Treatment response with mepolizumab in severe eosinophilic asthma patients with previous omalizumab treatment.

BACKGROUND: We performed post hoc analyses to evaluate the effect of humanized monoclonal antibody mepolizumab in patients with severe eosinophilic asthma previously treated with omalizumab. METHODS: Data were collected from two randomized double-blind, placebo-controlled studies: MENSA (NCT01691521: 32-week treatment phase) and SIRIUS (NCT01691508: 24-week treatment phase). Active treatment was 75 mg intravenous mepolizumab (MENSA) or 100 mg subcutaneous mepolizumab (MENSA, SIRIUS). Patients had evidence of eosinophilic inflammation ≥150 cells/µl (at screening) or ≥300 cells/µl (during the previous year). Primary outcomes were the rate of exacerbations (MENSA) and the percentage reduction in oral corticosteroid (OCS) dose (SIRIUS). Other outcomes included lung function (forced expiratory volume in 1 s and morning peak expiratory flow), Asthma Control Questionnaire (ACQ-5), St George's Respiratory Questionnaire (SGRQ) scores, and safety. RESULTS: Overall, 576 patients were included from MENSA and 135 from SIRIUS, with 13% and 33% previously receiving omalizumab, respectively. In MENSA, mepolizumab reduced the rate of exacerbations by 57% (prior omalizumab) and 47% (no prior omalizumab) vs placebo. In SIRIUS, reductions in OCS use were comparable regardless of prior omalizumab use. Despite reducing chronic OCS use, mepolizumab also resulted in similar reductions in exacerbation rate relative to placebo in both subgroups. Asthma control and quality of life improved with mepolizumab vs placebo in both studies independent of prior omalizumab use, as shown by ACQ-5 and SGRQ scores. Adverse events were also comparable irrespective of prior omalizumab use. CONCLUSIONS: These post hoc analyses indicate that patients with severe eosinophilic asthma respond positively to mepolizumab regardless of prior use of omalizumab.

[Patients in the IDEAL cohort: A snapshot of severe asthma in France]. / Les patients de la cohorte IDEAL : une photographie de l'asthme sévère en France.

INTRODUCTION: This paper reports the French data from a post-hoc analysis of the international IDEAL study, which aimed to describe a recent cohort of patients with severe asthma, the impact of the disease on quality of life, as well as the population of patients eligible for treatment with omalizumab, mepolizumab and reslizumab. METHODS: Eligible patients were≥12 years of age, with severe asthma (GINA steps 4 and 5). RESULTS: A total of 129 patients were included in this post-hoc analysis. Their mean age was 53 years, the majority were overweight, they were mainly women (64%) and had at least one medical comorbidity (85%). More than half had suffered from asthma for more than 25 years and were non-smokers. Lung function was moderately impaired. Blood eosinophil count was≥150 cells/µL in 66% of patients,≥300 cells/µL in 34% of patients, and≥500 cells/µL in 12% of patients. One out of three patients was currently treated with omalizumab and 24% had maintenance oral corticosteroids. Asthma was poorly controlled with a negative impact on quality of life (ACQ≥1.5) in 67% of patients. In this population 40% of patients were eligible for omalizumab, 27% for mepolizumab and 2% for reslizumab. CONCLUSIONS: These findings show that a considerable proportion of patients with severe asthma remain uncontrolled and are not eligible for any of the available biological treatments. This underlines the need for therapeutic innovations in this disease.

The additive effect of co-occurring anxiety and depression on health status, quality of life and coping strategies in help-seeking tinnitus sufferers.

OBJECTIVE: Evaluating the effect of anxiety and depression on clinical measures of general health, tinnitus-specific quality of life, and coping abilities. DESIGN: Two hundred sixty-five chronic, subjective tinnitus sufferers were divided into four psychological symptom groups according to cut-off scores on anxiety and depression subscales of the Hospital Anxiety and Depression Scale: (1) no-symptoms, (2) anxiety-only, (3) depression-only, and (4) anxiety-plus-depression. General health-related quality of life (SF-36), tinnitus-specific quality of life (tinnitus reaction questionnaire and tinnitus handicap inventory), and coping abilities (tinnitus coping style questionnaire) were assessed and analyzed across these four psychological symptom groups, which did not differ on age, gender, marital, and working status. RESULTS: Statistically significant and clinically relevant differences on general health-related and tinnitus-specific quality of life and coping abilities were identified when comparing anxiety-plus-depression subgroup with the subgroups anxiety-only, depression-only, or no-symptoms. Highest associations were seen between the anxiety-plus-depression subgroup and impaired quality of life and maladaptive coping. CONCLUSIONS: Our results demonstrate the additive effect of both anxiety and depression in impairing general health-related and tinnitus-specific quality of life and application of coping strategies, and reiterate the need for investigating both symptoms in the clinical evaluation of tinnitus patients.

