Publications by authors named "Carol J MacArthur"

34 Publications

Drug-Induced Sleep Endoscopy Findings in Children With Obstructive Sleep Apnea With vs Without Obesity or Down Syndrome.

JAMA Otolaryngol Head Neck Surg 2021 Feb;147(2):175-181

Oregon Health and Science University, Portland.

Importance: Persistent obstructive sleep apnea after adenotonsillectomy is common in children with Down syndrome or obesity. Drug-induced sleep endoscopy could help to identify anatomic differences in these patients that might affect surgical decision-making.

Objective: To assess drug-induced sleep endoscopy findings in surgically naive children with obstructive sleep apnea with obesity or Down syndrome and compare these findings with children without obesity or Down syndrome.

Design, Setting, And Participants: This cross-sectional analysis of data from a prospective cohort study of patients enrolled between May 1, 2015, and December 31, 2019, was conducted at an academic tertiary care children's hospital and included a consecutive sample of surgically naive children (age 2-18 years) who underwent drug-induced sleep endoscopy at the time of adenotonsillectomy for sleep-disordered breathing. Indications for sleep endoscopy included severe sleep apnea, age older than 7 years, obesity, African American race, and Down syndrome.

Exposures: Drug-induced sleep endoscopy.

Main Outcomes And Measures: Sleep endoscopy findings were scored according to the Sleep Endoscopy Rating Scale. Ratings at 6 anatomic levels for children with obesity and those with Down syndrome were compared with controls without obesity or Down syndrome using several measures of effect size (Cohen d, Cramer V, and η2).

Results: A total of 317 children (158 girls [50%]; 219 [69%] White, 20 [6%] Black, and 103 [34%] Hispanic; mean [95% CI] age, 9.6 [9.2-10.0] years) were included, of whom 115 (36%) were controls without obesity or Down syndrome, 179 (56%) had obesity without Down syndrome, and 23 (7%) had Down syndrome. The mean apnea-hypopnea index was 16 (95% CI, 13-19), and the mean minimum O2 saturation was 83% (95% CI, 81%-85%). Compared with controls without obesity or Down syndrome, children with Down syndrome demonstrated greater overall obstruction (mean sleep endoscopy rating scale total score of 5.6 vs 4.8; Cohen d, 0.46), and greater tonsillar (percentage of complete obstruction: 65% vs 54%), tongue base (percentage of complete obstruction: 26% vs 12%), and arytenoid obstruction (percentage of at least partial obstruction, 35% vs 6%). Children with obesity had greater tonsillar (percentage of complete obstruction, 74% vs 54%) and less base of tongue obstruction (percentage of complete obstruction, 2% vs 12%) compared with controls.

Conclusions And Relevance: In this cohort study, surgically naive children with obesity with obstructive sleep apnea had predominantly tonsillar obstruction, whereas children with Down syndrome demonstrated greater obstruction of the tonsils, tongue base, and arytenoids compared with controls. Routine drug-induced sleep endoscopy should be considered in surgically naive children with Down syndrome to help inform the surgical plan.
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http://dx.doi.org/10.1001/jamaoto.2020.4548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716249PMC
February 2021

Endoscopic ear surgery in children with down syndrome.

Int J Pediatr Otorhinolaryngol 2020 Apr 15;131:109884. Epub 2020 Jan 15.

Oregon Health & Science University, USA.

Introduction: Children with Down syndrome (DS) have a high incidence of chronic middle ear disease. Surgery to manage this disease is challenging due to the severity of illness and narrow ear canal dimensions. Endoscopic ear surgery is used to manage tympanic membrane and middle ear disease with the advantages of improved visualization and avoidance of post-auricular incisions. However, its application in children with DS has not been reported. We aim to compare the outcomes of endoscopic versus microscopic ear surgery in children with DS.

Methods: All patients with DS who underwent tympanoplasty without mastoidectomy between 2012 and 2018 were identified, and their charts retrospectively reviewed. Rate of residual perforation, hearing, surgical time, and surgical details were recorded.

Results: 37 surgeries in 26 patients were identified that met inclusion criteria. Two subgroups were analyzed. The first included 14 cases that were done using traditional microscopic visualization (MV). The second included 17 cases that had substantial or exclusive use of endoscopic visualization (EES). Due to a learning curve, the number of cases done endoscopically increased over time. The average age in MV was 13.9 years vs 11.0 in EES. The MV cases included 2 with cholesteatoma vs 4 in EES. In cases with adequate follow up, residual perforations were found in 1/13 MV, and 4/17 EES. All of the residual perforation cases in EES used acellular porcine submucosa grafts. None of the cases in MV used this material. Average air bone gap reduction was seen in both groups; 4.2 dB in MV, 9.8 dB in EES. Average surgical time was similar between groups; 124 min in MV, 115 min in EES. All cases in MV required a post-auricular incision and approach to the middle ear. Only four cases in EES required this approach. Six cases in EES did not require any incision outside of the ear canal for either graft harvest or middle ear approach.

Conclusion: Endoscopic and microscopic ear surgery in children with DS have similar outcomes. There were no statistical differences in hearing results, surgical times, or residual tympanic membrane perforations, although the rate of perforations in the endoscopic group trended higher. Most endoscopic cases did not require conversion to a post-auricular approach. Endoscopic surgery allows some DS patients to avoid any incision outside of the ear canal.
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http://dx.doi.org/10.1016/j.ijporl.2020.109884DOI Listing
April 2020

Advanced practice providers and children's hospital-based pediatric otolarynology practices.

Int J Pediatr Otorhinolaryngol 2020 Feb 7;129:109770. Epub 2019 Nov 7.

Connecticut Children's Medical Center, Hartford, CT, USA; Department of Otolaryngology - Head and Neck Surgery, University of Connecticut School of Medicine, Farmington, CT, USA.

Introduction: Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting.

Methods: Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice.

Results: A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale.

Discussion: The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity.
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http://dx.doi.org/10.1016/j.ijporl.2019.109770DOI Listing
February 2020

Intratympanically Delivered Steroids Impact Thousands More Inner Ear Genes Than Systemic Delivery.

Ann Otol Rhinol Laryngol 2019 Jun;128(6_suppl):134S-138S

3 OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, OR, USA.

Objectives: Glucocorticoids are given for sensorineural hearing loss, but little is known of their molecular impact on the inner ear. Furthermore, in spite of claims of improved hearing recovery with intratympanic delivery of steroids, no studies have actually documented the inner ear molecular functions that are enhanced with this delivery method.

