Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma.

Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK(del2-3)) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK(del2-3) was autophosphorylated in NB-1 cells as well as in ALK(del2-3)-transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK(del2-3)-transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK(del2-3)-expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

Progressive sensorineural hearing impairment in professional fishery divers.

There have been many reports of a high rate of hearing impairment in divers. A prospective study was performed to determine whether sensorineural hearing acuity in the same divers deteriorated faster than in a normal population as they continued diving. After an observation period of approximately 5 years, audiometric examination was performed on a group of professional fishery divers who had normal hearing or sensorineural hearing loss at the time of initial study. Thirty-three ears of 18 divers were included in statistical analyses. The average hearing deterioration in the divers in 5 years, after elimination of the aging effect, was 6.6 dB (SD 4.5) and was statistically significant. We concluded that the hearing acuity of our subjects deteriorated faster than that of normal Japanese.

Effects of a small dose of triazolam on P300.

Ten healthy men (mean age, 33.9 years) participated in two experimental sessions cross-overed randomly in a double-blind manner: one with the placebo and another with 0.125 mg of triazolam (TRZ). Resting electroencephalography and event-related potential under oddball paradigm were recorded before the drug administration, and 1, 2, 4, 6 and 8 h after that. P300 waveforms were analyzed by peak amplitudes and 30-ms bin data. Triazolam may cause cognitive dysfunction without general sedation or apparent sleepiness, and this effect appeared 2 h, 4 h and 6 h, most prominently 6 h, after TRZ administration.

[The volume ratio between squamosal and petrosal air cells divided by Körner's septum].

Pneumatized air cells of the temporal bone are embryologically divided into two portions; the squamosal portion and the petrosal portion. These two portions are anatomically separated by the petrosquamous fissure and petrosquamous lamina, the so-called Körner's septum. In this study, the volumes of the two portions were measured with Target Imaging CT in 5 normal ears (3 subjects) with a clearly recognizable Körner's septum. The combined volume of the two portions, in all CT slices, was also measured. The squamosal portion occupied 32.7% of the total air cell volume, on average, and the petrosal portion was 67.3%. A positive correlation was observed between the total air cell volume of the temporal bone and the volume ratio of the petrosal portion. When the volume of each part was examined according to the CT slice level, from high to low, the maximum volume of the squamosal portion was at the slice level of the epitympanic cavity. The volume of the petrosal portion was prominent at the slice level of the epitympanic cavity and the upper antrum. These results that the petrosal portion plays a more important role than the squamosal portion in pneumatization of the temporal bone. This analysis with Target Imaging CT provides useful information for understanding the middle ear pathology resulting from poor pneumatization of the temporal bone.

[Area and volume relationship of temporal bone air cells].

The area and volume of the air cell system of fifty normal temporal bones were investigated. The area on a plain X-ray, Sonnenkalb projection, was measured by a planimetric method and a rectangular dimensional method by Imai in 1978. The volumes of the temporal bone air cells on high-resolution CT were calculated separately as partial volumes divided in all CT planes. The sum of the partial volumes was calculated as the total volume of the air cells. The relationship between the area and the total volume of the air cell system was analyzed statistically. The ratio of the partial spatial volume, e.g. the tympanic cavity and the apical air space, to the total volume of the temporal bone air cells was also calculated. The results were as follows: 1) The relationship between the two measurements were as follows: planimetric method, Y = 0.901X - 2.26 (r = 0.885), and rectangular dimensional method, Y = 0.542X - 2.57 (r = 0.876). 2) The ratio of the volume of the tympanic cavity to the total volume of the air cell system was 6.74 +/- 4.07%. The larger the total volume, the smaller the ratio. 3) The ratio of the apical space was 7.09 +/- 4.98%, and the larger the total volume, the larger the ratio.

[Analysis of middle ear cavity gas composition by mass spectrometry].