Rupture of Reissner's membrane during acute endolymphatic hydrops in the guinea pig: a model for Ménière's disease?

CONCLUSION: The changes in cochlear function during a destructive acute endolymphatic hydrops were relatively small. This might be consistent with the hypothesis that an endolymphatic hydrops is a marker of disordered inner ear homeostasis rather than the cause of the clinical symptoms of Ménière's disease. OBJECTIVE: Assessment of cochlear function during induction of a destructive acute endolymphatic hydrops. MATERIALS AND METHODS: During repetitive microinjections of 0.5 microl of artificial endolymph at a rate of 50 nl/s the 2f1-f2 and f2-f1 cochlear microphonics distortion products (CMDP) and 2f1-f2 distortion products otoacoustic emissions (DPOAE) were recorded in the guinea pig. RESULTS: A 'catastrophe' occurred in the inner ear when 2.5-3.5 microl of artificial endolymph was injected. A rupture of Reissner's membrane was then found, most often in the apical turn of the cochlea. This rupture had only minor effects on the endocochlear potential, whereas it caused a marked decrease in 2f1-f2 DPOAE amplitude. The 2f1-f2 and f2-f1 CMDP amplitude increased during each injection prior to the rupture. After the rupture the f2-f1 CMDP amplitude decreased during each injection, possibly due to a shift of the cochlear transducer operating point position.

Functional imaging of the central auditory system using PET.

In the last few decades functional neuroimaging tools have emerged to study the function of the human brain in vivo. These techniques have increased the knowledge of how the brain processes stimuli of different sensory modalities, including auditory processing. Positron emission tomography (PET) has been used for nearly 20 years to study changes in cerebral blood flow associated with auditory stimulation in normal and hearing impaired subjects. PET studies gave insight into the neural base of processing basic sound features such as frequency and intensity, but complex stimuli such as speech and music have also been investigated extensively. Knowledge of the normal auditory function of the brain helps us to understand the neural base of hearing deficits and provides ideas for possible treatments. Although functional magnetic resonance imaging (fMRI) is replacing PET in many neuroimaging studies nowadays, PET still holds unique advantages and can give us valuable knowledge about the auditory cortex and auditory perception.

The relationship of the round window membrane to the cochlear aqueduct shown in three-dimensional imaging.

The round window membrane and cochlear aqueduct complex in the guinea pig are reconstructed with 3D-imaging, using orthogonal plane fluorescence optical sectioning (OPFOS). The 3D-images show that the periotic duct and the aqueduct are connected to a pouch-like extension of the round window. The function of this may be regulation of aqueduct flow resistance under the influence of a pressure difference between inner ear fluid and middle ear.

Morphology of the endolymphatic sac in the guinea pig after an acute endolymphatic hydrops.

The role of the endolymphatic sac (ES) in endolymph volume homeostasis is speculative. The present study investigates changes of the ES's epithelia and luminal filling after induction of an acute endolymphatic hydrops. After microinjection of 1.1 mul artificial endolymph into scala media of the cochlea, guinea pigs were terminated immediately (n = 6) or after different time intervals ; 1/2 h (n = 3), 1 h (n = 4) and 2 h (n = 4). Inner ear specimens were processed for light and/or transmission electron microscopy. The non-injected contralateral ear served as a histological control. Correct injection was confirmed by detection of microspheres in the endolymphatic compartment after the same microinjection procedure. In all specimens, ribosome rich cells and intraluminal macrophages appeared to be actively involved in degradation of homogeneous substance (HS) by secreting lytic enzymes and digestion, respectively. Amazingly, in our study no ES differences were found between injected and non-injected ears and no distinct changes were observed in guinea pigs terminated after different time intervals. The ES's luminal HS was always present and often to a large extent. This is in contrast with [Hear. Res. 138, 81] dramatic changes were observed. Endolymph volume homeostasis is a complex mechanism, in which the role of HS remains obscure.

