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Objective: Estimate the transmucosal CO(2) and O(2) rate-constants for adult middle ears (MEs).Methods: Ten adults with healthy MEs had a unilateral myringotomy. A custom-fitted acrylic mold with a valved line to a mass spectrometer (MS) and central tube coupled to a 3-way valve and connected to a pressure transducer (the probe) was sealed with adhesive glue within the ipsilateral ear-canal. A second 3-way valve was attached to the probe valve, a flow-regulated tank gas source and paired syringes. Volumes of the ME and probe were measured. On sequential days, the probe+ME was washed for 15-min with 6% O(2), Balance N(2) and 25% O(2), 6% CO(2), Balance N(2) to create transmucosal CO(2) and O(2) gradients, respectively. After washing, the probe+ME was isolated from the gas source, and baseline and 10-min gas samples were obtained for MS analysis of gas partial-pressures. The rates of change in ME CO(2) and O(2) pressures were divided by their established transmucosal gradients to yield CO(2) and O(2) rate-constants.Results: The average (±STD) transmucosal CO(2) and O(2) rate-constants were 0.062 ± 0.034 (N=10, range: 0.032-0.119) and 0.011 ± 0.009 (N=8, range: 0.002-0.032)mmHg/min/mmHg, respectively. The average half-life for the CO(2) and O(2) gradient was 11.1 and 61.6 min. The average CO(2):O(2) rate-constant ratio was 8.1 ± 4.0 (N=8, range: 3.6-14.6).Conclusions: For adult human MEs, transmucosal CO(2) exchange is rapid and much faster than transmucosal O(2) exchange. The estimated CO(2)/O(2) rate-constant ratio for the human ME is not consistent with that predicted for diffusion-limited gas exchange across a water-based barrier. [ABSTRACT FROM AUTHOR]

Background: In adults and children with respiratory syncytial virus (RSV) infection, a polymorphism in the interleukin 6 (IL-6) promoter at position -174 predicts illness magnitude. In addition, polymorphisms in the interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) genes are associated with immune responsiveness and the frequency of complications. Here, the effect of these polymorphisms on illness and seroconversion during infection with rhinovirus type 39 (RV39) was evaluated.Methods: Seventy-two adults were genotyped for the selected polymorphisms, experimentally exposed to RV39, and followed to track infection, seroconversion, and symptoms and signs of illness. Regression analysis was used to determine whether these polymorphisms predicted seroconversion and illness magnitude in 57 infected subjects.Results: The low-production IL-6 -174 phenotype (C/C genotype) was associated with greater symptom magnitudes, and the IFN-gamma phenotype +874 predicted the frequency of seroconversion. No relationship between the IL-10 or TNF-alpha polymorphisms and any measured outcome was documented. The concentration of IL-6 protein, as measured in nasal wash fluids from subjects, was positively correlated with symptom magnitude, but it was independent of the IL-6 -174 genotypes representing the high- and low-production phenotypes.Conclusions: These results document statistically significant associations between the IL-6 -174 and IFN-gamma +874 polymorphisms and specific responses to experimental RV39 infection. For the IL-6 -174 polymorphism, the results replicate those for experimental RSV infection. [ABSTRACT FROM AUTHOR]

Objectives: Air-inflation in humans and monkeys with significant negative middle ear pressure or with middle ear inflammation was shown to cause greater than ambient middle ear pressure initially, followed by a rapid rate of pressure decrease to approach the preinflation value.Study Design: A mathematical model of middle ear pressure regulation is presented and used to simulate air-inflation of the normal and diseased middle ear.Materials and Methods: The model represents the total volume of the middle ear as consisting of three subcompartments representing the airspace, effusion, and mucosa/blood. Gas exchange among those compartments was assumed to be diffusion limited, and the gas exchange between the mucosa/blood compartment and systemic blood was assumed to be perfusion limited. Disease was modeled as an increase in mucosal blood flow or, alternatively, as an increase in the volumes of the effusion and mucosa/blood compartments.Results: The predictions of the model agree better with the experimental data when the increased rate of pressure change after middle ear inflation in diseased ears is driven by an increased volume of the effusion compartment as opposed to an increased perfusion rate. The responsible mechanism is a rapid redistribution among subcompartments of the gas volume introduced into the air compartment.Conclusions: These results suggest that middle ear inflation with inert gas can be used to diagnose the presence and relative amount of middle ear effusion, and that current protocols for treating otitis media with effusion using inflation need to be modified to optimize their intended effect. [ABSTRACT FROM AUTHOR]

Objective: To examine the hypothesis that diverse ties to friends, family, work, and community are associated with increased host resistance to infection.Design: After reporting the extent of participation in 12 types of social ties (eg, spouse, parent, friend, workmate, member of social group), subjects were given nasal drops containing 1 of 2 rhinoviruses and monitored for the development of a common cold.Setting: Quarantine.Participants: A total of 276 healthy volunteers, aged 18 to 55 years, neither seropositive for human immunodeficiency virus nor pregnant.Outcome Measures: Colds (illness in the presence of a verified infection), mucus production, mucociliary clearance function, and amount of viral replication.Results: In response to both viruses, those with more types of social ties were less susceptible to common colds, produced less mucus, were more effective in ciliary clearance of their nasal passages, and shed less virus. These relationships were unaltered by statistical controls for prechallenge virus-specific antibody, virus type, age, sex, season, body mass index, education, and race. Susceptibility to colds decreased in a dose-response manner with increased diversity of the social network. There was an adjusted relative risk of 4.2 comparing persons with fewest (1 to 3) to those with most (6 or more) types of social ties. Although smoking, poor sleep quality, alcohol abstinence, low dietary intake of vitamin C, elevated catecholamine levels, and being introverted were all associated with greater susceptibility to colds, they could only partially account for the relation between social network diversity and incidence of colds.Conclusions: More diverse social networks were associated with greater resistance to upper respiratory illness. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic central nervous system (CNS) neurodegenerative and neuroinflammatory disease marked by a host immune reaction that targets and destroys the neuronal myelin sheath. MS and correlating animal disease models show comorbidities, including intestinal barrier disruption and alterations of the commensal microbiome. It is accepted that diet plays a crucial role in shaping the microbiota composition and overall gastrointestinal (GI) tract health, suggesting an interplay between nutrition and neuroinflammation via the gut-brain axis. Unfortunately, poor host health and diet lead to microbiota modifications that could lead to significant responses in the host, including inflammation and neurobehavioral changes. Beneficial microbial metabolites are essential for host homeostasis and inflammation control. This review will highlight the importance of the gut microbiota in the context of host inflammatory responses in MS and MS animal models. Additionally, microbial community restoration and how it affects MS and GI barrier integrity will be discussed., (© 2024 Federation of European Biochemical Societies.)

