Background Aminoglycosides (AGs) and glycopeptides are antibiotics essential for treating life-threatening respiratory infections in patients with cystic fibrosis (CF). The goal of this study was to examine the effects of cumulative intravenous AG (amikacin and/or tobramycin) and/or glycopeptide (vancomycin) dosing on hearing status. Methods Hearing thresholds were measured from 0.25 to 16.0 kHz, in 81 participants with CF. Participants were categorized into two groups: normal hearing in both ears (≤25 dB HL for all frequency bands) or hearing loss (>25 dB HL for any frequency band in either ear). Participants were also characterized by their cumulative intravenous (IV)-AG (with or without vancomycin) exposure by comparing the total number of lifetime cumulative IV doses to a method that additionally accounts for the total number of doses per day (weighted method) per course of treatment. Results Participants in the hearing loss group were significantly older than those in the normal-hearing group. After adjusting for gender and age at the time of hearing test, participants in the two highest-quartile exposure groups were more likely to have permanent sensorineural hearing loss than those in the two lowest-quartile exposure groups. Conclusions Cumulative IV antibiotic dosing has a significant negative effect on hearing sensitivity in patients with CF, when controlling for age and gender effects. A trend for increasing odds of hearing loss was associated with increasing cumulative IV-antibiotic dosing.

Objectives Wideband acoustic immittance (WAI) measures such as pressure reflectance, parameterized by absorbance and group delay, equivalent admittance at the tympanic membrane (TM), and acoustic stapedius reflex threshold (ASRT) describe middle-ear function across a wide frequency range, compared to traditional tests employing a single frequency. The objective of this study was to obtain normative data using these tests for a group of normal hearing adults and investigate test-retest reliability using a longitudinal design. Design A longitudinal prospective design was used to obtain normative test and retest data on clinical and WAI measures. Subjects were 13 males and 20 females (mean age = 25 y). Inclusion criteria included normal audiometry and clinical immittance. Subjects were tested on two separate visits approximately one month apart. Reflectance and equivalent admittance at the TM were measured from 0.25 to 8.0 kHz under three conditions: at ambient pressure in the ear canal and with pressure sweeps from positive to negative pressure (downswept) and negative to positive pressure (upswept). Equivalent admittance at the TM was calculated using admittance measurements at the probe tip which were adjusted using a model of sound transmission in the ear canal and acoustic estimates of ear-canal area and length. Wideband ASRTs were measured at tympanometric peak pressure (TPP) derived from the average TPP of downswept and upswept tympanograms. Descriptive statistics were obtained for all WAI responses, and wideband and clinical ASRTs were compared. Results Mean absorbance at ambient pressure and TPP demonstrated a broad band-pass pattern typical of previous studies. Test-retest differences were lower for absorbance at TPP for the downswept method compared to ambient pressure at frequencies between 1.0 and 1.26 kHz. Mean tympanometric peak-to-tail differences for absorbance were greatest around 1.0 to 2.0 kHz and similar for positive and negative tails. Mean group delay at ambient pressure and at TPP were greatest between 0.32 and 0.6 kHz at 200 to 300 μs, reduced at frequencies between 0.8 and 1.5 kHz, and increased above 1.5 kHz to around 150 μs. Mean equivalent admittance at the TM had a lower level for the ambient method than at TPP for both sweep directions below 1.2 kHz, but the difference between methods was only statistically significant for the comparison between the ambient method and TPP for the upswept tympanogram. Mean equivalent admittance phase was positive at all frequencies. Test-retest reliability of the equivalent admittance level ranged from 1 to 3 dB at frequencies below 1.0 kHz, but increased to 8 to 9 dB at higher frequencies. The mean wideband ASRT for an ipsilateral broadband noise activator was 12 dB lower than the clinical ASRT, but had poorer reliability. Conclusions Normative data for the WAI test battery revealed minor differences for results at ambient pressure compared to tympanometric methods at TPP for reflectance, group delay, and equivalent admittance level at the TM f...

Levodopa dose and severity of Parkinson's disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxydopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2-10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED 50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories ( Ͼ 0.7) and for each AIM category in regard to total AIM score ( Ͼ 0.7). In rats that received levodopa doses that were greater than the ED 50 , rates of amphetamine-induced rotation were significantly correlated with total AIM scores ( ϭ 0.413). However, of those rotating Ͼ5 times/min, 34% had relatively low AIM scores (Ͻ8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores ( ϭ 0.388). However, in those rats that had Ͼ85% TH loss, 30% had AIM scores Ͻ8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility.The tremor, rigidity, and akinesia of Parkinson's disease (PD) are caused by progressive loss of dopamine innervation in the basal ganglia. Symptoms of PD can be largely alleviated by treatment with the dopamine precursor levodopa. However, chronic treatment is often complicated by the emergence of levodopa-induced dyskinesia (LID), which is characterized by involuntary choreiform or dystonic movements of the face, trunk, or limbs. After 1 year of levodopa treatment, more than 60% of PD patients reportedly show signs of LID, and new cases occur at an incidence of 10% per year (Grandas et al., 1999). Risk factors for LID include young age of PD onset, duration and dose of levodopa treatment, severity and duration of PD symptoms, and female gender (Nutt, 1992;Schrag and Quinn, 2000;Zappia et al., 2005). However, it is also clear that not all PD patients develop LID despite the presence of multiple risk factors. Because LID can severely limit the usefulness of levodopa treatment (Hurtig, 1997), this has prompted much research aimed at discovering mechanisms that underlie the development of LID in PD.In the last few decades, there has been steady advancement in using the hemi-parkinsonian rat to investigate LID. In this model of PD, rats receive a unilateral intracerebral injection of 6-hydroxydopamine (6-OHDA) that causes ipsilateral destruction of dopamine-containing ne...

Levodopa (L-DOPA) is the 'gold standard' to treat Parkinson's disease. Unfortunately, dyskinesias detract from its efficacy. Current dyskinesia treatments, including amantadine and dextromethorphan, are thought to work via N-methyl-D-aspartate (NMDA) antagonism, but this hypothesis has not been tested. The NMDA antagonists MK-801and HA-966 failed to suppress expression of dyskinesias in the 6-hydroxydopamine rat. Dyskinesias, however, were suppressed by the NMDA and sigma (σ)-1receptor ligand dextromethorphan and by the σ-1 antagonist BMY-14802. Antidyskinetic effects of dextromethorphan may be mediated via mechanisms other than NMDA, including the σ-1 receptor and other binding sites common to dextromethorphan and BMY-14802.