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Biomedical subjects

Jeffrey P Harris

Publications and source records attributed to Jeffrey P Harris.

18 recordsLinked to original sources
PubMed2006

Mastoid obliteration.

Mastoid obliteration is commonly performed to reduce the size of mastoidectomy cavity following canal wall-down tympanomastoidectomy for chronic otitis media. The indications and techniques for mastoid obliteration as well as total tympanomastoid obliteration will be reviewed. The vast majority of obliteration techniques consist of either local flaps or free grafts (bone, cartilage, fat, hydroxyapatite). The radiographic and histopathologic features of mastoid obliteration will also be reviewed.

Chronic Disease↗
PubMed2006

Transforming growth factor beta expression during an inner ear immune response.

OBJECTIVES: The involvement of transforming growth factor beta (TGF-beta), a strong mediator of fibrogenesis, during cochlear immune responses was investigated. METHODS: An inner ear adaptive immune response to antigen was created in mice that were painlessly sacrificed 3 to 48 hours and 7 days after initiation of the immune response. The cochleas were assayed by immunocytochemistry for TGF-beta and latency-associated peptide (LAP). RESULTS: We found LAP expressed in normal cochleas and the endolymphatic sac, in the small round cells in the cochlear scalae and the mesothelial cells under the basilar membrane, and in the endolymphatic sac perisaccular area. We found TGF-beta expressed in infiltrated, inflammatory cells in the scalae and the endolymphatic sac lumen 3 hours after cochlear antigen challenge. At this time, LAP immunoreactivity was decreased. This rapid shift in immunoreactivity provides evidence for activation of TGF-beta during an immune response. This reversal of expression persisted for 48 hours, but conditions reverted to normal after 7 days. Surgical controls did not show TGF-beta expression. CONCLUSIONS: We conclude that TGF-beta activation occurs in the early phase of a cochlear adaptive immune response and is down-regulated as the response resolves. This finding suggests that the process of cochlear fibrosis starts early and that proper treatment could prevent cochlear fibrosis.

Animals↗
PubMed2005

Cochlear microperfusion: experimental evaluation of a potential new therapy for severe hearing loss caused by inflammation.

HYPOTHESIS: Cochlear microperfusion will be a useful treatment of severe sensorineural hearing loss caused by inflammation. BACKGROUND: Viruses, bacteria, and autoimmunity can initiate inflammation in the inner ear. The acute phase is associated with elevations in cytokines, nitrous oxide, and cellular infiltrates and the breakdown of the blood-labyrinthine barrier. The chronic phase leads to irreversible ossification of the labyrinth. METHODS: The authors developed cochlear microperfusion to facilitate removal of inflammatory cells and their byproducts during the acute phase of inflammation. Using a ventral approach to the guinea pig cochlea, the authors displaced resident perilymph by delivering perfusate into the scala vestibuli and collecting the effluent from the scala tympani. The authors evaluated the benefit of the procedure in an animal model of severe hearing loss caused by inflammation. RESULTS: Healthy controls undergoing cochlear microperfusion with phosphate-buffered saline incurred a mean hearing loss of 16 dB (n=4). This hearing loss was associated with the creation of two cochleostomies and not the perfusion itself. Sterile labyrinthitis (n=5) generated by perfusion of the cochlea with antigen consistently produced severe hearing loss over the initial 48 hours, and this hearing loss persisted for the subsequent 7 days. Therapeutic cochlear microperfusion, performed within the first 24 hours of developing severe hearing loss (n=9), immediately restored on average 24 dB (p <0.007) of hearing. CONCLUSION: Cochlear microperfusion is a promising new technique for treating severe deafness caused by inflammation. The benefit may be sustained when combined with local delivery of immunosuppressive agents to the inner ear.

Animals↗
PubMed2005

Serial audiometry in a clinical trial of AIED treatment.

