Frequency-specific efficacy of intratympanic steroid on idiopathic sudden sensorineural hearing loss.

Background: Hearing recovery would be different in each sound frequency in patients with idiopathic sudden sensorineural hearing loss (ISSNHL).Aims/objectives: To analyze frequency-specific efficacy of intratympanic steroid on ISSNHL.Materials and methods: Of a total of 381 patients with ISSNHL (hearing threshold ≥40 dB; ≤30 days until treatment), 174 patients (174 ears) received systemic steroid plus hyperbaric oxygen therapy (HBO group), and 207 patients (208 ears) received systemic plus intratympanic steroid (IT group). Hearing thresholds at 125-8000 Hz were measured at every octave before and after treatment.Results: % of patients with hearing gains ≥10 dB in the IT group was significantly higher for 500 Hz and the average of 5 mid-frequencies, tended to be higher for 1000 Hz, but was significantly lower for 8000 Hz, compared to the HBO group. Multiple regression analysis showed that hearing recovery was negatively correlated with patients' age for 125/2000/4000/8000 Hz and with days from onset to treatment for all frequencies, and also revealed better hearing recovery at 500/1000 Hz in the IT group than in the HBO group.Conclusions: Intratympanic steroid is more effective than hyperbaric oxygen to yield better hearing outcomes at mid-frequencies and would be advantageous to restore sound/speech perception.Significance: Superiority of intratympanic steroid over hyperbaric oxygen for treating ISSNHL was verified.

Efficacy of Intratympanic Steroid on Idiopathic Sudden Sensorineural Hearing Loss: An Analysis of Cases With Negative Prognostic Factors.

Purpose We retrospectively studied the efficacy of intratympanic steroid administration in comparison with hyperbaric oxygen (HBO) therapy for idiopathic sudden sensorineural hearing loss (ISSNHL) with negative prognostic factors. Method We enrolled 301 patients (302 ears) with ISSNHL (average hearing level at 250-4000 Hz ≥ 40 dB; time from onset to treatment ≤ 30 days). From August 2002 to March 2009, 174 patients (174 ears) received systemic steroid plus HBO therapy (HBO group), and from June 2015 to January 2018, 127 patients (128 ears) received systemic plus intratympanic steroid (IT group). Hearing outcomes were evaluated by 6 indices: cure rate, marked-recovery rate (percent of patients with hearing gain ≥ 30 dB), recovery rate (percent of patients with hearing gain ≥ 10 dB), hearing gain, hearing level after treatment, and percent hearing improvement compared to the unaffected contralateral ear. Results The recovery rate was significantly higher in the IT group than in the HBO group (80.5% vs. 68.4%, p = .019). The IT group showed a higher recovery rate than the HBO group in patients aged ≥ 60 years ( p = .010), patients with early (≤ 7 days from onset) treatment ( p = .005), patients with initial hearing levels ≥ 90 dB ( p = .037), and patients with vertigo/dizziness ( p = .040). The IT group also showed higher hearing gain and percent hearing improvement than the HBO group in patients with vertigo/dizziness ( p = .046 and p = .026, respectively). Conclusions Systemic plus intratympanic steroid is more effective for ISSNHL than systemic steroid plus HBO, particularly in patients with negative prognostic factors, such as old age, profound hearing loss, and/or presence of vertigo/dizziness.

Efficacy of intratympanic steroid administration on idiopathic sudden sensorineural hearing loss in comparison with hyperbaric oxygen therapy.