Methods: To assess steroid-driven processes in the inner ear, gene chip analyses were conducted on mice treated systemically with the glucocorticoids prednisolone or dexamethasone or the mineralocorticoid aldosterone. Other mice were given the same steroids intratympanically. Inner ears were harvested at 6 hours and processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34 000 genes. Results were statistically analyzed for up or down expression of each gene against control (untreated) mice.

Results: Analyses showed approximately 17 500 genes are normally expressed in the inner ear and steroids alter expression of 55% to 82% of these. Dexamethasone changed expression of 9424 (53.9%) inner ear genes following systemic injection but 14 899 ear genes (85%) if given intratympanically. A similar pattern was seen with prednisolone, as 7560 genes were impacted by oral delivery and 11 164 genes (63.8%) when given intratympanically. The mineralocorticoid aldosterone changed expression of only 268 inner ear genes if given orally, but this increased to 10 124 genes (57.9%) if injected intratympanically. Furthermore, the glucocorticoids given actually impacted more inner ear genes via the mineralocorticoid receptor than the glucocorticoid receptor.

Conclusions: Thousands of inner ear genes were affected by steroids, and this number increased significantly if steroids were delivered intratympanically. Also, the impact of glucocorticoids on inner ear mineralocorticoid functions is more substantial than previously known. Thus, the application of therapeutic steroids for hearing loss needs to be reassessed in light of their more comprehensive impact on inner ear genes. Furthermore, simply ascribing the efficacy of steroids to immunosuppression no longer appears to be warranted.
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http://dx.doi.org/10.1177/0003489419837562DOI Listing
June 2019

Simultaneous intra-operative sclerotherapy and surgical resection of cervicofacial venous malformations.

Int J Pediatr Otorhinolaryngol 2019 Mar 25;118:143-146. Epub 2018 Dec 25.

Department of Neuro-Interventional Radiology, Oregon Heath & Science University, USA.

Objectives: To review simultaneous intra-operative sclerotherapy (IOS) with immediate surgical resection for the treatment of cervicofacial venous malformations (VMs) at a single institution. While pre-operative sclerotherapy (POS) has been reported in the literature, simultaneous intra-operative sclerotherapy and surgery in the operating room has not.

Methods: The database from the Hemangioma and Vascular Birthmarks Clinic was reviewed. All patients in both groups had biopsy-proven VMs.

Results: IOS was used in 11 surgical patients with average age 17 years. Sclerotherapy was performed with sodium tetradecyl sulfate 3%, absolute alcohol or bleomycin. Immediately after IOS, and under the same anesthetic, all patients had either complete resection or debulking of the VMs. Eight patients had complete resolution of their VM and 3 had improvement. Average duration of the combined procedures done under a single anesthetic was 121 min. The POS approach was used for 6 surgical patients with average age 7 years. Sclerotherapy agents used were absolute alcohol or sodium tetradecyl sulfate 3%. All patients underwent complete resection of the VM 24-72 h after sclerotherapy under a separate surgical session. Five patients experienced complete resolution of their VM and one has had further sclerotherapy for recurrent disease. Interventional Radiology suite sclerotherapy times were on average 70 min. Surgical times were on average 142 min. Total combined anesthesia times for the two procedures added together were 212 min. Treatment time was significantly shorter in the IOS group (p = 0.0015).

Conclusions: Simultaneous IOS at the time of surgical resection has been successful in our hands. IOS has the advantage of a single procedure and decreased cost to the patient. In the era of reducing pediatric exposure to anesthesia, this approach is especially attractive in the pediatric population. As well, at approximately $100/minute cost to the patient to be in either the Interventional Radiology Suite or in the operating room, the reduced length of the procedures seen in the IOS approach results in lower overall cost to the patient.
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http://dx.doi.org/10.1016/j.ijporl.2018.12.017DOI Listing
March 2019

Is Routine Electrocardiography Necessary Before Initiation of Propranolol for Treatment of Infantile Hemangiomas?

Pediatr Dermatol 2016 Nov 7;33(6):615-620. Epub 2016 Sep 7.

Oregon Health and Science University, Portland, OR.

Background: In recent years propranolol has become the treatment of choice for infantile hemangiomas (IHs). There is broad variation in the approach to propranolol initiation in clinical practice. This retrospective study explored the effectiveness of routine pre-treatment ECG in screening infants being considered for systemic treatment with propranolol.

Methods: All patients seen in the outpatient pediatric dermatology clinics at Oregon Health and Sciences University (OHSU) and The Mayo Clinic Rochester (MCR), as well as those seen in multidisciplinary vascular anomalies clinics, who had ECGs obtained prior to planned initiation of propranolol for treatment of IH from 2008 to 2013, were identified. A total of 162 patients were included in the study.

Results: We found that 43% (69) of routine ECGs were read as abnormal, leading to 28 formal consultation appointments with pediatric cardiologists. After either formal consultation or informal discussion with cardiology, no patients with initially "abnormal" ECGs were ultimately excluded from treatment with propranolol based on routine ECG findings. Additionally no patients in our cohort experienced an adverse effect during treatment that could have been predicted or prevented by ECG prior to initiation of the propranolol.

Conclusion: Our findings suggest that routine ECG may not be necessary or helpful in the vast majority of patients treated with propranolol for IHs.
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http://dx.doi.org/10.1111/pde.12972DOI Listing
November 2016

Quality of life improvement after pressure equalization tube placement in Down syndrome: A prospective study.

Int J Pediatr Otorhinolaryngol 2016 Sep 4;88:168-72. Epub 2016 Jul 4.

Department of Otolaryngology, Head & Neck Surgery, Oregon Health & Science University, Portland, OR, USA. Electronic address:

Objective: To evaluate quality-of-life changes after bilateral pressure equalization tube placement with or without adenoidectomy for the treatment of chronic otitis media with effusion or recurrent acute otitis media in a pediatric Down syndrome population compared to controls.

Study Design: Prospective case-control observational study.

Methods: The OM Outcome Survey (OMO-22) was administered to both patients with Down syndrome and controls before bilateral tube placement with or without adenoidectomy and at an average of 6-7 months postoperatively. Thirty-one patients with Down syndrome and 34 controls were recruited. Both pre-operative and post-operative between-group and within-group score comparisons were conducted for the Physical, Hearing/Balance, Speech, Emotional, and Social domains of the OMO-22.