Background: Farnesol (FOL) prevents the onset of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS)., Objective: We examined the transcriptomic profile of the brains of EAE mice treated with daily oral FOL using next-generation sequencing (RNA-seq)., Methods: Transcriptomics from whole brains of treated and untreated EAE mice at the peak of EAE was performed., Results: EAE-induced mice, compared to naïve, healthy mice, overall showed increased expression in pathways for immune response, as well as an increased cytokine signaling pathway, with downregulation of cellular stress proteins. FOL downregulates pro-inflammatory pathways and attenuates the immune response in EAE. FOL downregulated the expression of genes involved in misfolded protein response, MAPK activation/signaling, and pro-inflammatory response., Conclusion: This study provides insight into the molecular impact of FOL in the brain and identifies potential therapeutic targets of the isoprenoid pathway in MS patients., Competing Interests: Declaration of Competing Interest Authors have no competing interests to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The gut-associated lymphoid tissue is a primary activation site for immune responses to infection and immunomodulation. Experimental evidence using animal disease models suggests that specific gut microbes significantly regulate inflammation and immunoregulatory pathways. Furthermore, recent clinical findings indicate that gut microbes' composition, collectively named gut microbiota, is altered under disease state. This review focuses on the functional mechanisms by which gut microbes promote immunomodulatory responses that could be relevant in balancing inflammation associated with autoimmunity in the central nervous system. We also propose therapeutic interventions that target the composition of the gut microbiota as immunomodulatory mechanisms to control neuroinflammation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Over the last few decades, the incidence of multiple sclerosis has increased as society's dietary habits have switched from a whole foods approach to a high fat, high salt, low dietary fiber, and processed food diet, termed the "Western diet." Environmental factors, such as diet, could play a role in the pathogenesis of multiple sclerosis due to gut microbiota alterations, gut barrier leakage, and subsequent intestinal inflammation that could lead to exacerbated neuroinflammation. This mini-review explores the gut microbiome alterations of various dietary strategies that improve upon the "Western diet" as promising alternatives and targets to current multiple sclerosis treatments. We also provide evidence that gut microbiome modulation through diet can improve or exacerbate clinical symptoms of multiple sclerosis, highlighting the importance of including gut microbiome analyses in future studies of diet and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hoffman, Doyle, Schumacher and Ochoa-Repáraz.)

Farnesol is a 15‑carbon organic isoprenol synthesized by plants and mammals with anti-oxidant, anti-inflammatory, and neuroprotective activities. We sought to determine whether farnesol treatment would result in protection against murine experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis (MS). We compared disease progression and severity in C57BL/6 mice treated orally with 100 mg/kg/day farnesol solubilized in corn oil to corn-oil treated and untreated EAE mice. Farnesol significantly delayed the onset of EAE (by ~2 days) and dramatically decreased disease severity (~80%) compared to controls. Disease protection by farnesol was associated with a significant reduction in spinal cord infiltration by monocytes-macrophages, dendritic cells, CD4 + T cells, and a significant change in gut microbiota composition, including a decrease in the Firmicutes:Bacteroidetes ratio. The study suggests FOL could protect MS patients against CNS inflammatory demyelination by partially modulating the gut microbiome composition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim was to examine whether trait positive and negative affect (PA, NA) moderate the stress-buffering effect of perceived social support on risk for developing a cold subsequent to being exposed to a virus that causes mild upper respiratory illness., Method: Analyses were based on archival data from 694 healthy adults (M age  = 31.0 years, SD = 10.7 years; 49.0% female; 64.6% Caucasian). Perceived social support and perceived stress were assessed by self-report questionnaire and trait affect by aggregating responses to daily mood items administered by telephone interview across several days. Subsequently, participants were exposed to a virus that causes the common cold and monitored for 5 days for clinical illness (infection + objective signs of illness)., Results: Two 3-way interactions emerged-Support × Stress × PA and Support × Stress × NA. The nature of these effects was such that among persons with high trait PA or low trait NA, greater social support attenuated the risk of developing a cold when under high but not low perceived stress; this stress-buffering effect did not emerge among persons with low trait PA or high trait NA., Conclusions: Dispositional affect might be used to identify individuals who may be most responsive to social support and support-based interventions., (© 2016 Wiley Periodicals, Inc.)

