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Biomedical subjects

Masafumi Sakagami

Publications and source records attributed to Masafumi Sakagami.

At least 19 recordsLinked to original sources

Primary malignant melanoma of the larynx: a case report and literature review.

A 56-year-old Japanese man presented with hoarseness and left sided neck swelling in June 2003. Endoscopy showed an irregular tumor extending from the anterior commissure to the left ventricle with dark pigmentation. A biopsy showed malignant melanoma. A total laryngectomy with left radical neck dissection was performed in July 2003, followed by chemohormonal therapy and radiotherapy to the neck. Multiple bone metastases were diagnosed in May 2004, and the patient died with disseminated disease in April 2005, 21 months after initial treatment. The medical literature on laryngeal malignant melanoma was reviewed, and suggested a very poor prognosis despite therapy with surgery, radiotherapy, and chemotherapy.

Biopsy, Fine-Needle↗

Voice rehabilitation with Provox2 voice prosthesis following total laryngectomy for laryngeal and hypopharyngeal carcinoma.

OBJECTIVE: To analyze the effectiveness of the Provox2 voice prosthesis for voice rehabilitation following total laryngectomy. METHODS: From September 2000 to December 2004, the Provox2 voice prosthesis was used for voice rehabilitation in 32 patients following total laryngectomy. The quality of speech with the Provox2 voice prosthesis was analyzed using the HRS rating scale, the maximum phonation time (MPT), incidence of complications and the in situ lifetime. The rate of speech restoration was further analyzed in 129 patients with total laryngectomy from 1996 to 2004. RESULT: Twenty-nine of 32 patients were able to restore speech using the Provox2 voice prosthesis, a speech restoration rate of 90.6%. The maximum phonation time (MPT) was measured in 18 patients using the Provox2 voice prosthesis. The mean MPT was 15.1 s, with a range of 8-28 s. MPT was not influenced by age, concurrent radiotherapy treatment, the location of the primary tumor or use of reconstructive surgery. The average lifetime of the Provox2 in patients with laryngeal carcinoma (12 patients) and hypopharyngeal carcinoma (17 patients) was 27.2 and 16.6 weeks, respectively, which was significantly different (P=0.024, non-parametric Mann-Whitney's U-test). The rate of speech restoration by the use of esophageal speech, and insertion of an artificial larynx was 62.7% for laryngeal carcinoma (59 cases) and 38.6% for hypopharyngeal carcinoma (70 cases), which was also significantly different (P<0.01, chi-square test). CONCLUSION: Provox2 voice prosthesis speech was very useful due to the higher rate of speech restoration, longer phonatory time, and better intelligibility. It was also thought that voice prosthesis speech was useful in conjunction with esophageal speech and an artificial larynx depending on the patient's condition or wishes.

Aged↗

Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury.

Hypersensitivity to mechanical stimulation is a well documented symptom of neuropathic pain, for which there is currently no effective therapy. Src-family kinases (SFKs) are involved in proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here we show that activation of SFKs induced in spinal cord microglia is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in SFK phosphorylation in the ipsilateral dorsal horn, and SFKs were activated in hyperactive microglia but not in neurons or astrocytes. Intrathecal administration of the Src-family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) suppressed nerve injury-induced mechanical hypersensitivity but not heat and cold hypersensitivity. Furthermore, PP2 reversed the activation of extracellular signal-regulated protein kinase (ERK), but not p38 mitogen-activated protein kinase, in spinal microglia. In contrast, there was no change in SFK phosphorylation in primary sensory neurons, and PP2 did not decrease the induction of transient receptor potential ion channel TRPV1 and TRPA1 in sensory neurons. Together, these results demonstrate that SFK activation in spinal microglia contributes to the development of mechanical hypersensitivity through the ERK pathway. Therefore, preventing the activation of the Src/ERK signaling cascade in microglia might provide a fruitful strategy for treating neuropathic pain.

Animals↗

Efficacy of mastoidectomy on MRSA-infected chronic otitis media with tympanic membrane perforation.

