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J Douglas Swarts

Publications and source records attributed to J Douglas Swarts.

18 recordsLinked to original sources
PubMed2006

Accuracy of CO2 conductance predicted using a morphometric model of the middle ear mucosa.

CONCLUSION: These results hold promise that morphometric analysis can be used to generate transMEM (middle ear mucosa) gas conductance estimates for MEM geometries representative of the shift from healthy to pathologic states (e.g. increased MEM thickness and capillary density). OBJECTIVES: Novel strategies to treat otitis media with effusion require a better understanding of how MEM geometry affects gas transport. Earlier studies developed techniques to empirically measure transMEM gas conductance and to estimate conductance using morphometric models of MEM geometry. We used chinchillas to determine the correspondence between experimentally measured transMEM CO2 conductance and that predicted by morphometric study of the MEM. MATERIALS AND METHODS: TransMEM CO2 conductance was measured unilaterally in 10 chinchillas; the animals were killed and the ME was removed and processed for morphometric analyses of MEM geometry. RESULTS: The average measured and estimated transMEM CO2 conductances were 4.87+/-2.30 x 10-10 and 1.75+/-0.29 x 10-10 mol/s/mmHg, respectively. The magnitude and direction of the estimate error were similar for all ears, suggesting a fixed, negative bias to the estimate. A theoretically consistent source for this bias was identified as the representation of the true diffusional length within a 3-D geometry using a 2-D modeling platform. Best estimate correction for this effect based on available data significantly reduced the estimate bias.

Animals↗
PubMed2005

Gene expression profiles of early pneumococcal otitis media in the rat.

OBJECTIVE: To define the gene expression patterns during the early phases of a bacterial middle ear infection in the rat model. METHOD: Using cDNA gene array technology, we profiled the mRNA expression of 1176 genes in a rat model of acute otitis media. We identified changes in gene expression two-fold or greater 12 and 48 h after bilateral ME inoculation with either tryptic soy broth (TSB) or Streptococcus pneumoniae in TSB. RESULTS: Transcripts of cytokines and cell adhesion molecules were up-regulated by 12 h, but returned to placebo transcription levels by 48 h. Three of six stress-response genes, including inducible nitric oxide synthase, GADD45 and heat shock protein 27 (HSP27) were up-regulated by 12 h, with HSP27 transcription levels continuing to rise through 48 h. All assayed transcription factors were up-regulated by 12 h, but only c-fos and c-jun up-regulation persisted to the 48-h time point. Up-regulation of apoptosis-related genes, except for bcl-x, was not evident until 48 h. These gene expression patterns reflected an early proinflammatory response consisting of cytokines, cell adhesion and stress-response molecules at 12 h followed by an up-regulation of apoptosis-related genes at 48 h. CONCLUSION: Downstream targets of several transcription factors, up-regulated transiently at 12 h, control secondary effects of S. pneumoniae infection, including apoptosis of neutrophils and mucosal epithelial cells, bone proliferation and promotion of leukocyte differentiation. These observations lead to a greater understanding of the early events in the pathogenesis of an AOM episode and highlight therapeutic targets, which may play a roll in the sequelae of AOM.

Animals↗
PubMed2004

Finite element analysis of active Eustachian tube function.

The inability to open the collapsible Eustachian tube (ET) has been related to the development of chronic otitis media. Although ET dysfunction may be due to anatomic and/or mechanical abnormalities, the precise mechanisms by which these structural properties alter ET opening phenomena have not been investigated. Previous investigations could only speculate on how these structural properties influence the tissue deformation processes responsible for ET opening. We have, therefore, developed a computational technique that can quantify these structure-function relationships. Cross-sectional histological images were obtained from eight normal adult human subjects, who had no history of middle ear disease. A midcartilaginous image from each subject was used to create two-dimensional finite element models of the soft tissue structures of the ET. ET opening phenomena were simulated by applying muscle forces on soft tissue surfaces in the appropriate direction and were quantified by calculating the resistance to flow (R(v)) in the opened lumen. A sensitivity analysis was conducted to determine the relative importance of muscle forces and soft-tissue elastic properties. Muscle contraction resulted in a medial-superior rotation of the medial lamina, stretching deformation in the Ostmann's fatty tissue, and lumen dilation. Variability in baseline R(v) values correlated with tissue size, whereas the functional relationship between R(v) and a given mechanical parameter was consistent in all subjects. ET opening was found to be highly sensitive to the applied muscle forces and relatively insensitive to cartilage elastic properties. These computational models have, therefore, identified how different tissue elements alter ET opening phenomena, which elements should be targeted for treatment, and the optimal mechanical properties of these tissue constructs.

