Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model.

Ménière's disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière's disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1ß production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk-/- mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière's disease pathogenesis.

Expression of artemin and GFRα3 in an animal model of migraine: possible role in the pathogenesis of this disorder.

BACKGROUND: Neurotrophic factors have been implicated in hyperalgesia and peripheral levels of these molecules are altered in migraine pathophysiology. Artemin, a vasculature-derived neurotrophic factor, contributes to pain modulation and trigeminal primary afferent sensitization through binding its selective receptor GFRα3. The distribution of artemin and GFRα3 in the dura mater raises an anatomy supports that they may be involved in migraine. In this study we evaluated the expression of artemin and GFRα3 in an animal migraine model that may be relevant for migraine. METHODS: In this study, using a rat migraine model by administration of nitroglycerin (NTG), we investigated the expression of artemin in the dura mater and GFRα3 in the trigeminal ganglia (TG) by means of quantitative reverse transcription-polymerase chain reaction, western blot and immunofluorescence labeling. RESULTS: Artemin immunoreactivity was found in the smooth muscle cells of dural vasculature and GFRα3 was present in cytoplasm of TG neurons. The mRNA levels of artemin and GFRα3 were significantly elevated after NTG treatment at 2 and 4 h respectively (P < 0.05). The expression of artemin protein was increased at 4 h and continually up to 8 h in the dura mater following NTG administration (P < 0.05). The expression of GFRα3 protein was elevated at 4 h and continually up to 10 h in the TG following NTG administration (P < 0.05). CONCLUSION: The findings suggest that artemin and GFRα3 play an important role in the pathogenesis of migraine and may represent potential therapeutic targets for the treatment of migraine.

[Visualization of endolymphatic hydrops in 3D-FLAIR MRI after intratympanic Gd-DTPA administration in Meniere's disease patients].

OBJECTIVE: To study the feasibility of endolymphatic visualization and the diagnosis of Meniere's disease by applying intratympanic gadolinium administration through the tympanic membrance and three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI). To study the relationship between the endolymphatic hydrops visualized by MRI and audio-vestibular functional tests, such as pure tone audiometry (PTA), electrocochleography (EcoG), caloric test and vestibular evoked myogenic potential (VEMP). METHODS: With a three Tesla magnetic resonance imaging (MRI) unit, 3D-FLAIR imaging was performed 24 hours after intratympanic gadolinium through the tympanic membrance in 32 patients with clinically diagnosed unilateral Meniere's Disease. We visualized the enhanced imaging of perilymphatic space in bilateral cochlea, vestibular and (or) canal, scoring scala tympani and scala vestibule of bilateral cochlear basal turn respectively and measuring the developing area of bilateral vestibule and the signal intensity ratio (SIR) between the vestibule and the brain stem subjectively. PTA, EcoG, caloric test and VEMP were performed. The relationship between the endolymphatic hydrops visualized by MRI and audio-vestibular functional tests were studied. RESULTS: The gadolinium appeared in almost all parts of the perilymph in cochlea, vestibular and (or) canals in all 32 patients' inner ears, so the endolymphatic space was clearly shown on 3D-FLAIR imaging. The scala vestibuli score value between the affected side and the healthy side were statistically significant (Z = 4.309, P < 0.05) . The developing vestibular area between the affected side and the healthy side [(6.04 ± 2.89) mm(2), (8.28 ± 3.04)mm(2)] were statistically significant (t = 3.322, P < 0.05) . Abnormal vestibular evoked myogenic potentials were significantly correlated with the developing vestibular area of the affected side (F = 11.96, P < 0.05) . Abnormal electrocochleography were significantly correlated with scala vestibuli score value of cochlear basal turn in the affected side (Z = 3.17, P < 0.05) . No significant correlation was found between the scala vestibuli score value or the developing vestibular area and caloric test or PTA findings. CONCLUSIONS: 3D-FLAIR MRI with intratympanic gadolinium injection through the tympanic membrance can discriminate the border between the perilymph and the endolymph and show endolymphatic hydrops. This method may provide radiographic reference for the diagnosis of Meniere's disease. The results of VEMP and electrocochleography might have appropriate correlation with degree of vestibular and cochlear hydrops.

