Changes in electrovestibular brainstem responses after aminoglycoside intoxication in guinea pigs.

OBJECTIVE: To verify the usefulness of short-latency vestibular responses evoked by a combination of round window electrical stimulation and sinusoidal rotation (electrovestibular brainstem responses; EVBRs) as a new monitoring tool of the vestibular function in animal experiments. METHODS: EVBRs were obtained before, during, and after treatment with aminoglycosides, along with compound action potential (CAP) audiograms. The changes in EVBRs were compared with morphological changes observed by scanning electron microscopy. RESULTS: EVBR amplitudes did not change in the group of guinea pigs treated with amikacin, but markedly decreased in the streptomycin and gentamicin- treated groups. CAP audiograms indicated a significant threshold elevation in the amikacin group, a moderate elevation in the gentamicin group, and no change in the streptomycin group. Under scanning electron microscopy, the loss of the sensory hair cells observed in the cristae ampullares was slight to moderate in the amikacin group, moderate to severe in the streptomycin group, and severe in the gentamicin group. CONCLUSION: EVBRs reflect overall pathological changes undergone by vestibular hair cells, and support the vestibular specificity of EVBRs.

Gentamicin blocks ACh-evoked K+ current in guinea-pig outer hair cells by impairing Ca2+ entry at the cholinergic receptor.

Aminoglycoside antibiotics such as gentamicin are known to block the medial olivocochlear efferent system. In order to determine whether this inhibition takes place at the postsynaptic cholinergic receptors in outer hair cells (OHCs), we studied the effects of these polycationic molecules on cholinergic currents evoked in isolated guinea-pig OHCs. The cholinergic response of OHCs involves nicotinic-like receptors (nAChRs) permeable to Ca2+ ions that activate nearby Ca2+-sensitive K+ channels (KCa(ACh) channels). The extracellular application of gentamicin and neomycin reversibly blocked ACh-evoked K+ current (IK(ACh)) with IC50 values of 5.5 and 3.2 microM, respectively. The results showed that the blocking mechanism of IK(ACh) was due to inhibition of Ca2+ influx via nAChRs. Our study also provides interesting insights into the functional coupling between nAChRs and KCa(ACh) channels in OHCs. By directly recording the cation current flowing through nAChRs (In(ACh)) using an intracellular solution containing 10 mM BAPTA, we measured an EC50 near 110 microM for ACh-evoked In(ACh). This EC50 for ACh is one order of magnitude higher than that measured indirectly on IK(ACh). This reveals a rather low affinity of ACh for its receptor but a very efficient coupling between nAChRs and KCa(ACh) channels. We also show that a high external Ca2+ concentration reverts the gentamicin inhibition of IK(ACh) and that gentamicin directly alters the cation current flowing through the nAChRs of OHCs. We propose that gentamicin acts as a non-competitive cholinergic blocker by displacing Ca2+ from specific binding sites at the nAChRs. This block of the nAChRs at the level of the postsynaptic membrane in OHCs could explain the inhibitory effect of gentamicin reported on the crossed medial olivocochlear efferent system in vivo.

[A case of Fabry's disease with chronic renal failure].

Fabry's disease is a genetic disorder caused by the absence of alpha-galactosidase (alpha-Gal), the gene of which is carried on the long arm of the X chromosome. This enzymatic defect leads to an accumulation of glycosphingolipids in the plasma and lysosomes of endothelial, perithelial, and smooth muscle cells, especially involving those of the cardiovascular, renal and cerebrovascular systems. We report one male case of Fabry's disease with renal deterioration. A 36-year-old man who was a classic case with acroparesthesia, angiokeratoma, and hypohidrosis from 10 years of age, was diagnosed to be a hemizygote of Fabry's disease at 27 years as a result of severe decreased alpha-Gal activity of his peripheral white blood cells. This patient was found to have a point mutation of a G to A transition in exon 1. In May, 1989, he was reported to have proteinuria with normal renal function and admitted to our hospital due to renal deterioration in September, 1993. Laboratory examinations revealed a serum urea nitrogen of 65 mg/dl and creatinine value of 6.9 mg/dl. Urinary protein excretion was 3.9 g/day and urinary sugar was negative. On the renal biopsy specimens, light microscopic examinations revealed multiple sclerosing and collaptic lesions in glomeruli without severe tubulo-interstitial damage, but with stenotic change of the small arteries and arterioles. Electron microscopic examinations revealed a large number of electron dense deposits in the tubules. We diagnosed this case as Fabry's disease with chronic renal failure, however the pathogenesis of this renal progressive deterioration remained obscure. In this case, degenerative changes in the renal vessels due to Fabry's disease may be associated with rapid deterioration in renal function.