Introduction: Middle ear (ME) pressure-regulation (MEPR) is a homeostatic mechanism that maintains the ME-environment pressure-gradient (MEEPG) within a range optimized for "normal" hearing., Objective: Describe MEPR using equations applicable to passive, inter-compartmental gas-exchange and determine if the predictions of that description include the increasing ME pressure observed under certain conditions and interpreted by some as evidencing gas-production by the ME mucosa., Methods: MEPR was modeled as the combined effect of passive gas-exchanges between the ME and: perilymph via the round window membrane, the ambient environment via the tympanic membrane, and the local blood via the ME mucosa and of gas flow between the ME and nasopharynx during Eustachian tube openings. The first 3 of these exchanges are described at the species level using the Fick's diffusion equation and the last as a bulk gas transfer governed by Poiseuille's equation. The model structure is a time-iteration of the equation: P ME g(t=(i+1)Δt)  = ∑ s (P ME s(t=iΔt) +(1/(β ME s V ME )∑ P (Қ P s (P C s(t=(iΔt) -P ME s(t=(iΔt) )). There, P ME g(t=iΔt) and P ME s(t=iΔt) are the ME total and species-pressures at the indexed times, P C s(t=iΔt) is the species-pressure for each exchange-compartment, β ME s V ME is the product of the ME species-capacitance and volume, Қ P s is the pathway species-conductance, and ∑ S and ∑ P are operators for summing the expression over all species or exchange pathways., Results: When calibrated to known values, the model predicts the empirically measured ME species-pressures and the observed time-trajectories for total ME pressure and the MEEPG under a wide variety of physiologic, pathologic and non-physiologic conditions., Conclusions: Passive inter-compartmental gas exchange is sole and sufficient to describe MEPR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Exposure to parental separation or divorce during childhood has been associated with an increased risk for physical morbidity during adulthood. Here we tested the hypothesis that this association is primarily attributable to separated parents who do not communicate with each other. We also examined whether early exposure to separated parents in conflict is associated with greater viral-induced inflammatory response in adulthood and in turn with increased susceptibility to viral-induced upper respiratory disease. After assessment of their parents' relationship during their childhood, 201 healthy volunteers, age 18-55 y, were quarantined, experimentally exposed to a virus that causes a common cold, and monitored for 5 d for the development of a respiratory illness. Monitoring included daily assessments of viral-specific infection, objective markers of illness, and local production of proinflammatory cytokines. Adults whose parents lived apart and never spoke during their childhood were more than three times as likely to develop a cold when exposed to the upper respiratory virus than adults from intact families. Conversely, individuals whose parents were separated but communicated with each other showed no increase in risk compared with those from intact families. These differences persisted in analyses adjusted for potentially confounding variables (demographics, current socioeconomic status, body mass index, season, baseline immunity to the challenge virus, affectivity, and childhood socioeconomic status). Mediation analyses were consistent with the hypothesis that greater susceptibility to respiratory infectious illness among the offspring of noncommunicating parents was attributable to a greater local proinflammatory response to infection., Competing Interests: The authors declare no conflict of interest.

Objective: Determine if the middle ear transmucosal nitrous oxide (N 2 O) exchange rate is affected by nasal inflammation caused by topical application of histamine., Methods: In a randomized, double-blind, crossover study, 20 adults were challenged intranasally with histamine (5 mg) and placebo on separate occasions. At each session, the subjects were fitted with a non-rebreathing mask and breathed room air for 20 minutes, 50% N 2 O:50% O 2 for 20 minutes, and 100% O 2 for 10 minutes. Throughout, heart rate, blood pressure, and blood O 2 saturation were monitored, and bilateral middle ear pressure was recorded by tympanometry every minute. The primary outcome measure was the slope of the middle ear pressure-time function for the 50% N 2 O:50% O 2 breathing period, which is a measure of the transmucosal N 2 O exchange-constant. The effects of challenge substance, session, and period on the measured vital signs and of treatment, session, ear disease history, and test ear on the pressure-time slopes were evaluated using repeated measures ANOVAs., Results: The post-challenge total symptom score and the slope of the middle ear pressure-time function were greater after histamine when compared to placebo challenge. Of the signs, only heart rate was affected, responding to challenge substance and study period., Conclusion: The transmucosal N 2 O exchange rate for the middle ear is increased during inflammation caused by nasal histamine exposure.

Objective: To describe the temporal pattern of otitis media with effusion (OME) resolution for a cohort of nonsyndromic cleft palate children enrolled before palatoplasty and followed through 5 years of age., Design: This is a prospective, longitudinal study of the time course for OME resolution in infants and children with palatal clefts., Setting: Cleft Palate Craniofacial Center of a tertiary care pediatric hospital., Participants: This study included 52 children with cleft palate (29 boys, 45 white, Veau 1 through 4) who had a Furlow-type palatoplasty between 10 and 24 months of age performed by one of six surgeons., Interventions: Standard cleft palate management was supplemented with study visits to the research clinic pre- and postpalatoplasty and then yearly to 6 years of age for assessments of middle ear status by interval history, otoscopy, and tympanometry., Main Outcome Measure: The main outcome measure was age at otitis media resolution defined as the age in years at the first in a sequence of "disease-free" diagnoses not interrupted or followed by any other diagnosis., Results: The cumulative percent OME resolution for ears/children at ages <1, 1, 2, 3, 4, 5 years was 4.1/4.4, 14.3/10.9, 31.6/21.7, 45.9/37.0, 56.1/50.0, and 70.4/60.9%. OME resolution followed a simple linear time curve with slopes of 13.5% (confidence interval [CI] = 12.2% to 14.8%, r(2) = .99) and 11.9% (CI = 10.1% to 13.6%, r(2) = .99) resolutions per year for ears and children, respectively., Conclusions: There is a natural, age-related pattern of resolution for persistent OME that affects most infants and young children with cleft palate that is not affected by palatoplasty.

Objectives: Determine if a 2-Step multivariate analysis of historical symptom/sign data for comorbid diseases can abstract high-level constructs useful in assigning a child's "risk" for different Otitis Media expressions., Methods: Seventeen items related to the symptom/sign expression of hypothesized Otitis Media comorbidities were collected by history on 141 3-year-old children. Using established criteria, the children were assigned to 1 of 3 groups: Control (no significant past Otitis Media, n=45), Chronic Otitis Media with Effusion (n=45) and Recurrent Acute Otitis Media (n=51). Principal Component Analysis was used to identify factors representing the non-redundant shared information among related items and Discriminant Analysis operating on those factors was used to estimate the best predictor equation for pairwise group assignments., Results: Six multivariate factors representing the assignable comorbidities of frequent colds, nasal allergy, gastroesophageal disease (specific and general), nasal congestion and asthma were identified and explained 81% of the variance in the 17 items. Discriminant Analysis showed that, for the Control-Chronic Otitis Media with Effusion comparison, a combination of 3 factors and, for the Control-Recurrent Acute Otitis Media comparison, a combination of 2 factors had assignment accuracies of 74% and 68%, respectively. For the contrast between the two disease expressions, a 2-factor combination had an assignment accuracy of 61%., Conclusion: These results show that this analytic methodology can abstract high-level constructs, comorbidities, from low-level data, symptom/sign scores, support a linkage between certain comorbidities and Otitis Media risk and suggest that specific comorbidity combinations contain information relevant to assigning the risk for different Otitis Media expressions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Determine if the middle ear (ME) trans-mucosal nitrous oxide (N2O) gas exchange rate can be pharmacologically modulated by the nasal application of a vasoconstrictor., Methods: In a randomized, double-blind, crossover study, 20 adults received a nasal spray challenge containing either oxymetazoline or saline (placebo). At each session, subjects were fitted with a non-rebreathing mask and breathed room air for 20 minutes, 50% N2O:50% O2 for 20 minutes, and 100% O2 for 10 minutes. Throughout, heart rate, blood pressure (BP), and blood O2 saturation were monitored, and bilateral ME pressure was recorded by tympanometry every minute. The primary outcome measure was the slope of the ME pressure-time function for the experimental period, a direct measure of the transMEM N2O exchange constant. The effects of treatment, session, and period on the measured vital signs and of treatment, session, disease history, and ear on the ME pressure-time slopes were evaluated for statistical significance using repeated measures ANOVAs., Results: The analysis documented a significant effect of period on O2 saturation (N2O > room air, P = .03) and of treatment on blood pressure (oxymetazoline > placebo, P < .02) and the ME pressure-time slope (placebo > oxymetazoline, P = .05)., Conclusion: The exchange rate across the ME mucosa of inert gases can be decreased by topical treatment of the nasal mucosa with oxymetazoline., (© The Author(s) 2015.)