[Short-term efficacy of semicircular canal occlusion in the treatment of intractable Meniere's disease].

OBJECTIVE: To investigate the short-term efficacy and safety of triple semicircular canal occlusion (TSCO) in the treatment of intractable Meniere's disease (MD), so as to provide an alternative surgical procedure for treating MD. METHODS: Seventeen patients, who had received standardized conservative treatment for at least one year with poor effect, underwent TSCO were retrospectively analyzed. Vertigo control and auditory function were evaluated. Pure tone audiometry, caloric test, and vestibular evoked myogenic potential (VEMP) were performed for evaluation of audiological and vestibular function. Postoperative follow-up period was 6 - 13 months, with an average of ten months. RESULTS: According to the preoperative staging of hearing, among the 17 patients, there were 2 cases in stage II (with an average hearing threshold of 25 - 40 dBHL) and 15 in stage III (41 - 70 dBHL). No vertigo was found during the follow-up period, with 100% control rate of vertigo. During the same period, we had performed endolymphatic sac decompression operation in 25 MD patients. The control rate of vertigo was 72.0%. The vertigo control rate of TSCO was significantly higher than that of endolymphatic sac decompression operation (χ(2) = 3.87, P < 0.05). Three months after surgery, 12 patients showed no significant change in comparison to primary status, 5 patients presented with an mild increase in the average hearing threshold of less than 20 dBHL, with 29.4% of hearing loss rate. Post-operatively, all patients suffered from temporary vertigo and balance disorders. Vertigo was disappeared in all patients within 3 days, while, balance disorders were disappeared in 10 patients within 1 - 2 weeks after surgery, and in another 7 patients within 2 months, with an average recovery time of 12.6 days. Three months after treatment, loss of semicircular canal function by caloric test was found in the operation side of all patients and no change in VEMP test was noted. All patients had no facial paralysis, cerebrospinal fluid leakage, and other complications. CONCLUSIONS: TSCO, which can reduce vertiginous symptoms in patients with intractable MD, represents an effective and safe therapy for this disorder. TSCO is expected to be used as an alternative procedure for the treatment of MD in selected patients suffering from moderate to severe hearing loss.

[Clinical value of dynamic posturography in the evaluation and rehabilitation of vestibular function of patients with benign paroxysmal positional vertigo].

OBJECTIVE: To explore the clinical value of dynamic posturography in the evaluation and rehabilitation of vestibular function of patients with benign paroxysmal positional vertigo (BPPV). METHODS: A total of 48 patients with BPPV of posterior semicircular canal in vertigo clinic of our hospital from May 2007 to December 2008 were retrospectively analyzed in this study. All patients underwent the inspection of caloric test, static posturography, and dynamic posturography. The vestibular tests were performed at two different time points: at onset when patients had typical nystagmus provoked by the Dix-Hallpike maneuver before treatment with the Epley maneuver (canalith repositioning maneuver, CRM), and at one week after treatment with CRM as their nystagmus disappeared. And results at theses two time points were compared. Eight patients whose dynamic balances were still abnormal after CRM accepted vestibular rehabilitation exercise using dynamic posturography, and re-examined 3 weeks later with dynamic posturography. RESULTS: Among 48 cases of BPPV, the abnormal rates of caloric test, static posturography, and dynamic posturography before CRM were 25.0%, 33.3% and 70.8%, respectively. The abnormal rate of dynamic posturography was much higher than that of caloric test or static posturography, and the differences were statistically significant (χ² = 4.84, 7.88; P < 0.05). After CRM, the abnormal rates of caloric test, static posturography, and dynamic posturography were 14.6%, 8.3% and 16.7%, respectively. After CRM, the abnormal rate of static and dynamic posturography showed significant reduction (χ² = 24.04, 10.08; P < 0.05), however, the results of caloric test showed no significant change (χ² = 3.20, P > 0.05). Eight patients whose dynamic balances were still abnormal after CRM, accepted vestibular rehabilitation exercise lasting 3 weeks using dynamic posturography. The dynamic balances were all improved to normal after vestibular rehabilitation. CONCLUSIONS: Dynamic posturography can quantitatively analyze postural balance, and is helpful in comprehensive evaluation of the vestibular function of BPPV patients. Impaired balance often presents in patients with BPPV. Treatment of BPPV using the canalith repositioning maneuver results in improved postural stability in static and dynamic posturography. However, not all patients have normal dynamic stability after successful CRM. The vestibular rehabilitation exercise using dynamic posturography is a helpful adjunct to the treatment for these patients.

