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Purpose The main concept analysis (MCA; Kong, 2009) quantifies the effectiveness and efficiency of information transfer during verbal discourse by means of four sets of sequential pictorial stimuli. This test was originally developed for a Cantonese-speaking population. The main goals of this study were (a) to translate and adapt the MCA to Dutch; (b) to establish normative data for healthy native Dutch-speaking adults; (c) to assess the effect of age, education level, and gender on MCA outcome; and (d) to establish inter- and intrarater reliability of the Dutch MCA. Method Language samples were collected from 60 healthy native Dutch speakers, equally recruited in different age (20–39 years, 40–59 years, 60–79 years) and education (middle and highly educated) categories through administration of the MCA. Utterances produced by at least 75% of the participants were included as a main concept in the Dutch MCA. Subsequently, age-specific normative data were established for each of the MCA parameters. Finally, an ICC was calculated in order to verify inter- and intrarater reliability of the Dutch MCA. Results The translated MCA consisted of 19 main concepts. Age-specific normative data were obtained. Both age and education level had a significant effect on MCA outcome. Information transfer in elderly was both less effectively and efficiently compared to young- and middle-aged adults. In addition, highly educated participants transferred information less efficiently compared to middle educated participants. Based on inter- and intrarater reliability measures, the Dutch MCA proved to be a reliable measuring instrument. Conclusions The MCA was translated to Dutch, and age-specific normative data were established for a healthy, Dutch-speaking population. The Dutch MCA is a reliable tool for eliciting and quantifying discourse production. Validation of the test for people with aphasia is necessary in order for the test to be useful in a clinical practice.

Behavioral studies on auditory deviance detection in patients with Parkinson's disease (PD) have reported contradictory results. The primary aim of this study was to investigate auditory deviance detection of multiple auditory features in patients with PD by means of objective and reliable electroencephalographic (EEG) measurements. Twelve patients with early-stage PD and twelve age- and gender-matched healthy controls (HCs) were included in this study. Patients with PD participated without their regular dopaminergic medication. All subjects underwent an audiometric screening and performed a passive multi-feature mismatch negativity (MMN) paradigm. Repeated-measures analysis of variance (ANOVA) demonstrated no significant differences between patients with PD and HCs regarding MMN mean amplitude and latency for frequency, duration and gap deviants. Nevertheless, a trend towards increased MMN mean amplitude and latency was found in response to intensity deviants in patients with PD compared to HCs. Increased intensity MMN amplitude may indicate that more neural resources are allocated to the processing of intensity deviances in patients with PD compared to HCs. The interpretation of this intensity-specific MMN alteration is further discussed in the context of a compensatory mechanism for auditory intensity processing and involuntary attention switching in PD.

Purpose Several studies have demonstrated increased auditory thresholds in patients with Parkinson's disease (PD) based on subjective tonal audiometry. However, the pathophysiological mechanisms underlying auditory dysfunction in PD remain elusive. The primary aim of this study was to investigate cochlear and olivocochlear function in PD using objective measurements and to assess the effect of dopaminergic medication on auditory function. Method Eighteen patients with PD and 18 gender- and age-matched healthy controls (HCs) were included. Patients with PD participated in medication on and off conditions. Linear mixed models were used to determine the effect of PD on tonal audiometry, transient evoked and distortion product otoacoustic emissions (OAEs), and efferent suppression (ES). Results Tonal audiometry revealed normal auditory thresholds in patients with PD for their age across all frequencies. OAE signal amplitudes demonstrated a significant interaction effect between group (PD vs. HC) and frequency, indicating decreased OAEs at low frequencies and increased OAEs at high frequencies in patients with PD. No significant differences were found between patients with PD and HCs regarding ES. In addition, no significant effect of medication status was found on auditory measurements in patients with PD. Conclusions Altered OAEs support the hypothesis of cochlear alterations in PD. No evidence was found for the involvement of the medial olivocochlear system. Altogether, OAEs may provide an objective early indicator of auditory alterations in PD and should complement subjective tonal audiometry when assessing and monitoring auditory function in PD.

New Findings: What is the main observation in this case? Several studies have reported progressive hypoxaemia once extracorporeal carbon dioxide removal is started in patients with hypercapnic respiratory failure, possibly attributable to an altered respiratory quotient. What insights does it reveal? In this quality control report, we show that the respiratory quotient exhibits only minimal alteration when extracorporeal carbon dioxide removal is started and assume that the progressive hypoxaemia is attributable to an increase in intrapulmonary shunt. Abstract: The use of extracorporeal carbon dioxide removal (ECCO 2R) has been proposed in patients with acute respiratory distress syndrome to achieve lung-protective ventilation and in patients with selective hypercapnic respiratory failure. However, several studies have reported progressive hypoxaemia, as expressed by a need to increase the inspired oxygen fraction (F iO 2) to maintain adequate oxygenation or by a decrease in the ratio of arterial oxygen tension (P aO 2) to F iO 2 once ECCO 2R is started. We present the case of a patient who was admitted to the intensive care unit for a coronavirus disease 2019 pneumonia and who was intubated because of hypercapnic respiratory insufficiency. Extracorporeal carbon dioxide removal was started, and the patient subsequently developed progressive hypoxaemia. To test whether the hypoxaemia was attributable to the ECCO 2R, blood samples were taken in different settings: (1) ‘no ECCO 2R’, blood flow 150 ml/min with a ECCO 2R gas flow of 0 L/min; and (2) ‘with ECCO 2R’, blood flow 400 ml/min with gas flow 12 L/min. We measured P aO 2, alveolar oxygen tension, P aO 2/F iO 2, alveolar–arterial oxygen tension difference, arterial carbon dioxide tension and the respiratory quotient (RQ) by indirect calorimetry in each setting. The RQ was 0.60 without ECCO 2R and 0.57 with ECCO 2R. The alveolar oxygen tension was 220.4 mmHg without ECCO 2R and increased to 240.3 mmHg with ECCO 2R, whereas P aO 2/F iO 2 decreased from 177 to 171. Our study showed only a minimal change in RQ when ECCO 2R was started. We were the first to measure the RQ directly, before and after the initiation of ECCO 2R, in a patient with hypercapnic respiratory failure.

