Gender differences in oral appliance treatment of obstructive sleep apnea.

PURPOSE: Although overall success rates for treating obstructive sleep apnea (OSA) with an oral appliance (OA) are high, they are significantly higher among females. To verify published data, the study's purpose was to evaluate a participant sample after one year of OA use. The primary outcome was treatment response, with responders defined as having an apnea-hypopnea index (AHI) < 10 at follow-up and/or reduced by ≥50% of baseline. Secondary measures were from standardized questionnaires. METHODS: A sample of 314 participants, predominately with moderate-to-severe OSA, were enrolled and instructed to use an OA every night. At baseline and one-year follow-up, polygraphic recordings and questionnaires, including sleepiness (measured using the Epworth sleepiness scale) and quality-of-life (measured using the Functional Outcomes of Sleep Questionnaire), were collected. RESULTS: Among the 314 participants, 192 completed the one-year evaluation: 51 females (27%) and 141 males (73%). Overall, OA treatment resulted in 78% and 77% responders among females and males, respectively. Neither the difference in improvement nor the absolute change in AHI differed significantly based on gender, at any OSA severity level. There were no significant gender differences in sleepiness or quality of life. Treatment-related adverse reactions were more common among females. CONCLUSION: Both females and males with OSA respond well to OA therapy, with nonsignificant gender differences in outcomes. Thus, the hypothesis that females respond better to OA treatment is rejected.

Hydrogen Gas Inhalation Attenuates Acute Impulse Noise Trauma: A Preclinical In Vivo Study.

OBJECTIVE: Molecular hydrogen (H2) has shown therapeutic potential in several oxidative stress-related conditions in humans, is well-tolerated, and is easily administered via inhalation.The aim of this preclinical in vivo study was to investigate whether impulse noise trauma can be prevented by H2 when inhaled immediately after impulse noise exposure. METHODS: Guinea pigs (n = 26) were subjected to impulse noise (n = 400; 156 dB SPL; 0.33/s; n = 11; the Noise group), to impulse noise immediately followed by H2 inhalation (2 mol%; 500 ml/min; 1 hour; n = 10; the Noise + H2 group), or to H2 inhalation (n = 5; the H2 group). The acoustically evoked ABR threshold at 3.15, 6.30, 12.5, 20.0, and 30.0 kHz was assessed before and 4 days after impulse noise and/or H2 exposure. The cochleae were harvested after the final ABR assessment for quantification of hair cells. RESULTS: Noise exposure caused ABR threshold elevations at all frequencies (median 35, 35, 30, 35, and 35 dB SPL, the Noise group; 20, 25, 10, 13, and 20 dB SPL, the Noise + H2 group; P < .05) but significantly less so in the Noise + H2 group (P < .05). Outer hair cell (OHC) loss was in the apical, mid, and basal regions 8.8%, 53%, and 14% in the Noise group and 3.5%, 22%, and 1.2% in the Noise + H2 group. The corresponding inner hair cell (IHC) loss was 0.1%, 14%, and 3.5% in the Noise group and 0%, 2.8%, and 0% in the Noise + H2 group. The difference between the groups was significant in the basal region for OHCs (P = .003) and apical (P = .033) and basal (P = .048) regions for IHCs. CONCLUSIONS: Acute acoustic trauma can be reduced by H2 when inhaled immediately after impulse noise exposure.

The outcome of oral appliance therapy on position-dependent obstructive sleep apnea: A multicenter randomized controlled trial.

