Toshifumi Sakata

A 'neural' response with 3-ms latency evoked by loud sound in profoundly deaf patients.

A large negative deflection with a latency of 3 ms was observed in the auditory brainstem response (ABR) waveforms of some patients with peripheral profound deafness. This deflection was termed the N3 potential. In this paper, we review patients with the N3 potential and discuss the characteristics of abnomral ABR waveforms. The origin of the N3 potential was also discussed, especially with respect to vestibular evoked potentials. In most of the patients, audiograms showed no response to the maximum output of an audiometer in the high-frequency range and a residual response in the low-frequency range. The N3 potentials were noted at intensities of 80 dB nHL or greater. As the stimulus intensity increased, the amplitude of the potential increased and the latency decreased. A high repetition rate (83.3/s) of the click stimulus influenced the latency and amplitude of the N3 potential. The potential was replicated on retest within less than a month, and had a consistent latency and amplitude over the scalp. The results indicate that the N3 potential is not an electrical artifact but a physiological neural response evoked by a loud sound. The N3 potential is most likely not an auditory evoked response from cochlear or a response from a semicircular canal, because it has a 3-ms latency, a sharp waveform, and is unassociated with vertigo. The results suggest that the N3 potential may be a saccular acoustic response.

Feeling of ear fullness in acute sensorineural hearing loss

Conclusions. This study revealed two characteristic findings of the feeling of ear fullness (FEF) in acute sensorineural hearing loss (ASNHL). First, that the appearance of FEF was not associated with the auditory function on audiograms; and second, that the disappearance of FEF is clearly associated with the hearing prognosis. Objective. FEF appears frequently in patients with ASNHL. However, there are few reports on this symptom and its mechanism has yet to be clarified. So we tried to investigate the character of FEF in ASNHL. Patients and methods. In this study, observations were made during the period from the first medical examination to 2 months after obtaining a steady audiogram on 227 ears from unilateral ASNHL cases, and the relationship between FEF and the audiograms was analyzed. Results. The FEF prevalence at the first medical examination was about 80% for any audiogram shape or hearing threshold. Moreover, the better the hearing prognosis, the higher the improvement rate of FEF.

A comparison between the feeling of ear fullness and tinnitus in acute sensorineural hearing loss

The feeling of ear fullness (FEF) occurs frequently in patients with acute sensorineural hearing loss; the same is true for tinnitus (TIN). However, the cause of FEF in these patients is unclear. This study included 171 ears of patients admitted with unilateral sudden deafness to the ENT division of Fukuoka University Hospital between January 2001 and December 2004. The results showed TIN was mainly associated with worse high-frequency hearing thresholds, where hearing loss was relatively severe, and this association became stronger after the hearing threshold stabilized. FEF was associated with the low-frequency region, where hearing loss was relatively mild, and this association disappeared after the hearing threshold stabilized. In conclusion, TIN is thought to originate in the region where hair cells are impaired; in contrast, FEF may originate from some functional factor rather than an organic lesion of the cochlea.

Advantage of early induction of opioid to control pain induced by irradiation in head and neck cancer patients

OBJECTIVE Although radiotherapy is effective for head and neck cancer patients, the local pain evoked by the irradiation itself reduces food intake and frequently halts the treatment. Thus, pain control is an important problem in radiotherapy for head and neck cancer. We performed to examine whether early induction of low-dose, opioid from mild pain improves dietary and caloric intake, while reducing weight loss. METHODS The subjects were 43 patients who were hospitalized for head and neck cancer from 2004 to 2008. They were patients who underwent radiation treatment but those who did not undergo preoperative treatment. They were divided into two groups, depending on whether the pain was mild or moderate when an opioid was introduced (MILD and MODERATE, N=23 and 20, respectively). RESULTS The visual analog scale scores for pain were significantly lower in the MILD than in the MODERATE group at between 25 and 50 Gy. The amount of oxycodone used for pain was significantly lower in the MILD than the MODERATE group. A regular diet was maintained for significantly longer in the MILD group. Caloric intake was significantly higher in the MILD group at over 20 Gy. Weight loss was significantly lower in the MILD group at over 20 Gy. The incidence of side effects was equal in both groups. CONCLUSION Our results indicated that the introduction of opioids for mild pain during radiotherapy controls the level of pain, improving food intake in head and neck cancer patients.