Neurostimulation as a new treatment for severe tinnitus: a pilot study.

BACKGROUND: Tinnitus is an uncomfortable symptom for the patient and an embarrassing one for the consulted physician. So far, there is no treatment that can be considered well established in terms of providing long-term reduction of tinnitus in excess of placebo effects. There is considerable evidence of pathophysiological similarity between tinnitus and chronic pain. Some forms of chronic pain can be treated by neurostimulation. OBJECTIVE: This study was designed to investigate the feasibility of neurostimulation of the cochlear nerve in order to reduce tinnitus. STUDY DESIGN: Pilot study. SETTING: Tertiary referral center. PATIENTS: Five patients with therapeutically refractory tinnitus were selected for this study. INTERVENTION: Placing a stimulation lead around the cochlear nerve through the suboccipital approach and connecting the stimulation lead to a pulse generator. MAIN OUTCOME MEASURES: The patients experienced 1) an absence of major or minor complications, such as death, meningitis, cranial nerve deficit, and vestibular problems; 2) tolerance of the procedure as considered by the patient; 3) relief of tinnitus in at least one patient. RESULTS: Implantation of the neurostimulation system was accomplished in each patient without any difficulty. None of the patients considered the treatment unbearable. No major or minor complications occurred in this study. Subjective tinnitus reduction was accomplished in four patients. CONCLUSION: Our preliminary data show that neurostimulation of the cochlear nerve is feasible, is bearable for the patient, and is a safe treatment modality without major complications. The effects on tinnitus are promising.

Morphometric parameters of the superior colliculus of albino and pigmented rats.

The superior colliculus (SC) or optic tectum of mammals consists of seven layers, numbered I-VII from superficial to deep, each of which has distinct connectivity patterns and electrophysiological response properties. The present study is devoted to a morphometrical analysis of neuronal diameters, densities, and numbers in different layers and regions of the SC of albino as well as pigmented rats in order to present a quantitative characterization of the collicular neuronal population involved in the different connectivities and functions of these compartments. The morphometric parameters were calculated from tracings of nuclei and cell bodies by means of Kontron-Videoplan equipment and a Micro PDP 11/23 computer. The mean soma diameter per superior colliculus appears to be 12.0 microns, the average neuronal density 70 cells per 0.001 mm3, and the total number of neurons about 600,000. The mean soma diameter gradually increases from superficial to deep layers (i.e., from 10.0 to 14.0 microns). Cellular density is highest in layer III, the retinal afferent layer (90 cells per 0.001 mm3), and decreases both in more superficial layers (to about 80 in layer I) and deeper layers (to about 44 in layer VII). About 25% of all collicular neurons are situated in layer II whereas layer I contains the lowest percentage of cells (4%). Rostrally within each collicular layer, cellular volumes are about 25% larger than caudally. On the other hand, neuronal densities are rostrally about 38% lower than caudally in all layers except for layers VI and VII. We conclude that collicular neurons, in contrast to collicular axons, are not arranged in distinct layers or clusters but basically establish a random network with only gradual transitions. In this respect, no statistically significant differences were observed between albino and pigmented rats.

Synaptic morphometry and synapse-to-neuron ratios in the superior colliculus of albino rats.

The superior colliculus of mammals is generally divided into seven layers on the basis of the distribution of myelinated fibers, which are densely packed in layers III, V, and VII but sparse in the other layers. The laminar distribution of afferents and efferents allows, in addition, for the distinction of a superficial visual zone (layers I-III) and a deeper multimodal and premotor zone (layers IV-VII). Collicular neurons, however, do not show a lamination pattern, but are rather homogeneously distributed with only gradual transitions (Albers et al.: J. Comp. Neurol. 274:357-370, '88). The present study analyses whether the distribution of collicular synapses is correlated with the laminar organization of collicular axons or rather with the more homogeneous distribution of collicular neurons. For this purpose, the size and density of synaptic terminals and contacts as well as synapse-to-neuron ratios were determined in all collicular layers of albino rats by means of quantitative analysis of electron microscopic pictures. The size of presynaptic terminals and contacts does not differ significantly between individual collicular layers. On average, presynaptic terminal diameter is 1,079 nm, and synaptic contact size 338 nm, while 23% of all contacts are of the symmetrical type with pleiomorphic vesicles. The average numerical synaptic density is 422 million per mm3. This value is significantly higher in layers I and II (on average 670 million per mm3) than in layers III-VII (on average 370 million per mm3). The synapse-to-neuron (S/N) ratios calculated show that collicular neurons have on average 6,120 synaptic contacts on their receptive surface. The S/N ratio is lowest in layer III (4,330), while this ratio is highest in layers I and VII (i.e., 8,970 and 8,560 respectively). Layer II has a significantly higher S/N ratio than layer III (i.e., 8,060 and 4,330, respectively). Our results show that the size of synaptic terminals and contacts is not correlated with the different connectivity patterns of the distinct collicular layers. However, the density of synapses as well as the synapse-to-neuron ratios show a certain degree of laminar differentiation. In particular the superficial visual zone appears to be inhomogeneous in this respect, since layers I and II have a significantly higher density of synapses and higher S/N ratios than layer III. The deeper collicular zone is more homogeneously organized with synaptic densities similar to that of layer III and gradually increasing synapse-to-neuron ratios from layer IV to layer VII.

