation to document the possible redistribution of fluid within the ME caused by the maneuver. RESULTS: Middle ear pressure remained within normal limits for the follow-up period in 11 of the 12 nonparalyzed left ears, in none of the 6 sham-inflated right ears, and in 3 of the 6 air-inflated right ears. Three air-inflated right ears developed flat tympanograms (ie, days 14 through 16). Magnetic resonance imaging documented inflammation and fluid in 1 of the 11 nonparalyzed left ears and in all sham-inflated right ears. Lesser degrees of inflammation and effusion based on MRI evaluations were noted for the 3 air-inflated right ears that retained near-ambient pressures when compared with the right 3 ears that developed a flat tympanogram. The MRI measure of effusion quantity within the tympanum was decreased acutely after inflation, but was simultaneously increased in the adjacent airspaces of the temporal bone. CONCLUSIONS: Repeated air inflation prevented the development of otitis media with effusion in 50% of the ears with functional eustachian tube obstruction. Postinflation MRI documented the displacement of fluid by inflation from the tympanum to the mastoid and petrous air cells. Using standard clinical evaluations such as tympanometry and otoscopy, this fluid redistribution can cause a false diagnosis of improvement.

The effects of changing middle ear pressure and gas partial pressure on mucosal blood flow and vascular permeability in the chinchilla.

OBJECTIVE: To determine if middle ear (ME) gas composition and/or total pressure regulates local mucosal blood flow (MBF) and vascular permeability. The hypotheses tested are: (1) relatively high local CO2 tensions and/or low O2 tensions increase the ME MBF and vascular permeability; and (2) sub-atmospheric total ME pressure provokes similar effects. METHODS: The responses of ME MBF and vascular permeability parameters were measured during 60 min exposures of chinchilla MEs to one of two test gas mixtures (16.3% O2, 5.1% CO2, balance N2, or 5.3% O2, 15.6% CO2, balance N2) applied at different levels of underpressure (ref. ambient). In the first set of experiments (n = 19), mucosal perfusion parameters were recorded using a Laser Doppler Flowmeter for 60 min before and 60 min after exposure to the experimental conditions. In the second set of experiments (n = 19 chinchillas, 38 ears), the MEs were exposed to the gas mixtures and then maintained for 60 min at ambient pressure or at negative pressures of -200, -400, -600 mmH2O. Fifty minutes into the experiment, the animals were injected intravenously with 60 mg/kg of horseradish peroxidase (HRP). The animals were killed and existing effusion was aspirated, its volume recorded and then analyzed for total protein. From surface preparations of the ME mucosa, vascular leakage sites were measured as percent total surface area using an image analysis program with the threshold window set to discriminate HRP stain. RESULTS: Throughout the 120 min in the first set of experiments, the measured MBF parameters decreased in all exposure groups. Comparisons among groups for the absolute magnitude of the change from baseline showed that high local CO2 partial pressures decreased MBF and ME underpressures increased MBF, but the effects did not achieve statistical significance. The results of the second set of experiments demonstrated no effect of gas composition on any of the measured parameters of vascular permeability. All measures of permeability were linearly related to the magnitude of the underpressure. CONCLUSION: These data support a role for total ME pressure, but not CO2 partial pressure in regulating ME MBF and vascular permeability.

Mucosal surface area determines the middle ear pressure response following establishment of sniff-induced underpressures.

INTRODUCTION: Miura and colleagues presented data that they interpreted as evidencing a pressure-regulating function of the mastoid mucosa. Specifically, they reported different responses after sniff-induced middle ear (ME) underpressure for ears with and without a history of otitis media with effusion (OME). To understand the mechanism underlying that effect, a previously developed mathematical model was adapted to their experiment and used to simulate the expected pressure-time functions under different conditions. METHODS: A simple, two-compartment model of passive, gradient-driven, trans-mucosal gas exchange was used to simulate ME pressure behaviour. Initial conditions for the free parameters of the model were taken from published data for humans and monkeys. Functions relating surface area to volume for geometric representations of the ME were constructed and used as model parameters. The effect of sniffing on ME gas partial pressure was modelled as a fractional reduction proportional to gas representation in the ME. RESULTS: The model accurately simulated the time course and magnitude of the post-sniffing pressure change reported for both normal and abnormal MEs. The post-sniffing pressure increase is driven by sniff-induced blood-ME partial pressure gradients for CO2, O2, and H2O, which cause passive counter-diffusion of those gases. The effect of disease on the rate of pressure increase is attributable to the reduced surface area for exchange caused by underdevelopment of the mastoid in ears with a history of OME. CONCLUSIONS: These results do not support a pressure-regulating role for the mastoid mucosa. Contrary to currently held beliefs, the model simulation suggests that small, not large mastoid volumes buffer ME pressure from rapid change due to trans-mucosal gas transfers.

Validation by magnetic resonance imaging of tympanometry for diagnosing middle ear effusion.