Applied immunology; Predictive markers; Viral infection Immunologia aplicada; Marcadors predictius; Infecció viral Inmunología aplicada; Marcadores predictivos; Infección viral Quantitative or qualitative differences in immunity may drive clinical severity in COVID-19. Although longitudinal studies to record the course of immunological changes are ample, they do not necessarily predict clinical progression at the time of hospital admission. Here we show, by a machine learning approach using serum pro-inflammatory, anti-inflammatory and anti-viral cytokine and anti-SARS-CoV-2 antibody measurements as input data, that COVID-19 patients cluster into three distinct immune phenotype groups. These immune-types, determined by unsupervised hierarchical clustering that is agnostic to severity, predict clinical course. The identified immune-types do not associate with disease duration at hospital admittance, but rather reflect variations in the nature and kinetics of individual patient’s immune response. Thus, our work provides an immune-type based scheme to stratify COVID-19 patients at hospital admittance into high and low risk clinical categories with distinct cytokine and antibody profiles that may guide personalized therapy. This work was supported by Health Holland LSHM20056 grant (PDK), in part from the European Union’s Horizon 2020 research and innovation program under grant agreement No 779295 (PDK), in part supported by the Erasmus foundation (BJAR), grant PI20/00416 from the Instituto de Salud Carlos III (RPB) and the European Regional Development Fund (ERDF) (RPB).

Parkinson's disease (PD) has increasingly been associated with auditory dysfunction, including alterations regarding the control of auditory information processing. Although these alterations may interfere with the processing of speech in degraded listening conditions, behavioural studies have generally found preserved speech-in-noise recognition in PD. However, behavioural speech audiometry does not capture the neurophysiological mechanisms supporting speech-in-noise processing. Therefore, the aim of this study was to investigate the neural oscillatory mechanisms associated with speech-in-noise processing in PD. Twelve persons with PD and 12 age- and gender-matched healthy controls (HCs) were included in this study. Persons with PD were studied in the medication off condition. All subjects underwent an audiometric screening and performed a sentence-in-noise recognition task under simultaneous electroencephalography (EEG) recording. Behavioural speech recognition scores and self-reported ratings of effort, performance, and motivation were collected. Time-frequency analysis of EEG data revealed no significant difference between persons with PD and HCs regarding delta-theta (2-8 Hz) inter-trial phase coherence to noise and sentence onset. In contrast, significantly increased alpha (8-12 Hz) power was found in persons with PD compared with HCs during the sentence-in-noise recognition task. Behaviourally, persons with PD demonstrated significantly decreased speech recognition scores, whereas no significant differences were found regarding effort, performance, and motivation ratings. These results suggest that persons with PD allocate more cognitive resources to support speech-in-noise processing. The interpretation of this finding is discussed in the context of a top-down mediated compensation mechanism for inefficient filtering and degradation of auditory input in PD.

There is accumulating evidence for auditory dysfunctions in patients with Parkinson's disease (PD). Moreover, a possible relationship has been suggested between altered auditory intensity processing and the hypophonic speech characteristics in PD. Nonetheless, further insight into the neurophysiological correlates of auditory intensity processing in patients with PD is needed primarily. In the present study, high-density EEG recordings were used to investigate intensity dependence of auditory evoked potentials (IDAEPs) in 14 patients with PD and 14 age- and gender-matched healthy control participants (HCs). Patients with PD were evaluated in both the on- and off-medication states. HCs were also evaluated twice. Significantly increased IDAEP of the N1/P2 was demonstrated in patients with PD evaluated in the on-medication state compared to HCs. Distinctive results were found for the N1 and P2 component. Regarding the N1 component, no differences in latency or amplitude were shown between patients with PD and HCs regardless of the medication state. In contrast, increased P2 amplitude was demonstrated in patients with PD evaluated in the on-medication state compared to the off-medication state and HCs. In addition to a dopaminergic deficiency, deficits in serotonergic neurotransmission in PD were shown based on increased IDAEP. Due to specific alterations of the N1-P2 complex, the current results suggest deficiencies in early-attentive inhibitory processing of auditory input in PD. This interpretation is consistent with the involvement of the basal ganglia and the role of dopaminergic and serotonergic neurotransmission in auditory gating.

Purpose of review A growing numerical and complexity of patients requiring nonoperating room anesthesia (NORA) necessitates a multidisciplinary approach of a highly experienced team in a highly technological setting of the cathlab or radiology suite. These requirements are even more magnified in the context of the coronavirus disease 2019 (COVID-19) pandemic. Recent findings This review describes the aspects of risk stratification both in adults and children with respect to patient morphology, airway management, cardiorespiratory function and finally future developments, which could beneficially interfere with imminent management in NORA. Moreover, some particular features related to COVID-19 are also discussed. Summary Apart from a thorough preoperative assessment, preventive strategies and well-chosen monitoring should be implemented to preclude inadvertent events in sometimes high-risk patients. Timely preventive measures and early recognition of complications could only be achieved by a multidisciplinary cooperating team. In addition, the implementation of safety measurements due to the infectious transmission to both the patients and care givers is crucial.

PurposeIn spite of all the efforts to implement workplace hearing conservation programs, noise-induced hearing loss remains the leading cause of disability for North American workers. Nonetheless, an individual's susceptibility to noise-induced hearing loss can be estimated by monitoring changes in hearing status in relation to the level of ambient noise exposure.The purpose of this study was to validate an approach that could improve workplace hearing conservation practices. The approach was developed using a portable and robust system designed for noisy environments and consisted of taking continuous measurements with high temporal resolution of the health status of the inner ear using otoacoustic emissions (OAEs).MethodA pilot study was conducted in a laboratory, exposing human subjects to industrial noise recordings at realistic levels. In parallel, OAEs were measured periodically using the designed OAE system as well as with a commercially available OAE system, used as a reference.ResultsVariations in OAE levels were analyzed and discussed along with the limitations of the reference and designed systems.ConclusionsThis study demonstrates that the monitoring of an individual's OAEs could be useful in monitoring temporary changes in hearing status induced by exposure to ambient noise and could be considered as a new tool for effective hearing conservation programs in the workplace.

Purpose Alterations in primary auditory functioning have been reported in patients with Parkinson's disease (PD). Despite the current findings, the pathophysiological mechanisms underlying these alterations remain unclear, and the effect of dopaminergic medication on auditory functioning in PD has been explored insufficiently. Therefore, this study aimed to systematically investigate primary auditory functioning in patients with PD by using both subjective and objective audiological measurements. Method In this case–control study, 25 patients with PD and 25 age-, gender-, and education-matched healthy controls underwent an audiological test battery consisting of tonal audiometry, short increment sensitivity index, otoacoustic emissions (OAEs), and speech audiometry. Patients with PD were tested in the on- and off-medication states. Results Increased OAE amplitudes were found when patients with PD were tested without dopaminergic medication. In addition, speech audiometry in silence and multitalker babble noise demonstrated higher phoneme scores for patients with PD in the off-medication condition. The results showed no differences in auditory functioning between patients with PD in the on-medication condition and healthy controls. No effect of disease stage or motor score was evident. Conclusions This study provides evidence for a top-down involvement in auditory processing in PD at both central and peripheral levels. Most important, the increase in OAE amplitude in the off-medication condition in PD is hypothesized to be linked to a dysfunction of the olivocochlear efferent system, which is known to have an inhibitory effect on outer hair cell functioning. Future studies may clarify whether OAEs may facilitate an early diagnosis of PD.