Results: Both groups experienced improvement of mean symptom scores post-operatively. Patients with Down syndrome reported significant post-operative improvement in mean Physical and Hearing domain item scores while control patients reported significant improvement in Physical, Hearing, and Emotional domain item scores. All four symptom scores in the Speech domain, both pre-operatively and post-operatively, were significantly worse for Down syndrome patients compared to controls (p ≤ 0.008).

Conclusions: Surgical placement of pressure equalizing tubes results in significant quality of life improvements in patients with Down syndrome and controls. Problems related to speech and balance are reported at a higher rate and persist despite intervention in the Down syndrome population. It is possible that longer follow up periods and/or more sensitive tools are required to measure speech improvements in the Down syndrome population after pressure equalizing tube placement ± adenoidectomy.
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http://dx.doi.org/10.1016/j.ijporl.2016.06.057DOI Listing
September 2016

Use of intravenous propranolol for control of a large cervicofacial hemangioma in a critically ill neonate.

Int J Pediatr Otorhinolaryngol 2016 May 12;84:52-4. Epub 2016 Feb 12.

Department of Otolaryngology - Head and Neck Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, PV01, Portland, OR 97239, USA.

Cervicofacial segmental infantile hemangiomas (IH) may result in airway obstruction requiring use of propranolol to induce hemangioma regression and reestablish the airway. We present the first case using intravenous (IV) propranolol for control of airway obstruction and rapid expansion of cervicofacial IH in the setting of necrotizing enterocolitis (NEC) impaired gastrointestinal function. Intravenous dosing of propranolol was tolerated well in a critically ill neonate with multisystem complications of prematurity.
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http://dx.doi.org/10.1016/j.ijporl.2016.02.005DOI Listing
May 2016

Implementation of a Pediatric Posttonsillectomy Pain Protocol in a Large Group Practice.

Otolaryngol Head Neck Surg 2016 Apr 16;154(4):720-4. Epub 2016 Feb 16.

Department of Otolaryngology-Head and Neck Surgery, Kaiser Permanente Northwest, Clackamas, Oregon, USA

Objective: In response to the increased risk of respiratory failure and death after tonsillectomy related to codeine use, Kaiser Permanente Northwest restricted use of opioids in patients <7 years old via electronic health record (EHR). However, opioids could be prescribed at physician discretion by overriding the EHR. This study aims to examine protocol compliance in a large group practice using EHR order sets and complication rates as compared with historical data.

Study Design: Case series with chart review.

Setting: Ambulatory care within a health maintenance organization.

Subjects And Methods: Procedural codes were used to identify children <7 years old who underwent tonsillectomy or adenotonsillectomy approximately 1.5 years before and after implementation of EHR protocol (n = 437). Primary outcome was opioid pain prescriptions received by patients. Secondary outcomes were emergency or urgent care utilization, postoperative bleeding, nausea, vomiting, dehydration, death, and reasons for prescribing opioid pain medication after EHR protocol implementation. Chi-square analysis and Fischer's exact testing were used to compare differences in event rates.

Results: Implementation of an age-based narcotic protocol significantly decreased physician narcotic prescribing from 82.2% to 15.4% (P < .0001). The most common reason for narcotic prescription after the intervention was the report of inadequate pain control by phone call (35%). There was no significant difference in rate of emergency or urgent care utilization between pre- and postimplementation groups (4% vs 6%, P = .29).

Conclusions: Implementation of an age-based narcotic restriction for posttonsillectomy patients using an EHR order set is an effective and safe way to influence physician prescription practices.
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http://dx.doi.org/10.1177/0194599815627810DOI Listing
April 2016

Assessment of pediatric obstructive sleep apnea using a drug-induced sleep endoscopy rating scale.

Laryngoscope 2016 06 17;126(6):1492-8. Epub 2016 Jan 17.

Oregon Institute of Occupational Health Sciences, Oregon Health and Science University, Portland, Oregon, U.S.A.

Objectives/hypothesis: Assess the reliability of a Sleep Endoscopy Rating Scale (SERS) and its relationship with pediatric obstructive sleep apnea (OSA) severity.

Study Design: Retrospective case series of pediatric patients who underwent drug-induced sleep endoscopy (DISE) at the time of surgery for OSA from January 1, 2013 to May 1, 2014.

Methods: Three blinded otolaryngologists scored obstruction on DISE recordings as absent (0), partial (+1), or complete (+2) at six anatomic levels: nasal airway, nasopharynx, velopharynx, oropharynx, hypopharynx, and arytenoids. Ratings were summed for a SERS total score (range, 0-12). Reliability was calculated using a κ statistic with linear weighting. SERS ratings and obstructive apnea-hypopnea index (OAHI) were compared using Spearman correlation. A receiver operating characteristic (ROC) analysis determined the ability of the SERS total score to predict severe OSA (OAHI >10).

Results: Thirty-nine patients were included (mean age, 8.3 ± 5.1 years; 36% obese; mean OAHI, 19.1 ± 23.7). Intrarater and inter-rater reliability was substantial-to-excellent (κ = 0.61-0.83) and fair-to-substantial (κ = 0.33-0.76), respectively. Ratings correlated best with OAHI for the oropharynx (r = 0.54, P = .02), hypopharynx (r = 0.48, P = .04), and SERS total score (r = 0.75, P = .002). In ROC analysis, a SERS total score ≥6 demonstrated sensitivity/specificity of 81.8%/87.5%, respectively, and correctly classified 84% of patients.

Conclusions: The SERS can be applied reliably in children undergoing DISE for OSA. Ratings of the oropharynx, hypopharynx, and SERS total score demonstrated significant correlation with OSA severity. A SERS total score ≥6 was an accurate predictor of severe OSA.

Level Of Evidence: 4. Laryngoscope, 126:1492-1498, 2016.
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http://dx.doi.org/10.1002/lary.25842DOI Listing
June 2016

Propranolol-responsive cranial nerve palsies in a patient with PHACES syndrome.

Int J Pediatr Otorhinolaryngol 2015 Oct 7;79(10):1778-81. Epub 2015 Aug 7.

Department of Otolaryngology - Head and Neck Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, PV01, Portland, OR 97239, USA.