INTRODUCTION: This multicenter trial on patients with obstructive sleep apnea (OSA) treated with an oral appliance aimed to determine the effect of sleeping positions. METHODS: A cohort of 314 patients with OSA were enrolled and evaluated at 8 weeks and 1 year, focusing on treatment effects. At baseline and the 2 follow-ups, new polygraphic registration comparing the proportion of treatment responders without position-dependent OSA (non-position-dependent OSA [non-POSA]) and with POSA was used. RESULTS: At the 8-week and 1-year follow-up, 205 and 139 patients were included, respectively. The proportion of responders (apnea-hypopnea index [AHI] <10 and/or ≥50% reduction in AHI) was 56% for the non-POSA group and 69% for the POSA group (not significant [NS]). The responders increased at the 1-year follow-up: 68% and 77% for the non-POSA and POSA groups (NS), respectively. The absolute change in AHI in all sleeping positions at 8 weeks was -12.9 (interquartile range, -25.0 to -0.5) in the non-POSA group and -10.5 (interquartile range, -19.9 to -5.3; NS) in the POSA group. However, the decrease in supine AHI was significantly greater among subjects with POSA. In contrast, the decrease in nonsupine AHI was significantly greater in the non-POSA group, an effect that remained at the 1-year follow-up. CONCLUSIONS: Our hypothesis that subjects with POSA at baseline would have a higher treatment response rate after oral appliance treatment compared with subjects without POSA was rejected. However, those with POSA had a significantly higher supine AHI decrease, and those without POSA had significantly less nonsupine AHI.

Evaluation of an extracorporeal ozone-based bactericide system for the treatment of Escherichia coli sepsis.

BACKGROUND: Sepsis is associated with substantial mortality rates. Antibiotic treatment is crucial, but global antibiotic resistance is now classified as one of the top ten global public health risks facing humanity. Ozone (O3) is an inorganic molecule with no evident function in the body. We investigated the bactericide properties of ozone, using a novel system of extracorporeal ozone blood treatment. We hypothesized that ozone would decrease the concentration of viable Escherichia coli (E. coli) in human whole blood and that the system would be technically feasible and physiologically tolerable in a clinically relevant model of E. coli sepsis in swine. METHODS: The E. coli strain B09-11822, a clinical isolate from a patient with septic shock was used. The in vitro study treated E. coli infected human whole blood (n = 6) with ozone. The in vivo 3.5-h sepsis model randomized swine to E. coli infusion and ozone treatment (n = 5) or E. coli infusion and no ozone treatment (n = 5). Live E. coli, 5 × 107 colony-forming units (CFU/mL) was infused in a peripheral vein. Ozone treatment was initiated with a duration of 30 min after 1.5 h. RESULTS: The single pass in vitro treatment decreased E. coli by 27%, mean 1941 to 1422 CFU/mL, mean of differences - 519.0 (95% CI - 955.0 to - 82.98, P = 0.0281). pO2 increased (95% CI 31.35 to 48.80, P = 0.0007), pCO2 decreased (95% CI - 3.203 to - 1.134, P = 0.0069), oxyhemoglobin increased (95% CI 1.010 to 3.669, P = 0.0113). Methemoglobin was not affected. In the sepsis model, 9/10 swine survived. One swine randomized to ozone treatment died from septic shock before initiation of the treatment. Circulatory, respiratory, and metabolic parameters were not affected by the ozone treatment. E. coli in arterial blood, in organs and in aerobic and anaerobic blood cultures did not differ. Hemoglobin, leucocytes, and methemoglobin were not affected by the treatment. CONCLUSIONS: Ozone decreased the concentration of viable E. coli in human whole blood. The system was technically feasible and physiologically tolerable in porcine sepsis/septic shock and should be considered for further studies towards clinical applications.

Inhalation of Molecular Hydrogen, a Rescue Treatment for Noise-Induced Hearing Loss.

Noise exposure is the most important external factor causing acquired hearing loss in humans, and it is strongly associated with the production of reactive oxygen species (ROS) in the cochlea. Several studies reported that the administration of various compounds with antioxidant effects can treat oxidative stress-induced hearing loss. However, traditional systemic drug administration to the human inner ear is problematic and has not been successful in a clinical setting. Thus, there is an urgent need to develop rescue treatment for patients with acute acoustic injuries. Hydrogen gas has antioxidant effects, rapid distribution, and distributes systemically after inhalation.The purpose of this study was to determine the protective efficacy of a single dose of molecular hydrogen (H2) on cochlear structures. Guinea pigs were divided into six groups and sacrificed immediately after or at 1 or 2 weeks. The animals were exposed to broadband noise for 2 h directly followed by 1-h inhalation of 2% H2 or room air. Electrophysiological hearing thresholds using frequency-specific auditory brainstem response (ABR) were measured prior to noise exposure and before sacrifice. ABR thresholds were significantly lower in H2-treated animals at 2 weeks after exposure, with significant preservation of outer hair cells in the entire cochlea. Quantification of synaptophysin immunoreactivity revealed that H2 inhalation protected the cochlear inner hair cell synaptic structures containing synaptophysin. The inflammatory response was greater in the stria vascularis, showing increased Iba1 due to H2 inhalation.Repeated administration of H2 inhalation may further improve the therapeutic effect. This animal model does not reproduce conditions in humans, highlighting the need for additional real-life studies in humans.