OBJECTIVES/HYPOTHESIS: The efficacy of intratympanic steroid administration was examined in comparison with hyperbaric oxygen (HBO) therapy in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). STUDY DESIGN: Retrospective study. METHODS: Two hundred seventy-six consecutive patients with ISSNHL (average hearing levels at 250, 500, 1,000, 2,000, and 4,000 Hz ≥ 40 dB; time from onset to treatment ≤30 days) were enrolled. All the patients were given intravenous hydrocortisone (400 mg/day) followed by tapered doses. In addition, 174 patients underwent HBO therapy (HBO group), and 102 patients received intratympanic dexamethasone injection (IT group). The hearing outcomes were evaluated by six indices; the cure rate, marked-recovery rate (percent of patients with hearing gains ≥30 dB), recovery rate (percent of patients with hearing gains ≥10 dB), hearing gain, hearing level after treatment, and hearing improvement rate compared to the unaffected contralateral ear. RESULTS: There was no significant difference in the cure rate, marked-recovery rate, hearing gain, hearing level after treatment, or hearing improvement rate between the two groups; however, the recovery rate was significantly higher in the IT group than in the HBO group (79.4% vs. 68.4%; P = .048). Multiple logistic regression analysis also showed that patients in the IT group were significantly more likely to recover than those in the HBO group (odds ratio: 2.045; 95% confidence interval: 1.097-3.812; P = .024). CONCLUSIONS: Systemic plus intratympanic steroid administration is more effective than systemic steroids plus HBO therapy, and can be a useful first-choice treatment for ISSNHL.

Upregulation of arginine vasopressin synthesis in the rat hypothalamus after kainic acid-induced seizures.

We examined the effects of kainic acid (KA)-induced seizures on arginine vasopressin (AVP) gene expression in the paraventricular (PVN) and the supraoptic nuclei (SON) of normal rats using in situ hybridization histochemistry. We also investigated the expression of the AVP-enhanced green fluorescent protein (eGFP) fusion gene after KA-induced seizures in transgenic rats. AVP heteronuclear (hn) RNA levels in the PVN and the SON were significantly increased at 3h and 24h after subcutaneous (s.c.) administration of KA in normal rats. AVP mRNA levels in the PVN and the SON did not change significantly at 3h, 24h and 1 week after s.c. administration of KA in normal rats. In KA-administered transgenic rats, AVP-eGFP fluorescence in the magnocellular and parvocellular divisions of the PVN and the SON were significantly stronger compared to vehicle-administered transgenic rats. By pretreatment with MK-801 (nonselective N-methyl-D-aspartate, NMDA, receptor antagonist), AVP-eGFP transgenic rats after administration of KA did not show preconvulsive symptoms or convulsions and AVP-eGFP fluorescence in the magnocellular and parvocellular divisions of the PVN and the SON of these rats was significantly reduced. These results suggested that KA-induced increases in AVP transcripts and AVP were prevented by MK801 because seizure activity was prevented or reduced.

Prediction of hearing outcomes by distortion product otoacoustic emissions in patients with idiopathic sudden sensorineural hearing loss.

OBJECTIVE: To investigate whether distortion product otoacoustic emissions (DPOAEs) can be a prognostic indicator of hearing outcomes in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). METHODS: Seventy-eight consecutive patients with ISSNHL were enrolled. DPOAEs were measured at the first hospital visit. Two primary pure tones with a frequency ratio (f2/f1) of 1.2 were used at non-equal sound pressure levels (L1/L2=80/70dB SPL). The DPOAE amplitude was measured at the 11 frequencies of 2f1-f2 with f2 varying from 593 to 6031Hz. All the patients received steroid administration in combination with hyperbaric oxygen (HBO) therapy. Hearing recovery was evaluated by the improvement in hearing compared to the unaffected contralateral ear. Correlations between the hearing improvement rate and five potential prognostic factors (the DPOAE amplitude, patient's age, days from onset to the start of treatment, initial hearing level, and presence of vertigo) were examined by simple and multiple regression analyses. RESULTS: The net DPOAE amplitude in patients with hearing improvement rate ≥50% was significantly larger than that with hearing improvement rate <50% at f2 frequencies of 3031 and 4812Hz (unpaired Student's t-test, p<0.05). A simple regression analysis showed that the hearing improvement rate significantly correlated with the net DPOAE amplitude at f2 frequencies of 3031 and 4812Hz, but not with that at the other f2 frequencies tested. The correlation coefficients were 0.528 and 0.522 for 3031 and 4812Hz, respectively, with p values <1×10(-6). In a multiple regression analysis, the partial correlation coefficients of the net DPOAE amplitude were 0.308 and 0.246 with p values of 0.008 and 0.036 for 3031 and 4812Hz, respectively. CONCLUSION: The significant correlation between hearing recovery and DPOAEs measured before treatment indicates that DPOAEs are a potentially useful means of predicting hearing prognosis in ISSNHL.

