Chisako Masumura

Microarray analysis of gene expression in the rat vestibular nucleus complex following unilateral vestibular deafferentation

To investigate the molecular background of vestibular compensation, a model of lesion‐induced plasticity, we used a microarray analysis to examine genes that show asymmetrical expression between the bilateral vestibular nucleus complexes (VNCs) 6 h following unilateral vestibular deafferentation (UVD). Asymmetrical gene expression was then validated by a real‐time quantitative PCR. Among the 88 genes for which the ipsilateral (ipsi) : contralateral (contra) was > 1.35, the number of known genes was 33 (38%), and the number of expressed sequence tag (EST) sequences was 55 (62%). Among the 130 genes for which the contra : ipsi was > 1.35, the number of known genes was 55 (42%), and the number of EST sequences was 75 (58%). Changes in some of the genes were consistent with previous studies; however, we found several new genes which could be functionally related to the molecular basis of the electrophysiological asymmetry between the VNCs following UVD. Ipsi > contra genes included the GABAA receptor rho subunit, regulatory proteins of G protein signaling, calcium signaling related molecules such as the voltage‐dependent calcium channel α2/δ subunit 1, calcineurin subunit Aβ and Ca2+ pump. Contra > ipsi genes included the neuronal high affinity glutamate transporter, 5‐hydroxytryptamine receptor 1D, mitogen‐activated protein kinase 12 and ubiquitin carboxy‐terminal hydrolase L1.

Increased BrdU incorporation reflecting DNA repair, neuronal de-differentiation or possible neurogenesis in the adult cochlear nucleus following bilateral cochlear lesions in the rat.

Neurogenesis is known to occur in response to injury in the brain, for example, as a result of neurodegenerative diseases. However, there have been few investigations into how the brain responds to damage to peripheral sensory nerves, in other areas such as the brainstem. Here, we report that bilateral surgical lesions of the cochlea result in increased incorporation of the DNA replication marker, bromodeoxyuridine (BrdU), in cells of the brainstem cochlear nucleus (CN) of the adult rat, suggesting either cell proliferation or DNA repair. Some of the BrdU-labelled cells colabelled for the mature neuron marker, NeuN and the GABAergic enzyme GAD-65, suggesting the possibility that neurogenesis might have occurred and resulted in the generation of new neurons with a GABAergic phenotype. However, some of the mature neurons also re-expressed immature neuronal intermediate filament and microtuble-associated proteins, without apoptotic neuronal death, which suggests that the colabelling of BrdU with NeuN and GAD-65 may not be a true reflection of neurogenesis, but injury-stimulated neuronal dedifferentiation. These results suggest the possibility that DNA repair, neuronal de-differentiation or possible neurogenesis occurs in the cochlear nucleus, in response to damage to the peripheral auditory system.

Bilateral vestibular deafferentation causes deficits in a 5-choice serial reaction time task in rats.

Peripheral lesions of the vestibular system have been associated with spatial memory deficits in animals and humans; however, no study to date has investigated the effects of such lesions on attention. In this study, we used a 5-choice serial reaction time task (5-CSRTT) to determine whether rats with bilateral vestibular deafferentation (BVD) had attention deficits at 5 months post-op. compared to sham controls. We found that BVD rats took longer than sham animals to reach the designated criterion of >70% correct responses (P=0.006), they made significantly fewer correct responses (P=0.005), and significantly more incorrect responses (P=0.000), while showing no difference in omissions and premature responses and a significant decrease in perseverative responses (P=0.03). BVD rats also responded with a significantly shorter response latency, whether their response was correct (P=0.001) or incorrect (P=0.002), and obtained their reward for a correct response more quickly (P=0.000). These results suggest that rats with bilateral vestibular loss exhibit deficits on a 5-CSRTT that cannot be explained by an inability to respond and that their speed of response is altered.

Magnetic resonance imaging of pleomorphic adenoma arising from the external auditory canal

Pleomorphic adenoma arising from the external auditory canal is a very rare neoplasm, and there has been no report on magnetic resonance (MR) imaging of pleomorphic adenoma of the external auditory canal. We report here a case of 65-year-old male with this tumour, measuring 12 mm in a diameter. Histopathology was confirmed from the specimen obtained at the surgical excision. MR revealed that the tumour had a well-defined margin showing hypointensity on T1-weighted images and hyperintensity on T2-weighted images relative to the parotid gland. The tumour was well enhanced by contrast material. No invasion to the surrounding tissue was observed. These MR findings were compatible with pleomorphic adenoma of the salivary gland origin. In treating pleomorphic adenoma of the external auditory canal, complete surgical excision is essential for the prevention of recurrence. It can be concluded that MR imaging is helpful for making a differential diagnosis of external auditory canal tumours and selection of adequate treatment.