Adolescent↗
PubMed2004

Cathepsin gene expression profile in rat acute pneumococcal otitis media.

OBJECTIVES/HYPOTHESIS: Acute otitis media, often caused by infection with Streptococcus pneumoniae, is characterized by inflammation of the middle ear mucosa. A prominent feature of the host response to bacterial infection of the middle ear mucosa is an influx of inflammatory cells that contributes to the local pool of inflammatory mediators by releasing additional inflammatory chemicals, which in turn cause further tissue injury. The objective was to identify candidate effector and signaling molecules involved in acute otitis media pathogenesis caused by S pneumoniae infection. STUDY DESIGN: Male Sprague-Dawley rats were randomly assigned to 1 of 5 groups, including 1 control group without treatment, 2 placebo groups (12 and 48 hours) and 2 infected groups (12 and 48 hours). The rat middle ear was bilaterally inoculated with either 25 microL of tryptic soy broth (TSB group) or 25 microL of TSB containing approximately 1.24 x 10(9) cfu/mL of S pneumonias type 6A (SP group). Rats were killed at 12 and 48 hours after inoculation and the middle ear mucosa was collected. Total RNA was extracted and pooled from each group for gene expression assays. METHODS: Gene expression profiles for rat middle ear mucosa at 12 and 48 hours after S pneumoniae or placebo inoculation were constructed using microarray technology (Clontech Atlas Rat 1.2 Array, 1176 cDNAs). Genes of interest were further validated by real-time polymerize chain reaction. RESULTS: Middle ear mucosa expression of a gene cluster encoding the lysosomal cysteine proteases, cathepsins B (Ctsb), L (Ctsl), and K (Ctsk), was modified after S pneumoniae challenge. Specifically, at 12 hours, Ctsk and Ctsl messenger RNA that was abundantly expressed in the normal middle ear mucosa was decreased, whereas Ctsb transcript was induced. The changes in Ctsb and Ctsk gene expression were sustained at 48 hours. CONCLUSION: The constitutive expression of Ctsk and Ctsl messenger RNA in normal middle ear mucosa supports a function in the maintenance of middle ear mucosa homeostasis, and their downregulation as an early event in acute otitis media may reflect a disruption in that function. The induction of Ctsb messenger RNA in the infected middle ear mucosa suggests a role in early tissue injury; thus, Ctsb may represent a potential target for molecular diagnostics and/or rational intervention during the development of acute otitis media.

Acute Disease↗
PubMed2003

Eustachian tube function in older children and adults with persistent otitis media.

OBJECTIVE: Otitis media (OM) is most common in infants and young children. Despite a dramatic reduction in its incidence after the age of six, the disease still occurs in older children, adolescents, and may even persist into adulthood. The goal of this study was to identify characteristics of eustachian tube (ET) function in an older population which may underlie their persistent OM. METHODS: Following a medical history and a head and neck examination, 38 subjects over 6 years of age (64 ears) had their ET function assessed with the forced-response test (FRT). Parameters derived from this test included opening and closing pressures as well as steady-state and active resistances. RESULTS: Adenoidectomy had previously been performed in 71% of the sample. Clinically, 5% of these subjects had evidence of nasopharyngeal inflammation. The distributions of closing pressure and steady-state resistance were very similar to the distributions of the historic normal controls. The distributions of opening pressure and active resistance were highly skewed relative to the control sample. All study subjects had either abnormal opening pressures or high active resistance, with 79% having both abnormalities. CONCLUSIONS: If nasopharyngeal inflammation and hypertrophied adenoids are significantly correlated to ET dysfunction and persistent OM, this sample should be free of middle-ear (ME) disease. However, these individuals suffer persistent OM due to ET dysfunction characterized by high opening pressures and high active resistances. The abnormalities underlying these skewed forced-response parameters must be identified and corrected if we are going to alleviate the ME disease in these and similar patients.

Acoustic Impedance Tests↗
PubMed2003

Rate of nitrous oxide exchange across the middle ear mucosa in monkeys before and after blockage of the mastoid antrum.

