Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study.

BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.

Consumer involvement in seafood as family meals in Norway: an application of the expectancy-value approach.

A theoretical model of involvement in consumption of food products was tested in a representative survey of Norwegian households for the particular case of consuming seafood as a common family meal. The empirical study is based on using structural equation approach to test construct validity of measures and the empirical fit of the theoretical model. Attitudes, negative feelings, social norms and moral obligation were proved to be important, reliable and different constructs and explained 63% of the variation in seafood involvement. Negative feelings and moral obligation was the most important antecedents of involvement. Both our proposed model and modified model with seafood involvement as a mediator fit well with the data and proved our expectations in a promising way.

The relationship between the acoustic reflex threshold and levels of loudness categories in hearing-impaired listeners.

When applied as a tool for hearing aid fitting, categorical loudness scaling (CLS) is time consuming and not feasible in all subjects. It is therefore desirable to use objective measures for accurate prediction of loudness categories among hearing-impaired individuals. The present study aimed at exploring whether loudness perception at the ART is constant with varying hearing threshold. Seventy-five subjects with various degrees of hearing impairment, measurable acoustic reflex and normal middle ear function participated. The HTLs, ARTs and the levels of six loudness categories at frequencies 0.5, 1, 2 and 4 kHz were determined for all subjects. Loudness at the ART was found to be correlated with the amount of hearing loss. On the basis of these results, it is concluded that the ART cannot be used for accurate estimation of loudness in hearing-impaired subjects.

The acoustic reflex threshold: not predictive for loudness perception in normally-hearing listeners.

The working hypothesis of an ongoing study is that the quick and reliable procedure of acoustic reflex threshold (ART) determination in conjunction with measurements of HTL may yield accurate estimates of loudness. The aim of this study was to investigate whether differences in loudness in normally-hearing subjects are reflected in the ARTs and to collect normal material with respect to pure-tone elicited ART and loudness categories. Categorical loudness scaling (CLS) and ART measurements were performed at frequencies of 0.5, 1, 2 and 4 kHz in 60 normally-hearing subjects (HTL<20 dB HL, 26 males, 34 females, aged 21-63 years) with no history or sequelae of middle ear disease. Subjects reporting disturbing tinnitus were excluded. The results show that the ART is not a predictor of individual loudness perception for normally-hearing subjects. Using a numerical scale (HTL=0, 'very soft'=5, 'soft'=15, 'OK'=25, 'loud'=35, 'very loud'=45 and 'too loud'=50) loudness for pure tones grows almost linearly at approximately 0.4 arbitrary loudness units per dB below the 'loud' category. Above the 'loud' category the slope is around 1 unit per dB. The median ART was 85 dB HL at frequencies of 0.5, 1, 2 and 4 kHz. No differences in loudness perception across frequencies were found.

Loudness perception is influenced by long-term hearing aid use.

The aim of this study was to explore possible differences in the perception of loudness between long-term hearing aid full-time users and non-users. Categorical loudness scaling using pure-tone stimuli was carried out by hearing-impaired subjects. The mean levels of loudness categories at one frequency (hearing threshold: 50-75 dB HL) in a group of 18 hearing aid users (daily use < or = 15 hours per day) were compared with the corresponding levels found in 18 hearing-impaired non-users with the same distribution of hearing thresholds. The results show that, for hearing losses of 50-75 dB HL, the mean level rated as 'loud' by long-term full-time users of hearing aids is 4.5 dB above the mean level of the corresponding category rated by non-users. This difference is statistically significant (P<0.05). No significant differences were found for the lower categories. Among those subjects who had been wearing hearing aids for at least six months, no significant correlation was found between the levels of the 'loud' category and the length of time that hearing aids had been used.

The relationship between the uncomfortable loudness level and the acoustic reflex threshold for pure tones in normally-hearing and impaired listeners--a meta-analysis.