Effects of the Putative Cognitive-Enhancing Ampakine, CX717, on Attention and Object Recognition Memory

Ampakines are a class of putative nootropic drug designed to positively modulate the AMPA receptor and have been investigated as a potential treatment for cognitive disorders such as Alzheimers Disease. Nonetheless, some ampakines such as CX717 have been incompletely characterized in behavioural pharmacological studies. Therefore, in this study, we attempted to further characterize the effects of the ampakine, CX717 (20 mg/kg s.c), on the performance of rats in a 5 choice serial reaction time (5CSRTT) and object recognition memory task, using rats with cognitive deficits caused by bilateral vestibular deafferentation (BVD) as a model. In the 5CSRTT, when the stimulus duration was varied from 5 to 2 sec, the number of incorrect responses was significantly greater for the BVD group compared to sham controls, but significantly less for the CX717 groups, with no significant interaction. With changes in inter-trial interval (ITI), there was a significant effect of surgery/drug and a significant effect of ITI on premature responses, and the BVD group treated with CX717 showed significantly fewer premature responses than the other groups. In the object recognition memory task, CX717 significantly reduced total exploration time and the exploration towards the novel object in both sham and BVD animals. These results suggest that CX717 can reduce the number of incorrect responses in both sham and BVD rats and enhance inhibitory control specifically in BVD rats, in the 5CSRTT. On the other hand, CX717 produced a detrimental effect in the object recognition memory task.

Analysis of benign paroxysmal positional nystagmus in children.

INTRODUCTION Benign paroxysmal positional vertigo (BPPV) is the most common vestibular disorder. However, BPPV in children has been studied less extensively than in the adult population. This is because the observation of benign paroxysmal positional nystagmus (BPPN) in children is technically very difficult and BPPV is rare in children. In this study, we present the only two cases of BPPV in children in which we successfully recorded and analyzed the BPPN. METHODS One case was an 11-year-old boy and the other was a 3-year-old girl. We analyzed their BPPN three-dimensionally. RESULTS Apogeotropic positional nystagmus was observed in the first case. We analyzed it to verify the presence of cupulolithiasis in the horizontal semicircular canal (HSCC). Geotropic positional nystagmus was observed in the second case, and the analyzed data indicated the presence of canalolithiasis in HSCC. Over the last decade, we have examined 3341 patients complaining of vertigo or dizziness. Among them, there were 63 children with the same complaint, so that the proportion of cases of BPPV in children was only 3% (2/63). DISCUSSION Among patients complaining of vertigo or dizziness, children with BPPV are rare (3%). However, we have recorded their BPPN to confirm that BPPV does occur in children and that their characteristics of positional nystagmus are generally identical to those in adults. We emphasize that this is the first report of a child as young as 3 years old being diagnosed with BPPV.

Unilateral vestibular deafferentation-induced changes in calcium signaling-related molecules in the rat vestibular nuclear complex.

Inquiries into the neurochemical mechanisms of vestibular compensation, a model of lesion-induced neuronal plasticity, reveal the involvement of both voltage-gated Ca(2+) channels (VGCC) and intracellular Ca(2+) signaling. Indeed, our previous microarray analysis showed an up-regulation of some calcium signaling-related genes such as the alpha2 subunit of L-type calcium channels, calcineurin, and plasma membrane Ca(2+) ATPase 1 (PMCA1) in the ipsilateral vestibular nuclear complex (VNC) following unilateral vestibular deafferentation (UVD). To further elucidate the role of calcium signaling-related molecules in vestibular compensation, we used a quantitative real-time polymerase chain reaction (PCR) method to confirm the microarray results and investigated changes in expression of these molecules at various stages of compensation (6 h to 2 weeks after UVD). We also investigated the changes in gene expression during Bechterews phenomenon and the effects of a calcineurin inhibitor on vestibular compensation. Real-time PCR showed that genes for the alpha2 subunit of VGCC, PMCA2, and calcineurin were transiently up-regulated 6 h after UVD in ipsilateral VNC. A subsequent UVD, which induced Bechterews phenomenon, reproduced a complete mirror image of the changes in gene expressions of PMCA2 and calcineurin seen in the initial UVD, while the alpha2 subunit of VGCC gene had a trend to increase in VNC ipsilateral to the second lesion. Pre-treatment by FK506, a calcineurin inhibitor, decelerated the vestibular compensation in a dose-dependent manner. Although it is still uncertain whether these changes in gene expression are causally related to the molecular mechanisms of vestibular compensation, this observation suggests that after increasing the Ca(2+) influx into the ipsilateral VNC neurons via up-regulated VGCC, calcineurin may be involved in their synaptic plasticity. Conversely, an up-regulation of PMCA2, a brain-specific Ca(2+) pump, would increase an efflux of Ca(2+) from those neurons and perhaps prevent cell damage following UVD.