PHACES syndrome is a neurocutaneous disorder characterized by the presence of segmental hemangiomas with associated anomalies of the posterior fossa, cerebral vasculature, cardiovascular system, eyes, and ventral or midline structures. We present the first case of propranolol-responsive congenital trigeminal and facial nerve palsies secondary to an intracranial hemangioma in a patient with PHACES syndrome.
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http://dx.doi.org/10.1016/j.ijporl.2015.07.040DOI Listing
October 2015

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

PLoS One 2015 15;10(7):e0132551. Epub 2015 Jul 15.

Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.

Background: Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts.

Methods: We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls.

Results: In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNFα secretion in myeloid dendritic cells.

Conclusions: The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132551PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503307PMC
May 2016

Correlative mRNA and protein expression of middle and inner ear inflammatory cytokines during mouse acute otitis media.

Hear Res 2015 Aug 25;326:49-58. Epub 2015 Apr 25.

Oregon Hearing Research Center, Department of Otolaryngology Head & Neck Surgery, Oregon Health & Science University, Portland, OR, USA.

Although the inner ear has long been reported to be susceptible to middle ear disease, little is known of the inflammatory mechanisms that might cause permanent sensorineural hearing loss. Recent studies have shown inner ear tissues are capable of expressing inflammatory cytokines during otitis media. However, little quantitative information is available concerning cytokine gene expression in the inner ear and the protein products that result. Therefore, this study was conducted of mouse middle and inner ear during acute otitis media to measure the relationship between inflammatory cytokine genes and their protein products with quantitative RT-PCR and ELISA, respectively. Balb/c mice were inoculated transtympanically with heat-killed Haemophilus influenzae and middle and inner ear tissues collected for either quantitative RT-PCR microarrays or ELISA multiplex arrays. mRNA for several cytokine genes was significantly increased in both the middle and inner ear at 6 h. In the inner ear, these included MIP-2 (448 fold), IL-6 (126 fold), IL-1β (7.8 fold), IL-10 (10.7 fold), TNFα (1.8 fold), and IL-1α (1.5 fold). The 24 h samples showed a similar pattern of gene expression, although generally at lower levels. In parallel, the ELISA showed the related cytokines were present in the inner ear at concentrations higher by 2-122 fold higher at 18 h, declining slightly from there at 24 h. Immunohistochemistry with antibodies to a number of these cytokines demonstrated they occurred in greater amounts in the inner ear tissues. These findings demonstrate considerable inflammatory gene expression and gene products in the inner ear following acute otitis media. These higher cytokine levels suggest one potential mechanism for the permanent hearing loss seen in some cases of acute and chronic otitis media.
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http://dx.doi.org/10.1016/j.heares.2015.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492826PMC
August 2015

Control of middle ear inflammatory and ion homeostasis genes by transtympanic glucocorticoid and mineralocorticoid treatments.

PLoS One 2015 26;10(3):e0119228. Epub 2015 Mar 26.

Oregon Hearing Research Center, Department of Otolaryngology, Head & Neck Surgery, Oregon Health & Science University, Portland, OR, 97239-3098, United States of America.

Hypothesis: Transtympanic steroid treatment will induce changes in ion homeostasis and inflammatory gene expression to decrease middle ear inflammation due to bacterial inoculation.

Background: Otitis media is common, but treatment options are limited to systemic antibiotic therapy or surgical intervention. Systemic glucocorticoid treatment of mice decreases inflammation and improves fluid clearance. However, transtympanic delivery of glucocorticoids or mineralocorticoid has not been explored to determine if direct steroid application is beneficial.

Methods: Balb/c mice received transtympanic inoculation of heat-killed Haemophilus influenzae (H flu), followed by transtympanic treatment with either prednisolone or aldosterone. Mice given PBS instead of steroid and untreated mice were used as controls. Four hours after steroid treatment, middle ears were harvested for mRNA extraction and 24 hours after inoculation middle ears were harvested and examined for measures of inflammation.

Results: H flu inoculation caused the increased expression of nearly all inflammatory cytokine genes and induced changes in expression of several genes related to cellular junctions and transport channels. Both steroids generally reversed the expression of inflammatory genes and caused ion and water regulatory genes to return to normal or near normal levels. Histologic evaluation of middle ears showed improved fluid and inflammatory cell clearance.

Conclusion: Improvement in middle ear inflammation was noted with both the glucocorticoid prednisolone and the mineralocorticoid aldosterone. This was due to reversal of inflammation-induced changes in middle ear cytokine genes, as well as those involved in ion and water homeostasis. Because glucocorticoids bind to the mineralocorticoid receptor, but not the reverse, it is concluded that much of the reduction of fluid and other inflammation measures was due to these steroids impact on ion and water transport channels. Further research is necessary to determine if this alternative mineralocorticoid treatment for otitis media will be clinically effective with fewer side effects than glucocorticoids.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374692PMC
March 2016

Outcomes of tympanostomy tube placement in children with Down syndrome--a retrospective review.

Int J Pediatr Otorhinolaryngol 2014 Feb 21;78(2):223-6. Epub 2013 Nov 21.

Department of Otolaryngology, Oregon Health Sciences University, Portland, OR, United States.

Objectives: Tympanostomy tubes are commonly used for treatment of chronic otitis media with effusion (COME) or recurrent acute otitis media (RAOM) in patients with Down syndrome, but hearing outcomes in this population have been mixed, and complications appear to be common. We aim to characterize outcomes and complications associated with tympanostomy tube placement in this population.

Methods: Retrospective review. All patients with Down syndrome presenting to a tertiary academic pediatric otolaryngology practice over a ten year period from 2002 to 2012 who received tympanostomy tubes for COME, RAOM, or hearing loss were reviewed.

Results: Long term follow up data was obtained in 102 patients, with average follow up 4.7 years. COME was the primary indication for tube placement in 100/102 (98%). Less than half of these patients (44%) initially failed their newborn hearing screen. Post operative hearing was found to be normal or near normal for the better hearing ear in 85/99 (85.9%), and normal to near normal in bilateral ears in 71/99 (71%). A majority (63.7%) of patients required two or more sets of tubes during the follow up period. Long term complications were common and were significantly increased if the patient required three or more sets of tubes, including chronic perforation (36.6% vs 8.2%, p<0.001), atelectasis (29.3% vs 1.6%, p<0.0001), and cholesteatoma (14.6% vs 0%, p=0.003).