Altered auditory processing has been increasingly recognized as a non-motor feature in parkinsonian disorders. This systematic review provides an overview of behavioral and electrophysiological literature on central auditory processing in patients with Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A systematic database search was conducted and yielded 88 studies that met the intelligibility criteria. The collected data revealed distinct impairments in a range of central auditory processes in PD, including altered deviance detection of basic auditory features, auditory brainstem processing, auditory gating and selective auditory attention. In contrast to PD, literature on central auditory processing in atypical parkinsonian disorders was relatively scarce, but provided some evidence for impaired central auditory processing in MSA and PSP. The interpretation of these findings is discussed and suggestions for further research are offered.

Chronic exposure to environment noise is associated with sleep disturbance and cardiovascular diseases. Assessment of population exposed to environmental noise is limited by a lack of routine noise sampling and is critical for controlling exposure and mitigating adverse health effects. Land use regression (LUR) model is newly applied in estimating environmental exposures to noise. Machine-learning approaches offer opportunities to improve the noise estimations from LUR model. In this study, we employed random forests (RF) model to estimate environmental noise levels in five Canadian cities and compared noise estimations between RF and LUR models. A total of 729 measurements and 33 built environment-related variables were used to estimate spatial variation in environmental noise at the global (multi-city) and local (individual city) scales. Leave one out cross-validation suggested that noise estimates derived from the RF global model explained a greater proportion of variation (R2: RF = 0.58, LUR = 0.47) with lower root mean squared errors (RF = 4.44 dB(A), LUR = 4.99 dB(A)). The cross-validation also indicated the RF models had better general performance than the LUR models at the city scale. By applying the global models to estimate noise levels at the postal code level, we found noise levels were higher in Montreal and Longueuil than in other major Canadian cities.

When making phone calls, cellphone and smartphone users are exposed to radio-frequency (RF) electromagnetic fields (EMFs) and sound pressure simultaneously. Speech intelligibility during mobile phone calls is related to the sound pressure level of speech relative to potential background sounds and also to the RF-EMF exposure, since the signal quality is correlated with the RF-EMF strength. Additionally, speech intelligibility, sound pressure level, and exposure to RF-EMFs are dependent on how the call is made (on speaker, held at the ear, or with headsets). The relationship between speech intelligibility, sound exposure, and exposure to RF-EMFs is determined in this study. To this aim, the transmitted RF-EMF power was recorded during phone calls made by 53 subjects in three different, controlled exposure scenarios: calling with the phone at the ear, calling in speaker-mode, and calling with a headset. This emitted power is directly proportional to the exposure to RF EMFs and is translated into specific absorption rate using numerical simulations. Simultaneously, sound pressure levels have been recorded and speech intelligibility has been assessed during each phone call. The results show that exposure to RF-EMFs, quantified as the specific absorption in the head, will be reduced when speaker-mode or a headset is used, in comparison to calling next to the ear. Additionally, personal exposure to sound pressure is also found to be highest in the condition where the phone is held next to the ear. On the other hand, speech perception is found to be the best when calling with a phone next to the ear in comparison to the other studied conditions, when background noise is present.

Purpose This study investigated the possible relationship between hypokinetic speech production and speech intensity perception in patients with Parkinson's disease (PD). Method Participants included 14 patients with idiopathic PD and 14 matched healthy controls (HCs) with normal hearing and cognition. First, speech production was objectified through a standardized speech intelligibility assessment, acoustic analysis, and speech intensity measurements. Second, an overall estimation task and an intensity estimation task were addressed to evaluate overall speech perception and speech intensity perception, respectively. Finally, correlation analysis was performed between the speech characteristics of the overall estimation task and the corresponding acoustic analysis. The interaction between speech production and speech intensity perception was investigated by an intensity imitation task. Results Acoustic analysis and speech intensity measurements demonstrated significant differences in speech production between patients with PD and the HCs. A different pattern in the auditory perception of speech and speech intensity was found in the PD group. Conclusions Auditory perceptual deficits may influence speech production in patients with PD. The present results suggest a disturbed auditory perception related to an automatic monitoring deficit in PD.

The application area of distortion product otoacoustic emissions (DPOAEs) is expanding beyond clinical routines, towards new measurement environments, protocols, wearable hardware and more robust algorithms. To enable systematic assessment of the performance of commercial and prototype OAE equipment under various measurement conditions without a need for recruitment of the test subjects, a DPOAE generator that produces a reliable and stable response is proposed. This article suggests simple design for such generator that is easy to reproduce by third parties. This design uses an approximate model for middle and inner ear dynamics focusing on typical operational conditions. The DPOAE generator is embedded in a head and torso simulator enabling testing for various probe fitting and also residual ear canal volume effects. Measurement of the DPOAE generator response with clinical equipment shows that the response obtained falls within the range of human normative data. It is also shown that the generator is applicable outside the clinical routines and is able to highlight differences in measurements obtained with different clinical OAE measurement devices.

Gene therapy approaches using recombinant adeno-associated virus serotype 2 (rAAV2) and serotype 8 (rAAV8) have achieved significant clinical benefits. The generation of rAAV Reference Standard Materials (RSM) is key to providing points of reference for particle titer, vector genome titer, and infectious titer for gene transfer vectors. Following the example of the rAAV2RSM, here we have generated and characterized a novel RSM based on rAAV serotype 8. The rAAV8RSM was produced using transient transfection, and the purification was based on density gradient ultracentrifugation. The rAAV8RSM was distributed for characterization along with standard assay protocols to 16 laboratories worldwide. Mean titers and 95% confidence intervals were determined for capsid particles (mean, 5.50×1011 pt/ml; CI, 4.26×1011 to 6.75×1011 pt/ml), vector genomes (mean, 5.75×1011 vg/ml; CI, 3.05×1011 to 1.09×1012 vg/ml), and infectious units (mean, 1.26×109 IU/ml; CI, 6.46×108 to 2.51×109 IU/ml). Notably, there was a significant degree of variation between institutions for each assay despite the relatively tight correlation of assay results within an institution. This outcome emphasizes the need to use RSMs to calibrate the titers of rAAV vectors in preclinical and clinical studies at a time when the field is maturing rapidly. The rAAV8RSM has been deposited at the American Type Culture Collection (VR-1816) and is available to the scientific community. © Mary Ann Liebert, Inc. 2014

Purpose Studying the variations in speech levels with changing background noise level and talker-to-listener distance for talkers wearing hearing protection devices (HPDs) can aid in understanding communication in background noise. Method Speech was recorded using an intra-aural HPD from 12 different talkers at 5 different distances in 3 different noise conditions and 2 quiet conditions. Results This article proposes models that can predict the difference in speech level as a function of background noise level and talker-to-listener distance for occluded talkers. The proposed model complements the existing model presented by Pelegrín-García, Smits, Brunskog, and Jeong (2011) and expands on it by taking into account the effects of occlusion and background noise level on changes in speech sound level. Conclusions Three models of the relationship between vocal effort, background noise level, and talker-to-listener distance for talkers wearing HPDs are presented. The model with the best prediction intervals is a talker-dependent model that requires the users' unoccluded speech level at 10 m as a reference. A model describing the relationship between speech level, talker-to-listener distance, and background noise level for occluded talkers could eventually be incorporated with radio protocols to transmit verbal communication only to an intended set of listeners within a given spatial range—this range being dependent on the changes in speech level and background noise level.