This study was performed to correlate tympanometric gradient with measurements of effusion quantity by use of MRI during an experimental otitis media with effusion episode in 4 cynomolgus monkeys. Paired results for the intensity values of the T(2)-weighted MRI scans and the tympanometric width measured in the right ear of all animals before and on days 15, 21, 29, and 36 after botulinum paralysis of the tensor veli palatini muscle were analyzed. All right ears showed a progressive increase during the study period in the signal intensity of the MRI. Whereas the average middle ear pressures decreased, the average tympanometric widths demonstrated a progressive increase during the course of the experimental otitis media with effusion. Significant correlations between tympanometric width and MRI measures of effusion were documented, confirming the high predictive value of the tympanometric width for diagnosing the presence and quantity of middle ear effusion.

MRI validation of the accuracy of tympanometric gradient for the diagnosis of OME.

Tympanometry provides a rapid, non-invasive and objective assessment of middle ear (ME) status and is widely used for the clinical diagnosis and follow-up of otitis media with effusion (OME). ME pressure, acoustic admittance and tympanometric gradient are the main test parameters used in making assignments to diagnostic classes (i.e. presence or absence of effusion, effusion quantity). Of these, the tympanometric gradient was suggested to be more sensitive to the presence of effusion, but this has not been demonstrated conclusively and no standard definition of that gradient is accepted. In this study, 10 cynomolgus monkeys with experimental OME were used to compare the diagnosis of OME made using three different methods to estimate tympanometric gradient with that provided by simultaneous magnetic resonance imaging (MRI) of the ME. All three methods of tympanometric gradient measurement were highly correlated with the quantity of ME effusion measured by the MRI. Although not significant, the MRI results were better correlated with those for the 'width' method when compared to either the 'difference' or the 'ratio' method of gradient estimation. This study demonstrates the use of MRI as a gold standard for evaluating the accuracy of other methods to diagnose ME effusion.

Middle ear inflation for diagnosis and treatment of otitis media with effusion.

An adult (18 years), healthy, male subject with persistent bilateral middle ear (ME) underpressure and a history of recurrent otitis media into his teen years was identified. The response of his MEs to air inflation was evaluated and showed an immediate pressure increase after a Valsalva maneuver followed by a rapid pressure drop to approach the pre-inflation levels. That response is consistent with the presence of ME effusion, which was not diagnosed by otoendoscopy or tympanometry, but was visualized bilaterally within the mastoid regions using magnetic resonance imaging (MRI). The patient was treated for 25 days with ME inflation (3/day) and then re-examined. On each treatment day, he recorded his ME pressure using tympanometry before and after one inflation maneuver. The patient's compliance with the treatment protocol was high, and successful gas transfers were documented on most days. Over the course of treatment, pre-inflation ME pressure became more normal bilaterally. When compared to the pre-treatment test, the post-treatment inflation test showed a similar rate of ME pressure decrease, but significantly higher terminal pressures. On follow-up but not during the pre-treatment period, discrete changes in ME pressure attributable to ET openings were noted during test sessions. MRI documented lesser amounts of effusion in the mastoid, but not complete disease resolution. The significance of these observations to the design of a well controlled clinical trail of ME inflation as a treatment for otitis media is discussed.

The impact of personality on the reporting of unfounded symptoms and illness.

This study examined the role of personality in the reporting of symptoms and illness not supported by underlying pathology. After assessment of the Big Five personality factors, 276 healthy volunteers were inoculated with a common cold virus. On each of the following 5 days, objective indicators of pathology, self-reported symptoms, and self-reported illness onset were assessed. Neuroticism was directly associated with reports of unfounded (without a physiological basis) symptoms in individuals at baseline and postinoculation in those with and without colds. Neuroticism was also indirectly associated with reports of unfounded illness through reports of more symptoms. Openness to Experience was associated with reporting unfounded symptoms in those with verifiable colds, whereas Conscientiousness was associated with reporting unfounded illness in those who were not ill.

Higher rates of pressure decrease in inflamed compared with noninflamed middle ears.

Recent clinical trials have renewed interest in middle ear inflation as a treatment for otitis media with effusion. However, air inflation in human beings with significant negative middle ear pressures was shown to be followed by a rapid pressure decrease to approach the preinflation values. In this experiment, the middle ears of anesthetized rhesus monkeys with unilateral inflammation were inflated at different times with air or N2, and pressures were recorded by tympanometry until they had stabilized or the animal had recovered from anesthesia. The results for air inflations reproduced those reported for human beings with negative pressures. Similarly, after N2 inflation a significantly greater rate of pressure decrease and significantly lesser terminal pressures were observed for inflamed ears when compared with the contralateral control ears. However, the rate of pressure decrease and the magnitude of the pressure drop were dampened by sequential N2 inflations. These observations have clinical implications with respect to the efficacy of inflation as a treatment for otitis media with effusion.

Repeated inflation does not prevent otitis media with effusion in a monkey model.