Conclusions: COME is a frequent problem in Down syndrome, and the majority of patients will require two or more sets of tubes during their childhood and achieve normal postoperative hearing. Long term complications of otitis media appear to be more common in this population and appear to correlate with increasing number of tubes placed. More investigation is required to determine optimal treatment strategies for COME in patients with Down syndrome.
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http://dx.doi.org/10.1016/j.ijporl.2013.10.062DOI Listing
February 2014

Otitis media impacts hundreds of mouse middle and inner ear genes.

PLoS One 2013 4;8(10):e75213. Epub 2013 Oct 4.

Department of Otolaryngology Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon, United States of America ; Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon, United States of America.

Objective: Otitis media is known to alter expression of cytokine and other genes in the mouse middle ear and inner ear. However, whole mouse genome studies of gene expression in otitis media have not previously been undertaken. Ninety-nine percent of mouse genes are shared in the human, so these studies are relevant to the human condition.

Methods: To assess inflammation-driven processes in the mouse ear, gene chip analyses were conducted on mice treated with trans-tympanic heat-killed Hemophilus influenza using untreated mice as controls. Middle and inner ear tissues were separately harvested at 6 hours, RNA extracted, and samples for each treatment processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34,000 genes.

Results: Statistical analysis of gene expression compared to control mice showed significant alteration of gene expression in 2,355 genes, 11% of the genes tested and 8% of the mouse genome. Significant middle and inner ear upregulation (fold change >1.5, p<0.05) was seen in 1,081 and 599 genes respectively. Significant middle and inner ear downregulation (fold change <0.67, p<0.05) was seen in 978 and 287 genes respectively. While otitis media is widely believed to be an exclusively middle ear process with little impact on the inner ear, the inner ear changes noted in this study were numerous and discrete from the middle ear responses. This suggests that the inner ear does indeed respond to otitis media and that its response is a distinctive process. Numerous new genes, previously not studied, are found to be affected by inflammation in the ear.

Conclusion: Whole genome analysis via gene chip allows simultaneous examination of expression of hundreds of gene families influenced by inflammation in the middle ear. Discovery of new gene families affected by inflammation may lead to new approaches to the study and treatment of otitis media.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075213PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790799PMC
July 2014

Genetic susceptibility to chronic otitis media with effusion: candidate gene single nucleotide polymorphisms.

Laryngoscope 2014 May 2;124(5):1229-35. Epub 2013 Oct 2.

Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon, U.S.A; Oregon Hearing Research Center, Oregon Health and Science University, Portland, Oregon, U.S.A.

Objectives/hypothesis: The genetic factors leading to a predisposition to otitis media are not well understood. The objective of the current study was to develop a tag-single nucleotide polymorphism (SNP) panel to determine if there is an association between candidate gene polymorphisms and the development of chronic otitis media with effusion.

Study Design: A 1:1 case/control design of 100 cases and 100 controls was used. The study was limited to the chronic otitis media with effusion phenotype to increase the population homogeneity.

Methods: A panel of 192 tag-SNPs was selected. Saliva for DNA extraction was collected from 100 chronic otitis media with effusion cases and 100 controls. After quality control, 100 case and 79 control samples were available for hybridization. Genomic DNA from each subject was hybridized to the SNP probes, and genotypes were generated. Quality control across all samples and SNPs reduced the final SNPs used for analysis to 170. Each SNP was then analyzed for statistical association with chronic otitis media with effusion.

Results: Eight SNPs from four genes had an unadjusted P value of <.05 for association with the chronic otitis media with effusion phenotype (TLR4, MUC5B, SMAD2, SMAD4); five of these polymorphisms were in the TLR4 gene.

Conclusions: Even though these results need to be replicated in a novel population, the presence of five SNPs in the TLR4 gene having association with chronic otitis media with effusion in our study population lends evidence for the possible role of this gene in the susceptibility to otitis media.
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http://dx.doi.org/10.1002/lary.24349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971016PMC
May 2014

Inner ear tissue remodeling and ion homeostasis gene alteration in murine chronic otitis media.

Otol Neurotol 2013 Feb;34(2):338-46

Oregon Hearing Research Center, and Department of Otolaryngology, Head and Neck Surgery, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.

Hypothesis: Studies were designed to ascertain the impact of chronic middle ear infection on the numerous ion and water channels, transporters, and tissue remodeling genes in the inner and middle ear.

Background: Permanent sensorineural hearing loss is a significant problem resulting from chronic middle ear disease, although the inner ear processes involved are poorly defined. Maintaining a balanced ionic composition of endolymph in the inner ear is crucial for hearing; thus, it was hypothesized that this may be at risk with inflammation.

Methods: Inner and middle ear RNA collected separately from 6-month-old C3H/HeJ mice with prolonged middle ear disease were subjected to qRT-PCR for 8 common inflammatory cytokine genes, 24 genes for channels controlling ion (sodium, potassium, and chloride) and water (aquaporin) transport, tight junction claudins, and gap junction connexins, and 32 tissue remodeling genes. Uninfected Balb/c mice were used as controls.

Results: Significant increase in inner ear inflammatory and ion homeostasis (claudin, aquaporin, and gap junction) gene expression, and both upregulation and downregulation of tissue remodeling gene expression occurred. Alteration in middle ear ion homeostasis and tissue remodeling gene expression was noted in the setting of uniform upregulation of cytokine genes.

Conclusion: Chronic inflammatory middle ear disease can impact inner ear ion and water transport functions and induce tissue remodeling. Recognizing these inner ear mechanisms at risk may identify potential therapeutic targets to maintain hearing during prolonged otitis media.
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http://dx.doi.org/10.1097/MAO.0b013e31827b4d0aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548044PMC
February 2013

Prenatal diagnosis of fetal cervicofacial anomalies.

Curr Opin Otolaryngol Head Neck Surg 2012 Dec;20(6):482-90

Oregon Health and Science University, Portland, Oregon 97239, USA.

Purpose Of Review: To review the current literature on prenatal diagnosis of cervicofacial anomalies that may require neonatal intervention or that require prenatal counseling by a maternal-fetal medicine team and otolaryngology, head and neck surgery.

