Temporal bone histopathologic abnormalities associated with mitochondrial mutation T7511C.

OBJECTIVES: We previously reported a mitochondrial T7511C mutation in the tRNA gene in a Japanese family with nonsyndromic hearing loss (HL). However, the temporal bone histopathology associated with T7511C has not been reported. The aim of the present study is to report histopathologic findings of a temporal bone from a patient in the Japanese family with this mutation. STUDY DESIGN: Single case study. METHODS: A temporal bone was obtained from the right ear of a male subject with progressive HL from 5 years of age and who died at 60 years of age from cerebral infarction. The bone was embedded, sectioned, and stained with hematoxylin-eosin for light microscopic study. Graphic reconstruction of the cochlea was performed using the method described by Schuknecht to determine loss of the stria vascularis and neurosensory elements including hair cells and spiral ganglion neurons. RESULTS: The most significant histopathologic finding was severe loss of spiral ganglion cells in all turns of the cochlea. Severe loss of neuronal filaments in Rosenthal's canal was also observed. The organ of Corti showed scattered loss of inner and outer hair cells in the basal turn. Partial atrophy of the stria vascularis was observed in all turns of the cochlea. CONCLUSION: Our results suggest that severe loss of spiral ganglion cells was the main cause of sensorineural HL associated with the T7511C mutation.

Proton therapy for head and neck malignancies at Tsukuba.

PURPOSE: To evaluate the effectiveness and feasibility of proton therapy for head and neck cancers. PATIENTS AND METHODS: From 1983 to 2000, 33 patients with head and neck malignancies but no history of surgical resection were treated with 250-MeV protons with or without X-ray irradiation. This study retrospectively evaluated local control, survival, and treatment sequelae of these patients. The median total target dose using protons with or without X-rays was 76 Gy (range: 42-99 Gy) and the median proton dose per fraction 2.8 Gy (range: 1.5-6.0 Gy). RESULTS: Overall 5-year survival and local control rates were 44% and 74%, respectively. One (3%) and six patients (18%) suffered from treatment-related acute and late toxicity > grade 3 (RTOG/EORTC acute and late radiation morbidity scoring criteria). One patient with a history of radiotherapy suffered from acute toxicity > grade 3. CONCLUSION: Proton therapy appeared to offer high local control rates with few toxicities relative to conventional radiotherapy. However, late toxicity was seen in areas where large radiation doses had been given.

Chondroblastoma of the temporal base with high mitotic activity.

A 24-year-old man presented with a rare chondroblastoma of the temporal base manifesting as local pain accompanied by difficulty in opening the mouth. Gross total removal was achieved at initial surgery, but the tumor demonstrated rapid and destructive regrowth from a very small residual volume without definite histological malignant transformation. Growth activity estimated by MIB-1 staining increased spontaneously from 2.5% at the initial operation to 18.7% at recurrence. Further extensive radical tumor removal by surgeons from multiple disciplines was performed. The patient has been free of recurrence for 3 years without radiotherapy. Chondroblastoma of the temporal bone is widely accepted as a benign tumor and regrowth after gross total removal is very rare. However, some cases of chondroblastoma have potentially high mitotic activity.

Outer hair cells functionally and structurally deteriorate during reperfusion.

Transient ischemia of the cochlea was induced in 65 albino guinea pigs by pressing the labyrinthine artery, and the effects of cochlear reperfusion on cochlear potentials (endocochlear potential, compound action potential and cochlear microphonics (CM)) and structural changes in hair cells were examined. Although 15 min ischemia did not elevate the post-ischemic CM pseudo-threshold as compared with the pre-ischemic value, ischemia of 30 min or longer significantly elevated the CM pseudo-threshold. CM amplitude tended to progressively decrease during the reperfusion period in the animals subjected to 45 or 60 min ischemia. After transient ischemia, outer hair cells (OHCs) were swollen and exhibited alterations of the nucleus. Severer structural deterioration of OHCs was induced by 4 h reperfusion than ischemia itself when the ischemic period was 45 or 60 min. Perilymphatic perfusion of dimethylthiourea, a hydroxyl radical scavenger, partially ameliorated the elevation of the CM pseudo-thresholds and the structural changes of OHCs. These results indicate that cochlear reperfusion induces functional and structural deterioration of OHC probably by hydroxyl radical generation.

Nonsyndromic hearing loss caused by a mitochondrial T7511C mutation.

