Intratympanic gentamicin for Ménière's disease.

BACKGROUND: Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. Aminoglycosides are sometimes administered directly into the middle ear to treat this condition. The aim of this treatment is to partially or completely destroy the balance function of the affected ear. The efficacy of this intervention in preventing vertigo attacks, and their associated symptoms, is currently unclear. OBJECTIVES: To evaluate the benefits and harms of intratympanic aminoglycosides versus placebo or no treatment in people with Ménière's disease. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with a diagnosis of Ménière's disease comparing intratympanic aminoglycosides with either placebo or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified).  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome.  MAIN RESULTS: We included five RCTs with a total of 137 participants. All studies compared the use of gentamicin to either placebo or no treatment. Due to the very small numbers of participants in these trials, and concerns over the conduct and reporting of some studies, we considered all the evidence in this review to be very low-certainty.  Improvement in vertigo This outcome was assessed by only two studies, and they used different time periods for reporting. Improvement in vertigo was reported by more participants who received gentamicin at both 6 to ≤ 12 months (16/16 participants who received gentamicin, compared to 0/16 participants with no intervention; risk ratio (RR) 33.00, 95% confidence interval (CI) 2.15 to 507; 1 study; 32 participants; very low-certainty evidence) and at > 12 months follow-up (12/12 participants receiving gentamicin, compared to 6/10 participants receiving placebo; RR 1.63, 95% CI 0.98 to 2.69; 1 study; 22 participants; very low-certainty evidence). However, we were unable to conduct any meta-analysis for this outcome, the certainty of the evidence was very low and we cannot draw any meaningful conclusions from the results.  Change in vertigo Again, two studies assessed this outcome, but used different methods of measuring vertigo and assessed the outcome at different time points. We were therefore unable to carry out any meta-analysis or draw any meaningful conclusions from the results. Global scores of vertigo were lower for those who received gentamicin at both 6 to ≤ 12 months (mean difference (MD) -1 point, 95% CI -1.68 to -0.32; 1 study; 26 participants; very low-certainty evidence; four-point scale; minimally clinically important difference presumed to be one point) and at > 12 months (MD -1.8 points, 95% CI -2.49 to -1.11; 1 study; 26 participants; very low-certainty evidence). Vertigo frequency was also lower at > 12 months for those who received gentamicin (0 attacks per year in participants receiving gentamicin compared to 11 attacks per year for those receiving placebo; 1 study; 22 participants; very low-certainty evidence).  Serious adverse events None of the included studies provided information on the total number of participants who experienced a serious adverse event. It is unclear whether this is because no adverse events occurred, or because they were not assessed or reported.  AUTHORS' CONCLUSIONS: The evidence for the use of intratympanic gentamicin in the treatment of Ménière's disease is very uncertain. This is primarily due to the fact that there are few published RCTs in this area, and all the studies we identified enrolled a very small number of participants. As the studies assessed different outcomes, using different methods, and reported at different time points, we were not able to pool the results to obtain more reliable estimates of the efficacy of this treatment. More people may report an improvement in vertigo following gentamicin treatment, and scores of vertigo symptoms may also improve. However, the limitations of the evidence mean that we cannot be sure of these effects. Although there is the potential for intratympanic gentamicin to cause harm (for example, hearing loss) we did not find any information about the risks of treatment in this review.  Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area and enable meta-analysis of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits.

Intratympanic corticosteroids for Ménière's disease.

