Relation between renin-angiotensin-aldosterone system and otosclerosis: a genetic association and in vitro study.

OBJECTIVE/HYPOTHESIS: Angiotensin II (Ang II) may be implicated in the regulation of bone remodeling, and its activity is related to several gene polymorphisms including AGT M235T for plasmatic and tissular concentrations of angiotensinogen (AGT), ACE I/D for the angiotensin-converting enzyme activity, and AT(1)R A/C(1166) for the Ang II receptor function. The objective of this study was to investigate the implication of this hormone in otosclerosis. STUDY DESIGN: Prospective case-control study. METHODS: The above-mentionedpolymorphisms were investigated in 186 patients with otosclerosis and 526 healthy controls, both groups originated from the French Caucasian population. Primary cell cultures of stapedial bone from patients with otosclerosis (n = 6) and control subjects (n = 5) were investigated for the messenger ribonucleic acid expressions of Ang II receptors (Types 1 and 2) and cellular AGT and the effect of Ang II (10(-7) mol/L, 24 h) on the alkaline phosphatase activity and the interleukin-6 secretion in the culture media. RESULTS: A significant association was found between otosclerosis and the AGT M235T and the ACE I/D polymorphisms. Higher proportions of TT (29% versus 16%; p < 0.01) and DD (50% versus 38%; p < 0.05) genotypes were observed in cases versus controls. No association was found between the AT(1)R A/C(1166) polymorphism and otosclerosis. Ang II receptor Types 1 and 2 and AGT were detected in the cultures. Ang II increased the in vitro secretion of interleukin-6 and decreased the alkaline phosphatase activity only in otosclerotic cells. CONCLUSION: These observations suggest a relation between the local renin angiotensin system activity and otosclerosis, opening new therapeutic insights.

Glucocorticoids inhibit diastrophic dysplasia sulfate transporter activity in otosclerosis by interleukin-6.

HYPOTHESIS/OBJECTIVE: Otosclerosis is a bone remodeling disorder localized to the otic capsule and associated with inflammation. In vitro, increased activity of the diastrophic dysplasia sulfate transporter (DTDST), which is implicated in bone metabolism, has been reported. Because glucocorticoids modulate the bone turnover and inhibit inflammatory processes, we investigated the effect of dexamethasone (Dex) on interleukin-6 and DTDST in otosclerosis. STUDY DESIGN: The authors conducted a prospective, case-control study. MATERIALS AND METHODS: Primary cell cultures were obtained from stapes and external auditory canals in otosclerosis (n = 21) and control patients (n = 18). Assays with [H]Dex evaluated specific binding sites in otosclerotic and control stapes. The effects of Dex (10 to 10 M) and RU486 (10 M), a glucocorticoid antagonist, were studied on DTDST activity by sulfate uptake. IL-6 secretion was measured in culture media before and after Dex (10 M, 24 hours). The effect of IL-6 (10 M, 24 hours) was assessed on DTDST activity in control stapes. RESULTS: : The number of specific Dex-binding sites was similar in all stapedial cultures. Dex inhibited DTDST activity (19.4 +/- 1.02 vs. 29.4 +/- 3.94 pmol/microg prot/5 minutes) only in otosclerotic stapes. This effect was dose-dependent, antagonized by RU 486 and only observed 24 hours after Dex exposure. Interleukin (IL)-6 stimulated DTDST activity in normal stapes, whereas Dex inhibited IL-6 production only in otosclerotic stapes. CONCLUSION: Dex inhibits the DTDST activity, at least in part, through a reduction of IL-6 secretion only in otosclerotic cells. This effect is mediated through the glucocorticoid receptors and may lead to the reduction of bone turnover.

Cyclooxygenase-2 regulates the degree of apoptosis by modulating bcl-2 protein in pleomorphic adenoma and mucoepidermoid carcinoma of the parotid gland.