The objective of the current study was to evaluate the predictive role of the olivocochlear efferent reflex strength in temporary hearing deterioration in young adults exposed to music. This was based on the fact that a noise-protective role of the medial olivocochlear (MOC) system was observed in animals and that efferent suppression (ES) measured using contralateral acoustic stimulation (CAS) of otoacoustic emissions (OAEs) is capable of exploring the MOC system. Knowing an individual's susceptibility to cochlear damage after noise exposure would enhance preventive strategies for noise-induced hearing loss. The hearing status of 28 young adults was evaluated using pure-tone audiometry, transient evoked OAEs (TEOAEs) and distortion product OAEs (DPOAEs) before and after listening to music using an MP3 player during 1 h at an individually determined loud listening level. CAS of TEOAEs was measured before music exposure to determine the amount of ES. Regression analysis showed a distinctive positive correlation between temporary hearing deterioration and the preferred gain setting of the MP3 player. However, no clear relationship between temporary hearing deterioration and the amount of ES was found. In conclusion, clinical measurement of ES, using CAS of TEOAEs, is not correlated with the amount of temporary hearing deterioration after 1 h music exposure in young adults. However, it is possible that the temporary hearing deterioration in the current study was insufficient to activate the MOC system. More research regarding ES might provide more insight in the olivocochlear efferent pathways and their role in auditory functioning.

The adult rat brain subventricular zone (SVZ) contains proliferative precursors that migrate to the olfactory bulb (OB) and differentiate into mature neurons. Recruitment of precursors constitutes a potential avenue for brain repair. We have investigated the kinetics and cellular specificity of transgene expression mediated by AAV2/1 vectors (i.e., adeno-associated virus type 2 pseudotyped with AAV1 capsid) in the SVZ. Self-complementary (sc) and single-stranded (ss) AAV2/1 vectors mediated efficient GFP expression, respectively, at 17 and 24 hr postinjection. Transgene expression was efficient in all the rapidly proliferating cells types, that is, Mash1(+) precursors (30% of the GFP(+) cells), Dlx2(+) neuronal progenitors (55%), Olig2(+) oligodendrocyte progenitors (35%), and doublecortin-positive (Dcx(+)) migrating cells (40%), but not in the slowly proliferating glial fibrillary acidic protein-positive (GFAP(+)) neural stem cell pool (5%). Because cell cycle arrest by wild-type and recombinant AAV has been described in primary cultures, we examined SVZ proliferative activity after vector injection. Indeed, cell proliferation was reduced immediately after vector injection but was normal after 1 month. In contrast, migration and differentiation of GFP(+) precursors were unaltered. Indeed, the proportion of Dcx(+) cells was similar in the injected and contralateral hemispheres. Furthermore, 1 month after vector injection into the SVZ, GFP(+) cells, found, as expected, in the OB granular cell layer, were mature GABAergic neurons. In conclusion, the rapid and efficient transgene expression in SVZ neural precursors mediated by scAAV2/1 vectors underlines their potential usefulness for brain repair via recruitment of immature cells. The observed transient precursor proliferation inhibition, not affecting their migration and differentiation, will likely not compromise this strategy.

Objective: The aim of this study was to investigate the diagnostic capacity of three different rotatory tests, and to investigate the clinical effectiveness of the caloric, rotatory, and vestibular evoked myogenic potential (VEMP) test. Design and study sample: Several rotatory testssinusoidal harmonic acceleration test (SHAT), pseudorandom rotation test (PRRT), velocity step test (VST)and a caloric and a VEMP test, were given to 77 patients (mean age 52 years) with a unilateral peripheral vestibular pathology, and 80 control subjects (mean age 48 years). Results: For the rotatory test, the highest diagnostic capacity was obtained with the 0.01 Hz SHAT frequency, followed by 0.1 and 0.05 Hz. A higher diagnostic accuracy was reached for the caloric and VEMP test. The caloric test demonstrated high sensitivity and specificity values, but the 0.01 Hz SHAT rotation appeared more sensitive, and the VEMP more specific, than the caloric test. Conclusion: A selection of the 0.01, 0.05, and 0.1 Hz SHAT rotations is suggested as the most ideal rotatory test protocol, and a combination of rotatory, caloric, and VEMP testing will result in a more complete examination of our vestibular system.

β-Secretase (BACE1) is an attractive drug target for Alzheimer disease. However, the design of clinical useful inhibitors targeting its active site has been extremely challenging. To identify alternative drug targeting sites we have generated a panel of BACE1 monoclonal antibodies (mAbs) that interfere with BACE1 activity in various assays and determined their binding epitopes. mAb 1A11 inhibited BACE1 in vitro using a large APP sequence based substrate (IC(50) ∼0.76 nm), in primary neurons (EC(50) ∼1.8 nm), and in mouse brain after stereotactic injection. Paradoxically, mAb 1A11 increased BACE1 activity in vitro when a short synthetic peptide was used as substrate, indicating that mAb 1A11 does not occupy the active-site. Epitope mapping revealed that mAb 1A11 binds to adjacent loops D and F, which together with nearby helix A, distinguishes BACE1 from other aspartyl proteases. Interestingly, mutagenesis of loop F and helix A decreased or increased BACE1 activity, identifying them as enzymatic regulatory elements and as potential alternative sites for inhibitor design. In contrast, mAb 5G7 was a potent BACE1 inhibitor in cell-free enzymatic assays (IC(50) ∼0.47 nm) but displayed no inhibitory effect in primary neurons. Its epitope, a surface helix 299-312, is inaccessible in membrane-anchored BACE1. Remarkably, mutagenesis of helix 299-312 strongly reduced BACE1 ectodomain shedding, suggesting that this helix plays a role in BACE1 cellular biology. In conclusion, this study generated highly selective and potent BACE1 inhibitory mAbs, which recognize unique structural and functional elements in BACE1, and uncovered interesting alternative sites on BACE1 that could become targets for drug development.