Respiratory outcomes after a 1-year treatment of obstructive sleep apnoea with bibloc versus monobloc oral appliances: a multicentre, randomized equivalence trial.

Objective: The benefit of bibloc over monobloc appliances in treating obstructive sleep apnoea (OSA) has not been evaluated in randomized trials. We hypothesized that these types of appliances would be equally effective.Material and methods: In this multicentre, randomized equivalence trial, patients with OSA received one type of bibloc or one type of monobloc treatment. At baseline, a 1-night polygraphy study was done, and this was repeated after 1 year. The outcome was any change in the apnoea-hypopnoea index (AHI) and the limits of equivalence between the two devices were set at ±5 AHI units.Results: Of 302 patients, 146 were randomly assigned to bibloc and 156 to monobloc appliances. In 88 and 104 patients, respectively, there were significant reductions in the AHI (p < .001) with a mean change of -16.7 (95% CI -19.4 to -14.1) in the bibloc and -11.8 (-14.9 to -8.7) in the monobloc groups. The proportions of responders defined as having an AHI <10 were 68% and 65% for the bibloc and monobloc groups, respectively. Treatment-related adverse events were mild, transient and the dropouts were more frequent in the bibloc group.Conclusions: Both types of treatments positively and significantly reduced respiratory disturbances, but at the 1-year follow-up, they were not significantly different in treating OSA, with a numerically greater reduction of the AHI value with the bibloc appliance. However, the higher proportion of treatment-related adverse events and higher proportion of dropouts among bibloc users should be balanced against the advantage of a greater reduction in the AHI.

A prospective 10-year cephalometric follow-up study of patients with obstructive sleep apnea and snoring who used a mandibular protruding device.

INTRODUCTION: This 10-year prospective cephalometric study evaluates the influence of a mandibular protruding device (MPD) in people with obstructive sleep apnea and snoring. METHODS: A baseline study population of 77 people was followed biennially. After 10 years, 65 people (45 MPD users and 20 stopped-MPD users) were reexamined. At baseline and after 10 years, a lateral cephalogram was taken in the upright position. RESULTS: MPD users showed significant changes in all cephalometric variables except for maxillary protrusion. The maxillary incisors were retroclined by a mean -4.2° (standard deviation [SD] 3.95; P <0.001), mandibular incisors were proclined by a mean 3.2° (SD, 5.02; P <0.001), and SNB was reduced by a mean -0.6° (SD 1.41; P = 0.01). In those who had stopped MPD use, these initial cephalometric values were retained. Significant changes in decreased overjet and overbite were seen in the MPD group but not in the MPD-stopped group. The length of the mandible (Cd-Pg) increased by a mean of 5.1 mm (SD 6.78; P <0.001) and 6.1 mm (SD 5.99; P <0.001) in MPD and MPD-stopped groups, respectively. The hyoid bone-mandibular plane distance (hy-ML) increased by a mean of 3.3 mm (SD, 2.90; P <0.001) and 3.8 mm (SD 3.67; P = 0.001) in MPD and MPD-stopped groups, respectively. CONCLUSIONS: Long-term nocturnal MPD use causes retroclination of the maxillary incisors and proclination of the mandibular incisors with consequent decreased overjet and overbite. Both MPD and MPD-stopped users obtained increased mandibular length and lower position of the hyoid bone, which can be a normal physiological change with age.

Middle Ear Administration of a Particulate Chitosan Gel in an in vivo Model of Cisplatin Ototoxicity.