Prefabricated free jejunal transfer: a new reconstructive technique for high pharyngeal defects.

A new method that uses a prefabricated free jejunal transfer has been applied to three cancer patients with pharyngoesophageal defects with a high pharyngeal deficit extending up to the nasopharynx. In this method, the jejunum harvested in the usual manner is divided into two segments with a single vascular pedicle. Its distal segment is used to reconstruct the cervical esophagus, and its proximal segment is turned over to create a mucosal patch to cover the high pharyngeal defects. The two segments are then co-apted in a side-by-side anastomosis. The esophagus can be reconstructed in a naturally straight shape without a curved portion or blind loop formation, thus leading to good swallowing function. In our series, all grafts survived well and there was no complication directly related to jejunal transfer. All patients could tolerate a soft diet without difficulty. This method is easy to perform and applicable to any shape or size of very high pharyngeal defects that cannot be reconstructed properly by other methods. Although patients with an advanced hypopharyngeal cancer usually have a poor prognosis, this technique allows a better quality of life for a probable short life span.

Average thresholds in the 8 to 20 kHz range in young adults.

The sound-pressure level thresholds in the extended high-frequency range (8 to 20 kHz) were measured in 25 non-hearing-impaired young adults from 20 to 29 years of age. The result was not unlike that obtained by previous investigators; the thresholds increased gradually as a function of frequency. However, two notable points were found: one that the threshold reached a plateau above 18 kHz, and the other that it decreased slightly at 12 kHz. As the subjects might respond to the low-frequency noise of the stimulus wave, the threshold became a plateau above 18 kHz. An acoustic resonance in the ear canal caused the threshold to decrease at 12 kHz. In clinical studies of extended high-frequency audiometry, the threshold data should be carefully evaluated above 18 kHz and at 12 kHz.

Average thresholds in the 8 to 20 kHz range as a function of age.

The sound-pressure thresholds at the extended high frequencies of 8-20 kHz were measured for 65 normal subjects aged between 10 and 69 years. The results are not unlike those obtained by previous investigators. The thresholds increased gradually as a function of frequency, except around 12 kHz and above 19 kHz, and also as a function of age. To clarify the connections between threshold, frequency and age, we introduced the regression lines for the threshold by analysing two ranges of frequencies (8-10 kHz and 14-19 kHz) and determining their slopes and intercepts. The regression line analysis reveals that the thresholds at 8-10 kHz tend to increase more at higher frequencies as subject age increased above 30 to 39 years, and those at 14-19 kHz increase translationally with increase of age. Our results did not contradict earlier reports on the pathological changes of the inner ear.

Dumbbell type jugular foramen meningioma extending both into the posterior cranial fossa and into the parapharyngeal space: report of 2 cases with vascular reconstruction.

Two cases with huge dumbbell type jugular foramen meningioma with extension into the parapharyngeal space are reported. A well co-ordinated surgical strategy for total resection to this high risk tumour with neurosurgeons, otolaryngologists and plastic surgeons is mandatory to minimise operative complications. Both of our patients presented with a cervical mass and lower cranial nerve palsies, and had huge dumbbell type masses extending from the posterior cranial fossa through the jugular foramen to the parapharyngeal space, encasing the cervical internal carotid artery. Gross total resection of the tumours was successfully achieved by basically a 2-stage operation. In the first stage, posterior fossa tumours were removed by the transjugular approach, combined with the petrosal approach in one case. In the second stage, cervical tumours were removed along with the cervical carotid artery by the transcervical and/or transmandibular approach, followed by vascular reconstruction from the ipsilateral carotid artery to the middle cerebral artery using saphenous vein graft. From these experiences, we recommend this 2-stage operation for large dumbbell type meningiomas extending to the infratemporal/parapharyngeal space. The intracranial tumour is removed at the first operation. The extracranial portion is resected at the second, and if necessary, the involved cervical carotid artery is resected and simultaneous revascularisation using saphenous vein graft is performed with a vascularised free muscle graft. This strategy could maximise the functional preservation on the one hand, and minimise the surgical risk, such as postoperative infection, on the other.