Objective The present study aimed at establishing clinically efficient stopping criteria for a multiple 80-Hz auditory steady-state response (ASSR) system. Methods In Experiment 1, data of 31 normal-hearing subjects were analyzed off-line to propose stopping rules. Consequently, ASSR recordings will be stopped when (1) all 8 responses reach significance and significance can be maintained for 8 consecutive sweeps; or (2) the mean noise levels were ⩽4nV (if p -values were between 0.05 and 0.1, measurements were extended once by 8 sweeps); or (3) a maximum amount of 48 sweeps was attained; whichever occurred first. In Experiment 2, these stopping criteria were applied on 10 normal hearing and 10 hearing-impaired adults to assess the efficiency. Results The application of these stopping rules resulted in ASSR threshold values that were comparable to other ASSR research. Furthermore, preliminary analysis of the response and noise amplitudes demonstrated slightly higher values for hearing impaired than normal-hearing subjects. Conclusions The proposed stopping rules can be used in adults to determine accurate ASSR thresholds within a time-frame of about 1h. Significance The use of these a priori stopping criteria might assist the clinician in their decision to terminate ASSR recordings.

The microphone in real ear (MIRE) protocol allows the assessment of hearing protector's (HPD) attenuation in situ by measuring the difference between the sound pressure outside and inside the ear canal behind the HPD. Custom-made earplugs have been designed with an inner bore to insert the MIRE probe containing two microphones, the reference microphone measuring the sound pressure outside and the measurement microphone registering the sound pressure behind the HPD. Previous research on a head and torso simulator reveals a distinct difference, henceforth called transfer function, between the sound pressure at the MIRE measurement microphone and the sound pressure of interest at the eardrum. In the current study, similar measurements are carried out on humans with an extra microphone to measure the sound pressure at the eardrum. The resulting transfer functions confirm the global frequency dependency found earlier, but also show substantial variability between the ears with respect to the exact frequency and amplitude of the transfer functions' extrema. In addition, finite-difference time-domain numerical models of an ear canal with earplug are developed for each individual ear by including its specific geometrical parameters. This approach leads to a good resemblance between the simulations and their corresponding measurements.

Objective The purpose of this study was to evaluate the reliability of the vestibular evoked myogenic potential (VEMP) response in a clinical setting when only a feedback mechanism is available for monitoring background EMG. Methods Sixty-one healthy subjects participated in the investigation of the within-session reliability, whereas fourteen of them were retested after one week for examination of the between-session reliability. VEMPs were recorded using 500Hz tone bursts with the subjects in a sitting position and their heads turned away from the test ear to the contralateral shoulder, thereby pushing their chin against the inflatable cuff of a blood pressure manometer, serving as feedback method. Results The feedback method revealed latency and amplitude values comparable to other data in the literature where different test conditions were applied. Excellent reliability with ICC values ranging from 0.78 to 0.96 and CV ME values ranging from 4% to 36%, was achieved for P1 and N1 latency, threshold and interpeak amplitude. Good reliability with ICC values of 0.65 and 0.68 and CV ME values of 170% and 189%, was obtained for the asymmetry ratio. Conclusions A unilateral muscle contraction controlled by a feedback mechanism resulted in reliable response parameters, comparable right to left and corresponding to literature data obtained in different test conditions. Significance The use of a blood pressure manometer as feedback mechanism combined with a meticulously controlled positioning of the head and contraction of the SCM muscle provides a reliable alternative in clinical settings, when the background muscle contraction cannot be measured or software related correction algorithms are not accessible.

Recreational music exposure is a potential risk factor for noise-induced hearing loss (NIHL). Augmented hearing protectors have been designed with modified attenuation characteristics to combine hearing protection and listening comfort. However, to date, only a few independent studies have assessed the performance of those augmented protectors in realistic exposure conditions. This study compares the listening experience and temporary effects on cochlear status with different types of earplugs after exposure to contemporary club music. Five different types of commercially available hearing protectors were worn, all commonly used during leisure-time music exposure. Four of them were augmented premolded earplugs and the fifth type was an inexpensive, standard earplug frequently distributed for free at music events. During five different test sessions of 30 min each, participants not professionally involved in music wore one particular type of protector. Contemporary club music was played at sound pressure levels (SPLs) representative of concerts and bars. After each listening session, a questionnaire on sound quality and general appreciation was completed. In addition, otoacoustic emissions (OAEs) were measured directly before and after music exposure. The reported appreciation clearly differed depending on the addressed characteristics and the specific earplug type. In this test group, the reported appreciation mainly depended on comfort and looks, while differences in sound quality were less noticeable. The changes in OAE amplitude before and after noise exposure were small in terms of clinical standards. Nevertheless, the observed temporary shifts differed systematically for the different types of hearing protectors, with two types of musician earplug showing a more systematic decline than the others. Further research with respect to actual use and achieved protection for real, unsupervised music exposure is warranted.

Background: Studies on the prevalence of multiple sclerosis have been carried out worldwide, showing a heterogeneous distribution between countries and even between the different regions of the same country. Methods: We estimated the regional and national prevalence of multiple sclerosis in France on 1 January 2003, based on the computerised database of the national farmer health insurance system (“Mutualite Sociale Agricole”). Results: There were 2667 cases of multiple sclerosis registered on the prevalence date, out of 4 098 477 affiliates. After standardisation on age, estimates for the national prevalence of multiple sclerosis in French farmers were 65.0 per 100 000 inhabitants (95% confidence interval 62.5 to 67.5), 41.9 per 100 000 in men (39.1 to 44.7) and 96.3 per 100 000 in women (92.0 to 100.6). The prevalence of multiple sclerosis was significantly higher in the north eastern regions (approximately 100 per 100 000 inhabitants) compared with the south western regions (around 50 per 100 000 inhabitants). Conclusion: Our study is the first to evaluate the overall prevalence of multiple sclerosis in France and its 22 regions using the same methodology. Our results may be generalised to the whole French population as there is no convincing evidence of an increased or decreased susceptibility to multiple sclerosis among farmers or persons living in the countryside. This places France among the countries of medium to high prevalence. Confirming the uneven distribution of multiple sclerosis that correlates with latitude, raises once more the question of the role of genetic and environmental factors in the susceptibility to multiple sclerosis.

Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described.