BACKGROUND: Middle ear (intratympanic, IT) administration is a promising therapeutic method as it offers the possibility of achieving high inner ear drug concentrations with low systemic levels, thus minimizing the risk of systemic side effects and drug-drug interactions. Premature elimination through the Eustachian tube may be reduced by stabilizing drug solutions with a hydrogel, but this raises the secondary issue of conductive hearing loss. AIM: This study aimed to investigate the properties of a chitosan-based particulate hydrogel formulation when used as a drug carrier for IT administration in an in vivo model of ototoxicity. MATERIALS AND METHODS: Two particulate chitosan-based IT delivery systems, Thio-25 and Thio-40, were investigated in albino guinea pigs (n = 94). Both contained the hearing protecting drug candidate sodium thiosulfate with different concentrations of chitosan gel particles (25% vs. 40%). The safety of the two systems was explored in vivo. The most promising system was then tested in guinea pigs subjected to a single intravenous injection with the anticancer drug cisplatin (8 mg/kg b.w.), which has ototoxic side effects. Hearing status was evaluated with acoustically evoked frequency-specific auditory brainstem response (ABR) and hair cell counting. Finally, in vivo magnetic resonance imaging was used to study the distribution and elimination of the chitosan-based system from the middle ear cavity in comparison to a hyaluronan-based system. RESULTS: Both chitosan-based IT delivery systems caused ABR threshold elevations (p < 0.05) that remained after 10 days (p < 0.05) without evidence of hair cell loss, although the elevation induced by Thio-25 was significantly lower than for Thio-40 (p < 0.05). Thio-25 significantly reduced cisplatin-induced ABR threshold elevations (p < 0.05) and outer hair cell loss (p < 0.05). IT injection of the chitosan- and hyaluronan-based systems filled up most of the middle ear space. There were no significant differences between the systems in terms of distribution and elimination. CONCLUSION: Particulate chitosan is a promising drug carrier for IT administration. Future studies should assess whether the physical properties of this technique allow for a smaller injection volume that would reduce conductive hearing loss.

Use of bibloc and monobloc oral appliances in obstructive sleep apnoea: a multicentre, randomized, blinded, parallel-group equivalence trial.

Background: The clinical benefit of bibloc over monobloc appliances in treating obstructive sleep apnoea (OSA) has not been evaluated in randomized trials. We hypothesized that the two types of appliances are equally effective in treating OSA. Objective: To compare the efficacy of monobloc versus bibloc appliances in a short-term perspective. Patients and methods: In this multicentre, randomized, blinded, controlled, parallel-group equivalence trial, patients with OSA were randomly assigned to use either a bibloc or a monobloc appliance. One-night respiratory polygraphy without respiratory support was performed at baseline, and participants were re-examined with the appliance in place at short-term follow-up. The primary outcome was the change in the apnoea-hypopnea index (AHI). An independent person prepared a randomization list and sealed envelopes. Evaluating dentist and the biomedical analysts who evaluated the polygraphy were blinded to the choice of therapy. Results: Of 302 patients, 146 were randomly assigned to use the bibloc and 156 the monobloc device; 123 and 139 patients, respectively, were analysed as per protocol. The mean changes in AHI were -13.8 (95% confidence interval -16.1 to -11.5) in the bibloc group and -12.5 (-14.8 to -10.3) in the monobloc group. The difference of -1.3 (-4.5 to 1.9) was significant within the equivalence interval (P = 0.011; the greater of the two P values) and was confirmed by the intention-to-treat analysis (P = 0.001). The adverse events were of mild character and were experienced by similar percentages of patients in both groups (39 and 40 per cent for the bibloc and monobloc group, respectively). Limitations: The study shows short-term results with a median time from commencing treatment to the evaluation visit of 56 days and long-term data on efficacy and harm are needed to be fully conclusive. Conclusion: In a short-term perspective, both appliances were equivalent in terms of their positive effects for treating OSA and caused adverse events of similar magnitude. Trial registration: Registered with ClinicalTrials.gov (#NCT02148510).

The feasibility of an encapsulated cell approach in an animal deafness model.