Air pressure-sensing ability of the middle ear-Investigation of sensing regions and appropriate measurement conditions

OBJECTIVE To study the association between ear diseases and the ability of the middle ear to sense air pressure changes, we elucidated the appropriate conditions for measurements and confirmed the pressure-sensing regions while quantitatively assessing the pressure-sensing ability of normal ears and of ears with traumatic perforation of the tympanic membrane. METHODS In 318 normal ears (159 volunteers), an air pressure of 40daPas(-1) was loaded on to the external auditory canals to measure the minimum pressure sensed by subjects as a result of air pressure changes. The minimum pressure was defined as the minimum sensory threshold for air pressure loading (MSTAP; daPa). In 40 of 318 normal ears (20 volunteers), the MSTAP was measured at 10daPas(-1). Next, topical anesthesia was administered to 5 normal ears (5 volunteers), and the MSTAP was measured. In 7 ears with traumatic tympanic membrane perforation (7 cases), the MSTAP was also measured at the first medical examination. The data were analyzed using Stat View 5.0 (SAS Institute Inc., Cary, NC, USA). To test the significance of the data, the Mann-Whitney U-test and the Wilcoxon test were used. RESULTS The mean (+/-S.D.) MSTAP at 40daPas(-1) was -39.2+/-12.2daPa with negative pressure and 39.5+/-12.4daPa with positive pressure. At 10daPas(-1), the MSTAP was -70.3+/-25.0daPa with negative pressure and 72.5+/-22.7daPa with positive pressure, and both the mean and S.D. values were higher than those obtained at 40daPas(-1). Briefly, the MSTAP at 40daPas(-1) produced less variance than that at 10daPas(-1). The MSTAP demonstrated gender- and age-related variations. Moreover, it increased after topical anesthesia was administered to the tympanic membrane. The MSTAP in patients with traumatic tympanic membrane perforation was -205.0+/-26.3daPa with negative pressure and 206.0+/-26.7daPa with positive pressure, and was significantly higher than that observed in case of normal ears. CONCLUSION For obtaining accurate measurements while estimating the pressure-sensing ability of the middle ear, the rate of pressure loading should be considered. Although we assume that the middle ear has pressure-sensing regions other than the tympanic membrane, we conclude that the tympanic membrane is the most sensitive pressure-sensing region in the middle ear.

Acute idiopathic sensorineural hearing impairment at frequency exceeding 8 kHz

Abstract Conclusions: Acute idiopathic sensorineural hearing impairment at a frequency exceeding 8 kHz (high-frequency range) was recognized in patients suffering from acute tinnitus without hearing loss. The cases in this study may contribute to clarifying the pathogenesis of tinnitus without hearing loss and evaluating its response to steroid therapy. Objectives: The aim of this study was to demonstrate the existence of acute idiopathic sensorineural hearing impairment only in the high-frequency range and to investigate its relation to tinnitus without hearing loss. Methods: Five patients aged 29 years or younger who consulted a hospital within a few days after the onset of unilateral tinnitus without hearing loss were studied. We conducted audiometry involving the high-frequency range on first medical examination and on improvement in tinnitus, and investigated the association between the hearing findings in the high-frequency range and a tinnitus prognosis. Results: All five patients showed abnormalities in the threshold in the high-frequency range on the affected side. In the three cases given prednisolone, tinnitus and the threshold abnormalities were reduced within 20 days. In contrast, tinnitus and the threshold abnormalities showed little change in two patients who were not treated.

C-myc and its Main Ubiquitin Ligase, Fbxw7, Influence Cell Proliferation and Prognosis in Adult T-cell Leukemia/lymphoma

Smoldering-type and chronic-type adult T-cell leukemia/lymphomas (ATLL) patients have relatively indolent clinical courses, but often progress into aggressive lymphoma-type and acute-type disease. We examined the roles of transcription factor C-MYC and its ubiquitin ligase FBXW7 in tumor tissues from 137 patients with ATLL. Immunohistochemical tests showed ≥50% of lymphoma cells in 78.7% (48/61) of lymphoma-type, and 64.9% (24/37) of acute-type samples expressed C-MYC, significantly higher than was seen in smoldering-type (3.6%) and chronic-type (9.1%) samples (P<0.01). Real-time polymerase chain reaction showed C-MYC mRNA expression in lymphoma-type and acute-type samples were significantly higher than in smoldering-type (P<0.01). C-MYC expression was highly correlated with its mRNA levels (&rgr;=0.65, P<0.0001), chromosomal amplification and duplication (&rgr;=0.3, P=0.045) and MIB1 labeling index (&rgr;=0.69, P<0.0001). Expression of FBXW7 protein and mRNA in lymphoma-type samples were significantly lower than those of smoldering-type (P<0.01 for each), and both were inversely correlated with C-MYC (protein: &rgr;=−0.4, P=0.0002; mRNA: &rgr;=−0.31, P=0.015). Seven patients with smoldering-type or chronic-type ATLL converted to acute-type, in 4 of whom C-MYC expression increased from <50% to ≥50%. Patients with ≥50% C-MYC or MIB1 had significantly worse prognosis than those with <50% C-MYC (P=0.0004) or MIB1 (P<0.0001), as did those with ≥7.5 C-MYC mRNA scores (P=0.033); whereas significantly better prognosis was associated with ≥50% FBXW7 protein (P=0.0006) or ≥0.17 FBXW7 mRNA (P=0.016). C-MYC and FBXW7 affect ATLL proliferation and progression, and low FBXW7 may increase C-MYC expression. C-MYC was a critical prognostic factor in ATLL patients.

ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line

Excess production of reactive oxygen species (ROS) is known to cause apoptotic cell death. However, the molecular mechanisms whereby ROS induce apoptosis remain elusive. Here we show that the NHL-repeat-containing protein 2 (NHLRC2) thioredoxin-like domain protein is cleaved by caspase-8 in ROS-induced apoptosis in the HCT116 human colon cancer cell line. Treatment of HCT116 cells with the oxidant tert-butyl hydroperoxide (tBHP) induced apoptosis and reduced NHLRC2 protein levels, whereas pretreatment with the antioxidant N-acetyl-l-cysteine prevented apoptosis and the decrease in NHLRC2 protein levels seen in tBHP-treated cells. Furthermore, the ROS-induced decrease in NHLRC2 protein levels was relieved by the caspase inhibitor z-VAD-fmk. We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase-8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and CRISPR-Cas9-mediated loss of NHLRC2 resulted in an increased susceptibility of HCT116 cells to ROS-induced apoptosis. These results suggest that excess ROS production causes a caspase-8-mediated decrease in NHLRC2 protein levels, leading to apoptotic cell death in colon cancer cells, and indicate an important role of NHLRC2 in the regulation of ROS-induced apoptosis.

Modulation of somatosensory abilities and the feeling of ear fullness in patients with acute sensorineural hearing loss

OBJECTIVE Patients with acute sensorineural hearing loss (ASNHL) often complain of a feeling of ear fullness (FEF) that is similar to the sensation experienced during barometric pressure changes. This suggests that modulation of somatosensory abilities may relate to the manifestation of FEF, whereas it cannot simply be assumed that somatosensory abilities would be directly affected by ASNHL. To examine this possible relationship, we estimated somatosensory abilities of the tympanic membrane, and investigated the relationship between them and the manifestation of FEF. METHODS To estimate somatosensory abilities of the tympanic membrane, 83 new patients demonstrating unilateral sudden deafness were studied. The air pressure was loaded through an exclusive device on the external auditory canals in order to measure the minimum change in air pressure sensed by the subjects. The minimum pressure was defined as the minimum sensory threshold for air pressure loading (MSTAP; daPa). We estimated patients somatosensory abilities and inquired about their experiences with FEF at the first medical examination (point 1) and at the time a steady audiogram was obtained (point 2). We also estimated MSTAP in 65 volunteers (130 ears) with no history of ear diseases and compared their MSTAP with that of sudden deafness patients. RESULTS MSTAP values (-64.0±32.2daPa, 60.5±26.0daPa) on the affected side with both negative pressure and positive pressure measured at point 1 were significantly higher than those (-40.7±15.0daPa, 40.0±12.7daPa) obtained at point 2 in all sudden deafness patients (p=0.0001, p=0.0001). There was no difference between MSTAP values (-39.6±10.7daPa, 39.9±11.4daPa) in normal subjects and those obtained at point 2 in all sudden deafness patients. On the other hand, significant differences of MSTAP with negative pressures between the affected and unaffected sides at point 1 were seen in 32 patients, and manifestation of FEF showed an insignificant association in these 32 patients (p<0.05). CONCLUSION Modulation of somatosensory abilities in ASNHL seemed to be the best possible explanation for results, suggesting that a rise in MSTAP may somehow be associated with FEF. Although it cannot be verified by result of the current study, consideration of the previous literature suggests that the phenomenon may be caused by cross-modality of hearing and somatosensory abilities.

Poorly Differentiated Clusters Predict a Poor Prognosis for External Auditory Canal Carcinoma

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare and offers a poor prognosis; more accurate prognostic biomarkers are required. Our laboratory recently demonstrated that tumor budding, characterized by tumor cell clusters (< 5 cells), and laminin 5-γ2 staining of SCC of the EAC are associated with shorter survival. However, clusters composed of ≥ 5 tumor cells are also found in the stroma. Previous reports of colorectal cancer suggest that poorly differentiated clusters (PDCs) are a negative prognostic indicator. Here, we report on the association between PDCs and prognosis in SCC of the EAC. PDCs and tumor budding were histopathologically and immunohistochemically (cytokeratin AE1/AE3) analyzed in 31 cases of pre-treatment biopsy SCC of the EAC. Clusters in the stroma composed of < or ≥ 5 cancer cells were defined as tumor budding or PDCs, respectively. Entire tumors were initially scanned to identify greatest PDC density. Tumors with low or high PDC density were classified as low- and high-grade, respectively. Patients with high-grade PDCs had a significantly poorer outcome than those with low-grade. Even in cases of low-grade tumor budding, those with high-grade PDCs had a poor prognosis. Multivariate analysis results indicated that high-grade PDCs were associated with poor prognosis. PDC grade can provide a more accurate prognosis than tumor budding in SCC of the EAC.