Heavy Metal Exposure: Molecular Pathways, Clinical Implications, and Protective Strategies.

Heavy metals are often found in soil and can contaminate drinking water, posing a serious threat to human health. Molecular pathways and curation therapies for mitigating heavy metal toxicity have been studied for a long time. Recent studies on oxidative stress and aging have shown that the molecular foundation of cellular damage caused by heavy metals, namely, apoptosis, endoplasmic reticulum stress, and mitochondrial stress, share the same pathways as those involved in cellular senescence and aging. In recent aging studies, many types of heavy metal exposures have been used in both cellular and animal aging models. Chelation therapy is a traditional treatment for heavy metal toxicity. However, recently, various antioxidants have been found to be effective in treating heavy metal-induced damage, shifting the research focus to investigating the interplay between antioxidants and heavy metals. In this review, we introduce the molecular basis of heavy metal-induced cellular damage and its relationship with aging, summarize its clinical implications, and discuss antioxidants and other agents with protective effects against heavy metal damage.

Taurine, Coenzyme Q10, and Hydrogen Water Prevents Germanium Dioxide-Induced Mitochondrial Dysfunction and Associated Sensorineural Hearing Loss in mouse.

Mitochondrial dysfunction has been implicated in numerous common diseases as well as aging and plays an important role in the pathogenesis of sensorineural hearing loss (SNHL). In the current study, we showed that supplementation with germanium dioxide (GeO2) in CBA/J mice resulted in SNHL due to the degeneration of the stria vascularis and spiral ganglion, which were associated with down-regulation of mitochondrial respiratory chain associated genes and up-regulation in apoptosis associated genes in the cochlea. Supplementation with taurine, coenzyme Q10, or hydrogen-rich water, attenuated the cochlear degeneration and associated SNHL induced by GeO2. These results suggest that daily supplements or consumption of antioxidants, such as taurine, coenzyme Q10, and hydrogen-rich water, may be a promising intervention to slow SNHL associated with mitochondrial dysfunction.

Efficacy of Mirror Biofeedback Rehabilitation on Synkinesis in Acute Stage Facial Palsy in Children.

OBJECTIVES: To evaluate the efficacy of mirror biofeedback rehabilitation for synkinesis in severe acute facial paralysis in children. METHODS: Eight pediatric patients with facial paralysis with an initial electroneurography (ENoG) value less than 10% who underwent mirror biofeedback rehabilitation (the child-rehabilitation group) were enrolled. Seven infants (under age 2 yr) who were unable to undergo rehabilitation (the infant-and-toddler control group) and adult patients (n = 13, range, 33-56 yr) who underwent rehabilitation (the adult-rehabilitation group) comprised the control groups. All the patients enrolled were baseline House-Brackmann (H-B) grade VI at onset. The patients began daily facial biofeedback rehabilitation using a mirror at the first sign of muscle contraction on the affected side and were instructed to keep their eyes symmetrically open using a mirror during mouth movements. The training was continued for 12 months after the onset of facial paralysis. The degree of oral-ocular synkinesis was evaluated by the degree of asymmetry in eye opening width during mouth movements. The synkinesis index was calculated as a percentage of the interpalpebral space width ([normal side - affected side]/normal side). Statistical analyses used non-parametric tests (the Kruskal-Wallis test and Steel-Dwass posthoc test). RESULTS: The synkinesis index was significantly lower in the child-rehabilitation group than in the infant-and-toddler control group or the adult-rehabilitation group (p < 0.001). CONCLUSION: Children who underwent mirror biofeedback rehabilitation had less synkinesis than the infant-and-toddler control group, suggesting that mirror biofeedback rehabilitation is more effective in preventing the exacerbation of synkinesis in children.

Aspiration Prevention Surgery under Local Anesthesia for Palliative Care in Patients with Head and Neck Cancer: A Report of Two Cases.