Vestibular function and vasopressin.

OBJECTIVE To investigate the relation between the vestibular system and vasopressin (AVP). MATERIAL AND METHODS We examined the effects of electrical and caloric vestibular stimulation on plasma AVP levels in anesthetized rats. Plasma AVP levels of patients with intractable Ménières disease who were subjected to endolymphatic drainage and steroid instillation surgery (EDSS) or intratympanic gentamicin (GM) injection were measured before and after these interventions. RESULTS Electrical vestibular stimulation increased plasma AVP levels in a current intensity-dependent manner. Plasma AVP levels were also increased by caloric stimulation with cold water. Plasma AVP levels decreased rapidly after EDSS, and were maintained at a low level even 6-12 months following EDSS or intratympanic GM injection. CONCLUSIONS Vestibular activation or inhibition-induced imbalance of intervestibular activities increased plasma AVP levels in rats. Therefore, vestibular disorder would seem to increase plasma AVP and thus worsen endolymphatic hydrops. EDSS rapidly decreased plasma AVP and would seem to reduce hydrops. Inhibition of vertigo spells by EDSS or intratympanic GM injection would reduce a possible stress response, resulting in a decrease in plasma AVP levels a long time after the treatments. This resultant decrease in AVP would beneficially inhibit the formation and/or maintenance of hydrops and thus prevent vertigo spells.

Factors relating to the vertigo control and hearing changes following intratympanic gentamicin for intractable Ménière's disease.

Objective: To look for factors relating to the vertigo control and hearing changes after intratympanic injections of gentamicin (GM). Study design: Prospective. Setting: Tertiary referral medical center. Patients: Twenty-eight patients with intractable Ménières disease. Interventions: Three intratympanic injections of GM (once per day for three consecutive days). Main Outcome Measures: Although five patients needed further GM injections or vestibular neurectomy because of poor control (Group I), 23 patients had their vertigo controlled for more than two years without further treatment (Group II). The number of vertigo spells per month, pure-tone audiometry, electrocochleography, caloric response, post-head shake nystagmus, and plasma vasopressin as a stress marker were examined. Results: Before GM injections, there was no difference in the number of vertigo spells per month between Groups I and II. However, the hearing thresholds were higher in Group I. Hearing improvement, increase in percentage of canal paresis and induction of post-head shake nystagmus were observed after GM injections only in Group II. Even in the 11 patients who showed an improvement in hearing of more than 10 dB (hearing improvement group), percentage of canal paresis was increased after GM. More, premedication plasma vasopressin levels were lower in the hearing improvement group as compared with the hearing loss/no changes group. Four of eight patients became negative for dominant negative summating potential in electrocochleography after GM injections in the hearing improvement group. Conclusion: Our data indicate that the frequency of vertigo is not a key factor in the vertigo control after GM injections, that induction of vestibular damage in the injected ear is essential for the control of vertigo and this effect is mostly pronounced in patients with milder hearing loss, and that hearing improvement is not only a consequence of good vertigo control but also affected by the stress level before treatment.

Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx

Thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx is highly unusual, with only three reported cases in the world literature. We describe the clinical presentation and radiologic findings in one patient with such rare lesions. A 46-year-old male with typical symptoms of Graves disease was found to have a mass on magnetic resonance imaging. An otolaryngologic examination revealed a nasopharyngeal mass lesion, which was endoscopically resected. The results of immunohistochemical staining for thyroid-stimulating hormone were positive. After the resection, the patients TSH was within normal limits. The clinical significance of the case and a brief literature review are presented.