Objective: To test the hypothesis that eustachian tube opening efficiency, measured as the fractional gradient equilibrated (FGE), is lower in 6-year-old children with no middle ear disease but a well-documented history of recurrent acute otitis media, as compared with children with a negative disease history (control)., Study Design: Cross-sectional study., Setting: Tertiary care pediatric hospital., Subjects and Methods: Bilateral eustachian tube function was evaluated in 44 healthy 6-year-old children (19 boys, 29 white). None had middle ear disease at the time of testing, but 23 had a history of recurrent acute otitis media. Twenty-one had no significant past otitis media. Eustachian tube function was measured with a pressure chamber protocol that established negative middle ear gauge pressures (referenced to the chamber pressure) and recorded that pressure before and after a swallow. FGE was calculated as the change in middle ear gauge pressure with swallowing divided by the preswallow pressure. Between-group comparisons of the preswallow pressures and FGEs were made with a 2-tailed Student's t test., Results: FGE was independent of the preswallow middle ear gauge pressure. For the 39 and 44 evaluable ears in the control and recurrent acute otitis media groups, the mean preswallow pressures were -194 daPa (95% confidence interval [95% CI] = -211 to -177) versus -203 (95% CI = -216 to -190; P > .40), and FGEs were 0.32 (95% CI = 0.21-0.43) vs 0.16 (95% CI = 0.08-0.24; P = .016), respectively., Conclusion: In children with past recurrent acute otitis media, residual eustachian tube opening inefficiency is maintained after they have "outgrown" their middle ear disease., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

The immunosuppressive effects of glucocorticoids (GCs) are well-established. However, whether the net effect of GC-elicited alterations in immune function is sufficient to influence a clinically relevant outcome in healthy adults has yet to be shown. The aim of the present study was to investigate whether inter-individual differences in basal salivary cortisol production are associated with increased risk and severity of infection and subsequent illness following experimental exposure to a virus that causes the common cold. The present analyses combine archival data from three viral-challenge studies. Participants were 608 healthy adults, aged 18 to 55 years (49.2% female; 65.8% white), who each completed a three-day saliva collection protocol; was subsequently exposed to a virus that causes the common cold; and monitored for 5 days for objective signs of infection (presence of challenge virus in nasal secretions) and clinical illness (mucus weight, mucociliary clearance time). Basal cortisol production (operationalized as the calculated area-under-the-curve averaged across the 3 days) showed a graded association with infection risk, with those producing higher levels of cortisol being at greater risk. Cortisol also showed a continuous association with duration of viral shedding, an indicator of viral replication and continuing infection, such that higher cortisol concentrations predicted more days of shedding. Cortisol was not, however, related to severity of objective illness. These findings are the first to demonstrate in healthy adults an association between basal cortisol production and an objectively measured and clinically relevant infectious disease outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To explore the association of self-rated health (SRH) with host resistance to illness after exposure to a common cold virus and identify mechanisms linking SRH to future health status., Methods: We analyzed archival data from 360 healthy adults (mean [standard deviation] age = 33.07 [10.69] years, 45.6% women). Each person completed validated questionnaires that assessed SRH (excellent, very good, good, fair, poor), socioemotional factors, and health practices and was subsequently exposed to a common cold virus and monitored for 5 days for clinical illness (infection and objective signs of illness)., Results: Poorer SRH was associated in a graded fashion with greater susceptibility to developing clinical illness (good/fair versus excellent: odds ratio = 3.21, 95% confidence interval = 1.47-6.99; very good versus excellent: odds ratio = 2.60, 95% confidence interval = 1.27-5.32), independent of age, sex, race, prechallenge immunity (specific antibody), body mass, season, education, and income. Greater illness risk was not attributable to infection, but to increased likelihood of developing objective signs of illness once infected. Poorer SRH also correlated with poorer health practices, increased stress, lower positive emotions, and other socioemotional factors. However, none of these (alone or together) accounted for the association between SRH and host resistance. Additional data (separate study) indicated that history of having colds was unrelated to susceptibility and hence also did not account for the SRH link with immunocompetence., Conclusions: Poorer SRH is associated with poorer immunocompetence, possibly reflecting sensitivity to sensations associated with premorbid immune dysfunction. In turn, poorer immune function may be a major contributing mechanism linking SRH to future health.

Sonotubometry is a simple test for Eustachian tube (ET) opening during a maneuver. Different sonotubometry configurations were suggested to maximize test accuracy, but no method has been described for comparing sonotubometry test results with those for a definitive measure of ET opening. Here, we present such a method and exemplify is use by an accuracy assessment of a simple sonotubometry configuration. A total of 502 data-sequences from 168 test sessions in 103 adult subjects were analyzed. For each session, subjects were seated in a pressure chamber and relative middle ear over- and under-pressures created by changing chamber pressure. At each pressure, the test sequence of bilateral tympanometry, bilateral sonotubometry while the subject swallowed twice, and bilateral tympanometry was done. Tympanometric data were expressed as the fractional gradient equilibrated (FGE) by swallowing and sonotubometric signals were analyzed to record the shape of detected sound signals. Tympanometric and sonotubometric tubal opening assignments were analyzed by cross-correlation. For the data sequences with FGE = 0 (n = 32) evidencing no tubal opening and one (n = 249) evidencing definitive tubal opening, detection of a sonotubometry sound signal during a swallow had a sensitivity and specificity of 74.2 and 65.6 % for identifying ET openings and an accuracy of 73.3 % for assigning ET opening/non-opening by swallowing. Measures of sound signal shape were significantly different between those groups. This protocol allows a sonotubometry accuracy assessment for detecting ET openings. For the test configuration used, accuracy was moderate, but this should improve as more sophisticated sonotubometry test configurations are evaluated.

