Publications by authors named "Anna Rita Fetoni"

42 Publications

Performance and characteristics of the Newborn Hearing Screening Program in Campania region (Italy) between 2013 and 2019.

Eur Arch Otorhinolaryngol 2021 Mar 25. Epub 2021 Mar 25.

Unit of Audiology, Department of Neurosciences, Reproductives and Odontostomatologic Sciences, University of Naples "Federico II", via Pansini 5, 80131, Napoli, Italy.

Purpose: Universal newborn hearing screening (UNHS) in the first month of life is crucial for facilitating both early hearing detection and intervention (EHDI) of significant permanent hearing impairment (PHI). In Campania region, UNHS has been introduced in 2003 by the Regional Council Resolution and started on January 2007. The aim of this paper is to update a previous article describing the performance of the program since its implementation in the period between 2013 and 2019.

Methods: A longitudinal retrospective study was carried at the Regional Reference Center III on 350,178 babies born in the analysis period. The paper reports the main results of overall coverage, referral rate, lost-to-follow-up rate,yield for PHI and shall determine various risk factor associations with hearing impairment RESULTS: In Campania region, 318,878 newborns were enrolled at I level, with a coverage rate of 91.06%, 301,818 (86.18%) Well Infant Nurseries (WIN) and 17,060 (5.35%) Neonatal Intensive Care Unit (NICU) babies. PHI was identified in 413 children, 288 (69.73%) bilaterally and 125 (30.26%) unilaterally. The overall cumulative incidence rate of PHI was 1.29 per 1000 live-born infants (95% CI 1.17-1.42) with a quite steady tendency during the whole study period.

Conclusions: This study confirms the feasibility and effectiveness of UNHS in Campania region also in a setting with major socioeconomic and health organization restrictions.The program meets quality benchmarks to evaluate the progress of UNHS. Nowadays, it is possible to achieve an early diagnosis of all types of HL avoiding the consequences of hearing deprivation.
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http://dx.doi.org/10.1007/s00405-021-06748-yDOI Listing
March 2021

miRNA and mRNA Profiling Links Connexin Deficiency to Deafness via Early Oxidative Damage in the Mouse .

Front Cell Dev Biol 2020 25;8:616878. Epub 2021 Jan 25.

Department of Biomedical Sciences, National Research Council (CNR) Institute of Biochemistry and Cell Biology, Rome, Italy.

Pathogenic mutations in the non-syndromic hearing loss and deafness 1 (DFNB1) locus are the primary cause of monogenic inheritance for prelingual hearing loss. To unravel molecular pathways involved in etiopathology and look for early degeneration biomarkers, we used a system biology approach to analyze Cx30 mice at an early cochlear post-natal developmental stage. These mice are a DFNB1 mouse model with severely reduced expression levels of two connexins in the inner ear, Cx30, and Cx26. Integrated analysis of miRNA and mRNA expression profiles in the cochleae of Cx30 mice at post-natal day 5 revealed the overexpression of five miRNAs (miR-34c, miR-29b, miR-29c, miR-141, and miR-181a) linked to apoptosis, oxidative stress, and cochlear degeneration, which have Sirt1 as a common target of transcriptional and/or post-transcriptional regulation. In young adult Cx30 mice (3 months of age), these alterations culminated with blood barrier disruption in the (), which is known to have the highest aerobic metabolic rate of all cochlear structures and whose microvascular alterations contribute to age-related degeneration and progressive decline of auditory function. Our experimental validation of selected targets links hearing acquisition failure in Cx30 mice, early oxidative stress, and metabolic dysregulation to the activation of the Sirt1-p53 axis. This is the first integrated analysis of miRNA and mRNA in the cochlea of the Cx30 mouse model, providing evidence that connexin downregulation determines a miRNA-mediated response which leads to chronic exhaustion of cochlear antioxidant defense mechanisms and consequent dysfunction. Our analyses support the notion that connexin dysfunction intervenes early on during development, causing vascular damage later on in life. This study identifies also early miRNA-mediated biomarkers of hearing impairment, either inherited or age related.
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http://dx.doi.org/10.3389/fcell.2020.616878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868390PMC
January 2021

Otitis media in children: Which phenotypes are most linked to allergy? A systematic review.