Gas compositions in the middle ear cavities of patients with a perforated tympanic membrane, and in normal subjects, were analyzed by mass spectrometry. The results showed that the gas in normal subjects consisted of nitrogen (83.7%), oxygen (9.2%) and carbon dioxide (6.2%). (The volume concentration of the various gases was expressed as a percentage of 713 mm Hg.) Thus, the concentrations of the various gases in the middle ear cavity differed greatly from those in the atmosphere. The low concentration of oxygen is suitable for microaerophilic bacteria and acts as a physiological barrier against bacterial infection. It was also found that the gas in patients with exudative otitis media consisted of nitrogen (77.9%), oxygen (15.6%) and carbon dioxide (5.5%), and in patients with chronic perforated otitis media, of nitrogen (77.8%), oxygen (16.9%) and carbon dioxide (4.4%). The concentration of oxygen in the middle ear cavity with perforated tympanic membrane is higher than that in the normal state because of diffusion of atmospheric gas into the middle ear cavity. In other words, perforation of the tympanic membrane exposes the middle ear cavity to a nonphysiological gaseous condition. The diffusion of atmospheric gas was simulated using small cylinders. Simulated results revealed that the atmospheric gas diffused rapidly. The change in the gas concentration during diffusion was approximated by an exponential function and a constant, and reproduced by a mathematical model. The change in the gas concentration in the middle ear cavity was usually approximated by two exponential functions and a constant. The constant represents the estimated final value of the gas concentration from which the effect of the diffusion is excluded. The final values were estimated for normal subjects and patients with perforated tympanic membrane. The final values in the normal subjects were almost equal to the measured values. The final value of carbon dioxide in the patients was greater than the measured value and nearly equal to the final value in the normal subjects. The final oxygen value in the patients was smaller than the measured value, but still greater than the final value in the normal subjects. The high oxygen concentration in the patients suggests enhanced oxygen metabolism.

[Antimutagenic and bactericidal substances in the fruit body of a Basidiomycete Agaricus blazei, Jun-17].

The fruit body of a Basidiomycete Agaricus blazei, Jun-17 (Himematsutake) was extracted with hexane and chloroform-methanol (2:1, v/v), and the antimutagenic effect of the extracts was examined using an Ames/Salmonella/microsome assay. Both extracts of Agaricus inhibited the mutagenicity of benzo[a]pyrene(B[a]P). The hexane extract was purified by silica gel column chromatography and high performance liquid chromatography (HPLC), and linoleic acid was isolated as a main substance having antimutagenic activity. Fr. IIa, IIb, IIc and IIb, which reduced the number of His+ revertant colonies induced by B[a]P, were separated from the chloroform-methanol extract by silica gel column chromatography and HPLC. An antimutagenic substance in Fr. IIa was linoleic acid. From Fr. IIb, a bactericidal, not antimutagenic, substance was isolated and identified as 13-hydroxy cis-9, trans-11-octadecadienoic acid (13ZE-LOH). Antimutagenic substances in Fr. IIc and IId were not purified. The possible source and mechanism of formation of 13ZE-LOH are discussed.

[Exostosis of the external auditory canal and sensorineural hearing loss in professional divers].

Audiometric survey and endoscopic study of the external auditory canal were performed on a group of 31 professional divers, all of whom had experienced frequent exposure to dysbaric conditions. The results are as follows. 1) Over 40% had exostosis of the external auditory canal. There was no relationship between the incidence of the exostosis and the length of their occupational career as a diver. Many of the divers had hearing loss whether they had exostosis or not. 2) Over 70% had sensorineural hearing loss, taking into account hearing loss due to aging. Most had no experience of inner ear barotrauma on descent, causing sudden a shift in hearing threshold. Deafness was related to the length of their occupational career as a diver. In conclusion, we speculate that repetitive small changes in barometric pressure on the outer ear influences the pressure on the middle ear and further on that of the perilymph, finally damaging the inner ear auditory system.

Aeration of the tympanomastoid cavity and the Eustachian tube.