OBJECTIVES: We tested the hypothesis that mastoid volume buffers the rate of change in middle ear pressure caused by transmucosal, inert gas exchange. STUDY DESIGN: Twelve monkeys were randomly assigned to group 1 or group 2. Right ears of group 1 had sham surgery and of group 2 had obstruction of the mastoid antrum. Before and after surgery, the time constant for transmucosal N(2)O exchange was estimated from N(2)O breathing experiments. The hypothesis predicts that the postoperative time constant measured for right ears of group 2 but not group 1 is greater than that measured before surgery. RESULTS: Mastoid antrum block significantly decreased right middle ear volume but did not affect the time constant for transmucosal N(2)O exchange. CONCLUSION: A mastoid gas-reserve function is not supported by the experimental data. SIGNIFICANCE: These results for monkeys and the theory developed to explain the effect of mastoid volume on transmucosal inert gas exchange suggest that the results for previous experiments in humans interpreted as evidencing a mastoid gas-reserve function are consistent with alternative explanations.

Animals↗
PubMed2003

Mucosal expression of genes encoding possible upstream regulators of Na+ transport during pneumococcal otitis media.

OBJECTIVE: Recently, we reported that gene transcripts encoding 3 Na+ transport proteins (pump, channel and exchanger) in the middle ear mucosa (MEM) were simultaneously suppressed at 12 and 48 h after Streptococcus pneumoniae (SP) challenge of rat middle ears. MATERIAL AND METHODS: From cDNA microarray screening of those specimens, several gene clusters, including Nos2 and the transcription factors Fos, Fosl1, Jun and Nfkb1, were identified as possible upstream regulators of Na+ transport protein expression. The altered expression of those genes in MEM was validated and quantified using real-time polymerase chain reaction and MEM protein expression for Atp1a1, Nos2 and Nfkb1 was studied using Western blot and/or immunohistochemistry assays. RESULTS: At both time-points. Atp1a1 mRNA and protein were decreased and Nos2 mRNA and protein were increased in MEM. While Nfkb1 protein was decreased at those times. the corresponding mRNA was increased at 12 h but decreased at 48 h. Gene expression for Fos was suppressed at both times, while that for Fosl1 and Jun was augmented at 12 h and suppressed at 48 h. Immunohistochemical study of specimens challenged with SP showed a swollen MEM with infiltration of inflammatory cells that stained positive for Nos2. CONCLUSION: Given the known activities of Nos2, these results can be interpreted as evidencing a transcriptional suppression of Na+ transport protein synthesis secondary to upregulated Nos2 expression during SP infection of the rat MEM. This proposed signaling pathway does not require the continuous upregulation of Nfkb1 or the other assayed transcription factors as early as 12 h after middle ear infection.

Acute Disease↗
PubMed2003

Effect of tensor veli palatini muscle paralysis on eustachian tube mechanics.

Several physiological functions, such as regulating middle ear (ME) pressure and clearing ME fluid into the nasopharynx, require an opening of the collapsed eustachian tube (ET). The ability to perform these functions has been related to several mechanical properties of the ET: opening pressure (Popen), compliance (ETC), and hysteresis (eta). These global properties may be influenced by the mechanics of the surrounding tissue and/or the mucosa-air interface. In this study, we investigated the influence of tissue mechanics by paralyzing the right tensor veli palatini (TVP) muscle in 12 cynomolgus monkeys via botulinum toxin injection. A previously developed modified forced-response protocol was used to measure Popen, ETC, and eta under normal conditions and after muscle paralysis. The loss of muscle tone and/or stiffness resulted in a significant decrease in Popen (p < .01) and a significant increase in ETC (p < .01). In addition, muscle paralysis reduced the viscoelastic properties of the TVP muscle and therefore resulted in a significant decrease in eta (p < .05). A comparison with previous measurements on the influence of surface tension mechanics indicates that the ET's compliance is primarily determined by tissue elastic properties. The ET hysteresis, however, is equally affected by viscoelastic tissue properties and surface tension hysteretic properties. Knowledge of how these physical components affect the global mechanical environment may lead to improved treatments for ET dysfunction that target the underlying mechanical abnormality.

Acoustic Impedance Tests↗
PubMed2002

Measurement of the viscoelastic compliance of the eustachian tube using a modified forced-response test.

OBJECTIVES: Eustachian tube compliance (ETC) was suggested to be an important determinate of function. Previous attempts to quantify ETC used summary measures that are not clearly related to the physical properties of the system. Here, we present a new method for measuring ETC that conforms more closely to the engineering definition of compliance. METHODS: The forced response test was modified to include oscillations in applied flow after the forced tubal opening. Pressure and flow were recorded during the standard and modified test in 12 anesthetized cynomolgus monkeys. The resulting pressure-flow, hysteresis loops were compared with those predicted by a simple fluid-structure model of the Eustachian tube with linear-elastic or viscoelastic properties. The tubal compliance index (TCI) and a viscoelastic compliance (C(v)) were calculated from these data for each monkey. RESULTS: The behavior of a viscoelastic, but not a linear elastic model accurately reproduced the experimental data for the monkey. The TCI and C(v) were linearly related, but the shared variance in these measures was only 63%. CONCLUSIONS: This new method for measuring ETC captures all information contained in the traditional TCI, but also provides information regarding the contribution of wall viscosity to Eustachian tube mechanics.