BACKGROUND: Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. Corticosteroids are sometimes administered directly into the middle ear to treat this condition (through the tympanic membrane). The underlying cause of Ménière's disease is unknown, as is the way in which this treatment may work. The efficacy of this intervention in preventing vertigo attacks, and their associated symptoms, is currently unclear. OBJECTIVES: To evaluate the benefits and harms of intratympanic corticosteroids versus placebo or no treatment in people with Ménière's disease. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with a diagnosis of Ménière's disease comparing intratympanic corticosteroids with either placebo or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified).  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects (including tympanic membrane perforation). We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome.  MAIN RESULTS: We included 10 studies with a total of 952 participants. All studies used the corticosteroid dexamethasone, with doses ranging from approximately 2 mg to 12 mg.  Improvement in vertigo Intratympanic corticosteroids may make little or no difference to the number of people who report an improvement in their vertigo at 6 to ≤ 12 months follow-up (intratympanic corticosteroids 96.8%, placebo 96.6%, risk ratio (RR) 1.00, 95% confidence interval (CI) 0.92 to 1.10; 2 studies; 60 participants; low-certainty evidence) or at more than 12 months follow-up (intratympanic corticosteroids 100%, placebo 96.3%; RR 1.03, 95% CI 0.87 to 1.23; 2 studies; 58 participants; low-certainty evidence). However, we note the large improvement in the placebo group for these trials, which causes challenges in interpreting these results.  Change in vertigo Assessed with a global score One study (44 participants) assessed the change in vertigo at 3 to < 6 months using a global score, which considered the frequency, duration and severity of vertigo. This is a single, small study and the certainty of the evidence was very low. We are unable to draw meaningful conclusions from the numerical results. Assessed by frequency of vertigo Three studies (304 participants) assessed the change in frequency of vertigo episodes at 3 to < 6 months. Intratympanic corticosteroids may slightly reduce the frequency of vertigo episodes. The proportion of days affected by vertigo was 0.05 lower (absolute difference -5%) in those receiving intratympanic corticosteroids (95% CI -0.07 to -0.02; 3 studies; 472 participants; low-certainty evidence). This is equivalent to a difference of approximately 1.5 days fewer per month affected by vertigo in the corticosteroid group (with the control group having vertigo on approximately 2.5 to 3.5 days per month at the end of follow-up, and those receiving corticosteroids having vertigo on approximately 1 to 2 days per month). However, this result should be interpreted with caution - we are aware of unpublished data at this time point in which corticosteroids failed to show a benefit over placebo. One study also assessed the change in frequency of vertigo at 6 to ≤ 12 months and > 12 months follow-up. However, this is a single, small study and the certainty of the evidence was very low. Therefore, we are unable to draw meaningful conclusions from the numerical results. Serious adverse events Four studies reported this outcome. There may be little or no effect on the occurrence of serious adverse events with intratympanic corticosteroids, but the evidence is very uncertain (intratympanic corticosteroids 3.0%, placebo 4.4%; RR 0.64, 95% CI 0.22 to 1.85; 4 studies; 500 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence for intratympanic corticosteroids in the treatment of Ménière's disease is uncertain. There are relatively few published RCTs, which all consider the same type of corticosteroid (dexamethasone). We also have concerns about publication bias in this area, with the identification of two large RCTs that remain unpublished. The evidence comparing intratympanic corticosteroids to placebo or no treatment is therefore all low- or very low-certainty. This means that we have very low confidence that the effects reported are accurate estimates of the true effect of these interventions. Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area, and enable meta-analysis of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits. Finally, we would also highlight the responsibility that trialists have to ensure results are available, regardless of the outcome of their study.

Lifestyle and dietary interventions for Ménière's disease.

BACKGROUND: Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. Lifestyle or dietary modifications (including reducing the amount of salt or caffeine in the diet) are sometimes suggested to be of benefit for this condition. The underlying cause of Ménière's disease is unknown, as is the way in which these interventions may work. The efficacy of these different interventions at preventing vertigo attacks, and their associated symptoms, is currently unclear. OBJECTIVES: To evaluate the benefits and harms of lifestyle and dietary interventions versus placebo or no treatment in people with Ménière's disease. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with Ménière's disease comparing any lifestyle or dietary intervention with either placebo or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified).  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome.  MAIN RESULTS: We included two RCTs, one related to diet, and the other related to fluid intake and sleep. In a Swedish study, 51 participants were randomised to receive 'specially processed cereals' or standard cereals. The specially processed cereals are thought to stimulate the production of anti-secretory factor - a protein that reduces inflammation and fluid secretion. Participants received the cereals for three months. The only outcome reported by this study was disease-specific health-related quality of life.  The second study was conducted in Japan. The participants (223) were randomised to receive abundant water intake (35 mL/kg/day), or to sleep in darkness (in an unlit room for six to seven hours per night), or to receive no intervention. The duration of follow-up was two years. The outcomes assessed were 'improvement in vertigo' and hearing.  As these studies considered different interventions we were unable to carry out any meta-analysis, and for almost all outcomes the certainty of the evidence was very low. We are unable to draw meaningful conclusions from the numerical results. AUTHORS' CONCLUSIONS: The evidence for lifestyle or dietary interventions for Ménière's disease is very uncertain. We did not identify any placebo-controlled RCTs for interventions that are frequently recommended for those with Ménière's disease, such as salt restriction or caffeine restriction. We identified only two RCTs that compared a lifestyle or dietary intervention to placebo or no treatment, and the evidence that is currently available from these studies is of low or very low certainty. This means that we have very low confidence that the effects reported are accurate estimates of the true effect of these interventions. Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area and enable meta-analyses of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits.