OBJECTIVES: To retrospectively evaluate the efficacy of mastoidectomy on methicillin-resistant Staphylococcus aureus (MRSA)-infected chronic otitis media in comparison with methicillin-susceptible Staphylococcus aureus (MSSA)-infected otitis media. METHODS: Between January 1998 and October 2003, 18 ears underwent surgery for MRSA-infected chronic otitis media with tympanic membrane perforation at the Department of Otolaryngology, Hyogo College of Medicine. Another 33 ears underwent surgery for MSSA-infected chronic otitis media with tympanic membrane perforation during the same period. The postoperative results of graft success rate, hearing results and other complications were compared between MRSA-infected and MSSA-infected ears with or without mastoidectomy, and discharging or dry ears. RESULTS: In MRSA, the mastoidectomy group tended to have a better graft success rate than the non-mastoidectomy group. In MSSA, there were almost the same graft success rate and hearing results between the mastoidectomy and non-mastoidectomy groups regardless of the presence of discharge. In MRSA-infected discharging ears, the rate of postoperative complications (ear drum perforation, persistent otorrhea, and dehiscence of skin incision) were significantly lower in the mastoidectomy group than in the non-mastoidectomy group (p=0.046). CONCLUSION: Mastoidectomy had significantly better results concerning postoperative complications in discharging ears with MRSA-infected chronic otitis media. We recommend performing tympanoplasty with mastoidectomy in MRSA-infected chronic otitis media.

Adolescent↗

Differential expression of capsaicin-, menthol-, and mustard oil-sensitive receptors in naive rat geniculate ganglion neurons.

The roles of capsaicin, menthol, and mustard oils and their receptors in geniculate ganglion (GG) neurons still remain to be elucidated. These receptors belong to the transient receptor potential (TRP) family. Capsaicin-, menthol-, and mustard oil-sensitive receptors are TRPV1, TRPM8, and TRPA1, respectively. The present study aimed to investigate the expression of TRPV1, TRPM8, and TRPA1 in naive rat GG neurons. Furthermore, we examined whether these TRP-expressing GG neurons are myelinated A-fiber or unmyelinated C-fiber neurons. Firstly, using reverse transcription-polymerase chain reaction, TRPV1 mRNA and TRPA1 mRNA were distinctly detected in the naive GG. TRPM8 mRNA was faintly detected. Secondly, using in situ hybridization, TRPV1 mRNA- or TRPA1 mRNA-labeled neurons (signal/noise ratio >or= 10) were observed in 15-20% of GG neurons. Few neurons were labeled by TRPM8 mRNA. Thirdly, neurofilament 200 (NF200) protein, a marker of mylinated A-fiber neurons, was detected in 57% of naive GG neurons. Coexpression of TRPV1 mRNA or TRPA1 mRNA with NF200 was detected in 10% of GG neurons. The present study confirmed the expression of the TRP receptors in the naive GG. The possible roles of TRP receptors in naive GG neurons in somatosensory or gustatory function were suggested.

Animals↗

Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats.

Patients with neuropathic pain frequently experience hypersensitivity to cold stimulation. However, the underlying mechanisms of this enhanced sensitivity to cold are not well understood. After partial nerve injury, the transient receptor potential ion channel TRPV1 increases in the intact small dorsal root ganglion (DRG) neurons in several neuropathic pain models. In the present study, we precisely examined the incidence of cold hyperalgesia and the changes of TRPA1 and TRPM8 expression in the L4 and L5 DRG following L5 spinal nerve ligation (SNL), because it is likely that the activation of two distinct populations of TRPA1- and TRPM8-expressing small neurons underlie the sensation of cold. We first confirmed that L5 SNL rats developed cold hyperalgesia for more than 14 days after surgery. In the nearby uninjured L4 DRG, TRPA1 mRNA expression increased in trkA-expressing small-to-medium diameter neurons from the 1st to 14th day after the L5 SNL. This upregulation corresponded well with the development and maintenance of nerve injury-induced cold hyperalgesia of the hind paw. In contrast, there was no change in the expression of the TRPM8 mRNA/protein in the L4 DRG throughout the 2-week time course of the experiment. In the injured L5 DRG, on the other hand, both TRPA1 and TRPM8 expression decreased over 2 weeks after ligation. Furthermore, intrathecal administration of TRPA1, but not TRPM8, antisense oligodeoxynucleotide suppressed the L5 SNL-induced cold hyperalgesia. Our data suggest that increased TRPA1 in uninjured primary afferent neurons may contribute to the exaggerated response to cold observed in the neuropathic pain model.