Physiological changes in body position affect the degree of opening and closing of human auditory tubes. Notable changes were observed in lateral body position concerning the opening rate of the auditory tubes, which corresponds to the changes in pressure within the lower portion of the middle ear cavity. This physiological mechanism seems to be related with the anatomical direction of the auditory tube and the natural mechanism for the protection of the middle ear cavity. When a change takes place which moves the compliance of the eardrum to the positive side (e.g. head position change or static lateral body position), observation suggests the possibility of venostatis and production of gas. Measurement of the oxygen tension in the middle ear cavity under atmospheric pressure revealed the existence of constant gas production which maintains the pressure in the middle ear cavity at the same level as atmospheric pressure. This result denies the influx of gas from the atmospheric environment into the middle ear cavity. These results stem from the intrinsic physiologic mechanism of the middle ear cavity, namely maintenance of effective auditory sound conduction (a function to keep eardrum compliance as close to zero as possible), by keeping the pressure within the middle ear cavity below the atmospheric pressure, either at the same level as or slightly higher than that of the environment pressure. Gas emission from the middle ear cavity in the atmospheric environment and a low oxygen tension are a natural physiologic mechanism to protect the middle ear cavity from infection and other hazards.

Physiology and pathophysiology of air-filled ear space and Eustachian tube function.

The function of the Eustachian tube under atmospheric pressure, on the grounds of our studies, is discussed as follows: (1) Criteria of natural valvular function of the auditory tube under a normal pressure environment. (2) Opening action of the Eustachian tube and mode of swallowing movement in comparison with soft palate movement. (3) High pressure environment and (opening action of) Eustachian tube. (4) Children undergoing tubing and their Eustachian tube function. (5) Ventilatory function of the Eustachian tube under normal pressure conditions. (6) Factors influencing changes in pressure in the tympanic cavity.

Epidemiological studies on benign paroxysmal positional vertigo in Japan.

In 1980, the Research Committee of Peripheral Vestibular Disorders in Japan, which is supported by the Ministry of Health and Welfare, was founded by 24 members, from several districts in Japan. The Committee's first task was to draft the diagnostic criteria for several peripheral vestibular disorders, such as benign paroxysmal positional vertigo (BPPV), and vestibular neuronitis. For the national epidemiological survey, they then collected the data on 101 cases of BPPV out of some 783 vestibular disorder patients. In addition, data on 103 patients of BPPV out of 559 vestibular disorder patients were also collected from the Neuro-otological Clinic of the Toyama Medical and Pharmaceutical University Hospital. From these epidemiological surveys, the incidence of BPPV in Japan was estimated at 10.7 per 100,000 population, while that of BPPV in Toyama was estimated at 17.3 per 100,000 population. The ratio of BPPV was higher in female than male patients in both surveys. The age at the onset of BPPV peaked in the fourth decade in both males and females. Compared with the other epidemiological features of Meniere's disease and sudden deafness with vertigo in the same surveys, it appeared that the characteristic features of BPPV are epidemiologically similar to those of Meniere's disease, but different from those of sudden deafness.

Fibers supplying the laryngeal musculature in the cranial root of the rabbit accessory nerve: nucleus of origin, peripheral course, and innervated muscles.

The location of the rabbit laryngeal motoneurons whose axons traverse the cranial root of the accessory nerve was studied with injection of HRP or nuclear yellow into the laryngeal muscles in combination with the intracranial severing of either the rootlets of the vagus nerve or those of the cranial root. The motoneurons were located in the diffuse cell group that forms a subnucleus occupying the caudal two-thirds of the nucleus ambiguus and sending fibers to the inferior laryngeal nerve. The caudal one-third of the diffuse cell group supplying the lateral cricoarytenoid muscle, was occupied only by these motoneurons, whereas in its rostral two-thirds, they were intermingled with motoneurons having axons that traversed the vagal rootlets. The thyroarytenoid and posterior cricoarytenoid motoneurons are present in the rostral two-thirds of the diffuse cell group; axons of the former traversed the rootlets of the cranial root, and of the latter traversed the vagal rootlets. On the other hand, the medial scattered cell group, located in the rostral one-third of the nucleus ambiguus and sending fibers to the cricothyroid muscle via the superior laryngeal nerve, contained only motoneurons with axons traversing the vagal rootlets. The above findings clarified that fibers of the cranial root enter the inferior laryngeal nerve after joining the vagus, and then reach the adductor muscles for the vocal fold, with their neurons of origin in a caudal portion of the nucleus ambiguus. The vagal rootlet fibers, with their neurons of origin situated more rostrally in the nucleus, innervate the tensor and abductor muscles via the superior and inferior laryngeal nerve, respectively.