Stimulation of resident cells by NF-κB activating cytokines is a central element of inflammatory and degenerative disorders of the central nervous system (CNS). This disease-mediated NF-κB activation could be used to drive transgene expression selectively in affected cells, using adeno-associated virus (AAV)-mediated gene transfer. We have constructed a series of AAV vectors expressing GFP under the control of different promoters including NF-κB -responsive elements. As an initial screen, the vectors were tested in vitro in HEK-293T cells treated with TNF-α. The best profile of GFP induction was obtained with a promoter containing two blocks of four NF-κB -responsive sequences from the human JCV neurotropic polyoma virus promoter, fused to a new tight minimal CMV promoter, optimally distant from each other. A therapeutical gene, glial cell line-derived neurotrophic factor (GDNF) cDNA under the control of serotype 1-encapsidated NF-κB -responsive AAV vector (AAV-NF) was protective in senescent cultures of mouse cortical neurons. AAV-NF was then evaluated in vivo in the kainic acid (KA)-induced status epilepticus rat model for temporal lobe epilepsy, a major neurological disorder with a central pathophysiological role for NF-κB activation. We demonstrate that AAV-NF, injected in the hippocampus, responded to disease induction by mediating GFP expression, preferentially in CA1 and CA3 neurons and astrocytes, specifically in regions where inflammatory markers were also induced. Altogether, these data demonstrate the feasibility to use disease-activated transcription factor-responsive elements in order to drive transgene expression specifically in affected cells in inflammatory CNS disorders using AAV-mediated gene transfer. © 2013 Chtarto et al., SCOPUS: ar.j, info:eu-repo/semantics/published

article i nfo Annoyance, recognition and detection of noise from a single wind turbine were studied by means of a two-stage listening experiment with 50 participants with normal hearing abilities. In-situ recordings made at close distance from a 1.8-MW wind turbine operating at 22 rpm were mixed with road traffic noise, and processed to simulate indoor sound pressure levels at LAeq 40 dBA. In a first part, where people were unaware of the true purpose of the experiment, samples were played during a quiet leisure activity. Under these conditions, pure wind turbine noise gave very similar annoyance ratings as unmixed highway noise at the same equivalent level, while annoyance by local road traffi cn oise was significantly higher. In a second experiment, listeners were asked to identify the sample containing wind turbine noise in a paired comparison test. The detection limit of wind turbine noise in presence of highway noise was estimated to be as low as a signal-to-noise ratio of -23 dBA. When mixed with local road traffic, such a detection limit could not be determined. These fi ndings support that noticing the sound could be an important aspect of wind turbine noise annoyance at the low equivalent levels typically observed indoors in practice. Partici- pants that easily recognized wind-turbine(-like) sounds could detect wind turbine noise better when sub- mersed in road traffic noise. Recognition of wind turbine sounds is also linked to higher annoyance. Awareness of the source is therefore a relevant aspect of wind turbine noise perception which is consistent with previous research.

The perceived negative influence of standard hearing protectors on communication is a common argument for not wearing them. Thus, “augmented” protectors have been developed to improve speech intelligibility. Nevertheless, their actual benefit remains a point of concern. In this paper, speech perception with active earplugs is compared to standard passive custom-made earplugs. The two types of active protectors included amplify the incoming sound with a fixed level or to a user selected fraction of the maximum safe level. For the latter type, minimal and maximal amplification are selected. To compare speech intelligibility, 20 different speech-in-noise fragments are presented to 60 normal-hearing subjects and speech recognition is scored. The background noise is selected from realistic industrial noise samples with different intensity, frequency, and temporal characteristics. Statistical analyses suggest that the protectors’ performance strongly depends on the noise condition. The active protectors with minimal amplification outclass the others for the most difficult and the easiest situations, but they also limit binaural listening. In other conditions, the passive protectors clearly surpass their active counterparts. Subsequently, test fragments are analyzed acoustically to clarify the results. This provides useful information for developing prototypes, but also indicates that tests with human subjects remain essential.

Objectives To determine the output levels of a commercially available MPEG layer-3 (MP3) player and to evaluate changes in hearing after 1 hour of listening to the MP3 player. Design First, A-weighted sound pressure levels (measured in decibels [dBA]) for 1 hour of pop-rock music on an MP3 player were measured on a head and torso simulator. Second, after participants listened to 1 hour of pop-rock music using an MP3 player, changes in hearing were evaluated with pure-tone audiometry, transient-evoked otoacoustic emissions, and distortion product otoacoustic emissions. Participants Twenty-one participants were exposed to pop-rock music in 6 different sessions using 2 types of headphones at multiple preset gain settings of the MP3 player. Main Outcome Measures Output levels of an MP3 player and temporary threshold and emission shifts after 1 hour of listening. Results The output levels at the full gain setting were 97.36 dBA and 102.56 dBA for the supra-aural headphones and stock earbuds, respectively. In the noise exposure group, significant changes in hearing thresholds and transient-evoked otoacoustic emission amplitudes were found between preexposure and postexposure measurements. However, this pattern was not seen for distortion product otoacoustic emission amplitudes. Significant differences in the incidence of significant threshold or emission shifts were observed between almost every session of the noise exposure group compared with the control group. Conclusions Temporary changes in hearing sensitivity measured by audiometry and otoacoustic emissions indicate the potential harmful effects of listening to an MP3 player. Further research is needed to evaluate the long-term risk of cumulative noise exposure on the auditory system of adolescents and adults.

Knowledge regarding the variability of transient-evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) is essential in clinical settings and improves their utility in monitoring hearing status over time. In the current study, TEOAEs and DPOAEs were measured with commercially available OAE-equipment in 56 normally-hearing ears during three sessions. Reliability was analysed for the retest measurement without probe-refitting, the immediate retest measurement with probe-refitting, and retest measurements after one hour and one week. The highest reliability was obtained in the retest measurement without probe-refitting, and decreased with increasing time-interval between measurements. For TEOAEs, the lowest reliability was seen at half-octave frequency bands 1.0 and 1.4 kHz; whereas for DPOAEs half-octave frequency band 8.0 kHz had also poor reliability. Higher primary tone level combination for DPOAEs yielded to a better reliability of DPOAE amplitudes. External environmental noise seemed to be the dominating noise source in normal-hearing subjects, decreasing the reliability of emission amplitudes especially in the low-frequency region.

To assess the impact of HAS (French national health authority) physician guides dedicated to diabetes on general practice, and the impact of additional individual information feedback.51 MSA funds participated in the study, consisting in two periods (April 2006-March 2007 and April 2007-March 2008). In total, 91 case physicians (who benefited from an individual information feedback) and 126 control physicians (who only received the HAS guide), having at least five diabetic patients covered by the agricultural health insurance scheme (Régime agricole) were included. A Chi2 test and a t-test were performed to compare both groups and both periods, respectively.In the control group, the most significant variations between both periods involved the annual follow-up performed by a specialist (cardiologist, ophtalmologist), whereas the differences in therapeutic treatment remained stable or almost stable, statins and aspirin being still underused in patients at increased risk of cardiovascular disease. Finally, the progression in laboratory follow-up remained slow: approximately 1-2% per year according to parameters. The additional information feedback (active group) only led to a significantly different change in cardiac follow-up and the use of aspirin as a platelet suppressive agent, as compared to the mere sending of the HAS guide (control group).The impact of HAS guides was limited and uneven in the management of diabetic patients, and was not conclusively strengthened by the additional information feedback. The form and diffusion of good practice recommendations and feedback should be reviewed to allow for a better appropriation.