Animals↗

Tympanosclerosis involving the ossicular chain: mobility of the stapes in association with hearing results.

CONCLUSION: The preoperative bone conduction level provides not only prognostic information but also information on the mobility of the stapes in tympanosclerosis. The surgical results depend upon the stapes mobility. OBJECTIVES: We aimed to evaluate operative findings and hearing results of tympanosclerosis involving the ossicular chain, in order to understand the pathophysiology and to establish better surgical treatment of tympanosclerosis. PATIENTS AND METHODS: Between January 1998 and March 2004, 29 patients (29 ears) with tympanosclerosis involving the ossicular chain underwent tympanoplasty at our hospital. Patients with myringosclerosis only, or with an associated cholesteatoma, were excluded from this study. The clinical and operational records and pre- and postoperative pure tone audiograms were reviewed retrospectively. RESULTS: Intact canal wall tympanoplasty was applied to all 29 patients. A non-staged operation was performed on 21 patients, and a staged operation was performed on the remaining 8 patients. In 25 patients (86.2%), the sclerotic lesion of the ossicles was located in the epitympanum. In the remaining four, the sclerotic lamella coated only the ossicular chain. On average, the preoperative air conduction hearing level of 57.9 dB was significantly improved to 46.3 dB after tympanoplasty. The success rate of middle ear surgery was 65.5% (19 of 29 patients), according to the criteria of the Otological Society of Japan. In 16 patients (55.2%), the mobility of the stapes was preserved (group A), while in the remaining 13 patients (44.8%), the stapes was fixed (group B). The mean preoperative bone conduction of 25.5 dB in group A was significantly better than that of 37.2 dB in group B. The hearing result significantly improved in group A but not in group B. The success rates were 75% (12 of 16 patients) in group A and 53.8% (7 of 13 patients) in group B.

Adolescent↗

Preliminary study on vestibular-evoked myogenic potential induced by bone-conducted stimuli.

OBJECTIVE: To study the relationship between vestibular-evoked myogenic potential evoked by air-conducted stimuli (A-VEMP) and those evoked by bone-conducted stimuli (B-VEMP). STUDY DESIGN: Prospective study. SETTING: University Hospital. PATIENTS: To determine the optimum stimulus conditions for B-VEMP, 40 ears of 20 healthy volunteers were used. To compare results of A-VEMP and B-VEMP, 60 ears of 30 healthy volunteers and 70 ears of 35 patients with unilateral vestibular disorder without conductive hearing loss were used. MAIN OUTCOME MEASURE: A-VEMP and B-VEMP were measured. Both examinations involved evaluation of the interaural ratio (IAR) of the p13-n23 peak-to-peak amplitude. To compare the relationship between A-VEMP and B-VEMP in healthy subjects and patients with unilateral vestibular disorder. RESULTS: The optimum stimulus for B-VEMP seemed to be a tone-burst sound with 8-ms duration at 250 Hz. In all healthy subjects, both A-VEMP and B-VEMP could be recorded. The mean IAR of B-VEMP (0.5 +/- 21.0%) was not significantly different from that of A-VEMP (0.2 +/- 19.4%). In patients with unilateral vestibular disorder, B-VEMP could not be detected in 10 ears in which A-VEMP also could not be detected. The IAR of A-VEMP was strongly correlated with that of B-VEMP (correlation coefficient, 0.98). CONCLUSION: The results of B-VEMP were almost the same as those for A-VEMP, at least, for patients without conductive hearing loss.

Acoustic Stimulation↗

[Treatment outcome in patients with taste disturbance].