Aspiration prevention (AP) surgery may improve the quality of life (QOL) of patients with severe dysphagia. However, not all patients can endure this type of surgery under general anesthesia because of their poor status. Herein, we describe the cases of 2 patients with head and neck cancer (HNC) who underwent AP surgery for palliative care. Although both patients had tracheostomy due to severe dysphagia and respiratory impairment and frequently needed suction, they were successfully managed with AP surgery under local anesthesia. A tracheostoma was reshaped to be sufficiently large for an airway to be secured without a cannula. Their respiratory failure gradually improved, and suction frequency markedly decreased after surgery; thus, they could receive medical treatment at home. When patients with HNC under palliative care have a tracheal cannula and cannot vocalize, AP surgery under local anesthesia is an option to improve their QOL.

A new training method for velopharyngeal dysfunction: Self-inhalation for hypernasality.

OBJECTIVE: There are various methods to treat velopharyngeal dysfunction including　surgery and rehabilitation therapy. Even if a rehabilitation program is effective, the evaluation of its efficacy remains subjective. In this paper, we propose a new method of rehabilitation training for velopharyngeal dysfunction focusing on the objective peak inspiratory flow (PIF) rate. METHODS: Four patients, who were diagnosed with velopharyngeal dysfunction without cleft palate at ENT clinic of the National Hospital Organization, Tokyo Medical Center, participated in this study. All patients underwent our original rehabilitation program for velopharyngeal dysfunction, a method using the In-Check Dial, Turbohaler model. As a self-training rehabilitation program, we asked them to inhale forcefully 10 times daily at home using the In-Check Dial to increase the value of PIF rate for 3 months. We measured the patients' PIF rates with the In-Check Dial at the ENT clinic at the initial visit and after the 3-month training. RESULTS: The PIF rates of the four patients without nasal clips were higher than the rates with nasal clips at the initial visit. After the training, PIF rate without a nasal clip of all patients increased than the rate at the initial visit, which represented significant difference (P < 0.05). Also, after 3 months, PIF rate without a nasal clip was higher or equal than the rates with a nasal clip at the initial visit except one case. Naso-pharyngo-laryngeal fiberscopy did not detect salivary pooling around larynx and mirror fogging test did not show nasal escape in the three of four patients after 3 months of training. All reported improvement in dysphagia and dysarthria. CONCLUSION: This new method can be used not only to evaluate velopharyngeal function but also as an effective self-training treatment.

Noisy vestibular stimulation increases gait speed in normals and in bilateral vestibulopathy.

BACKGROUND: Galvanic vestibular stimulation delivered as zero-mean current noise (noisy GVS) has been shown to improve static and dynamic postural stability probably by enhancing vestibular information. OBJECTIVE: /Hypothesis: To examine the effect of an imperceptible level of noisy GVS on dynamic locomotion in normal subjects as well as in patients with bilateral vestibulopathy. METHODS: Walking performance of 19 healthy subjects and 12 patients with bilateral vestibulopathy at their preferred speed was examined during application of noisy GVS with an amplitude ranging from 0 to 1000 µA. The gait velocity, stride length and stride time were analyzed. RESULTS: Noisy GVS had significant effects on gait velocity, stride length and stride time in healthy subjects as well as in patients with bilateral vestibulopathy (p < 0.05). The optimal amplitude of noisy GVS improved gait velocity by 10.9 ±â€¯1.2%, stride length by 5.7 ±â€¯1.2% and stride time by 4.6 ±â€¯7% (p < 0.0001) compared to the control session in healthy subjects. The optimal stimulus improved gait velocity by 12.8 ±â€¯1.3%, stride length by 8.3 ±â€¯1.1% and stride time by 3.7 ±â€¯7% (p < 0.0001) in patients with bilateral vestibulopathy. The improved values of these parameters of locomotion by noisy GVS in the patients were not significantly different from those in healthy subjects in the control condition (p > 0.4). CONCLUSION: Noisy GVS is effective in improving gait performance in healthy subjects as well as in patients with bilateral vestibulopathy.

Intravenous olfactory test latency correlates with improvement in post-infectious olfactory dysfunction.