Pediatr Allergy Immunol 2021 Apr 11;32(3):524-534. Epub 2021 Jan 11.

Department of Head and Neck Surgery - Otorhinolaryngology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: Allergic rhinitis is a common childhood disease responsible for a major impact on quality of life and healthcare resources. Many hypotheses have been proposed to explain the link between allergy and otitis media, although a definitive mechanism has not been identified yet. One of the major critical points is that authors failed in distinguishing among different phenotypes of middle ear inflammation. This review pointed out literature evidence from the laboratory and clinical experience linking allergy to different phenotypes of otitis media in children.

Methods: We performed a systematic review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) process. Our search yielded 3010 articles that were finally screened. This resulted in 20 manuscripts of which the full texts were included in a qualitative analysis. We paid particular attention in distinguishing among phenotypes of otitis media.

Results: Clinical evidence and analyses of biomarkers suggested that allergy may be linked to some phenotypes of otitis media and, in particular, to otitis media with effusion (OME) and acute re-exacerbations in children with middle ear effusion. It was not possible to perform the analysis for allergy and acute and chronic otitis media because of paucity and heterogeneity of data.

Conclusion: Allergy should be considered in the diagnostic workup of children with OME as well as OME should be excluded in children with persistent moderate to severe AR. In these cases, clinicians should evaluate prompt and accurate treatment of allergy in improving outcomes, although futures studies are required to increase evidence supporting that anti-allergy treatment may be effective in the recovery and outcome of otitis media with effusion.
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http://dx.doi.org/10.1111/pai.13431DOI Listing
April 2021

Styrene targets sensory and neural cochlear function through the crossroad between oxidative stress and inflammation.

Free Radic Biol Med 2021 Feb 8;163:31-42. Epub 2020 Dec 8.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Department of Neuroscience, Università Cattolica Del Sacro Cuore, Roma, Italy.

Background: Although styrene is an established ototoxic agent at occupational exposure levels, the mechanisms of styrene toxicity in the auditory system are still unclear.

Objectives: The aim of this study was to identify the consequences of styrene chronic exposure in cochlear structures, looking for the mechanisms of ototoxicity of this organic compound and focusing on cell targets and oxidative stress/inflammatory processes.

Methods: Male adult Wistar rats were exposed to styrene (400 mg/kg by gavage for 5 days/week, 3 consecutive weeks). Hearing loss was evaluated by measuring auditory brainstem responses (ABR), morphological analysis were performed to evaluate hair cell and spiral ganglion neuron survival, as well as synaptic damage. Analysis of apoptotic (p53) and inflammatory (NF-κB, TNF-α, IL-1β and IL-10) mediators were performed by immunofluorescence analysis and western blot.

Results: Styrene ototoxic effects induced a hearing loss of about 35-40 dB. Immunofluorescence and western blotting analyses demonstrated that styrene administration induced redox imbalance and activated inflammatory processes, targeting sensory hair cell and neural dysfunction by a cross-talk between oxidative and inflammatory mediators.

Discussion: Major findings connect styrene ototoxicity to an interplay between redox imbalance and inflammation, leading to the intriguing assumption of a mixed sensory and neural styrene-induced ototoxicity. Thus, in a clinical perspective, data reported here have important implications for styrene risk assessment in humans.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.12.001DOI Listing
February 2021

Celecoxib Exerts Neuroprotective Effects in β-Amyloid-Treated SH-SY5Y Cells Through the Regulation of Heme Oxygenase-1: Novel Insights for an Old Drug.

Front Cell Dev Biol 2020 29;8:561179. Epub 2020 Sep 29.

Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore, Rome, Italy.