A second primary squamous cell carcinoma arising in a radial forearm flap used for reconstruction of the hypopharynx.

A 63-year-old man had undergone hypopharyngectomy for hypopharyngeal carcinoma in 1985. A free radial forearm flap was used for reconstruction of the pharynx. Ten years after the surgery, a second primary squamous cell carcinoma occurred in the neopharynx. Persistent exposure to alcohol, saliva and foodstuffs was considered as a possible cause of second primary carcinoma. Long-term follow-up is indicated in patients undergoing reconstruction using cutaneous or musculocutaneous flaps.

Analysis of tumor recurrence following anterior skull base surgery.

In order to elucidate the predictive factors for tumor recurrence following skull base surgery and the significance of salvage surgery in cases of recurrence, we retrospectively surveyed the incidence, site, and time of local recurrences in 20 patients who underwent either anterior or anterolateral skull base surgery for malignant tumors invading the anterior cranial fossa between 1989 and 1995 at the University of Tokyo Hospital. Nineteen patients underwent total resections of malignancies, with recurrences and/or metastases occurring in 13. Local recurrences occurred at the skull base in 5 patients (group A), outside the skull base in 4 patients (group B), and in both locations in 2 patients (group C). The mean time interval between surgery and recurrence was 29 months in group A, and 4.2 months in groups B and C. The local recurrence-free rates were 51% at 1 year and 34% at 5 years. Both brain and/or dural invasion and a microscopic positive surgical margin were proven to be predictive factors for tumor recurrences. The 3-year local recurrence-free rate was 20% in patients with dural invasions and 83% in those without. The incidence of recurrence-free patients was 79% in cases with negative margins, with no patient being recurrence-free in positive cases. All recurrences found more than 6 months after the initial surgery resulted in patients being salvaged successfully by a second operation.

Complications of craniofacial surgery for tumors involving the anterior cranial base.

OBJECTIVE: To evaluate the risk factors for postoperative complications among patients undergoing craniofacial resection for the treatment of anterior cranial base tumors, a retrospective analysis of patients treated in University of Tokyo Hospital between September 1987 and November 1996 was conducted. METHODS: Twenty-nine patients underwent 33 craniofacial resections for tumors involving the anterior cranial base. Twenty-three of the 29 patients had malignant tumors and 6 patients had benign tumors. Anterior craniofacial resection was performed using a combination of intracranial and extracranial approaches. Radiotherapy and neoadjuvant chemotherapy were administrated to some patients. RESULTS: Severe intracranial infections were more common among patients who underwent partial frontal lobectomies (P < 0.03). These infections occurred only in patients who had been treated previously with a craniotomy (P < 0.02) and a total radiation dose of > or =60 Gy (P = 0.06). Neither management of the extracranial structures nor methods of reconstruction of the cranial base showed significant correlation with major postoperative complications. CONCLUSION: Compared with previous reports, craniofacial resection has become a relatively safe and effective procedure for the treatment of tumors involving the anterior cranial base. However, additional care should be taken with patients who have experienced a previous craniotomy, frontal lobe involvement, or radiotherapy with a total dose of > or =60 Gy.

The significance of arytenoid edema following radiotherapy of laryngeal carcinoma with respect to residual and recurrent tumour.

We sometimes experience patients with persistent or progressive arytenoid edema, among which residual or recurrent cancer is often accompanied. Because it is difficult to distinguish tumour rest or recurrence from normal tissue sequelae in the early period after irradiation, it is important to know both the contributing factors for arytenoid edema, and the incidence of residual or recurrent tumours in patients with postirradiation laryngeal edema. We therefore reviewed the charts of 67 patients with early laryngeal carcinoma who had received a curative dose of irradiation in the last 5 years. Fourteen patients (20.9%) had moderate or severe laryngeal edema persisting for or developing at more than 3 months after completion of a course of definitive radiotherapy. The incidence was highest in supraglottic T2 disease, followed by glottic T2 tumour. Of the 14 patients with edema, six (42.9%) had persistent or recurrent disease. The primary disease was uncontrolled in 18 patients, 17 of whom received successful salvage surgery. In patients without residual tumours, the edema was usually moderate and resolved within a year, although four patients had chronic edema lasting more than a year after treatment. All four had supraglottic T2 lesions and received 70 Gy of X-ray. We also reviewed, for sake of comparison, the records of 38 patients treated with radiotherapy at doses of more than 40 Gy between 1975 and 1980, when endoscopic microsurgery for laryngeal cancer was introduced as a primary part of treatment. The incidence of persistent or late developed edema over the period, though not significant, was 36.8%: nearly twice that of the last 5 years. Microscopic endolaryngeal surgical procedures seem to have been a causal factor for edema in this period.