The importance of taste has been recently evaluated from the standpoint of quality of life, but few reports exist on the clinical status of taste disturbance. We classified taste disturbance by cause and studied the effect of treatment and recovery duration. Subjects were 321 patients with taste disturbance, i.e., 131 men and 190 women (mean age: 59.9 years). Electrogustometry (EGM) and filter paper disks (FPD) were used to assess taste function in all subjects. We also asked them all about the degree of symptoms using visual analog scale (VAS). Statistical analysis was done using the unpaired t-test, with p<0.05 considered significant. Patients were treated with zinc sulfate, ferrotherapy, herbal medicine, and minor tranquilizers. Causes of taste disturbance were classified into idiopathic, post-common-cold, drug-induced, psychogenic, constitutional, and iron deficiency. Idiopathic taste disturbance was the commonest cause (125 cases, 38.9%), followed by drug-induced (62 cases, 19.3%), and post common cold (38 cases, 11.8%). Drug induced and psychogenic taste disturbance have increased. Recovery from symptoms was 79/103 (76.7%) in idiopathic taste disturbance, 24/33 (72.7%) in post-common-cold, and 14/17 (82.4%) in iron deficiency. Recovery took 22.2 weeks. Recovery was 32/50 cases (62.4%) in drug induced, taking 48 weeks. For all causes, EGM and FPD results were not associated with the degree of symptoms. Both tests tended to show delayed improvement compared to symptoms. Cases taking more than 6 months from symptom onset to medical examination showed significantly lower improvement and longer recovery time than those taking 6 months on less (p = 0.04).

Adult↗

[Clinical investigation using a self-rating depression scale in subjects with psychosomatic taste disorders].

In recent years, the number of patients with psychologenesis taste disorders has increased. In this study, related psychological factors were examined in 258 patients (85 men, 173 women) using a self-rating depression scale (SDS). The results were as follows: 1) 189 patients reported normal psychological factors, 2) 173 patients reported neurotic sates, and 3) 40 patients reported positive correlations with a depressive sates, Most of the patients, self-reported results were not correlated with taste function tests. On the other hand, the patients with depression had reduced salivary secretion tests results. Only 50% of the patients with depression recovered their taste functions. These results suggest that the SDS test may be useful for diagnosing taste disorders and monitoring effects of treatment.

Depression↗

Taste function after section of chorda tympani nerve in middle ear surgery.

OBJECTIVE: To investigate prospectively the clinical manifestations and the functional recovery of taste after section of chorda tympani nerve (CTN) during middle ear surgery, the subjective and objective study on the patients was performed. METHODS: Thirty-five patients underwent surgery with unilateral (n=32) or bilateral (n=3) section of CTN between January 2000 and April 2002. The patients were asked about taste symptoms before surgery and 2 weeks and 2 years after surgery. The CTN function was also measured with electrogustometry (EGM) at the same time points. RESULTS: In unilateral section of CTN, 19/32 (59.4%) complained of taste disorder and 11/32 (34.4%) tongue numbness. Most of these taste symptoms disappeared within 2 years although the EGM threshold did not recover. 16/17 patients (94.1%) who used to cook everyday had little difficulty in flavoring dishes. In bilateral section of CTN, the patients had no problem of taste at 2 years after surgery, either. CONCLUSION: These findings help explain the potential complications to the patients before surgery, although the number of cases was small in this series.

Adolescent↗

Taste disturbance after tonsillectomy and laryngomicrosurgery.

OBJECTIVE: To investigate the incidence of taste disturbance after tonsillectomy and laryngomicrosurgery. STUDY DESIGN: A prospective study. METHODS: Thirty-five consecutive patients underwent tonsillectomy with electric coagulator at Kanebo Memorial Hospital from September 2002 to May 2004. Another 35 consecutive patients underwent laryngomicrosurgery in a routine way during the same period. Both procedures were performed by two experienced doctors. The postoperative taste function was evaluated with questionnaire, electrogustometry (EGM), and serum levels of Zn, Cu and Fe. RESULTS: After tonsillectomy, 3/35 patients (8.6%) complained of taste disturbance, due to the pressure on the tongue in two, and Zn deficiency after lack of intake in one. All three patients recovered taste within 1.5 months. None of our patients had taste disturbance due to surgical insult of the lingual branch of the glossopharyngeal nerve. After laryngomicrosurgery, only one patient (2.9%) complained of taste disturbance with elevation of the EGM threshold that resulted from the pressure on the tongue. In addition, abnormal sensation in the tongue occurred in 9 cases (25.7%) after tonsillectomy and in 2 cases (5.7%) after laryngomicrosurgery, and feeling of thirst occurred in 12 cases (34.3%) and in 8 cases (22.9%), respectively. CONCLUSION: Taste disturbance occurs in few cases when experienced surgeons perform tonsillectomy or laryngomicrosurgery. However, it is recommended to inform the patients of the potential postoperative complications such as taste disturbance and abnormal sensation of the tongue.