Surgical interventions for Ménière's disease.

BACKGROUND: Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. First-line treatments often involve dietary or lifestyle changes, medication or local (intratympanic) treatments. However, surgery may also be considered for people with persistent or severe symptoms. The efficacy of different surgical interventions at preventing vertigo attacks, and their associated symptoms, is currently unclear. OBJECTIVES: To evaluate the benefits and harms of surgical interventions versus placebo or no treatment in people with Ménière's disease. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with definite or probable Ménière's disease comparing ventilation tubes, endolymphatic sac surgery, semi-circular canal plugging/obliteration, vestibular nerve section or labyrinthectomy with either placebo (sham surgery) or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified).  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome.  MAIN RESULTS: We included two studies with a total of 178 participants. One evaluated ventilation tubes compared to no treatment, the other evaluated endolymphatic sac decompression compared to sham surgery.  Ventilation tubes We included a single RCT of 148 participants with definite Ménière's disease. It was conducted in a single centre in Japan from 2010 to 2013. Participants either received ventilation tubes with standard medical treatment, or standard medical treatment alone, and were followed up for two years. Some data were reported on the number of participants in whom vertigo resolved, and the effect of the intervention on hearing. Our other primary and secondary outcomes were not reported in this study. This is a single, small study and for all outcomes the certainty of evidence was low or very low. We are unable to draw meaningful conclusions from the numerical results. Endolymphatic sac decompression We also included one RCT of 30 participants that compared endolymphatic sac decompression with sham surgery. This was a single-centre study conducted in Denmark during the 1980s. Follow-up was predominantly conducted at one year, but additional follow-up continued for up to nine years in some participants. Some data were reported on hearing and vertigo (both improvement in vertigo and change in vertigo), but our other outcomes of interest were not reported. Again, this is a single, very small study and we rated the certainty of the evidence as very low for all outcomes. We are therefore unable to draw meaningful conclusions from the numerical results.  AUTHORS' CONCLUSIONS: We are unable to draw clear conclusions about the efficacy of these surgical interventions for Ménière's disease. We identified evidence for only two of our five proposed comparisons, and we assessed all the evidence as low- or very low-certainty. This means that we have very low confidence that the effects reported are accurate estimates of the true effect of these interventions. Many of the outcomes that we planned to assess were not reported by the studies, such as the impact on quality of life, and adverse effects of the interventions. Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area and enable meta-analyses of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits.

The Relationship Between Disorders of Bone Metabolism and Benign Paroxysmal Positional Vertigo: A Systematic Review.

OBJECTIVES: Several studies have reported an association between benign paroxysmal positional vertigo (BPPV) and bone mineral density or serum vitamin D levels. The aim of this review is to provide further clarification regarding the relationship between BPPV and calcium metabolism. DESIGN: PubMed and MEDLINE databases were systematically reviewed to identify all English language papers regarding the relationship between BPPV and the following terms: osteoporosis, osteopenia, bone mineral density, serum vitamin D levels, and bone metabolism. RESULTS: Of the 456 identified records, 28 studies were eligible for this review. Most were retrospective studies with inherent limitations and often conflicting results. While the literature is not conclusive, osteoporosis in patients of at least 50 years old appears to have an association with BPPV. Similarly, an association was observed between recurrent BPPV and vitamin D deficiency. CONCLUSION: There is only weak evidence to support the relationship between BPPV and osteoporosis or low serum 25-hydroxyvitamin D levels. Further prospective studies with more robust methodologies are needed to clarify the association between BPPV and disorders of bone metabolism.