OBJECTIVES: The aims of the present study were to identify a mutation in a Japanese family showing nonsyndromic sensorineural hearing loss and to relate the mutation to characteristics of patients, including audiovestibular findings. STUDY DESIGN: Familial cohort study. METHODS: Mutation analysis was performed using genomic DNA extracted from blood samples. Subjects underwent audiovestibular examinations, including pure-tone audiograms, tympanometry, self-recording audiometry, acoustic reflex threshold, speech discrimination testing, evoked and distortion-product otoacoustic emissions, auditory brainstem responses, and caloric testing. RESULTS: We identified a T7511C mutation in the mitochondrial tRNA(Ser(UCN)) gene previously reported in one other family. The degree of heteroplasmy for the T7511C mutation ranged from 84% to 92%, and did not correlate with age at examination or severity of hearing loss. Extensive audiologic evaluation suggested both cochlear and retrocochlear involvement. CONCLUSION: Families with maternally transmitted nonsyndromic hearing loss should be investigated for mutations in the tRNA(Ser(UCN)) gene.

Long-term observations on the reversibility of cochlear dysfunction after transient ischemia.

To examine the reversibility of functional damage to the cochlea after transient ischemia, cochlear ischemia of 0-60 min was induced in 34 albino guinea pigs. Thresholds of auditory brainstem response (ABR) were then followed for 5 days after ischemia. Although the ABR threshold returned to almost the pre-ischemic value after 15 min ischemia, ischemia of 30 and 60 min duration induced irreversible dysfunction. Aminoguanidine, an inducible NO synthase (iNOS) inhibitor, significantly ameliorated the post-ischemic cochlear dysfunction induced by 60 min ischemia. Morphological findings of the hair cells were consistent with these functional results. These results indicate that ischemia of 30 min or longer induces irreversible damage to the cochlea and that iNOS plays injury-producing roles in this type of injury.

Does endogenous or exogenous adenosine facilitate the functional recovery of the cochlea after ischemia?

The present study was undertaken to determine whether adenosine attenuates cochlear dysfunction induced by transient ischemia. Adenosine or erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, was administered by perilymphatic perfusion to albino guinea pigs that were subjected to cochlear ischemic episodes of 30-minute duration. The threshold shift of the compound action potential (CAP) from the preischemic value was significantly reduced in the animals perfused with EHNA 1 hour after the onset of reperfusion. However, perfusion of adenosine at concentrations of 100 micromol/L to 10 mmol/L did not reduce the postischemic CAP threshold shift by either 1 hour or 4 hours after the onset of reperfusion. These results suggest that the elevation of the adenosine concentration did not exert a protective effect on the cochlear ischemia-reperfusion injury, and that the protective action of EHNA is unrelated to elevating the adenosine concentration.

Determination of prednisolone in the cochlear tissue.

Although glucocorticoids are widely used to treat inner ear diseases, glucocorticoid concentration has never been determined in the cochlear tissue. The aim of the present study was to measure the prednisolone concentration in the cochlear tissue after intravenous administration. At 0.5, 1, 2, 4 or 8 h after the injection (100 mg/kg), cochlea, hepatic and brain tissue and serum were removed, and prednisolone extracted from these samples was measured using high-performance liquid chromatography. Although prednisolone was not detected in the brain tissue, it was detected in the hepatic tissue and serum, demonstrating the peak value at 30 min after administration and a rather rapid decline with time thereafter. Prednisolone was also detected in the cochlear tissue, but the uptake and elimination patterns were entirely different from other samples. The prednisolone level in the cochlea reached the peak value 1 h after administration and gradually declined. The present study shows that the prednisolone administered is gradually transported to the cochlear tissue from blood and remains at higher concentrations than in the hepatic tissue or serum over several hours. It is highly likely that this slow elimination is closely related to the therapeutic effect of steroids in inner ear diseases.

Effect of ketamine, dextromethorphan, and MK-801 on cochlear dysfunction induced by transient ischemia.

Overstimulation of the N-methyl-D-aspartate (NMDA) glutamate receptor has been implicated as a factor in the pathogenesis of hypoxic-ischemic injury in the central nervous system. To evaluate the role played by NMDA antagonists in ischemia-reperfusion injury of the cochlea, 3 noncompetitive NMDA antagonists--ketamine, dextromethorphan, and MK-801--were administered to 53 albino guinea pigs subjected to transient ischemia of 30 minutes' duration, and the threshold shifts of the compound action potential were compared with those of nontreated animals 4 hours after the onset of recirculation. Ketamine and dextromethorphan moderately ameliorated the compound action potential threshold shifts, whereas MK-801, the most potent NMDA receptor antagonist among these 3 agents, did not show any protective effect. These results indicate that the action antagonizing the NMDA receptor has no protective effect against ischemia-reperfusion injury of the cochlea, and that ketamine and dextromethorphan act as protective agents for the cochlea via other pathways.