The formation and aggregation of amyloid-β-peptide (Aβ) into soluble and insoluble species represent the pathological hallmarks of Alzheimer's disease (AD). Over the last few years, however, soluble Aβ (sAβ) prevailed over fibrillar Aβ (fAβ) as determinant of neurotoxicity. One of the main therapeutic strategies for challenging neurodegeneration is to fight against neuroinflammation and prevent free radical-induced damage: in this light, the heme oxygenase/biliverdin reductase (HO/BVR) system is considered a promising drug target. The aim of this work was to investigate whether or not celecoxib (CXB), a selective inhibitor of the pro-inflammatory cyclooxygenase-2, modulates the HO/BVR system and prevents lipid peroxidation in SH-SY5Y neuroblastoma cells. Both sAβ (6.25-50 nM) and fAβ (1.25-50 nM) dose-dependently over-expressed inducible HO (HO-1) after 24 h of incubation, reaching statistical significance at 25 and 6.25 nM, respectively. Interestingly, CXB (1-10 μM, for 1 h) further enhanced Aβ-induced HO-1 expression through the nuclear translocation of the transcriptional factor Nrf2. Furthermore, 10 μM CXB counteracted the Aβ-induced ROS production with a mechanism fully dependent on HO-1 up-regulation; nevertheless, 10 μM CXB significantly counteracted only 25 nM sAβ-induced lipid peroxidation damage in SH-SY5Y neurons by modulating HO-1. Both carbon monoxide (CORM-2, 50 nM) and bilirubin (50 nM) significantly prevented ROS production in Aβ-treated neurons and favored both the slowdown of the growth rate of Aβ oligomers and the decrease in oligomer/fibril final size. In conclusion, these results suggest a novel mechanism through which CXB is neuroprotective in subjects with early AD or mild cognitive impairment.
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http://dx.doi.org/10.3389/fcell.2020.561179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550645PMC
September 2020

Publisher Correction: The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity.

Sci Rep 2020 Sep 30;10(1):16468. Epub 2020 Sep 30.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Roma, Italia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-70073-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527566PMC
September 2020

Anti-oxidant and anti-inflammatory effects of caffeic acid: in vivo evidences in a model of noise-induced hearing loss.

Food Chem Toxicol 2020 Sep 5;143:111555. Epub 2020 Jul 5.

Fondazione Policlinico Universitario A, Gemelli IRCCS, Roma, Italy; Department of Head and Neck Surgery, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address:

Scope: The imbalance of cellular redox status, in conjunction with the activation of inflammatory processes, have been considered common predominant mechanisms of noise-induced hearing loss. The identification of novel natural products as potential therapeuticstargeting oxidative stress and inflammatory pathways is an emerging field. Here, we focused on the polyphenol caffeic acid (CA), the major representative of hydroxycinnamic acids and phenolic acid, in order to investigate its protective capacity in a model of sensorineural hearing loss induced by noise.

Methods And Results: Hearing loss was induced by exposing animals (Wistar rats) to a pure tone, 120 dB, 10 kHz for 60 min. By using auditory brainstem responses (ABRs) and immunofluorescence analysis, we found that CA protects auditory function and limits cell death in the cochlear middle/basal turn, damaged by noise exposure. Immunofluorescence analysis provided evidence that CA mediates multiple cell protection mechanisms involving both anti-inflammatory and anti-oxidant effects by decreasing NF-κB and IL-1β expression in the cochlea and opposing the oxidative/nitrosative damage induced by noise insult.

Conclusions: These results demonstrate that the supplementation of polyphenol CA can be considered a valid therapeutic strategy for attenuating noise-induced hearing loss and cochlear damage targeting both inflammatory signalling and cochlear redox balance.
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http://dx.doi.org/10.1016/j.fct.2020.111555DOI Listing
September 2020

Assessment and Management of Platinum-Related Ototoxicity in Children Treated for Cancer.

Cancers (Basel) 2020 May 17;12(5). Epub 2020 May 17.

Pediatric Oncology Unit, Fondazione Policlinico Universitario A.Gemelli IRCCS, Universita' Cattolica Sacro Cuore, 00168 Rome, Italy.