Potassium ferricyanide: a stabilizer for horseradish peroxidase.

Sodium nitroprusside has been used as a stabilizing agent for HRP histochemistry since 1919. However, it is known to have toxic effects orally, intravenously, and subcutaneously. In order to avoid the use of sodium nitroprusside as a stabilizer in HRP histochemistry, we have tested other chemically related compounds to stabilize the reaction product equally well. We will show that potassium ferricyanide is an excellent stabilizer of the chromogen reaction product. In addition, the reaction product remains stable without noticeable changes over a period of several months. As it is far less toxic than sodium nitroprusside, it should be the stabilizer of choice, especially in those laboratories where the histochemical HRP reaction is used frequently.

Cochlear aqueduct flow resistance depends on round window membrane position in guinea pigs.

The resistance for fluid flow of the cochlear aqueduct was measured in guinea pigs for different positions of the round window membrane. These different positions were obtained by applying different constant pressures to the middle ear cavity. Fluid flow through the aqueduct was induced by small pressure steps superimposed on these constant pressures. It was found that the resistance for fluid flow through the aqueduct depended on the round window position but not on flow direction. The results can be explained by special fibrous structures that connect the round window with the entrance of the aqueduct. It was also found that the equilibrium inner ear pressure depends on middle ear pressure, indicating that the aqueduct does not connect the inner ear with a cavity with constant pressure.

Effect of probiotic bacteria on prevalence of yeasts in oropharyngeal biofilms on silicone rubber voice prostheses in vitro.

The proliferation of yeasts in the mixed bacterial and fungal biofilms colonising silicone rubber voice prostheses in laryngectomised patients is the main cause of malfunctioning of the valve mechanism on the oesophageal side of the prostheses. Indwelling voice prostheses usually have to be replaced every 3-4 months. The consumption of probiotic bacteria is largely motivated by health claims related to the urogenital and lower digestive tract, but not to the upper digestive tract. The present study examined the influence of probiotic bacteria on the prevalence of yeasts in oropharyngeal biofilms on silicone rubber voice prostheses, as formed in a modified Robbins device. Exposure of oropharyngeal biofilms on voice prostheses to suspensions of Bifidobacterium infantis 420 or Enterococcus faecium 603 did not significantly reduce the number of yeasts in the biofilm. However, suspensions of Lactobacillus fermentum B54, L. rhamnosus 744 or L. lactis cremoris SK11 led to a reduction in the number of yeasts harvested from the voice prostheses. Suspensions of L. casei Shirota and Streptococcus thermophilus B significantly reduced the number of yeasts in the biofilm to 39% and 33%, respectively. The reduction brought about in yeast prevalence in the mixed biofilm was greatest by exposure to a suspension of L. lactis 53, with yeast prevalence only 4% of the control. In conclusion, the study demonstrated that the prevalence of yeasts in oropharyngeal biofilms on silicone rubber voice prostheses might be controlled by consumption of probiotic bacteria.

MR of the inner ear in patients with Cogan syndrome.