OBJECTIVE: Investigate the efficacy of repeated middle ear inflation with an inert gas (argon) for preventing the development of middle ear effusion in monkeys with functional eustachian tube obstruction. STUDY DESIGN: Prospective controlled trial of daily middle ear inflation with five monkeys assigned to the inflation group and four to the control group. METHODS: The right tensor veli palatini muscle of nine monkeys was paralyzed with botulinum toxin. Tympanometry was done before the procedure and then daily for 21 days. Presence and distribution of effusion were assessed before paralysis and on day 15 using magnetic resonance imaging (MRI). In five right ears inflation was done beginning at the first observation of negative middle ear pressure of < or =200 mm H2O and repeated on all days with pressures < or =-100 mm H2O. Four right ears served as uninflated controls. RESULTS: Right middle ear pressure decreased in all animals over the course of the study. Pressure returned to near-ambient levels immediately following the argon inflation but was decreased to control levels at the subsequent observation on the following day. MRI at day 15 documented effusion in all right ears with no quantifiable differences in amount or distribution between ears that were and were not inflated with argon. CONCLUSIONS: Repeated inflation with an inert gas does not prevent middle ear effusion in monkeys with functional eustachian tube obstruction.

Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus.

The roles of interleukin (IL)-6 and IL-8 in mediating the symptoms and signs of influenza A infection were examined. Adults were intranasally inoculated with a rimantadine-sensitive strain of influenza A HlNl virus and treated with rimantadine or placebo. Viral shedding, secretion weights, symptom scores, and concentrations of IL-6 and IL-8 in nasal lavage fluids were compared between treatment groups. Viral shedding was associated with increases in local and systemic symptoms, in expelled secretion weights, and in levels of IL-6 and IL-8. Compared with placebo, rimantadine treatment reduced viral shedding, systemic symptoms, and levels of IL-8. Days of viral shedding and IL-6 but not IL-8 concentrations were significantly correlated with the other measures of symptoms and signs. These data support a causal relationship between viral replication, cytokine production, and symptom expression, and they suggest that IL-6 may have a role in mediating symptom and sign expression during influenza A infection.

Effects of nasal obstruction on Eustachian tube function and middle ear pressure.

To evaluate the relationship between nasal obstruction and otitis media, 10 ferrets were studied before and after either unilateral (E = 5) or bilateral (n = 5) nasal obstruction. Observations included otomicroscopic assessments of middle ear status, tympanometric recordings of middle ear pressure and forced-response, inflation-deflation and continuous monitoring tests of Eustachian tube function. During the 6 8 week post-obstruction follow-up period no animal developed evidence of otitis media. Abnormal positive middle ear pressures lasting for the period of follow-up occurred only in the animals with bilateral nasal obstruction. Eustachian tube function test results showed these pressures to be generated during swallowing. No changes in the passive function of the tube were documented in either group, but changes in active function consistent with alterations in the pressure gradient between the middle ear and the nasopharynx were observed in both groups.

Personality and tonic cardiovascular, neuroendocrine, and immune parameters.

Although there is now abundant evidence that certain personality features constitute risk factors for negative health outcomes, personality measures have received little attention to date in the behavioral immunology literature. The present study assessed the relationship between major dimensions of personality and tonic cardiovascular, neuroendocrine, and immunologic parameters in 276 healthy adults. Participants who scored low in agreeableness tended to have higher levels of systolic blood pressure, diastolic blood pressure, and epinephrine. Low levels of extraversion were associated with higher blood pressure, epinephrine, norepinephrine, and natural killer cell cytotoxicity. Neuroticism was generally unrelated to physiologic outcomes. Personality was not associated with leukocyte subset counts. The magnitude of relationships between personality and physiology was modest, with personality measures accounting for 1 to 7% of the variance in selected physiological parameters. Health practices did not mediate associations between personality and physiologic outcomes. However, a substantial proportion of the relationship between extraversion and natural killer cell cytotoxicity was accounted for by their common association with epinephrine and to a lesser extent norepinephrine. These findings are consistent with the notion that personality contributes to basal physiology and provide a foundation for further research on the relationship between personality and natural killer cell cytotoxicity.

Diminished IL-10 production in subjects with allergy after infection with influenza A virus.

BACKGROUND: Recent studies have documented a link between respiratory viral infections and the expression of asthma and other allergic disorders. Results from other studies have suggested that diminished production of IL-10, an anti-inflammatory cytokine, may contribute to the pathophysiologic features of these diseases. OBJECTIVE: The objective of this study was to determine whether diminished IL-10 production and TH2 cytokine skewing occur in allergic, as compared with nonallergic, subjects after experimental infection with the influenza A virus. METHODS: PBMCs were isolated from 11 subjects with allergy and 14 subjects with no allergy before and after influenza A infection and stimulated with either mitogen (PHA) or antigen (influenza A). Supernatants were assayed for IL-10, IL-4, and IFN-gamma by ELISA. RESULTS: PBMC IL-10 production was significantly diminished in subjects with allergy, as compared with subjects with no allergy, after experimental infection with influenza A virus. However, significant TH2 skewing and enhanced airway symptoms were not observed in these same subjects. CONCLUSIONS: These data provide further support that subjects with allergy have an intrinsic inability to upregulate IL-10 production in response to inflammatory stimuli and extend this observation to include respiratory viral infections. Future studies in this area could lead to a better understanding of the pathogenesis of asthma and other allergic disorders