Topical azole treatments for otomycosis.

BACKGROUND: Otomycosis is a fungal infection of the outer ear, which may be treated with topical antifungal medications. There are many types, with compounds belonging to the azole group ('azoles') being among the most widely used. OBJECTIVES: To evaluate the benefits and harms of topical azole treatments for otomycosis. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The search date was 11 November 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in adults and children with otomycosis comparing any topical azole antifungal with: placebo, no treatment, another type of topical azole or the same type of azole but applied in different forms. A minimum follow-up of two weeks was required. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) clinical resolution as measured by the proportion of participants with complete resolution at between two and four weeks after treatment (however defined by the authors of the studies) and 2) significant adverse events. Secondary outcomes were 3) mycological resolution and 4) other less serious adverse effects. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included four studies with 559 participants from Spain, Mexico and India. Three studies included children and adults; one included only adults. The duration of symptoms was not always explicitly stated. Mycological resolution results were only reported in one study. The studies assessed two comparisons: one type of topical azole versus another and the same azole but administered in different forms (cream versus solution). A. Topical azoles versus placebo None of the studies assessed this comparison. B. Topical azoles versus no treatment None of the studies assessed this comparison. C. One type of topical azole versus another type of topical azole i) Clotrimazole versus other types of azoles (eberconazole, fluconazole, miconazole) Three studies examined clotrimazole versus other types of azoles. The evidence is very uncertain about the difference between clotrimazole and other types of azole in achieving complete clinical resolution at four weeks (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.59 to 1.07; 3 studies; 439 participants; very low-certainty evidence). The anticipated absolute effects are 668 per 1000 for clotrimazole versus 835 per 1000 for other azoles. One study planned a safety analysis and reported no significant adverse events in either group. The evidence is therefore very uncertain about any differences between clotrimazole and other types of azole (no events in either group; 1 study; 174 participants; very low-certainty evidence). Clotrimazole may result in little or no difference in mycological resolution at two weeks follow-up (RR 1.01, 95% CI 0.96 to 1.06; 1 study; 174 participants; low-certainty evidence) or in other (less serious) adverse events at two weeks follow-up (36 per 1000, compared to 45 per 1000, RR 0.79, 95% CI 0.18 to 3.41; 1 study; 174 participants; very low-certainty evidence). ii) Bifonazole cream versus bifonazole solution One study compared bifonazole 1% cream with solution. Bifonazole cream may have little or no effect on clinical resolution at two weeks follow-up when compared to solution, but the evidence is very uncertain (RR 1.07, 95% CI 0.73 to 1.57; 1 study; 40 ears; very low-certainty evidence). Bifonazole cream may achieve less mycological resolution compared to solution at two weeks after the end of therapy, but the evidence for this is also very uncertain (RR 0.53, 95% CI 0.29 to 0.96; 1 study; 40 ears; very low-certainty evidence). Five out of 35 patients sustained severe itching and burning from the bifonazole solution but none with the bifonazole cream (very low-certainty evidence). AUTHORS' CONCLUSIONS: We found no studies that evaluated topical azoles compared to placebo or no treatment. The evidence is very uncertain about the effect of clotrimazole on clinical resolution of otomycosis, on significant adverse events or other (non-serious) adverse events when compared with other topical azoles (eberconazole, fluconazole, miconazole). There may be little or no difference between clotrimazole and other azoles in terms of mycological resolution. It may be difficult to generalise these results because the range of ethnic backgrounds of the participants in the studies is limited.

Systematic review of middle ear implants: do they improve hearing as much as conventional hearing AIDS?