OBJECTIVE: We analyzed pure-tone and speech audiometric results from a prospective trial of anti-inflammatory treatment of subjects with active autoimmune inner ear disease (AIED). We sought to characterize the pattern and size of the treatment effect as reflected in clinical audiometry and to identify audiometric predictors of response to steroid treatment of AIED. SUBJECTS: Adult participants demonstrated clinically established criteria for AIED (n = 116). Eligibility required audiometric evidence of active AIED as indicated by idiopathic sensorineural hearing loss with threshold elevations within 3 months of enrollment. METHODS: We evaluated audiometric changes after 4 weeks of treatment with pharmacologic doses (60 mg/day) of prednisone. We examined the relationship between audiometric pure-tone thresholds at baseline and changes in word intelligibility score (WIS) using parametric and nonparametric analyses. Magnitudes of change were assessed using independent or paired t-tests. Separate analyses were performed on subgroups that did or did not show improved WIS score with steroid treatment. RESULTS: Overall mean pure-tone averages improved from baseline to closeout of prednisone treatment in better hearing ears from 52.4 to 48.3 dB (p < .0001). Mean WIS improved in the better ear from 71.4% to 78.1% (p < .0001). Of pure-tone measures, only the six-tone average showed significant correlation with both the absolute improvements in WIS and with the percentage change in WIS after treatment. Individual frequencies at baseline showed no significant relationship with changes in WIS score after treatment. In 69 (59.5%) of 116 subjects, WIS improved (range, 2-80%) in the better ear. In these subjects, the baseline pure-tone thresholds and pure-tone averages correlated significantly and positively with improvement in WIS. CONCLUSIONS: Steroid treatment in AIED-mediated hearing loss produce variable but significant hearing gains. Neither a focal, cochleotopic region of greatest vulnerability to AIED nor frequency-specific amenability to treatment were evident. We did observe that analysis of predictors and the degree of treatment effect vary with different approaches to measuring change in the WIS. Depending on the approach adopted, the size of the treatment effect may be greatest across intermediate hearing levels at baseline. These observations offer an audiometric database that may enable greater precision in judging clinically meaningful parameters for future studies of AIED treatment and other interventions for sensorineural hearing loss.

Adolescent↗
PubMed2004

Innate immunity contributes to cochlear adaptive immune responses.

Inner ear immune responses mediated by antigen-specific processes are thought to contribute to hearing loss in humans. Systemic activation of innate immunity contributes to immune responses in the central nervous system. We hypothesized that activation of innate immunity can prime the inner ear for adaptive immune responses and exacerbate disease. Mice were systemically immunized with antigen. Three weeks after initial antigen exposure, the antigen was injected intrathecally coincident with systemic injection of lipopolysaccharide (LPS), an activator of innate immunity. Responses were measured by quantifying the leukocyte infiltrate and cochlear IL-1beta expression. LPS stimulation markedly amplified the adaptive immune response to exogenous antigen in the inner ear. These data indicate that the cochlea is activated by systemic events that stimulate innate immunity and when antigen is present in the inner ear, a robust cochlear adaptive response is generated. If true in humans, this implies that priming may be an important component in the development of immune-mediated hearing loss.

Adjuvants, Immunologic↗
PubMed2004

Intratympanic gentamicin therapy for Ménière's disease: a meta-analysis.

OBJECTIVE: This study compared the effectiveness of five different techniques of intratympanic gentamicin administration for Ménière's disease. DATA SOURCES: A MEDLINE search of the English language literature from 1978 to 2002 was performed using the key words "intratympanic," "gentamicin," "therapy," "Ménière's," and "disease." STUDY SELECTION: Inclusion criteria to select articles for meta-analysis were clear description of gentamicin delivery technique, clearly reported vertigo control results, and report of hearing loss posttreatment. Seven studies (n = 218) describing the multiple daily dosing technique (delivery three times per day for >or=4 d), two studies (n = 84) describing the weekly dosing technique (weekly injections for four total doses), eight studies (n = 253) of the low-dose technique (one to two injections with retreatment for recurrent vertigo), four studies (n =156) of continuous microcatheter delivery, and six studies (n =269) of the titration technique (daily or weekly doses until onset of vestibular symptoms, change in vertigo, or hearing loss) were entered into the model. DATA EXTRACTION: Vertigo control results were stratified into complete, substantial, or poor control. Hearing results were separated by profound, partial, or no hearing loss. Individuals undergoing caloric testing were separated by degree of vestibular ablation (complete versus partial) and analyzed for vertigo control (n = 301) and hearing loss (n = 333) after treatment. DATA SYNTHESIS: Comparisons between the rates of complete vertigo control, effective vertigo control (complete plus substantial control), overall hearing loss (partial plus profound), and profound hearing loss by delivery method were based on a parametric empirical Bayes analysis using binomial generalized linear models and backward variable selection (joining). Relative risk for vertigo control and hearing loss by partial or complete ablation was examined study by study using residual maximum likelihood to carry out a parametric empirical Bayes analysis. CONCLUSION: The titration method of gentamicin delivery demonstrated significantly better complete (81.7%, p = 0.001) and effective (96.3%, p < 0.05) vertigo control compared with other methods. The low-dose method of delivery demonstrated significantly worse complete vertigo control (66.7%, p < 0.001) and trends toward worse effective vertigo control (86.8%, p = 0.05) compared with other methods. The weekly method of delivery trends toward less overall hearing loss (13.1%, p = 0.08), and the multiple daily method demonstrated significantly more overall hearing loss (34.7%, p < 0.01) compared with other groups. No significant difference in profound hearing loss was found between groups. Degree of vestibular ablation after gentamicin therapy is not significantly correlated with the resulting vertigo control or hearing loss status.