CONCLUSION: This cohort study showed that onset latency in the intravenous olfactory test (IVO) may help predict when olfaction in patients with post-infectious olfactory dysfunction (PIOD) improves. OBJECTIVES: To identify factors that predict the olfactory improvement period in patients with PIOD. METHODOLOGY/PRINCIPAL: All consecutive patients presenting with PIOD in 1994-2014 who were followed up for 2 years were identified retrospectively. The ability of demographic/clinical factors (age, sex, body mass index, presence/absence of allergic rhinitis, treatment/non-treatment with herbal medicines, patient dependence on herbal medicine treatment, presence/absence of diabetes mellitus, and smoking status) and olfactory test factors (response/no response and onset latency and duration in the IVO test, and detection and recognition scores on the T&T olfactory test) to predict the olfactory improvement period (defined respectively as the time from PIOD onset or olfactory testing to the first self-report of olfaction improvement) was analyzed by univariate and multivariate regression. RESULTS: Of the 187 PIOD patients, the prognostic ability of demographic/clinical factors was analyzed in 65. None predicted the olfactory improvement period. Of the 65 patients, 20 did not respond in the IVO test. In the remaining 45 patients, onset latency (but not the other olfactory test factors) was a significant prognosticator of olfactory improvement period (R2=0.24, p = 0.003).

Distinct neural mechanisms of tonal processing between musicians and non-musicians.

OBJECTIVE: Both behavioral and neural responses to deviant melody endings can be enhanced through musical training. Yet it is unknown whether there are any differences in the neural responses of musicians and non-musicians given no difference in their behavioral responses. It is also unknown whether the melody preceding the fixed final tone influences the sense of completion. METHODS: We recorded neuromagnetic responses in ten musicians and ten non-musicians while they were evaluating the sense of completion associated with melodies. RESULTS: The sense of a melody's completion was influenced by the combination of the preceding melody and the ending tones. The N1 had shorter latency in musicians, while the sustained field had larger amplitudes in non-musicians. CONCLUSIONS: Musicians and non-musicians rated the sense of completion similarly, yet neural responses differed between the groups. SIGNIFICANCE: These findings suggest that neural processes in musicians and non-musicians may be distinct even when the sense of completion is assessed similarly in both groups. In other words, there might be specific tonal processing available to non-musicians which can compensate for their lack of musical training.

The diagnostic value of vestibular evoked myogenic potentials in patients with Meniere's disease.

OBJECTIVE: To estimate the sensitivity and specificity of vestibular evoked myogenic potentials (VEMPs) in comparison with caloric test in diagnosing Meniere's disease (MD) among patients with dizziness. METHODS: Data were retrospectively collected from 1,170 consecutive patients who underwent vestibular tests. Among them, 114 patients were diagnosed as having unilateral definite MD. VEMPs in response to clicks and short tone burst stimulation as well as caloric tests were performed. The sensitivity and specificity of each test were evaluated. The results of each test were compared with hearing level and staging of MD. RESULTS: The sensitivity and specificity of VEMPs were 50.0% and 48.9%, while those of the caloric test were 37.7% and 51.2%, respectively. There was no significant difference in hearing level between patients appropriately or inappropriately identified by VEMPs, whereas there was a significant difference in those of the caloric test. Combined use of VEMP and caloric test increased the sensitivity to 65.8%. CONCLUSION: Although the sensitivity and specificity of VEMPs in diagnosing MD were not high, they were comparable to those of caloric test. VEMPs as well as caloric testing may give additional information as part of a diagnostic test battery for detecting vestibular abnormalities in MD.

Ocular vestibular evoked myogenic potentials in response to air-conducted sound and bone-conducted vibration in vestibular schwannoma.