OBJECTIVE: A systematic review to determine whether middle ear implants (MEIs) improve hearing as much as hearing aids. DATA SOURCES: Databases included MEDLINE, EMBASE, DARE, and Cochrane searched with no language restrictions from 1950 or the start date of each database. STUDY SELECTION: Initial search found 644 articles, of which 17 met the inclusion criteria of MEI in adults with a sensorineural hearing loss, where hearing outcomes and patient-reported outcome measures (PROMs) compared MEI with conventional hearing aids (CHAs). DATA EXTRACTION: Study quality assessment included whether ethical approval was gained, the study was prospective, eligibility criteria specified, a power calculation made and appropriate controls, outcome measures, and analysis performed. Middle ear implant outcome analysis included residual hearing, complications, and comparison to CHA in terms of functional gain, speech perception in quiet and in noise, and validated PROM questionnaires. DATA SYNTHESIS: Because of heterogeneity of outcome measures, comparisons were made by structured review. CONCLUSION: The quality of studies was moderate to poor with short follow-up. The evidence supports the use of MEI because, overall, they do not decrease residual hearing, result in a functional gain in hearing comparable to CHA, and may improve perception of speech in noise and sound quality. We recommend the publication of long-term results comparing MEI with CHA, reporting a minimum of functional gain, speech perception in quiet and in noise, complications, and a validated PROM to guide the engineering of the new generation of MEI in the future.

Physicians' knowledge of the epidemiology, diagnosis, and management of otitis media: design of a survey instrument.

OBJECTIVE: To develop a survey instrument with good internal consistency and test-retest reliability to explore the level of knowledge among Nova Scotia family physicians concerning the risk factors, signs and symptoms, and treatment of otitis media and the use of pneumatic otoscopy. DESIGN: Prospective cohort design. SETTING: Fee-for-service family practices in Nova Scotia. PARTICIPANTS: A convenience sample of 25 family physicians. MAIN OUTCOME MEASURES: Test-retest reliability and internal consistency of the survey. RESULTS: The constructs including "signs and symptoms of otitis media with effusion" and "comprehensive knowledge scores" showed excellent internal consistency with Kuder-Richardson 20 scores greater than 0.7 whereas the construct "signs and symptoms of acute otitis media" has a Kuder-Richardson 20 score of 0.54 after deletion of several items. The Cohen kappa and Spearman rho tests showed the survey has very good test-retest reliability. CONCLUSION: The questionnaire that we developed proved to have very good internal consistency and test-retest reliability. We hope to use this questionnaire to explore the practice patterns of family physicians in managing otitis media disease.

Vestibular schwannoma: how much residual hearing is useful?

OBJECTIVE: The objective of this study was to determine the usefulness of residual hearing in the tumour ear in vestibular schwannoma patients. DESIGN: A prospective case series study. SETTING: The study was performed at the Queen Elizabeth Health Sciences Centre in Halifax, Nova Scotia. METHODS: Thirty-three vestibular schwannoma patients and 13 controls underwent QuickSIN (Etymotic Research Inc, Elk Grove, IL) speech-in-noise testing with the tumour and good ears open and occluded. Nine testing conditions used three speakers with speech signal from the tumour side, the front, and the good ear side, with noise in other speakers. MAIN OUTCOME MEASURES: Tumour ear contribution (TEC) was calculated by the decrease in score with the index ear occluded. Multiple regression analysis and correlation coefficients were used to determine predictors of TEC. RESULTS: The strongest correlation was between the pure-tone average (PTA) and the TEC with signal from the tumour side. The speech discrimination score (SDS) was also significantly correlated with TEC in this condition. Neither PTA nor SDS correlated well with TEC with signal from other directions. Multiple regression analysis with TEC and sound from the tumour ear as the dependent variable showed that the SDS and PTA of the tumour ear are significant independent predictors (p = .049 and .037, respectively). There are no obvious breakpoints in the PTA or SDS to make 50%, 50 dB, or other operating points "special." CONCLUSION: The main contribution of residual hearing is in signals from the tumour side. The various rules are more or less equivalent in discriminating between those who will have a high TEC and those who will not.

Investigation of the effects of deracoxib and piroxicam on the in vitro viability of osteosarcoma cells from dogs.