[Surgical management and preservation of laryngeal function for senile patients with advanced laryngeal carcinoma].

OBJECTIVE: To explore the methods of surgical treatment and preservation of laryngeal function in senile patients with advanced laryngeal carcinoma. METHODS: A retrospective data review of 87 advanced laryngeal carcinoma patients aged over 65 years was carried out. Of these 87 patients treated by different modes of surgery, 48 had supraglottic cancer, 35 glottic cancer and 4 subglottic cancer. The surgery modes consisted of major partial laryngectomy in 36 patients, subtotal partial laryngectomy with laryngoplasty in 21 and total laryngectomy in 30. All patients received postoperative radiotherapy to a dose of 50-60 Gy. Kaplan-Meier method was used to analyze the survival. RESULTS: The overall 3- and 5-year survival rate was 73.2% and 67.4%, respectively. The ultimate rate of larynx preservation was 65.5%. Of 57 patients with partial laryngectomy, 46 were decannulated with a decannulation rate of 80.7%. Yet, in all patients, the nasal feeding tube was removed and food intake per os was resumed. All patients who underwent partial laryngectomy regained their phonation function. CONCLUSION: It is safe and effective to treat and preserve laryngeal function surgically in the senile patients with advanced laryngeal carcinoma. The key points to achieve this are selection of proper patient, renovation of surgical procedure and improvement of surgical skill.

[Surgical management of aged patients with hypopharyngeal carcinoma and preservation of laryngeal function].

BACKGROUND & OBJECTIVE: The prolongation of life expectancy results in an increasing number of aged patients with hypopharyngeal carcinoma who have poor surgical tolerance because of degenerative organ functions. This study was to explore the surgical methods and preservation of laryngeal function for aged patients with hypopharyngeal carcinoma. METHODS: Clinical data of 84 patients with hypopharyngeal carcinoma who aged above 60 years, treated from 1996 to 2001, were retrospectively reviewed. Of the 84 cases, 68 were originated from pyriform sinus, 5 from postcricoid area, 11 from posterior pharyngeal wall; 57 patients received partial laryngectomy with laryngeal function preservation, 27 received total laryngectomy. Kaplan-Meier method and log-rank test were used to evaluate the survival rates. RESULTS: The overall 3- and 5-year survival rates were 60.7% and 53.3%, respectively. The 3- and 5-year survival rates of laryngeal function preservation group was not significantly different from those of total laryngectomy group (63.2% vs. 55.6%, P = 0.37; 56.7% vs. 46.3%, P > 0.05). In laryngeal function preservation group, 39 (68.4%) had all functions preserved (voice, respiration, and deglutition), and 18 (31.6%) partially preserved (voice and deglutition). CONCLUSION: It is safe and effective to treat aged hypopharyngeal carcinoma patients with surgery, and is possible to preserve laryngeal function in T3-4 stage aged patients who have no involvement of contralateral larynx, no invasion to esophagus, and no deglutition difficulty.