OBJECTIVE: To clarify the origin and pathways of ocular vestibular evoked myogenic potentials (oVEMPs) to air-conducted sound (ACS), we compared the results of oVEMPs with ACS, with oVEMPs with bone-conducted vibration (BCV), cervical VEMPs (cVEMPs) with ACS, and the caloric test in patients with unilateral vestibular schwannoma (VS). STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: Forty-five patients with untreated unilateral VS. MAIN OUTCOME MEASURE: Each patient underwent vestibular tests, including oVEMPs to ACS, oVEMPs to BCV, cVEMPs to ACS, and caloric tests. The correlations among these tests were evaluated. RESULTS: Of the 45 patients recruited, 28 patients (63%) showed reduced or absent oVEMPs to ACS solely on the affected side. There were no significant differences in abnormal response ratios among oVEMPs to ACS, oVEMPs to BCV, cVEMPs to ACS, or the caloric test. The results of oVEMPs to ACS had a significant correlation with those of oVEMPs to BCV and the caloric test (p < 0.05) but not with those of cVEMPs to ACS (p > 0.05). CONCLUSION: These findings support the hypothesis that oVEMP in response to ACS are predominantly mediated by the superior vestibular nerve and probably reflect the function of the utricle.

Ocular vestibular evoked myogenic potential elicited from binaural air-conducted stimulations: clinical feasibility in patients with peripheral vestibular dysfunction.

CONCLUSION: Ocular vestibular evoked myogenic potentials (oVEMPs) to binaural air-conducted stimulation (ACS) may provide a convenient way of assessing the crossed vestibulo-ocular reflex in patients with vestibular dysfunction as well as in healthy subjects. OBJECTIVE: To investigate the clinical feasibility of using oVEMPs in response to binaural ACS to assess normal subjects and patients with vestibular dysfunction. METHODS: The study investigated 24 normal subjects (14 men and 10 women, aged from 23 to 60 years) and 14 patients with unilateral peripheral vestibular dysfunction. Each subject underwent oVEMP testing in response to monaural ACS and binaural ACS (500 Hz tone burst, 135 dBSPL). RESULTS: In normal subjects, bilateral oVEMPs were elicited in 75% of subjects in response to monaural ACS and in 91% in response to binaural ACS. Asymmetry ratios (ARs) of the responses to binaural ACS were significantly smaller than those of the responses to monaural ACS (p < 0.01). In patients with unilateral vestibular dysfunction, there were no significant differences in the amplitude, latency, or AR of the responses between monaural and binaural ACS. Approximately 30% of patients showed reduced ARs to binaural ACS relative to monaural ACS, primarily due to contamination by uncrossed responses elicited in healthy ears.

Trial of Chinese medicine Wu-Ling-San for acute low-tone hearing loss.

PURPOSE: We used new criteria to elucidate the demographics of acute low-tone sensorineural hearing loss (ALHL) and tested the Chinese medicine Wu-Ling-San as a treatment for ALHL. PROCEDURES: We reviewed the medical records of patients with ALHL seen at the outpatient clinic of the Social Insurance Central General Hospital in Tokyo from April 2006 through August 2011. Patients were treated with an oral steroid, a diuretic, or Wu-Ling-San; alone or in combination. RESULTS: We identified 130 definite and 48 probable ALHL cases. The mean age and male-to-female ratio in probable cases were significantly higher than those in definite cases (p < 0.05). The steroid-Wu-Ling-San combination was significantly more effective (100% recovery) than the diuretic alone (59%), Wu-Ling-San alone (62%), or the steroid-diuretic combination (60%, p < 0.05). CONCLUSIONS: ALHL can develop in older patients more frequently than we expected. The steroid-Wu-Ling-San combination is a possible new treatment for ALHL.

The mitochondrial A3243G mutation involves the peripheral vestibule as well as the cochlea.