Platinum compounds are a group of chemotherapeutic agents included in many pediatric and adult oncologic treatment protocols. The main platinum compounds are cisplatin, carboplatin, and oxaliplatin. Their use in clinical practice has greatly improved long-term survival of pediatric patients, but they also cause some toxic effects: ototoxicity, myelosuppression, nephrotoxicity, and neurotoxicity. Hearing damage is one of the main toxic effects of platinum compounds, and it derives from the degeneration of hair cells of the ear, which, not having self-renewal capacity, cannot reconstitute themselves. Hearing loss from platinum exposure is typically bilateral, sensorineural, and permanent, and it is caused by the same mechanisms with which platinum acts on neoplastic cells. According to available data from the literature, the optimal timing for the audiological test during and after treatment with platinum compounds is not well defined. Moreover, no substances capable of preventing the onset of hearing loss have been identified.
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http://dx.doi.org/10.3390/cancers12051266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281210PMC
May 2020

Prospective Evaluation of Cognitive Functions After Rehabilitation With Cochlear Implant or Hearing Aids: Preliminary Results of a Multicentric Study on Elderly Patients.

Am J Audiol 2019 Oct 16;28(3S):762-774. Epub 2019 Oct 16.

ENT Audiology and Phoniatrics Unit, University Hospital of Pisa, Italy.

Objective Recent literature has shown a growing interest in the relationship between presbycusis and cognitive decline, but significant evidence about the long-term benefit of rehabilitation on cognitive functions has not been reported yet. The aim of the study was to analyze audiological and neuropsychological performances in patients with cochlear implant (CI) or hearing aids (HAs) over time. Materials and Method Forty-four bilaterally deaf patients aged more than 60 years (25 with CI candidacy and 19 with HA candidacy) were enrolled. Patients were subjected to audiological evaluation, to a battery of neuropsychological tests (Mini-Mental State Examination [MMSE], Rey Auditory Verbal Learning Task [RAVLT], Rey-Osterreith Complex Figure Test, Digit/Corsi Span Forward and Backward, Multiple Features Target Cancellation, Trail-Making Test, Stroop Test, and Phonological and Semantic Word Fluency), and to a quality of life assessment (Short Form 36, Glasgow Benefit Inventory, Glasgow Health Status Inventory) at the baseline and after a long-term follow-up (6-12 months). Results Speech recognition scores in quiet and in noise were significantly improved even 6 months after auditory rehabilitation. Significant differences between pre- and post-rehabilitation scores were reported in physical and emotional impacts in life, general global health, vitality, and social activities. MMSE and RAVLT scores were significantly improved in both groups after 6 months of follow-up, suggesting a global involvement of memory domain. Mnesic performances remained unchanged between the first and second follow-up, but a further significant improvement in executive functions (Stroop Test) was detected in patients with CI reevaluated 12 months after implantation. A significant correlation of the RAVLT with signal-to-noise ratio at +10 dB speech-in-noise scores and the MMSE with signal-to-noise ratio at 0 dB speech-in-noise scores suggests the pivotal role of executive functions in recognition in noisy environment. Conclusions Our preliminary data confirm that hearing deprivation in aged patients represents a truly modifiable risk factor for cognitive decline, which can be positively faced by acoustic rehabilitation. The improvement of short- and long-term memory performances and the amelioration of executive and attentive functions suggest that hearing restoration with both HAs and CI may provide a recovery of superior cognitive domains probably through a reallocation of cortical resources altered by hearing deprivation.
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http://dx.doi.org/10.1044/2019_AJA-HEAL18-18-0176DOI Listing
October 2019

The dual role of curcumin and ferulic acid in counteracting chemoresistance and cisplatin-induced ototoxicity.

Sci Rep 2020 01 23;10(1):1063. Epub 2020 Jan 23.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Roma, Italia.

