Farnesol brain transcriptomics in CNS inflammatory demyelination.

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.

The immunomodulatory roles of the gut microbiome in autoimmune diseases of the central nervous system: Multiple sclerosis as a model.

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.

Farnesol induces protection against murine CNS inflammatory demyelination and modifies gut microbiome.

Farnesol is a 15­carbon 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.

Offspring of parents who were separated and not speaking to one another have reduced resistance to the common cold as adults.

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.

Dispositional Affect Moderates the Stress-Buffering Effect of Social Support on Risk for Developing the Common Cold.

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 (Mage = 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.

Basal salivary cortisol secretion and susceptibility to upper respiratory infection.

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.

Resolution of Otitis Media With Effusion in Children With Cleft Palate Followed Through Five Years of Age.

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.

Self-Rated Health in Healthy Adults and Susceptibility to the Common Cold.

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.

Does hugging provide stress-buffering social support? A study of susceptibility to upper respiratory infection and illness.

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.

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.

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-1ß, 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.

A method to assess the accuracy of sonotubometry for detecting Eustachian tube openings.

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.

Childhood environments and cytomegalovirus serostatus and reactivation in adults.

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.

Gut microbiota in multiple sclerosis and animal models.

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.

Childhood socioeconomic status, telomere length, and susceptibility to upper respiratory infection.

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.

Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults.

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.

Gut microbiome-modulated dietary strategies in EAE and multiple sclerosis.

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.

Parenthood and host resistance to the common cold.

OBJECTIVE: To determine whether parenthood predicts host resistance to the common cold among healthy volunteers experimentally exposed to a common cold virus. METHODS: Participants were 795 healthy volunteers (age range = 18-55 years) enrolled in one of three viral-challenge studies conducted from 1993 to 2004. After reporting parenthood status, participants were quarantined, administered nasal drops containing one of four common cold viruses, and monitored for the development of a clinical cold (infection in the presence of objective signs of illness) on the day before and for 5 to 6 days after exposure. All analyses included controls for immunity to the experimental virus (prechallenge specific antibody titers), viral strain, season, age, sex, race/ethnicity, marital status, body mass, study, employment status, and education. RESULTS: Parents were less likely to develop colds than nonparents were (odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.31-0.73). This was true for both parents with one to two children (OR = 0.52, 95% CI = 0.33-0.83) and three or more children (OR = 0.39, 95% CI = 0.22-0.70). Parenthood was associated with a decreased risk of colds for both those with at least one child living at home (OR = 0.46, 95% CI = 0.24-0.87) and those whose children all lived away from home (OR = 0.27, 95% CI = 0.12-0.60). The relationship between parenthood and colds was not observed in parents aged 18 to 24 years but was pronounced among older parents. CONCLUSIONS: Parenthood was associated with greater host resistance to common cold viruses.

Postpalatoplasty Eustachian tube function in young children with cleft palate.

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.

Eustachian tube function in adults without middle ear disease.

OBJECTIVES: We sought to develop normative values for 5 eustachian tube function (ETF) test protocols in adults without otitis media (OM). METHODS: Twenty adults (19 to 48 years of age) without a recent history of OM (5 had OM in childhood) underwent unilateral myringotomy and were evaluated for ETF by use of the forced response, inflation, deflation, forcible "sniff", and Valsalva test protocols. When possible, these tests were repeated on a second day. RESULTS: Normative values for the parameters of these protocols in adult subjects without a recent history of OM were developed. Between-day data for the forced response test were highly correlated. A percentage of these tests showed eustachian tube "constriction" during swallowing--an abnormal condition. The percent reduction in applied pressures for the inflation and deflation tests was high, indicative of good ETF. Few subjects had a positive "sniff" test, whereas most had a positive Valsalva test, and the results for both tests were effort-dependent. CONCLUSIONS: Results of ETF tests in adults with and without recent OM have not been published. Normative data are now available for comparison with ETF test results in adults with OM. These protocols will be used to evaluate the efficacy of surgical procedures designed to improve ETF.

CO(2) gas exchange across the human tympanic membrane is not appreciably affected by pathology.

Past in vivo studies in humans showed that the tympanic membrane (TM) is permeable to physiological gases. Animal studies show that transTM CO(2) conductance is increased by TM pathology. The objective of the study was to determine if transTM CO(2) exchange in humans is affected by atrophic and sclerotic pathologies. The study used an ear canal (EC) probe (ECP) constructed from a custom-fitted acrylic body, a glass capillary tube enclosing an oil meniscus to maintain ambient ECP + EC pressure and a silica glass microtube linked to a mass spectrometer (MS) for measuring gas composition that was hermetically sealed within the ear canal of the test ear. ECP + EC volume was measured and gas samples taken at 10 min intervals for 1 h. The fractional CO(2) pressure measured in the ECP + EC for each sample was regressed on time and the slope of the function multiplied by the ECP + EC volume and divided by the estimated transTM CO(2) gradient at the start of the experiment to yield transTM CO(2) conductance (microL/min/Pa). Data were complete for 15 normal, 13 sclerotic and 9 atrophic TMs. The average (+std) transTM CO(2) conductances were 1.76 × 10(-4) + 7.27 × 10(-5), 2.26 × 10(-4) + 1.5 × 10(-4) and 2.36 × 10(-4) + 1.14 × 10(-4) microL/min/Pa/TM for the normal, sclerotic and atrophic TMs, respectively. A pairwise comparison of data for the normal and atrophic TMs under the directional hypothesis of a greater CO(2) exchange rate for thinner TMs approached statistical significance (P = 0.07). A similar pairwise comparison for the sclerotic and normal TMs did not approach statistical significance (P = 0.28). The effect of TM pathologies on CO(2) conductance was limited.