OBJECTIVES/HYPOTHESIS: To evaluate vestibular function in patients with the mitochondrial A3243G mutation. STUDY DESIGN: Data from patients with the A3243G mutation attending an academic tertiary referral center were prospectively recorded. METHODS: The clinical histories of 13 unrelated patients with the mitochondrial A3243G mutation (six mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; and seven maternally inherited diabetes and deafness) were recorded, in particular their history of vestibular symptoms. Vestibular examinations including caloric testing and vestibular evoked myogenic potentials in response to air-conducted sound (ACS-VEMPs) were performed. In seven patients who showed abnormal ACS-VEMP, VEMP in response to galvanic stimuli (galvanic-VEMP) were also recorded. RESULTS: Eleven of the 13 patients had vestibular symptoms. The age of onset of vestibular symptoms was significantly later than the ages of onset of hearing loss and diabetes mellitus (P < .05). Ten of the 13 patients showed abnormal caloric responses, whereas 12 patients showed abnormal ACS-VEMPs on one or both sides. All of the seven patients who underwent galvanic-VEMP testing showed normal responses. CONCLUSIONS: The A3243G mutation is associated with vestibular dysfunction involving both the superior and inferior vestibular nerve systems. Furthermore, our results from galvanic-VEMP testing suggests that a labyrinthine lesion is primarily responsible for the symptoms of vestibular dysfunction.

Frequency tuning properties of ocular vestibular evoked myogenic potentials.

Loud air-conducted sound or bone-conducted vibration produces vestibular-dependent electromyographic responses both in the cervical muscles (cervical vestibular evoked myogenic potentials) and in the extraocular muscles (ocular vestibular evoked myogenic potentials; oVEMPs). Although previous frequency tuning measurements of cervical vestibular evoked myogenic potentials have provided important information for a clinical application, those of oVEMPs have rarely been studied. We explored the frequency tuning properties of oVEMPs in 12 healthy participants. Our results indicate that the best frequencies of the oVEMPs to air-conducted sound and bone-conducted vibration are 500 and 250 Hz, respectively. The difference in the best frequencies between the two stimuli may originate from the difference in the end organs (saccule or utricle), preferentially activated by each stimulus.

Effect of vitamin C depletion on age-related hearing loss in SMP30/GNL knockout mice.

Using senescence marker protein 30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize vitamin C (VC), we examined whether modulating VC level affects age-related hearing loss (AHL). KO and wild-type (WT) C57BL/6 mice were given water containing 1.5 g/L VC [VC(+)] or 37.5mg/L VC [VC(-)]. At 10 months of age, KO VC(-) mice showed significant reduction in VC level in the inner ear, plasma, and liver, increase in auditory brainstem response (ABR) thresholds, and decrease in the number of spiral ganglion cells compared to WT VC(-), WT VC(+), and KO VC(+) mice. There were no differences in VC level in the inner ear, ABR thresholds, or the number of spiral ganglion cells among WT VC(-), WT VC(+), and KO VC(+) mice. These findings suggest that VC depletion can accelerate AHL but that supplementing VC may not increase VC level in the inner ear or slow AHL in mice.

Novel subtype of idiopathic bilateral vestibulopathy: bilateral absence of vestibular evoked myogenic potentials in the presence of normal caloric responses.

To characterize clinical features of those patients who showed an absence of vestibular evoked myogenic potential (VEMP) responses in the presence of normal caloric responses bilaterally, we reviewed clinical records of 1,887 consecutive outpatients who complained of balance problems, and identified three patients, who showed absent VEMPs in the presence of normal caloric responses bilaterally with unknown causes. All three patients had episodes of recurrent vertigo without spontaneous, gaze-evoked, or positional nystagmus at the time of examination. They complained of oscillopsia while moving their body or head and showed positive Romberg's signs. Drawing on these cases, we underscore the importance of examining the function of the inferior vestibular nerve system, even with no nystagmus and normal caloric findings, in patients complaining of dizziness or oscillopsia during locomotion.

N1 component reflects difference of terminal chords in three-chord sequences.

We understand from experience that musical contexts are formed when chords are combined according to the rules of harmony. In this study, the N1 component of the auditory-evoked potential was measured using comparable three-chord sequences; these sequences were constructed as a consecutive task (cf. C-C-C vs. Cm-Cm-Cm; control) and a cadence task (cf. C-G-C vs. C-G-Cm). In the cadence task, compared with cadences ending with a major chord (anticipated chord), those ending with a minor chord (unanticipated chord) showed a significantly larger amplitude of N1 waves. These components of auditory-evoked potentials reflect the effect of chord progression in musical perception and suggest that the musical context is recognized at least 100 ms after a chord is played.