For patients with profound hearing loss a cochlear implant (CI) is the only treatment today. The function of a CI depends in part of the function and survival of the remaining spiral ganglion neurons (SGN). It is well known from animal models that inner ear infusion of neurotrophic factors prevents SGN degeneration and maintains electrical responsiveness in deafened animals. The purpose with this study was to investigate the effects of a novel encapsulated cell (EC) device releasing neurotrophic factors in the deafened guinea pig. The results showed that an EC device releasing glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) implanted for four weeks in deafened guinea pigs significantly preserved the SGNs and maintained their electrical responsiveness. There was a significant difference between BDNF and GDNF in favour of GDNF. This study, demonstrating positive structural and functional effects in the deafened inner ear, suggests that an implanted EC device releasing biologically protective substances offers a feasible approach for treating progressive hearing impairment.

Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig.

Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest. Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin. Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed. Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects. Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.

Cisplatin-induced metabolome changes in serum: an experimental approach to identify markers for ototoxicity.

BACKGROUND: Ototoxicity from treatment with the anticancer drug cisplatin remains a clinical problem. A wide range of intracellular targets of cisplatin has been found in vivo. AIM: To investigate cisplatin-induced change of the serum metabolite profile and its association with ototoxicity. MATERIAL AND METHODS: Guinea pigs (n = 14) were treated with cisplatin (8 mg/kg b.w., i.v.) 30 min after administration of the otoprotector candidate sodium thiosulfate (group STS; n = 7) or sodium chloride (group NaCl; n = 7). Ototoxicity was evaluated by ABR (3-30 kHz) before and 4 d after drug treatment, and by assessment of hair cell loss. A blood sample was drawn before and 4 d after drug treatment and the polar metabolome in serum was analyzed using LC-MS. RESULTS: Cisplatin-treatment caused significant threshold elevations and outer hair cell (OHC) loss in both groups. The ototoxicity was generally lower in group STS, but a significant difference was reached only at 30 kHz (p = .007). Cisplatin treatment altered the metabolite profile significantly and similarly in both groups. A significant inverse correlation was found between L-acetylcarnitine, N-acetylneuraminic acid, ceramide, and cysteinylserine and high frequency hearing loss in group NaCl. The implication of these correlations should be explored in targeted studies.

Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

A prospective 10-year follow-up dental cast study of patients with obstructive sleep apnoea/snoring who use a mandibular protruding device.

OBJECTIVES: This 10-year prospective study aimed to measure and evaluate the teeth position and occlusion following 10-year nocturnal use of a mandibular protruding device (MPD) in subjects with obstructive sleep apnoea (OSA) or snoring. MATERIALS AND METHODS: Seventy-seven consecutive patients diagnosed with OSA/snoring were treated with an MPD. Fabrication of dental casts with jaw registration indexes in the intercuspal position was carried out at baseline and at follow-up, a construction bite was made, and an MPD was fitted. At the 10-year follow-up, all subjects (n = 74) were invited to participate. The dental casts were analysed in a series of measurements. RESULTS: Sixty subjects were included in the follow-up examination-41 were still using the device and 19 had ceased using the MPD. The MPD users showed significant changes in all analysed variables-decrease of overjet (-1.8 mm), overbite (-1.5 mm)-except the mandibular intercanine width and the maxillary anteroposterior relationship. Subjects who had ceased using their MPD retained their initial values, with the exception of a decreased overbite. The MPD users also showed an increased number of subjects with mesio-occlusion and posterior infra-occlusion; those who had ceased using their MPD mostly retained their initial status. CONCLUSIONS: Long-term nocturnal use of an MPD may cause both favourable and unfavourable occlusion changes, such as a decrease of the overjet and overbite or posterior infra-occlusion, and these changes may continue to develop during treatment with an MPD. Subjects with a Class III relationship may not be a suitable group for treatment with an MPD due to the mesial drift of the mandibular teeth.

Structural changes in the inner ear over time studied in the experimentally deafened guinea pig.