Diurnal changes of arginine vasopressin-enhanced green fluorescent protein fusion transgene expression in the rat suprachiasmatic nucleus.

We have recently developed a new transgenic rat line expressing an arginine vasopressin (AVP)-enhanced green fluorescent protein (eGFP) fusion gene. The AVP-eGFP transgene is expressed in the paraventricular (PVN) and supraoptic (SON) nuclei and the suprachiasmatic nucleus (SCN) of the hypothalamus. Transgene expression in the PVN and SON showed an exaggerated response to salt loading and nociceptive stimulation. However, the expression of the AVP-eGFP transgene in the SCN did not change under these stressful conditions. Here, we examined daily profiles of the expression of the AVP-eGFP transgene in the SCN in comparison with the endogenous AVP and Period (Per1 and Per2) genes. While all of these genes elicited diurnal patterns of expression in the SCN, the rate of rhythmic change of transgene expression was significantly greater than that of the endogenous AVP gene. We also examined the effect of a light stimulus on the expression of the AVP-eGFP, AVP, Per1 and Per2 genes in the SCN of transgenic rats. Ninety minutes after a light stimulus, AVP-eGFP mRNA and AVP hnRNA levels in the SCN were significantly decreased, while Per2 mRNA levels were significantly increased. In addition, we observed the eGFP fluorescence in the SCN and recorded the electrophysiological properties of a dissociated SCN eGFP-positive neuron. The AVP-eGFP transgenic rat is a useful animal model to study the diurnal change and dynamics of the AVP system, and enables the facile identification of SCN AVP neurons both in vivo and in vitro.

Centrally administered relaxin-3 induces Fos expression in the osmosensitive areas in rat brain and facilitates water intake.

The expression of the relaxin-3 gene, detected as a new member of the insulin superfamily using human genomic databases, is abundantly present in the brain and testis. Intracerebroventricularly (icv) administered relaxin-3 stimulates food intake. Icv administered relaxin (identical to relaxin-2 in humans) affects the secretion of vasopressin and drinking behavior. Relaxin-3 partly binds relaxin family peptide receptor 1, which is a specific receptor to relaxin. Thus, we hypothesized that relaxin-3 would have physiological effects in the body fluid balance. However, the effects of relaxin-3 in the body fluid balance remain unknown. In the present study, we revealed that icv administered relaxin-3 induced dense Fos-like immunoreactivity (Fos-LI) in the rat hypothalamus and circumventricular organs including the organum vasculosum of the lamina terminalis, the median preoptic nucleus, supraoptic nucleus (SON), the subfornical organ (SFO) and the paraventricular nucleus (PVN), that are related to the central regulation of body fluid balance. Icv administered relaxin-3 (54, 180 and 540 pmol/rat) also induced a significant increase in c-fos gene expression in a dose-dependent manner in the SON, SFO and PVN. Further, icv administered relaxin-3 (180 pmol/rat) significantly increased water intake, and the effect was as strong as that of relaxin-2 (180 pmol/rat). These results suggest that icv administered relaxin-3 activates osmosensitive areas in the brain and plays an important role in the regulation of body fluid balance.

Specific expression of an oxytocin-enhanced cyan fluorescent protein fusion transgene in the rat hypothalamus and posterior pituitary.

We have generated rats bearing an oxytocin (OXT)-enhanced cyan fluorescent protein (eCFP) fusion transgene designed from a murine construct previously shown to be faithfully expressed in transgenic mice. In situ hybridisation histochemistry revealed that the Oxt-eCfp fusion gene was expressed in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) in these rats. The fluorescence emanating from eCFP was observed only in the SON, the PVN, the internal layer of the median eminence and the posterior pituitary (PP). In in vitro preparations, freshly dissociated cells from the SON and axon terminals showed clear eCFP fluorescence. Immunohistochemistry for OXT and arginine vasopressin (AVP) revealed that the eCFP fluorescence co-localises with OXT immunofluorescence, but not with AVP immunofluorescence in the SON and the PVN. Although the expression levels of the Oxt-eCfp fusion gene in the SON and the PVN showed a wide range of variations in transgenic rats, eCFP fluorescence was markedly increased in the SON and the PVN, but decreased in the PP after chronic salt loading. The expression of the Oxt gene was significantly increased in the SON and the PVN after chronic salt loading in both non-transgenic and transgenic rats. Compared with wild-type animals, euhydrated and salt-loaded male and female transgenic rats showed no significant differences in plasma osmolality, sodium concentration and OXT and AVP levels, suggesting that the fusion gene expression did not disturb any physiological processes. These results suggest that our new transgenic rats are a valuable new tool to identify OXT-producing neurones and their terminals.