Objectives/hypothesis: Determine if oral treatment with a vasoconstrictor decreases the blood to middle ear exchange rate of the perfusion-limited gas, nitrous oxide (N2O)., Study Design: Randomized, double-blind, crossover study., Methods: Ten adult subjects with and 10 without past middle ear disease completed paired experimental sessions, identical except for oral treatment with either pseudoephedrine hydrochloride or lactose placebo. At each session, subjects were fitted with a nonrebreathing mask and breathed room air for 20 minutes (acclimation period), 50% N2O:50% O2 for 20 minutes (experimental period), and 100% O2 for 10 minutes (recovery period). Throughout, heart rate, blood pressure, and O2 saturation were monitored, and bilateral middle ear pressures were recorded by tympanometry every minute. The primary outcome was the slope of the middle ear pressure-time function for the experimental period, which estimates the volume N2O exchange rate. Using repeated measures analysis of variance, the effects of group (disease history), treatment (active vs. placebo), and period (1 vs. 2) on the recorded vital signs, and of group, treatment, and ear (left/right) on the middle ear pressure-time slope were evaluated for statistical significance., Results: Statistically significant effects of period on O2 saturation (period 2 > period 1) and of treatment on heart rate (active > placebo) were documented. Only treatment was statistically significant for the middle ear pressure-time slope, with a shallower slope characterizing the active treatment session., Conclusions: The volume exchange rate across the middle ear mucosa of perfusion-limited gases can be modulated pharmacologically. Theoretically, similar drugs can be used to reduce the requisite eustachian tube opening efficiency for adequate middle ear pressure regulation., Level of Evidence: 1b., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Perceived social support has been hypothesized to protect against the pathogenic effects of stress. How such protection might be conferred, however, is not well understood. Using a sample of 404 healthy adults, we examined the roles of perceived social support and received hugs in buffering against interpersonal stress-induced susceptibility to infectious disease. Perceived support was assessed by questionnaire, and daily interpersonal conflict and receipt of hugs were assessed by telephone interviews on 14 consecutive evenings. Subsequently, participants were exposed to a virus that causes a common cold and were monitored in quarantine to assess infection and illness signs. Perceived support protected against the rise in infection risk associated with increasing frequency of conflict. A similar stress-buffering effect emerged for hugging, which explained 32% of the attenuating effect of support. Among infected participants, greater perceived support and more-frequent hugs each predicted less-severe illness signs. These data suggest that hugging may effectively convey social support., (© The Author(s) 2014.)

Importance: Eustachian tube (ET) dysfunction predisposes ears to otitis media, tympanic membrane retraction, retraction pocket and perforation, or cholesteatoma., Objective: To develop a method to quantitatively measure the eustachian tube (ET) component movements and their interactions captured by transnasal videoendoscopy of the ET during swallowing., Design, Setting, and Participants: A blinded analysis of ET mechanics in 33 adults, aged 18 to 54 years, with no middle ear disease at present but without (group 1 [n = 16]) or with (group 2 [n = 17]) history of disease, conducted at a clinical research laboratory., Interventions: Videoendoscopy of the ET orifice at the nasopharynx., Main Outcomes and Measures: Eustachian tube component translations and structural interactions during a swallow and the between-group differences in those variables. After topical anesthesia of the nose, a 45° telescope was introduced unilaterally and focused on the ipsilateral ET orifice. A video recording of ET component movements was made during 3 swallows. Swallow and ET opening durations and times to selected events were calculated. Images at 3 time points were analyzed by measuring the apex angle, the medial-lateral luminal width, and the medial angles between a frame-normal horizontal line through the apex and fixed points on the torus and medial and lateral luminal walls. Linear and angular variables during a swallow were expressed as change from baseline., Results: Luminal opening was driven by soft palate elevation-related medial rotation of the torus and medial wall, coupled with lateral wall fixedness. The magnitude of the change from baseline for most variables was statistically greater than 0. Swallow time, palatal elevation time, time interval between maximum palatal elevation, and maximum eustachian tube opening time were not different between groups 1 and 2. Opening time was longer (mean [SD], 0.49 [0.28] vs 0.67 [0.51] seconds; P = .03) in group 2. Higher magnitude of torus rotation (mean [SD], 36.05° [12.96°] vs 27.72° [9.45°]; P = .002) with maximum soft palate elevation in group 1 resulted in greater degree of eustachian tube orifice widening (mean [SD], 0.34% [0.47%] vs -0.02% [0.49%]; P = .001) compared with the resting position in that group., Conclusions and Relevance: This methodology has application in developing quantitative descriptions of ET mechanics in groups of persons without and with history or suspected ET dysfunction. A lesser degree of soft palate elevation during swallow that derives the ET medial lamina rotation and widening of the ET orifice may be associated with poor ET function and higher risk for otitis media. Videoendoscopic evaluation of the ET orifice may assist in diagnosing presence and mechanism of ET dysfunction.