PURPOSE: To determine whether the bony and soft-tissue obliterations of the intralabyrinthine fluid spaces reported in pathologic studies of patients with Cogan syndrome can be detected with MR or CT. METHODS: The inner ears of six patients with Cogan syndrome were studied. High-resolution CT was performed in five patients; all six patients were studied with MR, including T1-weighted spin-echo images with and without gadolinium administration, T2-weighted spin-echo images, and three-dimensional Fourier transform constructive interference in steady state images. RESULTS: In two patients, small calcified obliterations were detected on CT but the three-dimensional Fourier transform constructive interference in steady state images revealed more extensive soft-tissue obliteration in five of the six patients. High signal inside the membranous labyrinth on precontrast T1-weighted images and contrast enhancement inside the membranous labyrinth on the postcontrast T1-weighted images were seen in one patient. CONCLUSIONS: The study showed that calcific obliteration and soft-tissue obliteration of the intralabyrinthine fluid spaces in patients with Cogan syndrome can be demonstrated radiologically and that soft-tissue obliteration is more frequent than calcified obliteration. MR detected the intralabyrinthine disease far more frequently than did CT. The three-dimensional Fourier transform constructive interference in steady state sequence proved to be the most sensitive MR sequence. Hyperintensity inside the membranous labyrinth on the precontrast T1-weighted images and enhancement on the contrast-enhanced T1 images were less frequent and probably represent leakage through the abnormal labyrinthine membrane from active disease.

Functional expression of human 5-HT1A receptors and differential coupling to second messengers in CHO cells.

The signal transduction linkages of the cloned human 5-HT1A receptor as expressed stably in CHO cells were studied. A transfected clonal cell line which expresses 900 +/- 36 fmol 5-HT1A receptor/mg protein (designated CHO-5-HT1A/WT-27) responded to 5-HT and/or 8-OH-DPAT by coupling to several second messenger pathways. The 5-HT1A receptor inhibited, but did not stimulate, membrane adenylyl cyclase activity and whole cell cAMP accumulation in a dose-dependent manner (for 5-HT, IC50 = 146 +/- 27 and 55 +/- 12 nM, respectively). Activation of the receptor was associated with other signal transduction linkages: (i) a 40-50% increase in hydrolysis of inositol phosphates (for 5-HT, EC50 = 1.33 +/- 0.15 microM for 5-HT), (ii) a transient elevation of cytosolic Ca2+ levels (apparent at 1-100 microM 5-HT) which was not affected by chelation of extracellular Ca2+ by EGTA, and (iii) an augmentation of [3H]-arachidonic acid release pharmacologically with the calcium ionophore A23187 or by activation of endogenous thrombin or P2 purinergic receptors (for 5-HT, EC50 = 1.22 +/- 0.17 microM). This pathway may be an amplification mechanism for signaling in anatomic regions with high concentrations of several neuro-transmitters, hormones or autacoids, such as at neuronal junctions or near areas of platelet aggregation. All linkages were sensitive to pertussis toxin pre-treatment (IC50 approximately 0.5-0.6 ng/ml x 4.5 h for all pathways), suggesting the involvement of Gi protein(s) in these signal transduction pathways. Coupling to varied signal transduction pathways in a single cell system may be a common feature of receptors which classically inhibit adenylyl cyclase such as the 5-HT1A receptor.

Clinical characteristics and diagnostic delay of head and neck cancer: results from a prospective study in Belgium.

A prospective study of head and neck cancer patients was started to gather information about topographic and clinical characteristics of head and neck cancer, alcohol and nicotine abuse and the delay in diagnosis. More than half of the patients consulted our institution with an advanced stage of disease. As was expected, we found a positive association between the size of the tumour and the clinical stage of the neck. Concerning nicotine and alcohol abuse, our results support the hypothesis that tobacco smoking is more strongly associated with lesions in sites heavily exposed to inhaled smoke, whereas alcohol consumption has a stronger effect on structures belonging to the 'food channel' and reservoir systems. We found no association between delay and tumour stage at diagnosis, but a statistically significant correlation was found between the delay and the tumour site. This leads us to conclude that the tumour stage is determined mostly by the biology of the tumour.

Dynamics of inner ear pressure release, measured with a double-barreled micropipette in the guinea pig.

The inner ear fluid pressure was measured in scala media of the guinea pig through one barrel of a double-barreled micropipette after a sudden volume increase or decrease, caused by injection or withdrawal of artificial endolymph through the other barrel. During injection or withdrawal, the inner ear pressure changed in the order of 1-10 cm water, but it returned to its initial value within a few seconds. The time constant for the pressure recovery depended on the flow direction. It was on average 1.1 s after a short overpressure and 2.8 s after underpressure. The obtained results could be fitted with a simple physical model, when it was assumed that inner ear pressure recovery is a non-linear process, governed by a pressure-dependent flow resistance and/or membrane compliance.