Robust up-regulation of nuclear red fluorescent-tagged fos marks neuronal activation in green fluorescent vasopressin neurons after osmotic stimulation in a double-transgenic rat.

The up-regulation in the expression of mRNA or protein encoded by the c-fos gene is widely used as a marker of neuronal activation elicited by various stimuli. To facilitate the detection of activated neurons, we generated transgenic rats expressing a fusion gene consisting of c-fos coding sequences in frame with monomeric red fluorescent protein 1 (mRFP1) under the control of c-fos gene regulatory sequences (c-fos-mRFP1 rats). In c-fos-mRFP1 transgenic rats, 90 min after hypertonic saline ip administration, nuclear mRFP1 fluorescence was observed abundantly in brain regions known to be osmosensitive, namely the median preoptic nucleus, organum vasculosum lamina terminalis, supraoptic nucleus, paraventricular nucleus, and subfornical organ. Immunohistochemistry for Fos protein confirmed that the distribution of Fos-like immunoreactivity in nontransgenic rats was similar to those of mRFP1 fluorescence after ip administration of hypertonic saline in the transgenic rats. Several double-transgenic rats were obtained from matings between transgenic rats expressing an arginine vasopressin-enhanced green fluorescent protein fusion gene (AVP-eGFP rats) and c-fos-mRFP1 rats. In these double-transgenic rats, almost all eGFP neurons in the supraoptic nucleus and PVN expressed nuclear mRFP1 fluorescence 90 min after hypertonic saline administration. The c-fos-mRFP1 rats are a powerful tool that enables the facile identification of activated neurons in the nervous system. Furthermore, when combined with transgenes expressing another fluorophore under the control of cell-specific regulatory sequences, activation of specific neuronal cell types in response to physiological cues can be readily detected.

Centrally administered adrenomedullin 5 activates oxytocin-secreting neurons in the hypothalamus and elevates plasma oxytocin level in rats.

We examined the effects of i.c.v. administration of adrenomedullin 5 (AM5) on the brain of conscious rats. We used porcine AM5 in the present study because rat AM5 has not been detected. We observed Fos-like immunoreactivity (LI) in the hypothalamus and brainstem of conscious rats after i.c.v. administration of AM5 (2 nmol/rat). Fos-LI, measured at 90 min post-AM5 injection, was observed in various brain areas, including the supraoptic (SON) and the paraventricular nuclei (PVN). Dual immunostaining for Fos/oxytocin (OXT) and Fos/arginine vasopressin (AVP) revealed that OXT-LI neurones predominantly colocalized Fos-LI compared with AVP-LI neurones in the SON and the PVN. Plasma OXT levels were significantly increased 5 min after i.c.v. administration of AM5 (1 nmol/rat) compared with vehicle and remained elevated in samples taken at 15 and 30 min without changes in plasma AVP levels at any time. In situ hybridization histochemistry showed that i.c.v. administration of AM5 (0.2, 1 and 2 nmol/rat) caused a marked induction of the expression of the c-fos gene in the SON and the PVN. This induction was significantly but not completely reduced by pretreatment with both the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37; 3 nmol/rat) and the AM receptor antagonist AM-(22-52; 27 nmol/rat). Although porcine AM5 has not been detected yet in the brain, these results suggest that centrally administered porcine AM5 may activate OXT-secreting neurosecretory cells in the hypothalamus partly through AM/CGRP receptors and elicit secretion of OXT into the systemic circulation in conscious rats.

Adrenomedullin 2/intermedin-like immunoreactivity in the hypothalamus and brainstem of rats.