Age-related anatomical and morphologic vestibular deterioration has already been elaborated. Demonstrating a corresponding degradation in physiologic function, however, entails a much higher challenge. The objective of this study was to investigate age-related changes using rotational tests, caloric tests, and the vestibular-evoked myogenic potentials (VEMP) test.Eighty healthy human subjects (38 men and 42 women) ranging in age from 18 to 80 yrs participated in this study and were subjected to an extensive vestibular test battery. Function tests included sinusoidal harmonic acceleration tests, a pseudorandom rotation test, velocity step tests, a caloric test, and a VEMP test.No significant age trends were noted for the sinusoidal harmonic acceleration test and velocity step tests response parameters, in contrast to subtle decreasing gain values with advancing age for the pseudorandom rotation test. Increasing slow-component velocity values were measured with the caloric test, whereas the frequency parameter showed no relevant age changes. The largest age trends were detected with the VEMP, with decreasing amplitudes, increasing thresholds, and decreasing N1 latencies. All asymmetry parameters remained stable across the different age categories.Only subtle age changes could be demonstrated with the rotational and caloric tests, in contrast to more pronounced age trends with the VEMP.

Objectives/Hypothesis: To evaluate the impact of a newborn hearing screening program on the management and outcome of deaf children and to identify underlying factors that may be responsible for the differences between high and low performing implanted children. Study Design: Retrospective cohort study of 391 implanted children in Flanders (Belgium). Methods: First, implanted children were sorted into two groups on account of screening age (early screened, n = 195 vs. late screened, n = 196). Both groups were compared with respect to several variables. Second, outcome of cochlear implantation was measured in terms of the child's speech perception and production skills (n = 355). A subgroup of high performing cochlear implant (CI) users was compared with low performing CI users with regard to several variables. Results: Early screened children differ significantly from late screened children with respect to age of hearing loss detection and age at cochlear implantation. Furthermore, early screening and implantation is associated with better auditory receptive skills and speech intelligibility. Additional impairments negatively influence both receptive and productive skills. In addition, children who communicate orally and wear bilateral cochlear implants perform better on speech production, whereas a better speech perception was found in children who became progressively deaf as opposed to congenitally deaf children. Conclusions: The results of this extensive study of profoundly deaf children with CIs in Flanders indicate that a newborn hearing screening program results in earlier intervention in deaf children, which beneficially influences the auditory receptive skills and speech intelligibility.

Rotational testing has been used in clinical practice to explore vestibular function. Frequently used stimulus algorithms include: sinusoidal harmonic acceleration test (SHAT), pseudorandom rotation test (PRRT), and velocity step test (VST). The aim of this study was to construct normative data as well as to evaluate the test-retest reliability of those rotational paradigms. One hundred and fifty subjects without vestibular history participated in the normative study. The SHAT was presented at 5 frequencies (0.01, 0.02, 0.05, 0.1, 0.2 Hz), whereas for the PRRT those frequencies were summed. The VST consisted of a rotation to the right and left and was administered twice. Thirty-two volunteers were retested to assess the test-retest reliability. Separate normative data were needed according to sex, stimulus type, and frequency for the SHAT and PRRT, and according to stimulus and direction for the VST. High reliability by means of the intraclass correlation coefficient (ICC) and the method error (ME) was obtained for the SHAT, PRRT, and VST gain, SHAT phase and asymmetry, and VST time constant parameters. The availability of data on the minimal detectable test-retest differences supports the evaluation of rotational responses on a retest session.

Objective There is still controversy regarding the effects of aging on evoked otoacoustic emissions (EOAEs), as well as on the efferent system measured by contralateral acoustic stimulation of EOAEs. The purpose of this study was to investigate the deterioration in EOAEs and efferent suppression (ES) in a representative sample statistically controlling for the differences in hearing thresholds. Methods Seventy-one ears (20–79 years) were included in the study, 47 of which had normal hearing thresholds, and 24 ears had a sensorineural high-frequency hearing loss caused by presbycusis. The effects of aging on transient evoked (TEOAEs) and distortion product OAEs (DPOAEs), and on ES were evaluated using multiple regression and correlation coefficients. Results EOAEs and ES were more strongly correlated with age, than with pure-tone thresholds (PTTs). Moreover, the increase in the amount of variance explained by the regression model using both predictors was larger for PTTs as compared to the variable age. Conclusions The deterioration of EOAEs and ES with advancing age is caused mainly by pure age-effects, and additionally by the reduction in hearing thresholds. Significance The relative contribution of age and hearing thresholds on EOAEs, as well as on ES is important for their interpretation in clinical settings.

This study aimed to evaluate the effect of impulse noise on otoacoustic emissions (OAEs) while a passive non-linear earplug or an active level-dependent earmuff was worn. Since none of the standardized attenuation measurement techniques, REAT (real ear at threshold), ATF (acoustic test fixture), or MIRE (microphone in real ear), is designed to test both types in real-wearing condition, OAEs, suitable for detecting subtle changes in the functional integrity of the cochlear outer hair cells, are used. First, DPOAEs (distortion product) and TEOAEs (transiently evoked) of 24 subjects were compared before, immediately after gunfire practice, and after one hour of non-exposure. Secondly, both types of OAEs were evaluated in 31 subjects before and after exposure during a five-day military practice. Significant differences existed between the ears in most cases; the emissions from the right ear had a tendency to be more robust. There were no significant changes in OAEs either before and after exposure, or in the second experiment over multiple days. These findings suggest that the HPDs are able to prevent cochlear damage.

The aim of this study was to construct a rotational test protocol after exploring the stimulus parameters of the rotatory vestibular test.Twenty-four normal subjects were submitted to three different rotational paradigms: the sinusoidal harmonic acceleration test (SHAT), the pseudorandom rotation test (PRRT), and the velocity step test (VST). We investigated the influence of frequency and velocity on gain, phase and asymmetry values for the SHAT and the PRRT. In the case of the VST, we examined the influence of velocity and deceleration on gain, slow component velocity at deceleration, time constant, nystagmus preponderance, and time constant asymmetry.Frequency affected the SHAT response parameters, with significant phase differences between the frequencies 0.01, 0.02, 0.05, 0.1, and 0.2 Hz, while velocity, if kept below 150 degrees/s, had no influence on the results. In the case of the VST, responses were influenced by stimulus velocity and not by stimulus deceleration, with significantly higher gain values for the velocities 50 and 250 degrees/s.A velocity of 50 degrees/s tested at the frequencies 0.01, 0.02, 0.05, 0.1, and 0.2 Hz was suggested for the SHAT and PRRT protocol, whereas a velocity of 100 degrees/s with a deceleration of 200 degrees/s2 was preferred for the VST. The relevance of this rotational protocol has yet to be established from patient data.