The objective of this study was to determine the potential of the acoustic reflex threshold (ART) as a predictor of the uncomfortable level (ULL) and to identify related areas for investigations in the future. Eleven studies reporting data from 141 normally-hearing and 240 impaired hearing subjects have been reviewed, focusing on methods, test conditions and subjects. Results and conclusions are discussed and new calculations have been performed on the reported data. The median difference between ART and ULL across studies and frequencies was 5 dB both in normally-hearing and impaired subjects. Some authors argue, that although a close relationship of mean values of the two measurements may exist, prediction of the ULL based on ART measurement will be inaccurate because of high inter-subject variability. A statistically significant correlation exists between the mean HTL, the mean ART and the mean ULL in impaired hearing, while a relationship between the mean ART and the mean ULL does not exist in normal hearing. Based on pooled data across frequencies from the reviewed studies the mean ULL= (0.64 x mean ART+38) dB HL. The discrepancies between the results found in the reviewed studies may be explained by different instructions and stimulus presentation orders when assessing the ULL, difficulty in assessing the sound pressure level in the ear canal, influence of varying background noise levels and different admission criteria. It is recommended that the relationship between different loudness levels and the ART be investigated in normally-hearing subjects and in subjects with different levels of impairment, using standardized instructions. To further provide uniformity of the test material groups should be selected according to history of middle ear diseases and the use of hearing aids.

Long-term test-retest reliability of category loudness scaling in normal-hearing subjects using pure-tone stimuli.

The present study investigates the test-retest reliability of category loudness scaling with pure tones for each of the scaling categories: 'very soft', 'soft', 'OK', 'loud', 'very loud' and 'too loud' at the audiometric frequencies 0.5, 1 kHz, 2 kHz and 4 kHz. Category loudness scaling at two sessions separated by between 1 and 4 weeks was obtained from 16 normal-hearing subjects who all had normal otoscopy, present acoustic reflexes at audiometric frequencies 0.5-4 kHz and middle ear pressure within +/-50 daPa. Intra-subject between-session reliability was found not to be frequency dependent, and comparison with other studies revealed that reliability is not dependent on the applied stimulus signal. Test-retest reliability varied between the different categories: In the categories 'very soft', 'loud', 'very loud' and 'too loud' the test reliability is in the same range as found for hearing thresholds determination, whereas for the 'soft' and 'OK' categories it is poorer. The greater uncertainty for intermediate levels should be considered when using category loudness scaling, e.g. for calculating hearing aid parameters.

Validation of play-conditioned audiometry in a clinical setting.

The aim of the present study was to investigate at what ages children were able to participate in play-conditioned audiometry in a clinical setting. Data concerning age and gender for 294 children (182 boys and 112 girls) were continuously recorded with details regarding audiometric method and number of successfully determined thresholds. Some children were tested more than once, resulting in a total of 449 examinations. The results are compared with those of other studies in which visual reinforced audiometry (VRA), condition-orientation reflex audiometry (COR) and play-conditioned audiometry are used, and show that in a clinical setting it is possible to determine at least one threshold in more than 35% of children tested at ages above 16 months. At 2 years of age, about 50% of the children are able to establish thresholds at least at three frequencies and from 3 years of age nearly 75% of the children could establish 6 thresholds or more. It is concluded that VRA, COR and play-conditioned audiometry should be considered along with objective hearing tests like brainstem audiometry (ABR) or measurement of otoacoustic emissions (OAE) when assessing hearing in infants and small children.

Evaluation of the list of numerals in the Danish speech audiometry material. Dantale.

The psychometric function for the list of numerals in the Danish 'Dantale' speech audiometry material was obtained by presenting the lists to 30 normally hearing subjects at eight different sound pressure levels. Six of the subjects participated in a test of a possible learning effect. The psychometric function is presented, showing that 50% speech recognition is reached at a mean of 15 dB SPL, and the slope of the function around the 50% value is 8.3% per dB. It was found that in no more than 7% of the cases was each numeral on the list confused with another numeral. A strong correlation between the recorded RMS value and the SRT for the individual numeral was found. The short-term learning effect was found to be negligible.

Comparative study of the usefulness of play-conditioned audiometry with wooden rings and electronic video peep show. Audiometric testing of children at the age of two years.

This study was conducted to investigate the effect of new technology in play-conditioned audiometry. The aim was to evaluate whether reinforcement equipment consisting of an electronic video peep show is more advantageous than conventional techniques using coloured wooden rings resulting in a lowering of the age for application of audiometry in children. Thirty-one healthy two-year-old children (18 boys and 13 girls) were tested at the standard audiometric frequencies from 125 to 8000 Hz using both techniques. Fifteen were tested using the wooden ring methods as the first test, and 16 were examined starting with the video peep show. A median of three thresholds (range 0-11 thresholds) was measured using the conventional technique compared to zero thresholds (range 0-11) with the video peep show. Twenty-seven of the tested children were able to establish reliable thresholds. The study did not demonstrate any advantage for determining thresholds using video peep show in comparison with the traditional wooden ring method in tested group of children at two years of age.