Adrenomedullin 2 (AM2) (identical to intermedin)-like immunoreactivity (LI) was examined in the rat brain by immunohistochemistry after intracerebroventricular administration of colchicine (100 microg/rat) and chronic salt loading (2% saline to drink) for 5 days. In both vehicle-treated and euhydrated rats, AM2-LI neurons were observed in the hypothalamus and brainstem, including in the organum vasculosum of the lamina terminalis, the median preoptic nucleus, the supraoptic nucleus (SON), the paraventricular nucleus (PVN), the ventromedial hypothalamic nucleus, the arcuate nucleus, the locus coeruleus, the nucleus of the tractus solitarius and the nucleus ambiguus. In colchicine-treated and salt loaded rats, AM2-LI neurons were visualized more strongly in the SON and the magnocellular part of the PVN than in those in each control. Some AM2-LI neurons appeared in the parvocellular part of the PVN in the colchicine-treated but not salt loaded rats. AM2-LI in the other areas of the hypothalamus and brainstem did not change after colchicine-treatment and chronic salt loading. These results suggest that AM2/intermedin in the hypothalamus and brainstem may play roles on neuroendocrine and autonomic functions, such as water/salt balance, in rats.

Prostaglandin E1 versus steroid in combination with hyperbaric oxygen therapy for idiopathic sudden sensorineural hearing loss.

OBJECTIVE: We conducted a controlled retrospective analysis of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) in order to investigate the effect of prostaglandin E1 (PGE1) plus hyperbaric oxygen (HBO) therapy in comparison with that of steroid plus HBO therapy. METHODS: One hundred and ninety-six consecutive patients with ISSNHL (hearing levels > or ==40dB; time from the onset of hearing loss to the start of treatment < or ==30 days) were enrolled. Ninety-five patients underwent PGE1 plus HBO therapy (PG group) and 101 underwent steroid administration plus HBO therapy (steroid group). Hearing recovery was evaluated by grade assessment and by the improvement in hearing compared to the unaffected contralateral ear. RESULTS: The hearing levels after treatment were 52.2+/-3.0 and 47.5+/-2.8dB, the hearing gains were 31.3+/-2.2 and 27.2+/-2.3dB, the cure rates were 28.4% and 28.7%, the recovery rates were 54.7% and 53.5%, and the hearing improvement rates were 48.4+/-5.1% and 53.9+/-4.2% in the PG and steroid groups, respectively. There were no significant differences between the two groups. CONCLUSION: We concluded that PGE1 and a steroid are equally effective in the treatment of ISSNHL when used together with HBO therapy. PGE1 plus HBO therapy can be one of the potential alternative treatments for ISSNHL, particularly in steroid-intolerant patients such as those with severe diabetes mellitus, an active peptic ulcer, or viral hepatitis.

Prostaglandin E1 in combination with hyperbaric oxygen therapy for idiopathic sudden sensorineural hearing loss.

CONCLUSIONS: Prostaglandin E1 (PGE1) is less effective than stellate ganglion block (SGB) in the treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) patients with severe hearing losses when used together with hyperbaric oxygen (HBO) therapy. In contrast with the systemic action of intravenous PGE1, SGB's localized vasodilating action may explain its advantage over intravenous PGE1. OBJECTIVES: To investigate the effect of PGE1 plus HBO therapy on ISSNHL in comparison with that of SGB plus HBO therapy. PATIENTS AND METHODS: We retrospectively analyzed 205 consecutive patients with ISSNHL (hearing levels > or = 40 dB; time from the onset of hearing loss to the start of treatment < or = 30 days). Ninety-five patients underwent intravenous PGE1 plus HBO therapy (PG group) and 110 underwent SGB plus HBO therapy (SGB group). Hearing recovery was evaluated by grade assessment and by hearing improvement compared to that in the unaffected contralateral ear. RESULTS: The overall hearing outcome was not statistically different between the two groups. For patients with initial hearing levels <80 dB, the groups had roughly equivalent hearing outcomes, whereas in patients with initial hearing levels > or = 80 dB, the hearing improvement rate was significantly higher in the SGB group than in the PG group (53.0 +/- 5.0% vs 35.3 +/- 6.8%; p <0.05).