The present study utilized a commercially available multiple auditory steady-state response (ASSR) system to test normal hearing adults (n=55). The primary objective was to evaluate the impact of the mixed modulation (MM) and the novel proposed exponential AM(2)/FM stimuli on the signal-to-noise ratio (SNR) and threshold estimation accuracy, through a within-subject comparison. The second aim was to establish a normative database for both stimulus types. The results demonstrated that the AM(2)/FM and MM stimulus had a similar effect on the SNR, whereas the ASSR threshold results revealed that the AM(2)/FM produced better thresholds than the MM stimulus for the 500, 1000, and 4000 Hz carrier frequency. The mean difference scores to tones of 500, 1000, 2000, and 4000 Hz were for the MM stimulus: 20+/-12, 14+/-9, 10+/-8, and 12+/-8 dB; and for the AM(2)/FM stimulus: 18+/-13, 12+/-8, 11+/-8, and 10+/-8 dB, respectively. The current research confirms that the AM(2)/FM stimulus can be used efficiently to test normal hearing adults.

The aim of the present study was to construct and compare two caloric test protocols, one for water irrigation, and one for air insufflation. A set of reference data was constructed and tabulated as well as the intersubject variability. The effect of age, sex, ear, and temperature, as well as a possible priming effect and order effect were investigated. Forty-seven subjects (18-58 years) without otological or vestibular history participated. Four response parameters were investigated: slow component velocity (SCV), frequency, unilateral weakness (UW), and directional preponderance (DP). Statistically higher SCV values were obtained for water compared to air, with statistically higher standard deviations for SCV water values. No influences of age, sex, ear, or temperature could be demonstrated on any of the response parameters. The same applied for the presence of an order effect and a priming effect. Comparing the two protocols to one another led the present authors to favour water as the standard irrigation medium, and air only in situations where water is contra-indicated.

An autoregulated tetracycline-inducible recombinant adeno-associated viral vector (rAAV-pTet(bidi)ON) utilizing the rtTAM2 reverse tetracycline transactivator (rAAV-rtTAM2) was used to conditionally express the human GDNF cDNA. Doxycycline, a tetracycline analog, induced a time- and dose-dependent release of GDNF in vitro in human glioma cells infected with rAAV-rtTAM2 serotype 2 virus. Introducing the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) downstream to the rtTAM2 coding sequence, resulted in a more rapid induction and a higher basal expression level. In vivo, 8 weeks after a single injection of the rAAV-rtTAM2-GDNF vector encapsidated into AAV serotype 1 capsids in the rat striatum, the GDNF protein level was 60 pg/mg tissue in doxycycline-treated animals whereas in untreated animals, it was undistinguishable from the endogenous level ( approximately 4 pg/mg tissue). However, a residual GDNF expression in the uninduced animals was evidenced by a sensitive immunohistochemical staining. As compared to rAAV1-rtTAM2-GDNF, the rAAV1-rtTAM2-WPRE-GDNF vector expressed a similar concentration of GDNF in the induced state (with doxycycline) but a basal level (without doxycycline) approximately 2.5-fold higher than the endogenous striatal level. As a proof for biological activity, for both vectors, downregulation of tyrosine hydroxylase was evidenced in dopaminergic terminals of doxycycline-treated but not untreated animals. In conclusion, the rAAV1-rtTAM2 vector which expressed biologically relevant doses of GDNF in the striatum in response to doxycycline with a basal level undistinguishable from the endogenous striatal level, as measured by quantitative ELISA assay, constitutes an interesting tool for local conditional transgenesis.

To evaluate the cost-effectiveness of spa therapy for rheumatic diseases and sequelae of bone and joint injuries.A prospective randomized, case-control design was used with health care cost reimbursements during the year before and after spa therapy as the measure of efficacy. Spa therapy is reimbursed by the national health insurance system in France, subject to prior agreement. The 220 patients who filed applications for spa therapy with the national health insurance payment center for northern France during the first half of 1994 were included in the study. Seventy-two patients met national health insurance system criteria for spa therapy (Group 1), the remaining 148 patients were assigned at random to spa therapy (Group 2, n = 74) or no spa therapy (Group 3, n = 74). This method allowed us to avoid selection bias during recruitment of our control group.Perceived morbidity was evaluated based on health care utilization, expressed as numbers of health care investigations or procedures and as days of medication use in mean recommended dosages. Health care cost reimbursements by the national health insurance system failed to decrease during the year after spa therapy, and increased in those patients who had already received spa therapy on one or more occasions. Only in the first-ever spa patients were decreases in health care utilization in the area of rheumatology seen during the year after spa therapy; the largest decreases were for use of nonsteroidal antiinflammatory drugs (from 49 to 26 days) and muscle relaxants. No differences in health care utilization were found in patients who had received spa therapy on at least one other occasion. Also, when criteria for spa therapy were not met, no differences in health care utilization were found between patients who did and did not receive spa therapy.These data suggest that current national health insurance policies regarding the reimbursement of spa therapy need to be reevaluated.

The aim of this study was to prospectively evaluate use of computed tomography (CT) of the lumbar spine in office practice. The "Caisse Maladie Régionale du Nord" provides health insurance to self-employed retailers and craft persons (92,500 people at the end of 1991). The authors prospectively studied 106 patients insured by this organisation (60 males, 46 females, mean age: 51.27 years) who underwent CT of the lumbar spine between August 2, 1991 and January 23, 1993. They examined all insurance claims (physician visits, surgery, drugs, physiotherapy, laboratory tests, imaging studies, and hospitalizations) filed by each study patient during the 4 months before and the 4 months after the index CT. Reason for the CT, specified on 65 of the 106 radiologist reports, were isolated low back pain and nerve root pain in 26.2% and 56.9% of the patients respectively. CT findings were discal prolapse in 27 patients (25.5%), facet joint osteoarthritis in 33 patients (31.3%), discal protrusion in 29 patients (27.4%) and were considered as normal in 19 patients (18%). CT was preceded by plain radiographs in 50% of patients, by a rheumatologist visit in 31%, by a visit to the sole general practitioner in 51%, by local steroid injection in 15%. During the 4 months subsequent to the index CT, 14 (13.2%) patients had surgery and one underwent chemonucleolysis. These findings suggest that consensus conference recommendations concerning lumbar spine CT are not currently being followed in France.

The use of in situ measurements of hearing protectors' (HPD's) attenuation following the microphone in real ear (MIRE) protocol is increasing. The attenuation is hereby calculated from the difference in sound levels outside the ear and inside the ear canal behind the HPD. Custom-made earplugs have been designed with an inner bore that allows inserting a miniature microphone. A thorough understanding of the difference, henceforth called transfer function, between the sound pressure of interest at the eardrum and the one measured at the inner bore of the HPD is indispensable for optimizing the MIRE technique and extending its field of application. This issue was addressed by measurements on a head-and-torso-simulator and finite difference time domain numerical simulations of the outer ear canal occluded by an earplug. Both approaches are in good agreement and reveal a clear distinction between the sound pressure at the MIRE microphone and at eardrum, but the measured transfer functions appear to be stable and reproducible. Moreover, the most striking features of the transfer functions can be traced down to the geometrical and morphological characteristics of the earplug and ear canal.