Anti-Bacterial Agents↗
PubMed2003

Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial.

CONTEXT: A number of therapies have been proposed for the long-term management of corticosteroid-responsive, rapidly progressive, bilateral sensorineural hearing loss (autoimmune inner ear disease [AIED]). Methotrexate has emerged as the benchmark agent but has not been rigorously evaluated for hearing improvement in patients with AIED. OBJECTIVE: To assess the efficacy of long-term methotrexate in maintaining hearing improvements achieved with glucocorticoid (prednisone) therapy in patients with AIED. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial conducted from February 3, 1998, to November 5, 2001, of 67 patients with rapidly progressive, bilateral sensorineural hearing loss at 10 tertiary care centers in the United States. INTERVENTION: Randomization to either oral methotrexate (15 to 20 mg/wk; n = 33) or placebo (n = 34), in combination with an 18-week prednisone taper. Follow-up examinations, including audiometric evaluation, were performed at 4, 8, 12, 24, 36, 48, and 52 weeks, or until hearing loss was documented. MAIN OUTCOME MEASURE: Maintenance of hearing improvement achieved from prednisone treatment. RESULTS: Sixty-seven patients (57.8%) enrolled in the prednisone challenge experienced hearing improvement. Twenty-five patients (37%) experienced hearing improvements in both ears. Of the individuals who reached study end points, 24 (80%) of 30 end points were because of measured hearing loss in the methotrexate group and 29 (93.5%) of 31 end points were because of measured hearing loss in the placebo group (P =.15). Methotrexate was no more effective than placebo in maintaining the hearing improvement achieved with prednisone treatment (hazard ratio, 1.31; 95% confidence interval, 0.79-2.17; P =.30). CONCLUSION: Methotrexate does not appear to be effective in maintaining the hearing improvement achieved with prednisone therapy in patients with AIED.

Audiometry↗
PubMed2003

Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation.

The inner ear is capable of rapidly mounting an immune response that can ultimately lead to cochlear degeneration and permanent hearing loss. The role of the endolymphatic sac in this immune process is not clear. In order to investigate the cytokine expression of cells within the endolymphatic sac, a secondary inner ear immune response to keyhole limpet hemocyanin (KLH) was created in mice. The animals were sacrificed 3-48 h and 7 days following initiation of the immune response. The cochleas and endolymphatic sacs were assayed by immunocytochemistry for IL-1beta, TNFalpha, and IL-6. Three hours after KLH challenge of the scala tympani, the perisaccular tissue of the endolymphatic sac contained more inflammatory cells than the scala tympani or endolymphatic sac lumen. Only a few of these cells, however, expressed the proinflammatory cytokines IL-1beta and TNFalpha between 3 and 12 h after KLH injection. On the other hand, TNFalpha, which plays an important role in the cochlear secondary immune response, was expressed in cells in the endolymphatic sac lumen. The maximum percentage of cells expressing TNFalpha was seen later than in the scala tympani. Animals treated with systemic injection of the TNF blocker, etanercept, showed a reduction in the number of cells in the endolymphatic sac lumen. It is concluded that the cells in the endolymphatic sac lumen contribute to the amplification of the adaptive immune response by expressing TNFalpha, while the infiltration of cells into the perisaccular connective tissue is part of the nonspecific, innate, cochlear immune response.