Ocular vestibular-evoked myogenic potentials (oVEMPs) require extraocular muscles but not facial or cochlear nerve activity.

OBJECTIVES: Cervical vestibular evoked myogenic potentials (cVEMPs) have been found to be useful for clinical testing of vestibular function. Recently, investigators showed that short-latency, initially negative surface EMG potentials can be recorded around the extraocular muscles (oVEMPs) in response to air-conducted sound (ACS), bone-conducted vibration (BCV), and head taps. Although these evoked potentials, which are located around the eyes, most likely originate primarily from the otolith-ocular pathway, the possibility of contamination by other nerve activities cannot be completely eliminated. The purpose of the present study was to clarify the origin of oVEMPs by examining these possibilities using clinical findings. METHODS: Twelve healthy subjects and 15 patients were enrolled. Of the 15 patients, 3 patients had undergone exenteration of the unilateral intraorbital contents, one had undergone exenteration of the right eyeball with preservation of extraocular muscles, 5 had facial palsy, and 6 had profound hearing loss. ACS and/or BCV were used in these subjects. RESULTS: Exenteration of the unilateral intraorbital contents resulted in absence of myogenic potentials on the affected side. On the other hand, exenteration of the eyeball with preservation of extraocular muscles did not have a major impact on the responses. There were no significant differences in the waveforms between healthy subjects and patients with facial palsy or profound hearing loss. CONCLUSIONS: The results suggested that short-latency, initially negative evoked potentials recorded below the eyes are not affected by cochlear or facial nerve activities and are dependent on the presence of extraocular muscles. SIGNIFICANCE: This study provides the evidence that oVEMPs originate from exraocular muscles activated through the vestibulo-ocular pathway.

Vestibular evoked myogenic potentials evoked by multichannel cochlear implant - influence of C levels.

CONCLUSIONS: This study showed that vestibular evoked myogenic potentials (VEMPs) evoked by cochlear implant (CI), could be related to the comfortable level (C level), particularly in the channels that are closer to the apical turn of the cochlea. OBJECTIVE: The purpose of this study was to investigate the correlation between VEMPs and C level of each channel. SUBJECTS AND METHODS: We investigated 24 children who underwent cochlear implantation. VEMPs were recorded from the operated ears with the CI switched 'off' or 'on'. To investigate the correlation between VEMPs and C level, we selected 13 patients with Nucleus 24 (SPrint), and divided them into group A (normal VEMPs) and B (absence of VEMPs). In these children, all the 22 electrodes were active, and were mapped in the same frequency range for each channel. RESULTS: Twenty children (83%) showed no VEMPs with the CI 'off'. Among them, 10 elicited VEMPs with the CI 'on', but the other 10 did not. In all channels, the mean C levels of CI were higher in group A than in group B. The p values in channels 1-12 were >0.10, in channels 13-16 were 0.06-0.09, and in channels 17-22 were 0.05-0.06, which were lower but not statistically significant.

Latency variation of auditory N1m responses to vocal and nonvocal sounds.

To investigate the temporal aspect of timbre processing, we recorded auditory-evoked neuromagnetic responses to periodic complex sounds, which were matched in all acoustic parameters except for two fundamental frequencies (F0s) and 12 spectral envelopes of vocal and nonvocal categories. Only for nonvocal sounds, a significant difference in N1m latency for F0 was detected in both hemispheres. A significant difference among stimuli was detected in both hemispheres for vocal and linear sounds, whereas only in the right hemisphere for instrumental sounds. Moreover, the results of paired comparison among F0s revealed that not only the vocal sounds but also some of the nonvocal sounds were F0-independent. This latency independence may be attributed to the relatively high power in the higher frequency spectrum.