Adolescent↗

Taste disorders: a survey of the examination methods and treatments used in Japan.

CONCLUSIONS: In Japan, the number of patients seeking treatment for taste disorders from otolaryngologists is approximately 240 000/year, and this number has almost doubled in the last 13 years. Taste examinations are routinely conducted in almost all university hospitals; testing is not as common in private clinics. Administration of zinc is the main treatment for taste disorders in Japan. OBJECTIVES: To investigate the number of patients who visited otolaryngologists for treatment of taste disorders between 2000 and 2002. In addition to determining changes in the number of patients that had occurred in the 13 years since the last study in 1990, the survey also sought to find out what types of taste examination were used to diagnose taste disorders in Japan and what therapies were used to treat them. MATERIAL AND METHODS: A questionnaire was mailed to 1559 members of the Japan Society of Stomato-pharyngology. RESULTS: The average number of patients with taste disorders who visited otolaryngological clinics between 2000 and 2002 was 244 858/year. This number is 1.77-fold greater than the number of patients reported by the last study in 1990 (138 575). Electrogustometry was used in 99% of university hospitals and in 20% of private clinics. The filter-paper disk method was also used in 57% of university hospitals and in 27% of private clinics. The main treatment was zinc administration. Most doctors (70%) prescribed polaprezinc, a zinc-containing drug that is used to treat peptic ulcers. Of these doctors, 78% stated that it effectively treated taste disorders and 11% that it did not.

Carnosine↗

Frequency dynamics shift of vestibular evoked myogenic potentials in patients with endolymphatic hydrops.

OBJECTIVE: To measure the frequency dynamics of the vestibular evoked myogenic potential in patients with endolymphatic hydrops. STUDY DESIGN: A prospective study. SETTING: A university hospital. SUBJECTS: The endolymphatic hydrops group consisted of 28 affected ears of patients with definite unilateral Ménière's disease and a control group of 36 ears of 20 healthy volunteers. INTERVENTIONS: Vestibular evoked myogenic potentials generated by tone bursts at 250, 500, 700, 1,000, 1,500, 2,000, and 4,000 Hz were measured in both groups. Vestibular evoked myogenic potentials were also measured after furosemide administration in six patients in the endolymphatic hydrops group. MAIN OUTCOME MEASURE: The frequency sensitivity of vestibular evoked myogenic potential, as evaluated by p13-n23 normalized amplitude. RESULTS: Peak amplitudes were noted at 500 Hz in the control group and at 1,000 Hz in the endolymphatic hydrops group. After furosemide loading, peak amplitude shifted to a lower frequency in four of six ears. CONCLUSION: The peak amplitude of vestibular evoked myogenic potentials in the endolymphatic hydrops group was at a higher frequency than in the control group. The frequency of the saccule (nu) should be proportional to radical(tau/sigma), where tau is the tension of membrane and sigma is its density. We advocate the hypothesis that the shift in frequency dynamics of vestibular evoked myogenic potential in patients with endolymphatic hydrops originates from the morphologic features of the saccule, analogous to an expanded balloon.

Acoustic Stimulation↗

Reevaluation of bilateral same-day surgery for bilateral perforated chronic otitis media.