Recent Findings: Ultrasound and MRI imaging are complementary in the prenatal diagnosis of fetal anomalies that may present with the need for the head and neck surgeon to assist with airway management at delivery or that require prenatal counseling. Team approaches to delivery of at-risk infants have improved and there is more experience with the ex-utero intrapartum treatment (EXIT) procedure. The importance of planning and simulation for EXIT is essential prior to delivery. Future directions include in-utero gene therapy and fetal surgery.

Summary: Advances in detection and treatment of fetuses at risk for airway obstruction at birth and for accurate diagnosis of facial clefting will allow teams to continue to improve outcomes for these infants. Increased experience of such teams will allow refinement of protocols and indices for decision making regarding which fetuses will need treatment on placental support and which will do well with traditional delivery with treatment teams on standby. This will allow improved risk profiles for both mother and child.
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http://dx.doi.org/10.1097/MOO.0b013e3283582e21DOI Listing
December 2012

Innate immunity gene single nucleotide polymorphisms and otitis media.

Int J Pediatr Otorhinolaryngol 2012 Jul 9;76(7):976-9. Epub 2012 Apr 9.

ENT Surgical Associates, Glendale, CA, United States.

Objective: Toll-like receptors (TLR) activate the innate immune system. Single nucleotide polymorphisms (SNPs) in TLR genes are linked to increased susceptibility to infections. TLR4-deficient mice have increased incidence and duration of otitis media. We hypothesize that SNPs in TLR genes are more common in otitis-prone children than in children without a history of otitis media.

Methods: Cases (n=70) included children undergoing surgery for otitis media. Control subjects (n=70) included children undergoing surgery for non-otologic indication. Genomic DNA was extracted from blood samples. RT-PCR genotyping was performed for TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791), TLR9 (rs5743836 & rs187084), and CD14 (rs2569190).

Results: There were no significant differences between the groups in family history, day care, smoke exposure, allergies or prevalence of the SNPs. The most common pre-op diagnosis in control subjects was obstructive sleep apnea (OSA).

Conclusions: TLR2, TLR4, TLR9 and CD14 gene SNPs were not more prevalent in otitis-prone children.
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http://dx.doi.org/10.1016/j.ijporl.2012.03.011DOI Listing
July 2012

Murine middle ear inflammation and ion homeostasis gene expression.

Otol Neurotol 2011 Apr;32(3):508-15

Oregon Hearing Research Center, Department of Otolaryngology, Head and Neck Surgery, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.

Hypothesis: Ion homeostasis genes are responsible for the movement of ions and water in the epithelium of the middle ear.

Background: It is not well known to what extent disruption of ion homeostasis is a factor in the accumulation of middle ear fluid during otitis media.

Methods: Balb/c mice were transtympanically injected with heat-killed Hemophilus influenza bacteria. Untreated and saline-injected mice were used as controls. Mice were euthanized at 6, 24, and 72 hours and 1 week after injection, the bullae harvested, and total ribonucleic acid isolated from the middle ear tissues. Ion homeostasis genes were analyzed with real-time quantitative reverse transcription-polymerase chain reaction from the following gene families: Na,K-ATPase, claudins, K transport channels, epithelial Na channels, gap junctions, and aquaporins. Inflammatory genes also were analyzed to document inflammation.

Results: All inflammatory genes analyzed were significantly upregulated, more at 6 hours than at 24 hours, with the exception of vascular endothelial growth factor and Mapk8. Most middle ear ion homeostasis genes experienced downregulation because of inflammation. This was most prominent in the aquaporin and Na,K-ATPase genes. Significant upregulation was seen in several genes in response to inflammation and saline independently.

Conclusion: The innate immune response to bacteria in the middle ear induces expression of several inflammatory genes. Coinciding with this inflammation is the downregulation of numerous ion homeostasis genes that are involved in ion and water transport and maintenance of tight junctions. This may explain the fluid accumulation within the middle ear seen with both acute and chronic otitis media.
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http://dx.doi.org/10.1097/MAO.0b013e31820e6de4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115485PMC
April 2011

Altered expression of middle and inner ear cytokines in mouse otitis media.

Laryngoscope 2011 Feb 13;121(2):365-71. Epub 2011 Jan 13.

Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.

Objectives/hypothesis: The inner ear is at risk for sensorineural hearing loss in both acute and chronic otitis media (OM), but the mechanisms underlying sensorineural hearing loss are unknown. Previous gene expression array studies have shown that cytokine genes might be upregulated in the cochleas of mice with acute and chronic OM. This finding implies that the inner ear could manifest a direct inflammatory response to OM that may cause sensorineural damage. Therefore, to better understand inner ear cytokine gene expression during OM, quantitative real-time polymerase chain reaction and immunohistochemistry were used in mouse models to evaluate middle and inner ear inflammatory and remodeling cytokines.

Study Design: Basic science experiment.

Methods: An acute OM model was created in Balb/c mice by a transtympanic injection of Streptococcus pneumoniae in one ear; the other ear was used as a control. C3H/HeJ mice were screened for unilateral chronic OM, with the noninfected ear serving as a control.

Results: Both acute and chronic OM caused both the middle ear and inner tissues in these two mouse models to overexpress numerous cytokine genes related to tissue remodeling (tumor necrosis factor-α, bone morphogenetic proteins, fibroblast growth factors) and angiogenesis (vascular endothelial growth factor), as well as inflammatory cell proliferation (interleukin [IL]-1α,β, IL-2, IL-6). Immunohistochemistry confirmed that both the middle ear and inner ear tissues expressed these cytokines.

Conclusions: Cochlear tissues are capable of expressing cytokine mRNA that contributes to the inflammation and remodeling that occur in association with middle ear disease. This provides a potential molecular basis for the transient and permanent sensorineural hearing loss often reported with acute and chronic OM.
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http://dx.doi.org/10.1002/lary.21349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075838PMC
February 2011

Simultaneous measurement of multiple ear proteins with multiplex ELISA assays.

Hear Res 2011 May 7;275(1-2):1-7. Epub 2010 Dec 7.

Oregon Hearing Research Center, Department of Otolaryngology-Head & Neck Surgery, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Mail Code NRC04, Portland, OR 97239-3098, USA.