Animals↗
PubMed2002

A rat model of otitis media with effusion caused by eustachian tube obstruction with and without Streptococcus pneumoniae infection: methods and disease course.

OBJECTIVE: To describe the clinical and histopathologic progression of a rat model of otitis media with effusion caused by eustachian tube obstruction (ETO) with and without Streptococcus pneumoniae infection. METHODS: In 164 rats, the left, bony eustachian tube was approached via a ventral incision and obstructed with dental material. Then 108 rats were infected via an intrabullar injection with S pneumoniae. At 48 hours, the infected rats were treated for 5 days with ampicillin. All ears were evaluated by weekly otomicroscopy. On each of days 1, 2, 7, 21, 35, 56, and 112, four rats were killed for histologic study. All effusions were cultured for bacteria. RESULTS: Fourteen rats died of surgical complications; effusion resolved by 2 weeks in 9 rats. During the first few days, infected ears with ETO had bulging tympanic membranes, followed by tympanic membrane retraction, purulent effusion, and otorrhea (50%) over the next few weeks, whereas uninfected ears with ETO developed retraction and serous effusion during the same time frame. At later times, all ears with ETO presented with retraction and serous or serous-mucoid effusion. S pneumoniae was recovered only from the infected ears with ETO (days 1 and 2), with some colonization by nonpathogenic microorganisms observed equally in both groups of ears. Histology showed a typical acute inflammatory reaction in the challenged ears with ETO through day 14 and then a chronic inflammation for all ears with ETO. CONCLUSION: The experimental methods provoked reproducible pathologic signs similar to those for otitis media with effusion. Given the availability of rat-specific reagents, this model is well suited for studies of cytokine elaboration during disease pathogenesis.

Animals↗
PubMed2002

Suppression of epithelial ion transport transcripts during pneumococcal acute otitis media in the rat.

Until recently, it was not feasible to conduct genome-wide screening for gene transcript variations that play key roles in the pathogenesis of otitis media. In this study microarray technology was used to profile differential gene expression patterns from rat middle ear mucosa at 12 and 48 h after Streptococcus pneumoniae challenge. Real-time polymerase chain reaction was performed for independent verification of the microarray results. Three ion transport mRNAs were simultaneously suppressed more than 4-fold at 12 h in bacteria-challenged ears, including Na,K-ATPase alpha I subunit (SPATPa1), sodium channel beta 2 subunit (SCNB2) and sodium-hydrogen exchange protein isoform 2 subunit (NHE2). At 48 h after infection, the mRNA levels of SCNB2 and NHE2 had decreased 7- and 10-fold, respectively, whereas the relatively abundant SPATPa1 transcript showed recovery. The downregulation of Na(+)-transporting transcripts suggests a reduced number of epithelial cells and transporting proteins and/or the dysfunction of sodium transporters secondary to the bacterial infection. These changes can disrupt the coupling of the apical Na + entry and basolateral Na + extrusion, deplete the electrochemical Na+ transmembrane gradient, disrupt the intracellular osmotic equilibrium and lead to intracellular acidification and the accumulation of excess sodium, water and other organic and inorganic molecules in the middle ear cavity. Any or all of these changes may contribute to the initiation and persistence of middle ear mucosa inflammation and effusion during an episode of bacterial acute otitis media.

Acute Disease↗
PubMed2002

Effect of 10 pharmacologic probes on mRNA levels of inducible nitric oxide synthetase and selected inflammatory cytokines in a rat model of acute otitis media.

Ten drugs were screened for their ability to decrease inflammatory mediator (IL-6, inducible nitric oxide synthetase [iNOS], IL-1beta and monocyte chemotactic protein [MCP-1]) expression in a rat model of acute otitis media caused by Streptococcus pneumoniae. Six adult rats were randomly assigned to each of 12 groups corresponding to uninfected controls and treatments with saline, aminoguanidine, anisomycin, dexamethasone, ketorolac, L-N(G)-nitroarginine methylester, methylprednisolone, mycophenolic acid, pentoxiphylline, tacrolimus or WEB2086. Forty-eight h after the start of treatment, the ears of the animals in the 11 treatment groups were challenged with S. pneumoniae. Forty-eight h later, all animals were killed and middle ear mucosa was harvested and assayed for RNA message. Messages for IL-6, iNOS and MCP-1 were significantly increased as a result of infection. Most treatments decreased MCP-1 and four decreased IL-6 and iNOS. Tacrolimus and dexamethasone decreased IL-6, iNOS and MCP-1. These results show that pharmacological agents can modify the expression of inflammatory mediators in this model and may have clinically relevant effects.

