Autologous replacement of the vocal fold: a new surgical approach for adduction-type spasmodic dysphonia

Many surgical approaches have been developed for the treatment of adduction-type spasmodic dysphonia (SPD). We developed and performed a new type of surgical approach (autologous replacement of the vocal fold). Our new surgical technique increases the advantages and decreases the disadvantages of previous surgical procedures in three ways: (1) It has similar effects to the previous procedures in that it prevents contraction of the thyroarytenoid muscle. (2) It decreases vocal-fold tension, as in framework surgery. (3) It reduces glottal incompetence, as does fibrinogen-glue injection, but it is more suitable because it is autologous. Furthermore, it produces increases in the mass and volume of the vocal-fold body and is also safe because the replacement tissue is autologous. The short-term results appear encouraging in preventing spastic voice while also avoiding vocal-fold atrophy. Long-term follow up will be necessary to determine the actual efficacy. However, this is clearly a possible choice as a surgical approach for treating adduction-type SPD.     

Time-intensity trading in bilateral congenital aural atresia patients

In an effort to examine the rules by which information of bilaterally applied bone-conducted signals arising from interaural time differences (ITD) and interaural intensity differences (IID) is combined, data were measured for continuous 500 Hz narrow band noise at 65-70 dB HL in 11 patients with bilateral congenital aural atresia. Time-intensity trading functions were obtained by shifting the sound image towards one side using ITD, and shifting back to a centered sound image by varying the IID in the same ear (auditory midline task). ITD values were varied from -600 to +600 micros at 200 micros steps, where negative values indicate delays to the right ear. The results indicate that time-intensity trading is present in patients with bilateral aural atresia. The gross response properties of time-intensity trading in response to bone-conducted signals were comparable in patients with bilateral aural atresia and normal-hearing subjects, though there was a larger inter-subject variability and higher discrimination thresholds across IIDs in the atresia group. These results suggest that the mature auditory brainstem has a potential to employ binaural cues later in life, although to a restricted degree. A binaural fitting of a bone-conducted hearing aid might optimize binaural hearing and improve sound lateralization, and we recommend now systematically bilateral fitting in aural atresia patients.     

Perceptual categorization of sound spectral envelopes reflected in auditory-evoked N1m

Magnetic responses to periodic complex sounds with equivalent acoustic parameters except for two different fundamental frequencies (F0) and 12 different spectral envelopes of vocal, instrumental, and linear shapes were recorded to determine the cortical representation of timbre categorization in humans. Responses at approximately 100 ms (N1m) to vocal and instrumental (nonlinear) sounds were localized significantly anterior to linear sound responses. N1m source strength for nonlinear sounds was significantly larger than that for linear sounds, and this difference was more marked in the left hemisphere than in the right. N1m peak latency only for vocal sounds was not affected by F0. Perceptual categorization was reflected in N1m source strength and location (linear or nonlinear), and in N1m latency (vocal or nonvocal).     

Serofendic acid promotes survival of auditory hair cells and neurons of mice

Serofendic acid is a newly discovered neuroprotective substance derived from fetal calf serum. It has previously been shown to protect cortical neurons from the cytotoxicity of nitric oxide, glutamate and oxygen species. In the present study, we examined the protective effects of serofendic acid on auditory hair cells exposed to aminoglycoside toxicity using explant cultures of mouse auditory epithelia. We also determined the effect of serofendic acid on auditory neurons experiencing neurotrophin deprivation using primary cultures of mouse spiral ganglion neurons. Supplementation with serofendic acid significantly promoted the survival of auditory hair cells and neurons, and its protective effects were stronger than those of the caspase inhibitor z-VAD-fmk. These findings demonstrate the great potential of serofendic acid for protection of the auditory system.     

Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN), and it has been suggested that dopamine is one of the main endogenous toxins in the genesis of PD. We demonstrated that thiol antioxidants (the reduced form of glutathione, N-acetyl-L-cysteine, and L-cysteine), which conjugate with one dopamine oxidation intermediate, o-quinone, provided almost complete protection from dopamine-mediated toxicity in SH-SY5Y, a human neuroblastoma cell line. In contrast, catalase partially provided protection against cell death caused by dopamine. These data suggest that the generation of dopamine oxidation intermediates, rather than hydrogen peroxide, plays a pivotal role in dopamine-induced toxicity. Iron accumulated in the SN of patients with PD can cause dopaminergic neuronal degeneration by enhancing oxidative stress. However, we found that iron reduced the total amounts of dopamine oxidation intermediates and enhanced the formation of melanin, a final product of dopamine oxidation. Also, addition of iron inhibited dopamine-induced cytotoxicity. These results suggest that iron can provide protection when it accelerates the conversion of dopamine oxidation intermediates.     