A recent advancement in enzyme-linked immunosorbent assay (ELISA) technology is the multiplex antibody array that measures multiple proteins simultaneously within a single sample. This allows reduction in sample volume, time, labor, and material costs, while increasing sensitivity over single ELISA. Current multiplex platforms include planar-based systems using microplates or slides, or bead-based suspension assay with microspheres. To determine the applicability of this technology for ear research, we used 3 different multiplex ELISA-based immunoassay arrays from 4 different companies to measure cytokine levels in mouse middle and inner ear tissue lysate extracts 24 h following transtympanic Haemophilus influenzae inoculation. Middle and inner ear tissue lysates were analyzed using testing services from Quansys Biosciences, Aushon Biosystems SearchLight (both microplate-based), MILLIPLEX MAP Sample (bead-based), and a RayBiotech, Inc (slide-based) kit. Samples were assayed in duplicate or triplicate. Results were compared to determine their relative sensitivity and reliability for measures of cytokines related to inflammation. The cytokine pg/ml amounts varied among the multiplex assays, so a comparison also was made of the mean fold increase in cytokines from untreated controls. Several cytokines and chemokines were elevated, the extent dependent upon the assay sensitivity. Those most significantly elevated were IL-1α, IL-1β, IL-6, TNFα, VEGF, and IL-8/MIP-2. The results of the multiplex systems were compared with single ELISA kits (IL-1β, IL-6) to assess sensitivity over the traditional method. Overall, the Quansys Biosciences and SearchLight arrays showed the greatest sensitivity, both employing the same multiplex methodology of a spotted array within a microplate well with chemiluminescent detection. They also were more sensitive than the traditional single ELISA performed with commercial kits and matched gene expression changes determined by quantitative RT-PCR. The Quansys array showed a limit of detection for ear IL-6 down to 2-4 pg/ml, indicating it is sufficiently sensitive to detect ear proteins present in low concentrations. Thus, the multiplex ELISA procedures appear suitable and reliable for the study of hearing related proteins, providing accurate, quantitative, reproducible results with considerable improvement in sensitivity and economy.
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http://dx.doi.org/10.1016/j.heares.2010.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087854PMC
May 2011

Steroid control of acute middle ear inflammation in a mouse model.

Arch Otolaryngol Head Neck Surg 2009 May;135(5):453-7

Department of Otolaryngology-Head & Neck Surgery and Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.

Objective: To investigate steroids for their potential for therapeutic approaches to control otitis media. Glucocorticoids and mineralocorticoids have differential effects on inflammation and fluid absorption, but little is known of their control of middle and inner ear manifestations of acute otitis media.

Design: Both glucocorticoid (prednisolone and dexamethasone) and mineralocorticoid (aldosterone and fludrocortisone) steroids were investigated for their ability to reduce inflammatory symptoms in a mouse otitis media model.

Setting: Academic medical center.

Subjects: Acute inflammation was induced by transtympanic injection of heat killed Streptococcus pneumoniae to 100 BALB/c mice.

Interventions: Twenty mice in each experimental group (prednisolone, dexamethasone, aldosterone, and fludrocortisone) were given a steroid in their drinking water the day before inoculation, and these treatments were continued until the mice were killed for histologic examination. Twenty control mice were treated with water only.

Main Outcome Measures: Histologic measure of inflammation: middle ear fluid, inflammatory cell number, and tympanic membrane thickness.

Results: Histologic middle ear morphometrics showed significant steroid effects at both 3 and 5 days in reduction of fluid area, cell number, and tympanic membrane thickness.

Conclusions: Glucocorticoids were most effective in controlling inflammation. Interestingly, the mineralocorticoids were also effective in reducing the inflammatory response at 5 days, suggesting that their fluid transport function helped clear disease. Thus, steroid control of middle ear disease may be useful in alleviating symptoms faster and reducing the risk to the inner ear.
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http://dx.doi.org/10.1001/archoto.2009.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079425PMC
May 2009

Control of chronic otitis media and sensorineural hearing loss in C3H/HeJ mice: glucocorticoids vs mineralocorticoids.

Otolaryngol Head Neck Surg 2008 Nov;139(5):646-53

Oregon Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, OR, USA.

Objective: The impact of glucocorticoids and mineralocorticoids on chronic otitis media (COM) in toll-like receptor 4-deficient C3H/HeJ mice was investigated.

Study Design: To evaluate control of COM by steroids with differences in their anti-inflammatory (prednisolone, dexamethasone), and fluid absorption functions (fludrocortisone, aldosterone). A minimum sample size of five animals for each group was required based on power analysis calculations. Sample sizes ranged from 7 to 17 mice per treatment group.

Subjects And Methods: Auditory brain stem response (ABR) thresholds were performed at baseline, 2 weeks and 4 weeks. Histopathologic test results were evaluated on all mice ears at the end of the study.

Results: Analysis of variance (ANOVA) of ABR threshold change showed significant treatment effects (P < 0.05) by both steroid types at all time intervals and ABR frequencies except 4 weeks/8 kHz. Histologic assessment showed prednisolone-treated mice (62%) had a higher rate of clearance of middle and inner ear inflammation than control mice (4%).

Conclusion: It was concluded that steroid treatments can improve the physiology of chronic middle and inner ear disease seen with COM.
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http://dx.doi.org/10.1016/j.otohns.2008.07.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907070PMC
November 2008

The effect of the palatoplasty method on the frequency of ear tube placement.

Arch Otolaryngol Head Neck Surg 2008 Oct;134(10):1085-9

Department of Otolaryngology/Head and Neck Surgery, Oregon Health & Science University, 3181 Sam Jackson Park Rd, Portland, OR 97239-3098, USA.

Objective: To determine whether the type of palate repair affects the frequency of subsequent ventilation tube placement.

Design: Combined retrospective and prospective cohort with more than 2 years clinical follow-up after palatoplasty.

Setting: Tertiary care children's hospital and clinic.

Patients: A total of 170 patients with cleft palate (with or without cleft lip) underwent palatoplasty between 1995 and 2003. Sixty-nine patients with less than 2 years of follow-up visits and 1 patient who did not require ear tubes were excluded from this analysis.

Interventions: Either traditional 2-flap palatoplasty (group A) or double-opposing Z-plasty (group B) was performed. The type of palatoplasty performed was based on the reconstructive surgeon's clinical decision. Ventilation tubes were placed for otitis media, conductive hearing loss, or eustachian tube dysfunction. Patients received routine follow-up care every 6 months or whenever acute problems arose. Data were analyzed with independent t tests, chi(2) tests, and Fisher exact tests.