Measurement of the mechanical compliance of the endolymphatic compartments in the guinea pig.

During injection of artificial endolymph into scala media of the guinea pig, fluid pressure was simultaneously measured in endolymph and perilymph with micropipettes. Pressure differences in the order of 10 Pa could reproducibly be measured upon injection of 2-4 microl of artificial endolymph with a rate of 50 nl/s. Injection of larger volumes damaged the endolymphatic system. From the results, values were derived for the compliances of the membranes surrounding scala media and the vestibular part of the endolymphatic system. The shape of the pressure-time curve during and between repetitive injections of fluid could well be described with a two-component model for the endolymphatic system, consisting of two compartments with compliant walls, connected through a flow resistance. With this model, a larger compliance was found for the second compartment (vestibular part of endolymphatic system) than for the first compartment, into which fluid was injected (scala media).

Low-voltage field-emission scanning electron microscopy of non-coated guinea-pig hair cell stereocilia.

The stereociliar structures of the guinea-pig cochlear organ of Corti were studied at low-voltage (1-5 kV) with field-emission scanning electron microscope (SEM) using various pre- and post-fixation methods, such as OTOTO (OsO4/thiocrbohydrazide/OsO4/thiocarbohydrazide/OsO4) and TAO (tannic acid/arginine/OsO4), and different dissection procedures of the cochlea. A perfusion and immersion pre-fixation with glutaraldehyde, in combination with removal of the bony wall and stria vascularis from the cochlea, followed by the TAO non-coating treatment gave the best result at 2 kV acceleration voltage. Due to these new technique, several interesting delicate structures of the stereocilia, in particular fine surface structures, were detected for the first time using SEM. These findings include the different types of cross-links and tip links, i.e., the fine surface morphology of the stereocilia and their attachments and imprints in the tectorial membrane (TM). One of the most interesting findings in this study is a network of long filamentous structures, which has been identified mainly at the top of the longest stereocilia and the undersurface of the TM and which may represent the glycocalyx. These findings and their possible implications in the process of mechanoelectrical transduction will be discussed.

The effect of nimodipine on cochlear potentials and Na+/K(+)-ATPase activity in normal and hydropic cochleas of the albino guinea pig.

In experimental endolymphatic hydrops (EEH) a decrease in the endocochlear potential (EP) has been reported and is thought to be due to decreased activity of the enzyme Na+/K(+)-ATPase in the stria vascularis. By stimulating Na+/K(+)-ATPase, the EP, and thereby cochlear function as a whole, might be restored. On the other hand, stimulation of stria vascularis Na+/K(+)-ATPase might result in excessive production of endolymph and thus produce or augment hydrops. In this study we have investigated the effect of intraperitoneally applied nimodipine on cochlear potentials and on Na+/K(+)-ATPase activity in the stria vascularis, both in normal cochleas (control) and in cochleas with EEH. Nimodipine is an L-type Ca(2+)-channel blocking agent with Na+/K(+)-ATPase stimulating properties at concentrations as low as 1.5 nM. The compound action potential (CAP), evoked by 2,4 and 8 kHz tone bursts was found to be depressed in the EEH ears with and without nimodipine treatment, and in the nimodipine treated control ears. Statistical analysis (ANOVA) showed that the effects of EEH and nimodipine on the CAP were additive. The negative summating potential (SP), measured extracochlearly at the apex, in response to 4 and 8 kHz tone bursts was significantly enhanced in the EEH ears. Nimodipine treatment did not affect the SP, neither in the control, nor in the EEH ears. Cytochemically, Na+/K(+)-ATPase activity appeared to be decreased in the oedematous stria vascularis of hydropic cochleas. No effect of nimodipine on Na+/K(+)-ATPase activity could be established ultracytochemically, neither in the controls nor in the EEH ears. In the lower turns of some of the nimodipine treated control cochleas a mild hydrops was seen during light-microscopic evaluation. Although it was not possible to prove a stimulatory effect of nimodipine on the enzyme Na+/K(+)-ATPase cytochemically, the finding of mild endolymphatic hydrops in nimodipine treated control ears suggests (a history of) increased endolymph production. This hydrops might be responsible for the depression of the CAP in the nimodipine treated ears.