OBJECTIVE: To evaluate the results of bilateral same-day surgery for bilateral perforated chronic otitis media in comparison with our previous report. STUDY DESIGN: Prospective study. PATIENTS: Seventeen patients ranging in age from 5 to 70 years (mean, 52.5 yr), with bilateral perforated chronic otitis media. METHODS: Two hundred cases of chronic otitis media were operated on at the Department of Otolaryngology, Hyogo College of Medicine from December 1998 to November 2002. Fifty-nine patients (29.5%) had bilateral disease and 17 patients (8.5%) underwent bilateral same-day surgery. RESULTS: The postoperative air-bone gap was less than 10 dB on both sides in 5 of 17 (29%) and less than 20 dB in 15 of 17 (88%). The postoperative hearing level was less than 20 dB in both ears in 4 of 17 (24%), less than 30 dB in 7 of 17 (41%), and less than 40 dB in 10 of 17 (59%). The rate of closure of the ear drum was 20 of 22 (91%) in the simple underlay myringoplasty series and 9 of 12 (75%) in the conventional myringoplasty/tympanoplasty series. The rate of closure of the ear drum on both sides was successful in 4 of 5 (80%) that underwent simple underlay myringoplasty/simple underlay myringoplasty and 8 of 12 (67%) that underwent simple underlay myringoplasty/conventional myringoplasty/tympanoplasty, whereas that on at least one side was successful in 100%. CONCLUSION: Bilateral same-day surgery for bilateral perforated chronic otitis media is possible if operative indications are considered. Furthermore, it will help patients save time and money.

Adolescent↗

Concurrent chemo-radiotherapy for nasopharyngeal carcinoma.

OBJECTIVE: Because of the low incidence of nasopharyngeal carcinoma (NPC) in Japan, few studies have reported on the use of concurrent chemo-radiotherapy (CCRT) for treatment of this disease. The present study investigated the efficacy and toxicity of CCRT with Carboplatin (CBDCA) and UFT for NPC. PATIENTS AND METHODS: CCRT with injection of CBDCA and oral administration of UFT was given to 21 patients in our institution during 1996-2000. We compared the patients treated with CCRT with those treated with RT alone from 1976 to 1995 or those treated with RT after chemotherapy (Pre-RT chemotherapy) from 1985 to 1995. Overall survival rate (OS), progression free survival rate (PFS) and cause specific survival (CSS) rate were analyzed. RESULTS: The actual 2-year OS, PFS, and CSS of CCRT were 85.7, 66.7 and 90%, respectively. The rates were improved compared to RT alone (37.9, 31.0, and 56.6%) and Pre-RT chemotherapy (58.8, 41.2, and 64.7%). The most frequent and severe acute toxicities were leukopenia (42.9%) and mucositis with grade 3-4 (28.6%), both of which eventually resolved. CONCLUSION: CCRT with CBDCA and UFT is considered to be an effective, convenient, and tolerable treatment, which improves survival rates for NPC patients. Therefore, we recommend this CCRT method for the treatment of NPC.

Adult↗

Localization of osteopontin at calcification sites of cholesteatoma: possible role as a regulator of deposition of calcium phosphate in the middle ear.

OBJECTIVE: Recently, we showed that osteopontin (OPN), a major acidic phosphorylated glycoprotein of bone, participates in the pathological calcification that occurs as a result of chronic otitis media. To investigate the possibility of OPN as a common regulator of the pathological calcification in the middle ear, we here examined whether or not OPN is localized at the calcification sites of cholesteatoma, which is clearly different from chronic otitis media in the pathogenesis. METHODS: Middle ear tissues including cholesteatoma were obtained from 32 cases who underwent tympanoplasty. The tissues of 29 cases were used for the immunohistochemistry of OPN and CD68, the marker of macrophages, and in situ hybridization of OPN mRNA. And those of the other three for reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Middle ear tissues including cholesteatoma were histologically classified as to the degree of calcification. In hyalinized tissues with macroscopic calcification, OPN was immunohistochemically found at the calcification sites. In inflammatory tissues with microscopic calcification, OPN was also found in the calcifying foci, and many OPN mRNA-expressing cells, as determined by in situ hybridization, were located near the foci. Moreover, immunohistochemical double staining for OPN and CD68 showed that the OPN-expressing cells were CD68-positive, indicating the cells were macrophages. In inflammatory tissues without calcification, immunohistochemistry of CD68 and in situ hybridization of OPN mRNA revealed that most OPN mRNA-expressing cells were CD68-positive. The expression of OPN mRNA in cholesteatoma tissues was also demonstrated by means of RT-PCR. CONCLUSION: OPN secreted by exudate macrophages was localized in the pathological calcification that occurs in association with cholesteatoma. These results are consistent with the observations in chronic otitis media. Therefore, it is suggested the possibility that OPN might contribute as a common regulator of the deposition of calcium phosphate in the middle ear.

Adolescent↗