Main Outcome Measures: Number of ear tubes placed after palatoplasty in each group.

Results: Group A had a mean (SE) of 2.9 (0.2) sets of tubes placed, while group B had a mean (SE) of 1.8 (0.2) sets of tubes. Group A had significantly more sets of ventilation tubes placed (P < .001) than group B. Subgroup analysis based on type of cleft was performed.

Conclusion: Children with cleft palate who underwent double-opposing Z-plasty had fewer sets of ear tubes placed postoperatively than patients who had traditional repair.
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http://dx.doi.org/10.1001/archotol.134.10.1085DOI Listing
October 2008

Gram-negative pathogen Klebsiella oxytoca is associated with spontaneous chronic otitis media in Toll-like receptor 4-deficient C3H/HeJ mice.

Acta Otolaryngol 2008 Feb;128(2):132-8

Department of Otolaryngology Head & Neck Surgery, Oregon Health & Science University, Portland, OR, USA.

Conclusion: This report confirms the presence of gram-negative Klebsiella bacteria in the middle ear of the C3H/HeJ mouse by culture, polymerase chain reaction (PCR), and electron microscopy. Identification of the bacterial pathogen supports the C3H/HeJ mouse as an excellent model for spontaneous chronic otitis media and its effects on the middle and inner ear.

Objectives: The C3H/HeJ mouse has a single amino acid substitution in its Toll-like receptor 4, making it insensitive to endotoxin and suppressing initiation of the innate immune system. This study explored the bacteriology of the resultant middle ear infection by culture, PCR, histology, and electron microscopy.

Materials And Methods: Twelve-month-old C3H/ HeJ mice were screened positive for spontaneous otitis media. Tympanocentesis and blood cultures of mice were carried out under sedation. Middle ear aspirate material and blood samples were then sent for culture and PCR. Mice were then sacrificed for bright-field and electron microscopy analysis.

Results: All tympanocentesis and blood specimens grew gram-negative Klebsiella oxytoca, which was confirmed by PCR. Histopathology confirmed an intense inflammatory reaction and gram-negative bacteria in the middle and inner ears. Electron microscopy of the middle ears revealed abundant rod-shaped Klebsiella bacteria, both free and being engulfed by neutrophils.
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http://dx.doi.org/10.1080/00016480701387124DOI Listing
February 2008

Head and neck hemangiomas of infancy.

Curr Opin Otolaryngol Head Neck Surg 2006 Dec;14(6):397-405

Department of Otolaryngology, Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon 97239, USA.

Purpose Of Review: Hemangiomas are the most common benign tumor in infancy, affecting approximately 10% of infants. More than half of hemangiomas involve the head and neck. Increased understanding of hemangiomas has come about from identification of immunohistochemical markers, developmental defects associated with certain hemangiomas, and morphologic and classification schemes (focal versus segmental).

Recent Findings: Immunohistochemical markers have been identified which are specific to hemangiomas in all phases of development and involution. Morphologic subtypes and anatomic locations have been identified that place an infant at higher risk for complications from the hemangioma. Hemangiomas associated with other developmental anomalies have been identified, which help guide the treating physician to tease out which infants will need more complete systemic investigations or imaging. Importantly for surgeons, studies have continued to identify which lesions may benefit from early intervention, either surgical or medical.

Summary: While full understanding of the mechanisms that turn on and turn off hemangiomas of infancy is not complete, progress has been made in identification of markers, subtypes at increased risk for complications, and in treatment. With continued work in these areas, we have increased knowledge of treatment options, optimal timing of surgical intervention, and ultimately, preventive options.
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http://dx.doi.org/10.1097/MOO.0b013e328010ba6bDOI Listing
December 2006

Mouse models of otitis media.

Curr Opin Otolaryngol Head Neck Surg 2006 Oct;14(5):341-6

Department of Otolaryngology-Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.

Purpose Of Review: Otitis media is one of the most prevalent inflammatory diseases in the pediatric population. The personal and societal costs for otitis media are significant. Problems arising from antibiotic use have led to considerable animal research efforts to better understand the mechanisms of acute otitis media and to develop new strategies for its prevention and treatment.

Recent Findings: Various animal models induce acute otitis media from a variety of interventions, including direct injection of whole bacteria or their products into the middle ear. The mouse model has begun to emerge as a model for otitis media. The mouse affords many advantages for in-vivo research, including ease of genetic manipulation, availability of numerous inbred and transgenic strains, and an extensively studied immune system. Experimental reagents for cellular and molecular studies are widely available for the mouse. The mouse is an excellent model for investigating the genetics and molecular bases for otitis media due to the extensive understanding of the mouse genome.

Summary: With the increased availability of knockout and transgenic mice, and the large amount of data to indicate that human disease is accurately modeled in the mouse, the mouse model is increasingly becoming a model of choice.
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http://dx.doi.org/10.1097/01.moo.0000244193.97301.d7DOI Listing
October 2006

Evaluation of the mouse model for acute otitis media.

Hear Res 2006 Sep 2;219(1-2):12-23. Epub 2006 Aug 2.

Department of Otolaryngology and Oregon Hearing Research Center, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, PV-01, Portland, OR 97239-3098, USA.

Various animal models have been employed for otitis media research. The mouse has been studied less, in spite of its many advantages. To better understand the suitability of the mouse for studies of otitis media, an evaluation was made of its middle ear inflammatory processes following inoculation with heat-killed Streptococcus pneumoniae (strain 6A), one of the three most common bacteria to cause otitis media in the human. A total of 94 BALB/c mice were injected transtympanically with three concentrations of heat-killed bacteria (10(4), 10(6), and 10(9) organisms per ml) and inflammation evaluated with both histologic examination and auditory brainstem response audiometry. Dose-related measures of the time course of inflammation showed it was maximal at 3 days. PBS-injected control mice also demonstrated some degree of middle ear inflammation. Therefore, inflammation measures from PBS injected mice were used as the threshold above which histologic inflammatory changes would be considered a response to bacteria. These quantitative comparisons of bacterial and PBS inoculations revealed the most significant middle ear measures of inflammation were amount of fluid in the middle ear, tympanic membrane thickness, and number of inflammatory cells. The induction of middle ear inflammation in the mouse demonstrated the applicability of this model for investigations of otitis media.
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http://dx.doi.org/10.1016/j.heares.2006.05.012DOI Listing
September 2006