Muscle oxygenation of the paralyzed lower limb in spinal cord-injured persons

PURPOSE: Even in the paralyzed lower limb muscle, EMG activity can be induced by imposing passive leg movement in standing posture in persons with spinal cord injury (SCI). The purpose of the present study was to ascertain whether the oxygenation level of the paralyzed lower limb muscle covaried with the muscle EMG activity during imposed passive leg movement. METHODS: Six motor-complete SCI subjects and four neurologically normal controls were placed on a gait-training apparatus that enabled the SCI subjects to stand and move their legs passively. After a 1-min resting stage, consecutive passive alternate leg movements were performed at different frequencies (0.8, 1, 1.2, and 1 Hz, for 3 min at each stage). To obtain postexercise data, subjects were kept in a standing posture for 5 min after passive movement ceased. The EMG activity and concentration changes in the oxygenated (oxy-) and deoxygenated hemoglobin (Hb) (deoxy-Hb) were continuously measured using near-infrared spectroscopy (NIRS) from the gastrocnemius muscle. RESULTS: In all SCI subjects, muscle EMG activity was observed during passive leg movement. The oxy-Hb level gradually increased, whereas the deoxy-Hb decreased, and these changes were independent of the total Hb changes. In the recovery stage, the total Hb level was found to exceed the preexercise level. In contrast to the SCI patients, the normal subjects showed neither EMG activity nor changes in oxy- or deoxy-Hb. CONCLUSION: The present results demonstrate that passive leg movement can induce not only muscular activity but also alteration of muscle oxygenation level in the paralyzed lower leg. Particularly, induced muscular activity seems to correlate with increased perfusion of the muscle.     

Actions of subtype-specific purinergic ligands on rat spiral ganglion neurons

In a previous study we showed that, in rat spiral ganglion neurons (SGNs), the adenosine 5'-triphosphate (ATP)-evoked currents were a combination of the activation of ionotropic receptors (the first fast current) and the activation of metabotropic receptors which secondarily opened non-selective cation channels. These two conductances imply the involvement of different receptor subtypes. In the present study, we tested three subtype-specific purinergic ligands: alpha,beta-methylene ATP (a;pha,beta-meATP) for P2X receptors, uridine 5'-triphosphate (UTP) for P2Y receptors and 2'-3'-O-(4-benzoylbenzoyl) ATP (Bz-ATP) for P2Z (P2X(7)) receptors. Application of 100 microM alpha,beta-meATP did not trigger any significant change in membrane conductance, while the SGNs were responsive to ATP. Pressure application of UTP (100 microM, 1 s) evoked an inward current averaging 344+/-169 pA at a holding potential of -50 mV. The conductance developed after a latency averaging 1.5+/-0.6 s, took 4-6 s to peak and reversed slowly within 15-30 s. The current-voltage curve reversed near 0 mV, suggesting a non-selective cation conductance, like the second component of the ATP conductance. Bz-ATP evoked an inward current which developed without latency, was sustained during ligand application and was rapidly inactivated at the end of application: the same characteristics as the first component of the ATP-evoked current. The Bz-ATP conductance reversed around -10 mV, indicating also a non-selective cation conductance. These results suggest that, in SGNs, ATP acts via two different receptor subtypes, ionotropic P2Z receptors and metabotropic P2Y receptors, and that these two receptor subtypes can assume different physiological roles.     

Cortical activation shortly after cochlear implantation

We evaluated the cortical activations in postlingually deaf cochlear implant (CI) users in the early period (0-2 months) of CI usage. The subjects were 8 early CI users and 8 normal subjects. With tone burst stimuli (1 kHz) delivered to the right side, strong and broad activation of the ipsilateral (right) primary auditory cortex with 2 peaks and weaker activation of the contralateral (left) temporal lobe were observed in early CI users, in a clear contrast with the normal subjects in whom activation was observed in a small area of the contralateral (left) primary cortex. With word stimuli, activation of the superior frontomedian cortex presumably including the supplementary motor area and the neighboring cingulate gyri was observed in early CI users, which was absent in normal subjects. The activation in the immediate association cortices near the primary area was lower in early CI users, while the periphery of the association cortex seemed to be more mobilized.     

4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2H-pyran-4-carboxamide, an orally active inhibitor of 5-lipoxygenase with improved pharmacokinetic and toxicology characteristics

Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When 1 was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED(50) = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.