[A study of eustachian tube function in fishermen (oikomi-gyohoh) divers].

The intranasal pressure at the opening of the auditory tube was compared by Valsalva's method with that of normal adults under atmospheric pressure to find the auditory tubal function of divers often exposed to hyperbaric conditions. It was found that the mean auditory tube opening pressure was higher in professional divers than in normal adults who had never been exposed to hyperbaric pressure. There are two ways of accommodating human auditory tubal ventilation: active opening and passive opening--the former is predominant in adults, the latter in children. The function of professional divers resembles the child type. This finding suggested that they were frequently exposed to a hyperbaric environment, and their auditory tube might not be opened and closed with each swallowing movement under atmospheric pressure, or the auditory tube and the middle ear themselves have been changed into a condition whereby they no longer needed the opening with each swallowing movement might under atmospheric pressure. Moreover, divers take various postures while they are diving, and in rapid dive, they often take a head-down posture. It was obvious that the auditory tube opens less readily in the head-down position. This phenomenon appears to represent the effect of hydrostatic venous pressure in water.

Localization of rabbit laryngeal motoneurons in the nucleus ambiguus.

The localization of rabbit laryngeal motoneurons in nucleus ambiguus was investigated using injection of a fluorescent labeling substance, i.e., nuclear yellow, into the individual laryngeal muscles. The nucleus ambiguus of the rabbit comprises four subnuclei, CoG, SGm, SGl, and DiG. The CoG is a group of compactly arranged neurons, and is situated in the rostral one-half of the nucleus. The SG, situated in its rostral one-third, is scattered around the CoG, with a subdivision into SGm and SGl. These subdivisions are medial and lateral to the CoG, respectively. The DiG is formed by diffusely arranged neurons, and is located in the caudal two-thirds of the nucleus. All labeled motoneurons were found in the ipsilateral nucleus ambiguus. The motoneurons supplying the cricothyroid muscle, which is innervated by the superior laryngeal nerve, were present in the SGm, with a clear rostralward segregation from the other motoneurons. The motoneurons supplying the muscles innervated by the inferior laryngeal nerve were located in the DiG, where they displayed a rostrocaudal myotopical arrangement in the order posterior cricoarytenoid, thyroarytenoid, and lateral cricoarytenoid. The posterior cricoarytenoid motoneurons were intermingled with the thyroarytenoid motoneurons in the rostral two-thirds of the DiG, and the former tended to be concentrated more rostrally than the latter. The lateral cricoarytenoid motoneurons were confined to the most caudal one-third of the DiG.

Function of the eustachian tube in an alternobaric environment. A study with special reference to the therapy of secretory otitis media in children.

The authors have obtained interesting data from the alternobaric treatment of secretory otitis media in children. Some functional differences of the Eustachian tube between adults and children were then studied by the combined use of sonotubometry and pressure loading. The results showed speculated that Eustachian tube function changes from infant type to adult type between the ages of 6 and 10 years.

Sonotubometric measurement of the eustachian tube function by means of band noise. A clinical view of the acoustic measurement of the eustachian tube.

The Eustachian tube is well known as an organ serving the ventilation and drainage of the tympanic cavity and mastoid. Ventilation is carried out by the opening and closing of the Eustachian tube accompanying swallowing movements. Until now there has been no instrument to quantify these motor activities of the tube necessary for its function as a ventilator. The author developed a generally applicable sonotubometer Model WIO-01 with the help of Siemens Hearing Institute K.K. for automatic measurement of the aforesaid tubal function with the use of 7 kHz full-octave band noise. In a sonotubometric trial with 32 adult female subjects, the duration of patency of the Eustachian tube was 288.5 +/- 1.38.5 ms, and the amplitude eliciting response was 16.4 +/- 8.3 dB. The positive response rate was 89.1%. In 89 children aged 4-12 years, a positive response was detected in 117 ears (61.9%). The mean duration of patency was 337.7 +/- 154.4 ms, and the amplitude 16.3 +/- 7.2 dB. It is physiological to have tubal opening and closing during natural swallowing. It is therefore important to understand the tubal function when dealing with tympanoplasty and diseases caused by tubal dysfunction.