OBJECTIVE: To determine whether exposure of canine osteosarcoma cells to deracoxib or piroxicam results in decreased viability, whether the cytotoxic effects of deracoxib and piroxicam involve induction of apoptosis, and whether deracoxib is a more potent inhibitor of osteosarcoma cell growth than piroxicam. SAMPLE POPULATION: 1 fibroblast and 3 osteosarcoma cell lines. PROCEDURE: Cell counts and viability assays were performed using osteosarcoma cells (POS, highly metastatic POS, and canine osteosarcoma cell 31) and fibroblasts after 72 hours of incubation with deracoxib at concentrations of 0.5 microM to 500 microM or piroxicam at concentrations of 1 microM to 1,000 microM. Percentage viability was determined for each concentration. A DNA fragmentation analysis was performed to assess drug-induced apoptosis. RESULTS: Concentration of deracoxib required for 50% inhibition of cell viability (IC50) was reached in all 3 osteosarcoma cell lines and ranged from 70 to 150 microM, whereas the IC50 for piroxicam was only reached in the POS cell line at 500 microM. Neither deracoxib nor piroxicam induced sufficient toxicity in fibroblasts to reach an IC50. Exposure of osteosarcoma cells to cytotoxic concentrations of deracoxib and piroxicam did not result in DNA fragmentation. CONCLUSIONS AND CLINICAL RELEVANCE: Intermediate and high concentrations of deracoxib and high concentrations of piroxicam were cytotoxic to osteosarcoma cells; neither drug inhibited cell viability at typical plasma concentrations in dogs. Deracoxib inhibited viability of cells at concentrations that did not affect fibroblast viability. There was no evidence of apoptosis induction for either drug; however, only 1 cell line was evaluated for apoptosis induction and only for a limited selection of drug concentrations.

Investigation of the effect of pamidronate disodium on the in vitro viability of osteosarcoma cells from dogs.

OBJECTIVE: To determine the effect of pamidronate disodium on the in vitro viability of osteosarcoma cells and non-neoplastic cells from dogs. SAMPLE POPULATION: 3 osteosarcoma and 1 fibroblast cell lines derived from dogs. PROCEDURE: Cell counts and cell viability assays were performed in cultures of osteosarcoma cells (POS, HMPOS, and COS31 cell lines) and fibroblasts after 24, 48, and 72 hours of incubation with pamidronate at concentrations of 0.001 to 1000 microM or with no drug (control treatment). Percentage viability was determined in cell samples for each concentration of pamidronate and each incubation time. A DNA fragmentation analysis was performed to assess bisphosphonate-induced apoptosis. RESULTS: Osteosarcoma cell viability decreased significantly in a concentration- and time-dependent manner at pamidronate concentrations ranging from 100 to 1000 microM, most consistently after 48 and 72 hours' exposure. In treated osteosarcoma cells, the lowest percentage cell viability was 34% (detected after 72 hours' exposure to 1000 microM pamidronate). Conversely, 72 hours' exposure to 1000 microM pamidronate did not significantly reduce fibroblast viability (the lowest percentage viability was 76%). After 72 hours of exposure, pamidronate did not cause DNA fragmentation in POS or HMPOS cells. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that pamidronate may have the potential to inhibit osteosarcoma growth in dogs, possibly through a nonapoptotic mechanism. The clinical relevance of these in vitro findings remains to be determined, but administration of pamidronate may potentially be indicated as an adjuvant treatment in chemotherapeutic protocols used in dogs.

The effect of topical tripeptide-copper complex on healing of ischemic open wounds.

OBJECTIVE: To evaluate the effects of topical glycyl-L-histidyl-L-lysine tripeptide-copper complex (TCC; Iamin 2% Gel; Procyte Corporation, Redmond, WA) on healing in ischemic open wounds. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Twenty-four adult male Sprague-Dawley rats. METHODS: Rats were divided into 3 groups: topical TCC, topical TCC vehicle (hydroxypropyl-methylcellulose), and no treatment (control). Six-mm-diameter, full-thickness wounds were created within an ischemic bipedicle skin flap on the dorsum of each rat. Each day, for 13 days, wound margins were traced, and the TCC and TCC vehicle groups were treated topically. Tracings were scanned, and wound perimeter and area were calculated. On days 6, 10, and 13, selected wounds were biopsied and analyzed for tumor necrosis factor alpha (TNF-alpha) and matrix metalloproteinases (MMP) 2 and 9. RESULTS: A significant decrease in wound area was seen in the TCC group, but not the vehicle group, when compared with the control group on days 3 to 5, 6 to 9, and 11 to 13 and when TCC was compared with TCC vehicle on days 3 and 9. On day 13, initial wound area had decreased by 64.5% in the TCC group, 45.6% in the vehicle group, and 28.2% in the control group. On days 6, 10, and 13, TCC-treated wounds contained significantly lower concentrations of TNF-alpha and MMP-2 and MMP-9 than control wounds. CONCLUSION: Topical TCC resulted in accelerated wound healing in ischemic open wounds. CLINICAL RELEVANCE: Topical TCC is an effective stimulant of healing of ischemic open wounds in rats and may have an application for the treatment of chronic wounds in other species. Clinical evaluation of topical TCC is warranted.