ATP activates a cation conductance and Ca(2+)-dependent Cl- conductance in Hensen cells of guinea pig cochlea.

Simultaneous whole cell patch-clamp and indo 1 fluorescence measurements were used to characterize ATP-evoked membrane currents and intracellular Ca2+ concentration ([Ca2+]i) changes in isolated Hensen cells of the guinea pig organ of Corti. At negative holding potential, ATP activated a biphasic inward current and a concomitant increase in [Ca2+]i. The initial current activated within < 50 ms, showed a reversal potential near 0 mV and was reversibly inhibited by 30 microM suramin, suggesting this conductance was mediated by ATP-gated nonselective cation channels. The delayed ATP-activated current was mainly carried by Cl- as indicated by its shift in reversal potential when intracellular Cl- was replaced by gluconate. This Cl- conductance appeared to be Ca(2+)-activated secondarily to Ca2+ influx, since it required the presence of extracellular Ca2+ and was suppressed when an intracellular solution containing 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid was used. In the absence of extracellular Ca2+, ATP still increased [Ca2+]i concomitant with a monophasic inward cation current, indicating Ca2+ release from intracellular stores. We conclude that Hensen cells have ionotropic and metabotropic P2 purinoceptors. They also have Ca(2+)-activated Cl- channels that can be activated by extracellular ATP, suggesting that purinoceptors in Hensen cells could play a regulatory role in ion and water balance of cochlear fluids.

Acetylcholine-induced potassium current of guinea pig outer hair cells: its dependence on a calcium influx through nicotinic-like receptors.

The cholinergic efferent inhibition of mammalian outer hair cells (OHCs) is mediated by a hyperpolarizing K+ current. We have made whole-cell tight-seal recordings from single OHCs isolated from the guinea pig cochlea to characterize the mechanism by which acetylcholine (ACh) activates K+ channels. After ACh application, OHCs exhibited a biphasic response: an early depolarizing current preceding the predominant hyperpolarizing K+ current. The current-voltage (I-V) relationship of the ACh-induced response displayed an N-shape, suggesting the involvement of Ca2+ influx. When whole-cell recording was combined with confocal calcium imaging, we simultaneously observed the ACh-induced K+ current (IK(ACh)) and a Ca2+ response restricted to the synaptic area of the cell. This IK(ACh) could be prevented by loading OHCs with 10 mM of the fast Ca2+ buffer bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid (or BAPTA), therefore allowing the observation of the ACh-induced early current in isolation. This early current revealed nicotinic features because it activated with an intrinsic delay in the millisecond range, reversed nearly in between potassium and sodium equilibrium potentials, and was blocked by curare. However, it was strongly reduced in the absence of external Ca2+, and its I-V relationship displayed an unusual outward rectification at positive membrane potentials and an inward rectification below -60 mV. The results indicate that the cholinergic response of mammalian OHCs involves a "nicotinic-like" nonspecific cation channel through which Ca2+ enters and triggers activation of nearby Ca2+-dependent K+ channels.

ATP activates non-selective cation channels and calcium release in inner hair cells of the guinea-pig cochlea.