Acute Disease↗
PubMed2002

Cytokine profiles in a rat model of otitis media with effusion caused by eustachian tube obstruction with and without Streptococcus pneumoniae infection.

OBJECTIVE: Cytokine expression was studied in a rat model of otitis media with effusion. METHODS: The left eustachian tube was obstructed (eustachian tube obstruction [ETO]) in 84 rats. Forty-two ears were challenged with, and those rats were treated from day 2 to day 7 with ampicillin. Twelve rats (6 per group) were killed on days 1, 2, 7, 21, 35, 56, and 112; mucosa was harvested and assayed for interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) gene expression, and effusion was assayed for IL-1beta, TNF-alpha, IL-6, IL-10, and macrophage inflammatory protein-2 (MIP-2) protein. RESULTS: Most cytokines were detectable in the effusion from infected ears with ETO on days 1 and 2 only. MIP-2 exhibited a biphasic response. Only effusion MIP-2 was consistently detected in uninfected ears with ETO. Three patterns of mucosal cytokine messenger RNA (mRNA) upregulation were observed: isolated early (IL-1beta, IL-8), isolated late (TNF-alpha, IFN-gamma), and biphasic (MCP-1, IL-6, TGF-beta) responses. Early cytokine mRNA upregulations were observed only in the infected ears with ETO, whereas late upregulations were observed in both groups. CONCLUSIONS: Early expression of the assayed cytokines occurred only in ears with active infection. For both groups, a late upregulation of cytokine message but not protein was documented. The profile of cytokine expression during otitis media episodes may be useful in defining etiology, disease stage, and prognosis.

Ampicillin↗
PubMed2002

Model-based evaluation of eustachian tube mechanical properties using continuous pressure-flow rate data.

Eustachian tube (ET) dysfunction has been implicated in the development of chronic otitis media, a common childhood disorder. An impaired ability to open the collapsible ET results in fluid accumulation in the middle ear and subsequent infection and inflammation. Abnormal ET function has been casually related to an abnormal mechanical environment. Previous attempts to quantify ET mechanics used summary measures that are not clearly related to the physical properties of the system. In this study, we modified a testing technique to obtain pressure and flow rate measurements in the ET and analyzed these data with a simple model of airflow in a collapsible tube. This model is based on fully developed flow in a noncircular duct and a nonlinear, time-dependent pressure-area relationship. The ability of this model to capture the observed pressure-flow phenomena was demonstrated in 12 cynomolgus monkeys. Correlation between model and experimental data resulted in quantitative estimates of ET compliance and wall viscosity. This technique, which can be implemented in a clinical setting, provides a more accurate description of ET mechanics and may, therefore, prove to be an important diagnostic tool. Future studies will use this technique to quantify the influence of various physiological parameters on ET mechanics.

Animals↗
PubMed2002

Effect of surface tension and surfactant administration on Eustachian tube mechanics.

Development of otitis media has been related to abnormal Eustachian tube (ET) mechanics. ET is a collapsible tube that is periodically opened to regulate middle ear pressure and to clear middle ear fluid into the nasopharynx. The ability to perform these physiological functions depends on several mechanical properties, including the ET's opening pressure (P(open)), compliance (ETC), and hysteresis (eta). In this study, a previously developed modified force-response protocol was used to determine ET mechanical properties after experimental manipulation of the mucosal surface condition. Specifically, these properties were measured in the right ear of six cynomologous monkeys under baseline conditions after "washing out" the normal ET mucous layer and after instillation of a pulmonary surfactant, Infasurf. Removal of the normal mucosa did not significantly alter P(open) but did result in a decrease in ETC and eta (P < 0.05). Treatment of the mucosa with Infasurf was effective in reducing P(open) and increasing both ETC and eta to baseline values (P < 0.05). These results indicate that the mucosa-air surface tension can affect the overall ETC and eta properties of the ET. In addition, this study indicates that surfactant therapy may only be beneficial in patients with rigid or inelastic ETs (large P(open) and low ETC and eta).

Animals↗