Objectives/hypothesis: Test the hypothesis that the eustachian tube (ET) function measured using standard manometric test methods is different between groups of ears with tympanostomy tubes inserted for recurrent acute otitis media (RAOM) and for chronic otitis media with effusion (COME)., Study Design: A cross-sectional study of ET function in populations of young children with different otitis media expressions., Methods: The results for forced-response testing of ET function were compared using a general linear model between 37 ears of 26 children and 34 ears of 26 children, aged 3 and 4 years, with ventilation tubes inserted for COME and RAOM, respectively., Results: There were no significant between-group differences in either the active measure of ET opening function, dilatory efficiency, or in the passive measures reflecting the magnitude of the forces that tend to hold the ET lumen closed, the opening and closing pressures, and passive trans-ET conductance., Conclusions: The results do not support the hypothesis that ET closing forces are less in ears with RAOM when compared to ears with COME, and from the results of earlier studies, ears without disease. Both groups were characterized by a low ET opening efficiency (referenced to ears of adults with no disease history). Because both disease expressions present the same pattern of ET dysfunction, other factors are required to explain why a subset of ears with that type of dysfunction develop RAOM, as opposed to the default expression of COME., Level of Evidence: 2b, (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Childhood adversity, defined in terms of material hardship or physical or emotional maltreatment has been associated with risk for infection with cytomegalovirus (CMV) among children and adolescents, and with CMV reactivation in children and adults. The present study examined whether different dimensions of childhood experience-those pertaining to socioeconomic status (SES), physical environment, or family relationships-relate differentially to CMV serostatus and reactivation during adulthood. Participants were 140 healthy adults, aged 18-55years (41% female; 64% white). Childhood environments were assessed retrospectively and included family SES (parental housing tenure); childhood neighborhood environment (urban residence; physical conditions; safety; and social atmosphere); residential exposures (parental smoking and physical condition of home); and family relationships (parental divorce; warmth; harmony; dysfunction; parental bonding). Approximately 39% (n=53) of participants were CMV+. In individual analyses controlling for age, sex, race, body mass, current adult SES and smoking status, fewer years of parental home ownership, having a parent who smoked, and living in a poorly maintained or unsafe neighborhood each were associated with greater odds of infection with CMV. By comparison, in individual analyses limited to CMV+ participants, less family warmth, less harmony, greater dysfunction, and suboptimal parental bonding each were related to higher antibody levels, independent of the aforementioned covariates. Findings were not attributable to current adult perceptions of psychological stress or relative levels of emotional stability. These results suggest that different types of childhood adversity may be associated with differential effects on CMV infection and latency., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Conclusions: Fractional gradient equilibrated (FGE) for ears with applied positive but not negative middle ear (ME)-ambient pressure gradients is highly sensitive to a cold-like illness (CLI)., Objective: The sequential development of eustachian tube (ET) dysfunction, ME under-pressure, and otitis media (OM) characterizes many children during a CLI. If linked, OM burden would be lessened by interventions that promote/preserve good ET function during a CLI. Evaluating this requires a quantitative ET function test for MEs with an intact tympanic membrane responsive to a CLI., Methods: Pressure chamber testing of ET function was performed at +200 and -200 daPa in 3 groups of adults: group I, 21 subjects with an extant CLI and groups II and III, 14 and 57 adults, respectively, without a CLI. ME-chamber pressure gradient was recorded by tympanometry before and after the subject swallowed twice. ET functional efficiency was quantified as the FGE, which was then compared among groups using a Mann-Whitney U test., Results: At chamber pressures of 200 daPa, the ME-chamber pressure gradient was negative, and FGE was low and not different among groups. At chamber pressures of -200 daPa that gradient was positive, and FGE was significantly higher in groups II and III when compared with group I.

Conclusions: Protocol limitations were identified and accounted for in the analysis. Percent gradient equilibrated (PGE) was affected by driving gradient direction in a similar manner to other efficiency measures. A finer resolution of possible age-related changes in eustachian tube opening efficiency is expected with the application of more sophisticated statistical models to the complete dataset at study end., Objective: To report the results of an interim analysis for an ongoing study designed to characterize the age-related changes in eustachian tube opening efficiency measured using a pressure chamber protocol in children without a history of middle ear disease., Methods: To date, 41 children aged 3 years without a history of otitis media have been enrolled in a longitudinal study of the age-related changes in eustachian tube function and evaluated at yearly intervals between 3 and 7 years of age. Eustachian tube opening efficiency, the percent of the applied pressure gradient equilibrated by swallowing, was measured by repeat tympanometry during a pressure chamber protocol. Data (120 tests) were analyzed using an ANOVA with variance partitioned by age (3 through 6 years), gradient direction (positive/negative), and ear (left/right)., Results: PGE was higher for left ears and positive driving gradients, but was not different among age groups.