1. ATP-evoked currents and Ca2+ signals were simultaneously recorded in isolated inner hair cells (IHC) of guinea-pig cochlea by combining conventional whole-cell or perforated patch clamp recording with indo-1 dual emission microfluorometry. 2. In most IHCs, voltage clamped near resting membrane potential (-40 mV), extracellular ATP evoked a rapid inward current (time constant, 150 ms). This current was concomitant with a slow rise in [Ca2+]i (time constant, 5 s). The ATP-evoked inward currents could be repeated several times with only a small run-down in amplitude (< 10%), while the ATP-evoked Ca2+ responses showed a rapid run-down (> 80% at the third ATP application). 3. The current-voltage relationship of ATP-evoked currents showed a reversal potential at -11 +/- 6 mV (n = 8), suggesting that ATP essentially activated a non-specific cationic conductance. On the contrary, the amplitude of the ATP-evoked Ca2+ responses did not show significant dependence on holding membrane potential. 4. The Ca2+ response showed an apparent Kd for ATP (EC50, 1.8 +/- 0.3 microM; Hill coefficient, 1.0 +/- 0.1) eightfold smaller than for the evoked currents (EC50, 13.7 +/- 3.0 microM; Hill coefficient, 2.0 +/- 0.7). 5. Perfusion with high extracellular Ca2+ solution (10 mM CaCl2) reduced the amplitude of the ATP-evoked currents by 90%, while perfusion with zero Ca2+ solution increased it by more than 100%. However, similar variations in external Ca2+ concentration did not change the amplitude of the ATP-evoked Ca2+ responses. Furthermore, intracellular heparin (1 mg mL-1), a potent inhibitor of InsP3 receptors, did not significantly change the amplitude of ATP-evoked currents but reduced the ATP-evoked Ca2+ response, suggesting again that the latter is related to Ca2+ release from intracellular stores. 6. The results suggested that two types of P2-purinergic receptor are expressed in IHCs: ATP-gated ion channels and ATP-activated metabotropic receptors. At submicromolar ATP concentrations, the metabotropic receptors raising intracellular [Ca2+] would hyperpolarize IHCs via Ca(2+)-sensitive K+ channels. The ATP-gated ion channels activated at higher ATP concentrations would mainly have a depolarizing effect on IHCs.

Auditory findings after stereotactic radiosurgery in acoustic neurinoma.

Auditory function after gamma knife stereotactic radiosurgery (GK) was evaluated in 22 patients with newly diagnosed unilateral acoustic neurinoma who had had some measurable hearing preoperatively. No tumor growth was observed in any patients. The preservation rates for useful hearing (n = 13) and any measurable hearing (n = 22) were 62% and 86%, respectively, at 2 years after GK. Postoperative hearing dysfunction was attributed to progressive cochlear impairment in 13 patients and to progressive injury in the retrocochlear auditory pathway in 5 patients. Hearing tended to be well preserved when caloric response was unchanged postoperatively. Preservation of hearing was not associated with the initial tumor volume, decrease of tumor size, maximum tumor dose, or peripheral tumor dose.

Direct measurements of Ca(2+)-activated K+ currents in inner hair cells of the guinea-pig cochlea using photolabile Ca2+ chelators.

Intracellular photorelease of Ca2+ from caged Ca2+ (DM-nitrophen or nitr5) and the patch-clamp technique in the whole-cell configuration were used to investigate Ca(2+)-activated currents in inner hair cells (IHCs) of the mammalian cochlea. Photoliberation of intracellular Ca2+ activated outward currents with a mean amplitude of 260 +/- 110 pA when IHCs were voltage-clamped, near the resting membrane potential, at -50 mV. The photoactivated currents were reversibly blocked by extracellular application of tetraethylammonium (TEA, 10 mM), neomycin (1 mM) and charybdotoxin (1 microM), but not by apamin. The voltage dependence of membrane currents activated by photolysis of DM-nitrophen demonstrated a reversal potential near the K+ equilibrium potential (Ek) and saturation near 0 mV. The presence of Ca(2+)-activated currents was further confirmed by the effects of extracellular adenosine 5'-triphosphate (ATP, 10 microM) and the Ca2+ ionophore ionomycin (10 microM). Both agents raised intracellular Ca2+ and simultaneously activated outward currents when IHCs were voltage-clamped near the resting membrane potential. In experiments where currents were activated by depolarizing voltage steps, nifedipine (50 microM) and Cd2+ (1 mM) reduced significantly (20-50%) the whole-cell outward currents, suggesting the presence of L-type Ca2+ currents activating K+ currents. These results are the first direct evidence for Ca(2+)-activated K+ currents in mammalian IHCs, these currents being potentially important for cell repolarization during sound-induced depolarization and synaptic transmission.

Occult follicular carcinoma metastasizing to the sinonasal tract.

We report a 34-year-old woman with a clinically occult primary carcinoma of the thyroid metastasizing to the sinonasal tract. The metastasis showed intensive vascularization and involved the nose, the maxillary, ethmoid and sphenoid sinuses, extending to the intracranial cavity. After embolization, the lesion was removed and histopathologically diagnosed as follicular carcinoma of the thyroid. A subsequent total thyroidectomy revealed an 8-mm primary lesion within the left lobe. Thyroid metastases, although rare, need to be considered in the differential diagnosis of hypervascular tumors in the sinonasal tract.