CONCLUSION: These results suggest that COX-2 and bcl-2 protein were overexpressed and that apoptosis was reduced in MEC compared to PMA, and that COX-2 may regulate the degree of apoptosis by modulating bcl-2 protein in PMA and MEC. OBJECTIVE: Cyclooxygenase (COX)-2 plays a crucial role in tumorigenesis and overexpression of COX-2 in vitro accompanied by overexpression of bcl-2 protein has been shown to reduce apoptosis. The purpose of this study was to verify that COX-2 regulates the degree of apoptosis by modulating bcl-2 protein in benign and malignant parotid gland tumors. : We examined archival formalin-fixed, paraffin-embedded tissue sections of 10 pleomorphic adenomas (PMAs) and 10 mucoepidermoid carcinomas (MECs) by immunostaining with anti-COX-2, anti-bcl-2 and anti-single-stranded DNA (ssDNA) antibodies. Labeling indices of the three antibodies were calculated using computer-assisted image analysis. RESULTS: Labeling indices (mean+/-SD) of anti-COX-2 antibody in PMA and MEC were 2.05+/-1.30 and 11.2+/-2.95, respectively (p < 0.001), those of anti-bcl-2 antibody were 2.00+/-1.28 and 9.68+/-4.05, respectively (p < 0.001) and those of anti-ssDNA antibody were 8.06+/-2.54 and 2.08+/-1.47; respectively (p <0.001). Correlation coefficients between the labeling indices of anti-COX-2 antibody and anti-bcl-2 antibody, anti-bcl-2 antibody and anti-ssDNA antibody and anti-COX-2 antibody and anti-ssDNA antibody were 0.88, -0.75 and -0.76, respectively (p <0.001).

Acquired atrophy of the long process of the incus.

Various lesions can cause conductive hearing loss in a patient with a normal tympanic membrane. These include congenital ossicular anomaly, otosclerosis, and congenital or acquired ossicular fixation and discontinuity. We had an experience with a patient who presented with a conductive hearing loss in both ears, in which small pieces of the long process of the incus were absent and had been replaced with fibrous tissues in both ears. No other abnormalities, such as postinflammatory changes or fixation of the ossicles, were found. Because the long process of the incus undergoes remodeling through resorption and rebuilding throughout life, failure of the remodeling or impaired vascular supply to the long process of the incus may have been the cause of the conductive hearing loss in this patient.

Effect of 17 beta-estradiol on diastrophic dysplasia sulfate transporter activity in otosclerotic bone cell cultures and SaOS-2 cells.

OBJECTIVE: Diastrophic dysplasia sulfate transporter (DTDST) is involved in the regulation of bone turnover, and its activity in otosclerosis has been shown to be abnormally high. Taking into account the role of estrogens in the progression of otosclerosis, the possible effect of estrogens on DTDST was investigated in otosclerotic bone cell cultures and in SaOS-2, a human osteoblastic cell line. MATERIAL AND METHODS: Primary bone cell cultures of stapes and external auditory canal (EAC) bone were obtained from 33 patients with otosclerosis and 18 control patients undergoing cerebellopontine angle tumor surgery. These cultures were assessed in parallel with SaOS-2 cells. Estrogen receptors (ERs) were detected using reverse transcriptase polymerase chain reaction. DTDST activity was assessed by sulfate uptake at baseline and after 24 h of incubation with 17 beta-estradiol at concentrations ranging from 10(-12) to 10(-6) M. RESULTS: Stapes and EAC cultures predominantly expressed mRNA of ER alpha, while ER beta expression was predominant in SaOS-2 cells. In stapes and EAC cultures no modification of DTDST activity was observed with 10(-8) M 17 beta-estradiol. In SaOS-2 cells, DTDST activity was inhibited by 17 beta-estradiol (93.5+/-9.21 vs 83.6+/-8.83 pmol/mg protein/5 min, n=29; mean of differences=10.0+/-3.22, paired t-test, p<0.01). CONCLUSION: DTDST activity is regulated by estrogens in SaOS-2 cells, but not in primary cell cultures from stapes and EAC. This difference in the regulation mechanisms may be related to the type of estrogen receptor expressed.

A case of atrophy of the masticatory muscles due to a masticatory habit.

We present a case of atrophy of the masticatory muscles due to a masticatory habit. The patient has had only left side molars for about 40 years. The atrophy of the masticatory muscles was detected incidentally when a brain radiological examination was performed. The patient had no subjective complaints on mastication.

Stomal recurrence after total laryngectomy for squamous cell carcinoma of the larynx.

OBJECTIVE: Stomal recurrence after total laryngectomy is one of the most serious issues in the management of laryngeal carcinoma. The management of stomal recurrence, including chemotherapy, radiotherapy, and surgery, has been reported as unsatisfactory. STUDY DESIGN AND SETTING: From 1985 to 1995, 69 patients underwent total laryngectomy for the treatment of laryngeal cancer at the University of Tokyo Hospital. To identify the risk factors for stomal recurrence, we analyzed these patients according to various clinicopathological factors. RESULTS: Stomal recurrence developed in 6 of 69 patients who underwent total laryngectomy for laryngeal carcinoma. Statistical analysis reveals that primary site, preoperative tracheotomy, and paratracheal lymph node metastasis are significant risk factors for stomal recurrence. CONCLUSION: Intensive follow-up should be performed for patients with glottic carcinoma who had preoperative tracheotomy, paratracheal lymph node metastasis, or both to detect stomal recurrence at an early stage.