Objective: Test the hypothesis that active Eustachian tube opening efficiency as measured by sonotubometry is higher in adults with no extant middle-ear disease and no history of previous otitis media (Group-1) when compared to adults with no middle-ear disease but a positive history for otitis media (Group-2)., Methods: Eustachian tube function for 1 ear of 33 otherwise healthy adult subjects, 16 assigned to Group-1 and 17 to Group-2, was tested by sonotubometry using a standard protocol. For each test, the sound envelopes for 3 swallows were abstracted independently by 2 observers from the data stream and 7 descriptive parameters related to sound envelope "shape" were calculated. Inter-relatedness among the values for the parameters was explored using correlation analysis. The contributions of swallow, observer and group to the variance in each parameter were evaluated for significance using a General Linear Model., Results: The shape parameters reflecting envelope height, area and rise and fall rates were highly inter-correlated, but those reflecting envelope widths were not. There was no effect of "swallow" on any of the parameters; but there was a significant "observer" effect on all measures of envelope width, greater for observer-2, and a significant "group" effect for 5 of the 7 shape parameters, all greater in Group-1., Conclusions: Quantifiable measures of the sound signal "shape" recorded by sonotubometry during swallowing were significantly different between the 2 groups of subjects. This is interpretable as evidencing a more efficient Eustachian tube opening-function in adults with healthy middle ears who do not have a previous history of otitis media when compared to similar adults with a history of prior otitis media. Inefficient Eustachian tube function as children may not be completely resolved by adulthood increasing adult otitis media risk when Eustachian tube function is down-graded by extant upper respiratory diseases that provoke nasopharyngeal inflammation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Low socioeconomic status (SES) during childhood and adolescence has been found to predict greater susceptibility to common cold viruses in adults. Here, we test whether low childhood SES is associated with shorter leukocyte telomere length in adulthood, and whether telomere length mediates the association between childhood SES and susceptibility to acute upper respiratory disease in adulthood. At baseline, 196 healthy volunteers reported whether they currently owned their home and, for each year of their childhood, whether their parents owned the family home. Volunteers also had blood drawn for assessment of specific antibody to the challenge virus, and for CD8+ CD28- T-lymphocyte telomere length (in a subset, n=135). They were subsequently quarantined in a hotel, exposed to a virus (rhinovirus [RV] 39) that causes a common cold and followed for infection and illness (clinical cold) over five post-exposure days. Lower childhood SES as measured by fewer years of parental home ownership was associated with shorter adult CD8+ CD28- telomere length and with an increased probability of developing infection and clinical illness when exposed to a common cold virus in adulthood. These associations were independent of adult SES, age, sex, race, body mass, neuroticism, and childhood family characteristics. Associations with infections and colds were also independent of pre-challenge viral-specific antibody and season. Further analyses do not support mediating roles for smoking, alcohol consumption or physical activity but suggest that CD8+ CD28- cell telomere length may act as a partial mediator of the associations between childhood SES and infection and childhood SES and colds., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: In children with ventilation tubes (VTs) inserted for chronic otitis media with effusion (COME), the authors sought to determine whether any parameter of Eustachian tube (ET) function measured by the forced response test (FRT) predicts disease recurrence after the VT becomes nonfunctional., Study Design: Prospective study of those factors that predict disease recurrence in children with VTs inserted for COME., Methods: Forty-nine subjects (73 ears; 28 male, 34 white, aged 5.3 ± 1.2 years) with COME had VTs inserted and were evaluable for disease status after the VT(s) became nonfunctional. The FRT was done when the VTs were patent, and results for the last test before the VT became nonfunctional were used in the analysis. After each VT became nonfunctional, the children were followed for disease recurrence over a 12-month period. Logistic regression was used to determine whether the ET opening pressure, closing pressure, and/or dilatory efficiency predicted disease recurrence. That model was expanded to include age, sex, race, history of adenoidectomy, previous VTs, and duration of VT patency as potential predictive factors., Results: Twenty-nine (40%) ears had recurrence of significant disease within 12 months after the VT became nonfunctional. For the complete logistic regression model, male gender (P = .03), nonwhite race (P = .02), shorter period of VT patency (P = .01), and low dilatory efficiency (P = .01) were significant predictors of disease recurrence., Conclusions: A measure of active ET function, dilatory efficiency, but not measures of passive function predicted disease recurrence within the 12 months after the VT became nonfunctional in children with COME., (Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: The study demonstrates the utility of eustachian tube (ET) function (ETF) test results for accurately assigning ears to disease state., Objectives: To determine if ETF tests can identify ears with physician-diagnosed ET dysfunction (ETD) in a mixed population at high sensitivity and specificity and to define the interrelatedness of ETF test parameters., Design, Setting, and Participants: Through use of the forced-response, inflation-deflation, Valsalva, and sniffing tests, ETF was evaluated in 15 control ears of adult subjects after unilateral myringotomy (group 1) and in 23 ears of 19 adult subjects with ventilation tubes inserted for ETD (group 2). Data were analyzed using logistic regression including each parameter independently and then a step-down discriminant analysis including all ETF test parameters to predict group assignment. Factor analysis operating over all parameters was used to explore relatedness., Exposures: ETF testing., Main Outcomes and Measures: ETF parameters for the forced response, inflation-deflation, Valsalva, and sniffing tests measured in 15 control ears of adult subjects after unilateral myringotomy (group 1) and in 23 ears of 19 adult subjects with ventilation tubes inserted for ETD (group 2)., Results: The discriminant analysis identified 4 ETF test parameters (Valsalva, ET opening pressure, dilatory efficiency, and percentage of positive pressure equilibrated) that together correctly assigned ears to group 2 at a sensitivity of 95% and a specificity of 83%. Individual parameters representing the efficiency of ET opening during swallowing showed moderately accurate assignments of ears to their respective groups. Three factors captured approximately 98% of the variance among parameters: the first had negative loadings of the ETF structural parameters; the second had positive loadings of the muscle-assisted ET opening parameters; and the third had negative loadings of the muscle-assisted ET opening parameters and positive loadings of the structural parameters., Conclusions and Relevance: These results show that ETF tests can correctly assign individual ears to physician-diagnosed ETD with high sensitivity and specificity and that ETF test parameters can be grouped into structural-functional categories.

Objective: This report reviews the literature to identify the advances in our understanding of the middle ear (ME)-Eustachian tube (ET) system during the past 4 years and, on that basis, to determine whether the short-term goals elaborated in the last report were achieved and propose updated goals to guide future otitis media (OM) research., Data Sources: Databases searched included PubMed, Web of Science (1945-present), Medline (1950 to present), Biosis Previews (1969-present), and the Zoological Record (1978 to present). The initial literature search covered the time interval from January 2007 to June 2011, with a supplementary search completed in February 2012., Review Methods: The panel topic was subdivided; each contributor performed a literature search and provided a preliminary report. Those reports were consolidated and discussed when the panel met on June 9, 2011. At that meeting, the progress was evaluated and new short-term goals proposed., Conclusions: Progress was made on 16 of the 19 short-term goals proposed in 2007. Significant advances were made in the characterization of ME gas exchange pathways, modeling ET function, and preliminary testing of treatments for ET dysfunction., Implications for Practice: In the future, imaging technologies should be developed to noninvasively assess ME/ET structure and physiology with respect to their role in OM pathogenesis. The new data derived from form/function experiments should be integrated into the finite element models and used to develop specific hypotheses concerning OM pathogenesis and persistence. Finally, rigorous studies of treatments, medical or surgical, of ET dysfunction should be undertaken.