Malabsorption of zinc in rats with acetic acid-induced enteritis and colitis.

Acute intestinal inflammation was established in rats by intraluminal administration of acetic acid into loops of distal ileum, proximal jejunum or ascending colon. The study included two control groups of intact (untreated) rats and sham-operated (saline-treated) rats for each intestinal segment. A third group of rats received acetic acid. Histological evaluation demonstrated that acetic acid treatment induced a mild inflammatory response. Two days after treatment, zinc absorption was measured using ligated 10-cm loops of each segment in which 65Zn was injected intraluminally. 65Zn absorption by the ileum, jejunum and colon was markedly reduced in those rats in which inflammation was induced by acetic acid. The liver showed the highest uptake of radioisotope, but the relative tissue distribution generally followed the amount of absorption. The surgical procedure itself seemed to reduce zinc absorption. No changes in [3H]leucine absorption were observed between sham-operated and acetic acid-treated controls. There was no significant serosal-->luminal secretion of intramuscularly injected 65Zn in any of the studied segments. Therefore, based upon the data obtained, we conclude that acetic acid-induced intestinal inflammation reduces absorption of zinc by the small and large intestine, and that a surgical procedure (laparotomy) also reduces zinc absorption. The mechanism of this inflammation is such that malabsorption shows some specificity.

Regulation of cysteine-rich intestinal protein by dexamethasone in the neonatal rat.

The cysteine-rich intestinal protein (CRIP) is an intestinal zinc-binding protein containing a single copy of a cysteine-rich domain known as the LIM motif. CRIP mRNA and protein levels increased in the rat small intestine throughout the suckling period, reaching highest levels by the late weanling stage. A similar developmental pattern of CRIP protein levels was also detected by an increase in zinc binding to CRIP-containing HPLC fractions of intestinal cytosol. Administration of the synthetic glucocorticoid hormone dexamethasone to neonates caused the precocious rise of CRIP mRNA and protein. In adult rats, CRIP mRNA levels were not significantly altered by dexamethasone. Maximal CRIP mRNA content was detected in cells from the mid-villus, as confirmed by expression of cryptdin mRNA. In this report we show the glucocorticoid regulation of the LIM motif-containing protein CRIP and suggest that glucocorticoid hormones play a role in developmental regulation of CRIP.

Mechanisms of caeruloplasmin biosynthesis in normal and copper-deficient rats.

To examine the mechanisms of holo-caeruloplasmin biosynthesis, we measured the serum caeruloplasmin concentration and oxidase activity, hepatic caeruloplasmin mRNA content and hepatocyte caeruloplasmin biosynthesis and secretion in normal and copper-deficient rats. Copper deficiency resulted in a near-complete loss of serum caeruloplasmin oxidase activity, yet only a 60% reduction in serum caeruloplasmin concentration and no change in the abundance of hepatic caeruloplasmin mRNA or the rate of caeruloplasmin biosynthesis. Both interleukin-1 alpha and lipopolysaccharide increased hepatic caeruloplasmin mRNA content and caeruloplasmin biosynthesis in normal and copper-deficient animals, but neither mediator increased caeruloplasmin oxidase activity in the copper-deficient group. Pulse-chase studies in primary hepatocytes from normal and copper-deficient rats revealed that the secretory rates for newly synthesized caeruloplasmin were identical, despite little or no holo-caeruloplasmin synthesis in hepatocytes of copper-deficient rats. We conclude that hepatocyte copper content has no effect on hepatic caeruloplasmin-gene expression or caeruloplasmin biosynthesis and that the incorporation of copper into newly synthesized caeruloplasmin is not a rate-limiting step in the biosynthesis or secretion of the apoprotein from rat hepatocytes.