Today a cochlear implant (CI) may significantly restore auditory function, even for people with a profound hearing loss. Because the efficacy of a CI is believed to depend mainly on the remaining population of spiral ganglion neurons (SGNs), it is important to understand the timeline of the degenerative process of the auditory neurons following deafness. Guinea pigs were transtympanically deafened with neomycin, verified by recording auditory brainstem responses (ABRs), and then sacrificed at different time points. Loss of SGNs as well as changes in cell body and nuclear volume were estimated. To study the effect of delayed treatment, a group of animals that had been deaf for 12 weeks was implanted with a stimulus electrode mimicking a CI, after which they received a 4-week treatment with glial cell-derived neurotrophic factor (GDNF). The electrical responsiveness of the SGNs was measured by recording electrically evoked ABRs. There was a rapid degeneration during the first 7 weeks, shown as a significant reduction of the SGN population. The degenerative process then slowed, and there was no difference in the amount of remaining neurons between weeks 7 and 18. © 2016 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Dendrogenin A and B two new steroidal alkaloids increasing neural responsiveness in the deafened guinea pig.

AIM: To investigate the therapeutic potential for treating inner ear damage of two new steroidal alkaloid compounds, Dendrogenin A and Dendrogenin B, previously shown to be potent inductors of cell differentiation. METHODS: Guinea pigs, unilaterally deafened by neomycin infusion, received a cochlear implant followed by immediate or a 2-week delayed treatment with Dendrogenin A, Dendrogenin B, and, as comparison artificial perilymph and glial cell-line derived neurotrophic factor. After a 4-week treatment period the animals were sacrificed and the cochleae processed for morphological analysis. Electrically-evoked auditory brainstem responses (eABRs) were measured weekly throughout the experiment. RESULTS: Following immediate or delayed Dendrogenin treatment the electrical responsiveness was significantly maintained, in a similar extent as has been shown using neurotrophic factors. Histological analysis showed that the spiral ganglion neurons density was only slightly higher than the untreated group. CONCLUSIONS: Our results suggest that Dendrogenins constitute a new class of drugs with strong potential to improve cochlear implant efficacy and to treat neuropathy/synaptopathy related hearing loss. That electrical responsiveness was maintained despite a significantly reduced neural population suggests that the efficacy of cochlear implants is more related to the functional state of the spiral ganglion neurons than merely their number.

A prospective 10-year follow-up polygraphic study of patients treated with a mandibular protruding device.

PURPOSE: This 10-year follow-up prospective study aimed to evaluate the effects of treatment with a mandibular protruding device (MPD) on respiratory parameters and subjective symptoms in patients with obstructive sleep apnea (OSA) or snoring. METHODS: Seventy-seven consecutive patients diagnosed with OSA or snoring were treated with an MPD. At baseline and the 10-year follow-up, a polygraphic examination and questionnaires on sleep quality were administrated and weight, and neck size was measured. RESULTS: At the 10-year follow-up, we examined 64 of the 77 patients and recorded their current treatment (45 MPD, 9 continuous positive airway pressure (CPAP), and 10 no treatment). For MPD patients, 89 % reported MPD use every night and 9 % several nights a week. Compared to baseline, MPD users with OSA had a significantly decreased oxygen desaturation index (ODI) (p = 0.006) and increased lowest arterial oxygen saturation, SaO2 nadir (p = 0.007) after 10 years. MPD treatment was successful for 70 % of OSA patients, yet 89 % subjectively considered themselves cured, indicating overestimation of the treatment effect. OSA patients who responded to treatment maintained baseline weight and neck size, while these increased for non-responders. Of the baseline snorers still using an MPD, 93 % maintained an ODI value of <5. All CPAP users had an ODI value of <5. Both OSA and snorers using an MPD had significantly fewer self- and relative reports of snoring, apnea, daytime tiredness, and poor night sleep quality (p < 0.001). CONCLUSIONS: MPD treatment is well tolerated and effective in a long-term, 10-year perspective. Weight gain may jeopardize MPD effects. Both patients and relatives reported significantly less snoring and fewer periods of apnea.

Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo.