Objectives: The Cephalic Index, an anthropometric measure of head shape, was reported to be different between individuals with and without signs of past or concurrent otitis media (OM). In this study, we compared the Cephalic Index and other measures of head shape among groups of children aged 36-48 months with a documented history of chronic OM with effusion (COME), recurrent acute OM (RAOM) and CONTROLS (few to no OM episodes) to test that hypothesis., Methods: In 41 CONTROL, 36 COME and 42 RAOM children, Maximum Head Width, Maximum Head Length and Head Circumference were measured and the Cephalic Index (Head Width/Head Length×100) was calculated. The four measures were compared among the three groups using a General Linear Model that included group, sex and race as factors and age as a covariate., Results: There were no differences among groups in the Cephalic Index or Head Length. Head Width was significantly smaller in the RAOM when compared to the CONTROL group and Head Circumference was significantly smaller in the RAOM and COME groups when compared to the CONTROL group. For all measures, the distribution of values showed significant overlap among groups., Conclusions: These results do not support the hypothesis that the Cephalic Index is different between young children with and without OM, but did document differences in Head Width and Circumference among groups. However, the large overlap in each measure for the three groups suggests that none capture sufficient information on Eustachian tube anatomy to predict disease presentation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Importance: Although leukocyte telomere length is associated with mortality and many chronic diseases thought to be manifestations of age-related functional decline, it is not known whether it relates to acute disease in younger healthy populations., Objective: To determine whether shorter telomeres in leukocytes, especially CD8CD28- T cells, are associated with decreased resistance to upper respiratory infection and clinical illness in young to midlife adults., Design, Setting, and Participants: Between 2008 and 2011, telomere length was assessed in peripheral blood mononuclear cells (PBMCs) and T-cell subsets (CD4, CD8CD28+, CD8CD28-) from 152 healthy 18- to 55-year-old residents of Pittsburgh, Pennsylvania. Participants were subsequently quarantined (single rooms), administered nasal drops containing a common cold virus (rhinovirus 39), and monitored for 5 days for development of infection and clinical illness., Main Outcome Measures: Infection (virus shedding or 4-fold increase in virus-specific antibody titer) and clinical illness (verified infection plus objective signs of illness)., Results: Rates of infections and clinical illness were 69% (n = 105) and 22% (n = 33), respectively. Shorter telomeres were associated with greater odds of infection, independent of prechallenge virus-specific antibody, demographics, contraceptive use, season, and body mass index (PBMC: odds ratio [OR] per 1-SD decrease in telomere length, 1.71 [95% CI, 1.08-2.72]; n = 128 [shortest tertile 77% infected; middle, 66%; longest, 57%]; CD4: OR, 1.76 [95% CI, 1.15-2.70]; n = 146 [shortest tertile 80% infected; middle, 71%; longest, 54%]; CD8CD28+: OR, 1.93 [95% CI, 1.21-3.09], n = 132 [shortest tertile 84% infected; middle, 64%; longest, 58%]; CD8CD28-: OR, 2.02 [95% CI, 1.29-3.16]; n = 144 [shortest tertile 77% infected; middle, 75%; longest, 50%]). CD8CD28- was the only cell population in which shorter telomeres were associated with greater risk of clinical illness (OR, 1.69 [95% CI, 1.01-2.84]; n = 144 [shortest tertile, 26%; middle, 22%; longest, 13%]). The association between CD8CD28- telomere length and infection increased with age (CD8CD28- telomere length × age interaction, b = 0.09 [95% CI, 0.02-0.16], P = .01, n = 144)., Conclusion and Relevance: In this preliminary study among a cohort of healthy 18- to 55-year-olds, shorter CD8CD28- T-cell telomere length was associated with increased risk for experimentally induced acute upper respiratory infection and clinical illness.

Objective: To determine the role played by the tensor veli palatini and levator veli palatini muscles (mTVP and mLVP, respectively) in eustachian tube (ET) opening., Design: Prospective study., Setting: Research laboratories at a tertiary care hospital., Patients: Fifteen healthy adults with normal middle ears and documented ET openings., Interventions: Submental and ground surface electrodes were placed. After anesthetizing and decongesting the nasal passages, paired electromyographic needle electrodes were inserted into both the mTVP and mLVP on the test side. A microphone was placed into the ipsilateral ear canal and the probe from a sound generator was introduced into the opposite nostril. A 45° telescope was used on the test side to video-record the soft palate and ET movements while the individual swallowed., Main Outcome Measures: Concurrent recordings of the ET openings by sonotubometry, the electromyographic activity for the LVP, TVP, and submental muscles, and video of the nasopharyngeal orifice of the ET during swallowing., Results: During swallowing, the median peak amplitude and duration of ET openings by sonotubometry were 30.6 mV and 196 milliseconds, respectively. For the mLVP and mTVP, the median peak amplitudes were 0.33 and 0.82 mV, and peak durations were 131 and 85 milliseconds, respectively. The mean onsets of muscle activity referenced to the sonotubometry peak amplitude were -0.28, -0.24, and -0.14 milliseconds for the mLVP, mTVP, and submental muscles, respectively. Video recording of ET movements were consistent with the timing of these events., Conclusions: The mTVP activity had a shorter duration but greater amplitude than the mLVP activity and was associated with peak ET opening by sonotubometry. The mLVP activity occurred before that of the mTVP, the submental muscle group, and peak ET opening. The mLVP contractions were associated with movements of the soft palate, anterior ET orifice, and rotation of the ET cartilage.

Objective: To characterize Eustachian tube function using the forced response test in young children with cleft palate with or without cleft lip after palatoplasty with tympanostomy tubes inserted prepalatoplasty and compare these results with those of a 1986 study that evaluated a similar population using identical methods., Setting: Outpatient research clinic., Patients/participants: A total of 34 children with cleft palate were tested at an average age of 18.6 ± 4.0 months. MAIN OUTCOME MEASUREs: Passive and active measures for the forced response test., Results: Of the sample, 13 ears could not be tested, and tests on 24 ears were incomplete. The forced response test showed that the passive Eustachian tube function parameters were similar to those of normal adults and children. The percentage of ears that showed tubal dilation with swallowing was 60%. The active resistance and dilatory efficiency were similar to those of a normal adult population., Conclusions: A 1986 study of Eustachian tube function in postpalatoplasty subjects with cleft palate (37 ears) aged 15 to 26 months documented Eustachian tube dilation with swallowing in 84% of the ears. In the present study, which focused on a similar population, the frequency of tubal dilation was 60%. Nonetheless, both frequencies are significantly greater than the dilation frequency of 27% reported for 56 ears of subjects with cleft palate tested between 3 months and 18 years with tympanostomy tubes inserted for persistent otitis media with effusion. This suggests that dilation during the forced response test may be a prognostic marker for those children with cleft palate who will resolve their ear disease at an early age.

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.