Nuclear zinc uptake and interactions and metallothionein gene expression are influenced by dietary zinc in rats.

Regulation of metallothionein gene expression by dietary zinc and the relationship of dietary zinc to nuclear zinc uptake was examined in growing rats. Zinc was fed at 5, 30 or 180 mg/kg, either in pelleted form for a 2-wk period (ad libitum) or for 2 h as a liquefied preparation (1 g in 4 mL). Two hours after the oral dose, the intestine and liver took up more zinc than other tissues. Nuclei purified from liver, kidney and spleen accumulated substantial amounts of zinc and directly reflected the dietary zinc level within the 2-h feeding period. Nuclei from kidney accumulated the largest amount of dietary zinc within 2 h, accounting for up to 6.2% of the total nuclear zinc concentration. Northern analysis demonstrated that metallothionein expression was proportional to dietary zinc intake in some tissues. It was greatest in kidney, followed in descending order by liver, intestine, spleen and heart. Thymus and lung metallothionein mRNA levels were not changed appreciably by dietary zinc intake. Chromatography of extracts from liver nuclei shows that 65Zn introduced into the portal supply is bound to discrete fractions of nuclear proteins. One of these fractions binds both 65Zn and a 32P-labeled oligonucleotide corresponding to the metal regulatory element of the metallothionein promoter. These results demonstrate that significant amounts of zinc from the diet are rapidly taken up by cell nuclei. Furthermore, they suggest that transcriptional regulation of the metallothionein gene and other genes with metal regulatory elements involves a direct interaction between the dietary supply and intranuclear factors that bind zinc.

The lack of correlation between experimental metastatic potential and platelet aggregating activity of B16 melanoma clones viewed in relation to tumor cell heterogeneity.

Two widely used B16 melanoma cell lines of low and high lung colonizing potential (B16-F1 and B16-F10) were compared in their ability to induce platelet aggregation. The results of these experiments showed a reproducible difference in platelet aggregating activity of these two cell lines which directly correlated with their lung colonizing potentials. However, when clones were derived from these heterogeneous cell lines and tested for experimental metastatic potential, platelet aggregating ability and Met-72 expression, no correlation could be attached to the platelet aggregating activity of the clones. Results of these experiments provide direct evidence that platelet aggregation is not an accurate index of experimental metastatic potential of tumor cell clones, nor is it an essential trait of all metastatic cells. The ability of tumor cells to induce platelet aggregation is examined and discussed in the context of cellular heterogeneity.

Effects of thromboxane A2 inhibition on osteogenic sarcoma cell-induced platelet aggregation.

There is evidence that tumors may stimulate platelet aggregation, causing release of thromboxane A2. Thromboxane A2 may potentiate tumor metastasis by stimulating tumor cell growth and proliferation and by enhancing platelet-tumor cell aggregate formation. Despite potential significance of thromboxane A2 in tumor metastasis, agents which inhibit thromboxane A2 synthesis have not been uniformly effective in reducing tumor metastasis. We, therefore, evaluated the effects of a thromboxane A2 receptor antagonist SQ-29,548 compared to those of a thromboxane A2 synthetase inhibitor OKY-046 on osteogenic sarcoma-induced platelet aggregation and thromboxane A2 release. Osteogenic sarcoma cells added to platelet-rich plasma caused complete and irreversible platelet aggregation as well as thromboxane A2 release. Preincubation of platelet-rich plasma with SQ-29,548 (2 to 20 nM) decreased platelet aggregation induced by tumor cells, but it had no effect on thromboxane A2 release. In contrast, preincubation of platelet-rich plasma with OKY-046 (0.1 to 10 microM) had no effect on platelet aggregation despite a decrease in thromboxane A2 synthesis. These results suggest that thromboxane A2 receptor blockers, rather than synthetase inhibitors, may prevent tumor cell-induced platelet aggregation.