Neurotrophic factors are secreted proteins responsible for migration, growth and survival of neurons during development, and for maintenance and plasticity of adult neurons. Here we present a novel secreted protein named Cometin which together with Meteorin defines a new evolutionary conserved protein family. During early mouse development, Cometin is found exclusively in the floor plate and from E13.5 also in dorsal root ganglions and inner ear but apparently not in the adult nervous system. In vitro, Cometin promotes neurite outgrowth from dorsal root ganglion cells which can be blocked by inhibition of the Janus or MEK kinases. In this assay, additive effects of Cometin and Meteorin are observed indicating separate receptors. Furthermore, Cometin supports migration of neuroblasts from subventricular zone explants to the same extend as stromal cell derived factor 1a. Given the neurotrophic properties in vitro, combined with the restricted inner ear expression during development, we further investigated Cometin in relation to deafness. In neomycin deafened guinea pigs, two weeks intracochlear infusion of recombinant Cometin supports spiral ganglion neuron survival and function. In contrast to the control group receiving artificial perilymph, Cometin treated animals retain normal electrically-evoked brainstem response which is maintained several weeks after treatment cessation. Neuroprotection is also evident from stereological analysis of the spiral ganglion. Altogether, these studies show that Cometin is a potent new neurotrophic factor with therapeutic potential.

Post-treatment effects of local GDNF administration to the inner ears of deafened guinea pigs.

For patients with profound hearing loss, a cochlear implant is the only treatment available today. The function of a cochlear implant depends in part on the function and survival of spiral ganglion neurons. Following deafferentation, glial cell-derived neurotrophic factor (GDNF) is known to affect spiral ganglion neuron survival. The purpose of this study was to assess delayed GDNF treatment after deafening, the effects of cessation of GDNF treatment, and the effects of subsequent antioxidants on responsiveness and survival of the spiral ganglion neurons. Three-week deafened (by local neomycin administration) guinea pigs were implanted in the scala tympani with a combined cochlear implant electrode and cannula. GDNF (1 µg/mL) or artificial perilymph was then delivered for 4 weeks, following which the animals received systemic ascorbic acid + Trolox or saline for an additional 4 weeks. Thresholds for electrically-evoked auditory brain stem responses (eABRs) were significantly elevated at 3 weeks with deafness, stabilized with GDNF, and showed no change with GDNF cessation and treatment with antioxidants or saline. The populations of spiral ganglion neurons were reduced with deafness (by 40% at 3 weeks and 70% at 11 weeks), and rescued from cell death by GDNF with no further reduction at 8 weeks following 4 weeks of cessation of GDNF treatment equally in both the antioxidant- and saline-treated groups. Local growth factor treatment of the deaf ear may prevent deterioration in electrical responsiveness and rescue auditory nerve cells from death; these effects outlast the period of treatment, and may enhance the benefits of cochlear implant therapy for the deaf.

In vivo infusion of UTP and uridine to the deafened guinea pig inner ear: effects on response thresholds and neural survival.

Nucleotides and nucleosides are known to function as neurotransmitters and neuromodulators but have recently been shown to have a trophic effect on neurons. It has previously been shown, in an animal model for cochlear implants, that local infusion of neurotrophic factors intervenes with the degenerative processes occurring after deafening and protects the auditory spiral ganglion neurons so that electrical responsiveness is maintained. Here we test the hypothesis that nucleosides and nucleotides have a similar effect on the acutely damaged inner ear. Pigmented guinea pigs received a cochlear implant electrode for measuring electrically evoked auditory brainstem responses and a miniosmotic pump for delivering drugs directly to the cochlea. The animals were deafened by a 48-hr infusion with 10% neomycin, followed by 23 days of treatment with primarily UTP, uridine nucleotides, or as control artificial perilymph. Electrically evoked responses were measured weekly, and at the end of the experiment the cochleae were collected and processed for morphological analysis and spiral ganglion neuron counting. Both UTP- and uridine-treated groups showed significantly better response after 23 days of treatment compared with the control group. The densities of spiral ganglion neuron were significantly higher for both treated groups compared with the control group treated with artificial perilymph. The results demonstrate that UTP and uridine rescue auditory neurons and suggest that drugs acting on purinoceptors could be of clinical importance.