Animals↗
PubMed2003

Blockage of immune-mediated inner ear damage by etanercept.

HYPOTHESIS: Etanercept will be able to reduce the inflammation and hearing loss associated with experimentally induced labyrinthitis. BACKGROUND: Inner ear immune responses cause hearing loss that may be reversible with pharmacologic treatment. Etanercept, tumor necrosis factor receptor blocker, was investigated in a guinea pig model of immune-mediated hearing loss. Sterile labyrinthitis was created by injection of keyhole limpet hemocyanin into the inner ear after systemic sensitization to keyhole limpet hemocyanin with adjuvant. Labyrinthitis involves infiltration of inflammatory cells and hearing loss detectable 3 to 5 days after challenge with keyhole limpet hemocyanin. METHODS: Etanercept was administered either systemically (2.5 mg) 30 minutes before intracochlear challenge with keyhole limpet hemocyanin, with a second intraperitoneal dose (2.5 mg) 3 days later or locally by long-term infusion into the scala tympani with an osmotic pump (5.0 microg/h for 7 days). Auditory evoked brainstem response thresholds were measured before and after treatment to determine hearing loss. Cochleas were evaluated for the amount of inflammation. RESULTS: Hearing loss in the untreated systemic group averaged 71 +/- 21 dB versus 37 +/- 32 dB in the etanercept-treated animals (t test, P < 0.001). There was also less inflammation in the cochleas from etanercept-treated animals (t test, P < 0.01). Hearing loss with local administration of etanercept was 59 +/- 31 dB in the nontreated ears and 18 +/- 8 dB in the treated ears (t test, P < 0.02). Inflammation was also less (t test, P < 0.01). Etanercept was not ototoxic. CONCLUSION: Prompt intervention with the anti-inflammatory drug etanercept significantly reduces inflammation sufficient for substantive hearing preservation.

Animals↗
PubMed2003

Relationship of tinnitus questionnaires to depressive symptoms, quality of well-being, and internal focus.

Twenty percent of people endure tinnitus to a degree that their quality of well-being and productivity in life are impaired, and up to 60% report depression. Four measures are widely used to assess tinnitus-related distress, yet the relationship among all four measures or their relationship to relevant psychiatric variables has yet to be studied. This study assessed the association between the four commonly used measures of tinnitus and their relationship to depressive symptoms, quality of well-being, and internal focus. Sixty-five people with tinnitus completed the following measures: Iowa Tinnitus Handicap Questionnaire (THQ); Tinnitus Reaction Questionnaire (TRQ); Tinnitus Handicap Inventory (THI); Tinnitus Questionnaire (TQ); Hamilton Rating Scale for Depression (HRSD); Beck Depression Inventory (BDI); Quality of Well-Being Scale (QWBS); Modified Somatic Perception Questionnaire (MSPQ); and Private Self-Consciousness Scale (PSCS). All the tinnitus measures were highly intercorrelated (r = .76-.90; all p values < .001), and related to depressive symptoms (r = .48-.66; p < .001) and QWBS (r = .37-.48; all p values < 0.008). The tinnitus measures correlated with the MSPQ (r = .37-.52; all p values < .01) but not with the PSCS. When controlling for the shared variance between tinnitus measures, the THQ independently predicted the HRSD, whereas the TRQ independently predicted the BDI.

Adult↗
PubMed2002

Immune-mediated hearing loss: basic mechanisms and options for therapy.

Immune responses are an important component of the defense of the inner ear against infection. However, immunity appears to be restricted in the labyrinth, as the inflammation associated with immune responses can damage the delicate cellular structures that mediate hearing and balance. When immunoregulation is compromised, either experimentally or through disease, immune-mediated inner ear damage and hearing loss can result. Because there are few resident leukocytes within the labyrinth, immunity and inflammation are mediated primarily by cells that enter the inner ear following the activation of post-capillary venules, which in the cochlea are the spiral modiolar veins. Activated lymphocytes are an important component of the infiltrating leukocytes, and their interactions with antigen mediate inner ear immunity. While evidence of autoimmunity specific to the inner ear is incomplete, an autoimmune origin is often suspected in idiopathic, bilateral, rapidly progressive hearing loss. Systemic immunosuppressive drugs can be effective in reversing such hearing loss, although at the cost of occasionally severe side-effects. Experimental evidence suggests that local therapy may be effective in treating this condition, if it were to target the infiltration of leukocytes into the labyrinth.

Animals↗
PubMed2002

Tumor necrosis factor-alpha, an initiator, and etanercept, an inhibitor of cochlear inflammation.

OBJECTIVES/HYPOTHESIS: The inner ear rapidly mounts an immune response that can lead to cochlear degeneration and permanent hearing loss. Identification of proinflammatory cytokine expression during the initiation of the response should lead to rational therapeutic strategies that block the response, reducing damaging sequelae. STUDY DESIGN: A cochlear immune response to keyhole limpet hemocyanin (KLH) injected into the inner ear or subarachnoid space of sensitized animals was created. Etanercept was administered to a group of animals to blunt the immune response. METHODS: Cochleae were immunoassayed for expression of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6 and evaluated for the amount of cochlear-infiltrated cells. RESULTS: Tumor necrosis factor-alpha and interleukin-1beta were expressed by infiltrated cells shortly after KLH injection. Tumor necrosis factor-alpha was expressed whether the antigen was introduced with or without surgical trauma. Interleukin-1beta was also expressed by the cochlear fibrocytes during the immune response and in surgical control animals, but not after intrathecal injection of antigen. Interleukin-6 expression was minimal during the response. Based on this observation, animals were treated with systemic injection of Etanercept, which reduced cochlear infiltrating cell number and cochlear fibrosis. CONCLUSION: Interleukin-1beta expression is a general cochlear response to trauma, whereas tumor necrosis factor-alpha expression in the infiltrated immunocompetent cells is the cytokine that induces amplification of the response that leads to cochlear disease.

Animals↗
PubMed2002

Immunological damage to the inner ear: current and future therapeutic strategies.

There is considerable evidence to suggest that hearing and vestibular function can be influenced by immunity in the inner ear. While immunity can protect against infections of the labyrinth, immune response also has the capacity to damage the delicate tissues of the inner ear. Antigenic challenge of the inner ear of sensitized animals leads to rapid accumulation of leukocytes, antibody production, hearing loss and tissue damage. Moreover, a number of systemic autoimmune disorders include hearing loss and vertigo as part of their constellation of symptoms. It also appears that autoimmune damage can exist as an entity confined to the labyrinth. Immune disorders of the inner ear are of special interest since they are among the few forms of hearing loss that are currently amenable to medical treatment. In addition, recent developments in understanding the intracellular pathways that participate in damage to the inner ear provide new opportunities for pharmacotherapy of immune-mediated disorders of hearing and balance.

Animals↗
PubMed2002

Malleus fixation: clinical and histopathologic findings.

The goals of this study were to review important clinical and histopathologic features of malleus fixation. Ten clinical cases and 10 histopathologic cases of malleus fixation were identified. For the clinical cases, preoperative clinical data, surgical findings, and preoperative and postoperative audiometric findings were reviewed. Ninety percent of the clinical cases achieved significant reduction of the air-bone gap after operation. Two thirds of these cases had an air-bone gap of 10 dB or less, and the remainder had air-bone gaps between 20 and 28 dB after operation. For the temporal bone cases, clinical data, histopathologic findings, and other otologic diagnoses were reviewed. Malleus fixation can be idiopathic or a result of trauma, chronic otitis media, or developmental anomalies. It is a cause of hearing loss that is likely to be more common than the number of diagnoses would indicate. Certain audiometric findings may lead one to suspect the diagnosis. The surgical approach used depends on the individual anatomy, and surgery is usually highly effective in improving hearing.

Adult↗
PubMedDate not supplied

A case against spiral ligament atrophy as a cause of Ménière's disease.

The etiology of Ménière's disease and endolymphatic hydrops has been very difficult to determine. In order to develop rational therapies for patients with Ménière's disease the etiology needs to be established. In the current study an examination was made of the spiral ligament in temporal bones from individuals with Ménière's and endolymphatic hydrops and normal control temporal bones. No evidence of atrophy in either the length or width or the fibrocyte cell density was seen in the temporal bones with Ménière's disease. The role of the spiral ligament in the development of endolymphatic hydrops is still unclear.

Animals↗