Platinum-based agents, such as cisplatin, form the mainstay of currently used chemotherapeutic regimens for several malignancies; however, the main limitations are chemoresistance and ototoxic side effects. In this study we used two different polyphenols, curcumin and ferulic acid as adjuvant chemotherapeutics evaluating (1) in vivo their antioxidant effects in protecting against cisplatin ototoxicity and (2) in vitro the transcription factors involved in tumor progression and cisplatin resistance. We reported that both polyphenols show antioxidant and oto-protective activity in the cochlea by up-regulating Nrf-2/HO-1 pathway and downregulating p53 phosphorylation. However, only curcumin is able to influence inflammatory pathways counteracting NF-κB activation. In human cancer cells, curcumin converts the anti-oxidant effect into a pro-oxidant and anti-inflammatory one. Curcumin exerts permissive and chemosensitive properties by targeting the cisplatin chemoresistant factors Nrf-2, NF-κB and STAT-3 phosphorylation. Ferulic acid shows a biphasic response: it is pro-oxidant at lower concentrations and anti-oxidant at higher concentrations promoting chemoresistance. Thus, polyphenols, mainly curcumin, targeting ROS-modulated pathways may be a promising tool for cancer therapy. Thanks to their biphasic activity of antioxidant in normal cells undergoing stressful conditions and pro-oxidant in cancer cells, these polyphenols probably engage an interplay among the key factors Nrf-2, NF-κB, STAT-3 and p53.
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http://dx.doi.org/10.1038/s41598-020-57965-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978317PMC
January 2020

Targeting dysregulation of redox homeostasis in noise-induced hearing loss: Oxidative stress and ROS signaling.

Free Radic Biol Med 2019 05 22;135:46-59. Epub 2019 Feb 22.

Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address:

Hearing loss caused by exposure to recreational and occupational noise remains a worldwide disabling condition and dysregulation of redox homeostasis is the hallmark of cochlear damage induced by noise exposure. In this review we discuss the dual function of ROS to both promote cell damage (oxidative stress) and cell adaptive responses (ROS signaling) in the cochlea undergoing a stressful condition such as noise exposure. We focus on animal models of noise-induced hearing loss (NIHL) and on the function of exogenous antioxidants to maintaining a physiological role of ROS signaling by distinguishing the effect of exogenous "direct" antioxidants (i.e. CoQ, NAC), that react with ROS to decrease oxidative stress, from the exogenous "indirect" antioxidants (i.e. nutraceutics and phenolic compounds) that can activate cellular redox enzymes through the Keap1-Nrf2-ARE pathway. The anti-inflammatory properties of Nrf2 signaling are discussed in relation to the ROS/inflammation interplay in noise exposure. Unveiling the mechanisms of ROS regulating redox-associated signaling pathways is essential in providing relevant targets for innovative and effective therapeutic strategies against NIHL.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.02.022DOI Listing
May 2019

Pioglitazone Represents an Effective Therapeutic Target in Preventing Oxidative/Inflammatory Cochlear Damage Induced by Noise Exposure.

Front Pharmacol 2018 8;9:1103. Epub 2018 Oct 8.

Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.

Recent progress in hearing loss research has provided strong evidence for the imbalance of cellular redox status and inflammation as common predominant mechanisms of damage affecting the organ of Corti including noise induced hearing loss. The discovery of a protective molecule acting on both mechanisms is challenging. The thiazolidinediones, a class of antidiabetic drugs including pioglitazone and rosiglitazone, have demonstrated diverse pleiotrophic effects in many tissues where they exhibit anti-inflammatory, anti-proliferative, tissue protective effects and regulators of redox balance acting as agonist of peroxisome proliferator-activated receptors (PPARs). They are members of the family of ligand regulated nuclear hormone receptors that are also expressed in several cochlear cell types, including the outer hair cells. In this study, we investigated the protective capacity of pioglitazone in a model of noise-induced hearing loss in Wistar rats and the molecular mechanisms underlying this protective effects. Specifically, we employed a formulation of pioglitazone in a biocompatible thermogel providing rapid, uniform and sustained inner ear drug delivery via transtympanic injection. Following noise exposure (120 dB, 10 kHz, 1 h), different time schedules of treatment were employed: we explored the efficacy of pioglitazone given immediately (1 h) or at delayed time points (24 and 48 h) after noise exposure and the time course and extent of hearing recovery were assessed. We found that pioglitazone was able to protect auditory function at the mid-high frequencies and to limit cell death in the cochlear basal/middle turn, damaged by noise exposure. Immunofluorescence and western blot analysis provided evidence that pioglitazone mediates both anti-inflammatory and anti-oxidant effects by decreasing NF-κB and IL-1β expression in the cochlea and opposing the oxidative damage induced by noise insult. These results suggest that intratympanic pioglitazone can be considered a valid therapeutic strategy for attenuating noise-induced hearing loss and cochlear damage, reducing inflammatory signaling and restoring cochlear redox balance.
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http://dx.doi.org/10.3389/fphar.2018.01103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187064PMC
October 2018

Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway.

Redox Biol 2018 10 7;19:301-317. Epub 2018 Aug 7.

CNR Institute of Cell Biology and Neurobiology, Monterotondo 00015, Italy; University of Padova, Department of Physics and Astronomy "G. Galilei", Padova, Italy. Electronic address:

Mutations in GJB2, the gene that encodes connexin 26 (Cx26), are the most common cause of sensorineural hearing impairment. The truncating variant 35delG, which determines a complete loss of Cx26 protein function, is the prevalent GJB2 mutation in several populations. Here, we generated and analyzed Gjb2 mice as a model of heterozygous human carriers of 35delG. Compared to control mice, auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) worsened over time more rapidly in Gjb2 mice, indicating they were affected by accelerated age-related hearing loss (ARHL), or presbycusis. We linked causally the auditory phenotype of Gjb2 mice to apoptosis and oxidative damage in the cochlear duct, reduced release of glutathione from connexin hemichannels, decreased nutrient delivery to the sensory epithelium via cochlear gap junctions and deregulated expression of genes that are under transcriptional control of the nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal regulator of tolerance to redox stress. Moreover, a statistically significant genome-wide association with two genes (PRKCE and TGFB1) related to the Nrf2 pathway (p-value < 4 × 10) was detected in a very large cohort of 4091 individuals, originating from Europe, Caucasus and Central Asia, with hearing phenotype (including 1076 presbycusis patients and 1290 healthy matched controls). We conclude that (i) elements of the Nrf2 pathway are essential for hearing maintenance and (ii) their dysfunction may play an important role in the etiopathogenesis of human presbycusis.
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http://dx.doi.org/10.1016/j.redox.2018.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129666PMC
October 2018

Anodal transcranial direct current stimulation affects auditory cortex plasticity in normal-hearing and noise-exposed rats.

Brain Stimul 2018 Sep - Oct;11(5):1008-1023. Epub 2018 May 31.

Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo F. Vito 1, 00168, Rome, Italy.

Background: Transcranial direct current stimulation (tDCS) is a non-invasive tool capable to modulate cortical functions by affecting neuronal excitability and synaptic plasticity.

Objective: Here we investigated the effects of anodal tDCS on auditory cortex (ACx) in normal-hearing rats and following a paradigm of noise-induced hearing loss (NIHL), that causes morphological alterations in ACx pyramidal neurons.

Methods: Male rats exposed to intense pure tone (10 kHz) were subsequently subjected to unilateral anodal tDCS of ACx and changes in dendritic morphology and spines were assessed by Golgi-Cox staining 30 days after the onset of the acoustic trauma. Molecular and functional changes were investigated by Western immunoblotting, immunofluorescence experiments and electrophysiological recordings in brain slices.

Results: We found that NIHL altered dendritic morphology by decreasing spine density, mostly in layer 2/3 pyramidal neurons. Interestingly, tDCS increased ACx spine density, targeting apical dendrites of layer 2/3 and 5/6 pyramidal neurons in rats with normal auditory function and both apical and basal arborizations in layer 2/3 of NIHL rats. Twenty-four hours after tDCS, Bdnf and synaptophysin levels in ACx increased both in normal-hearing and noise-exposed rats. Field recordings showed that basal synaptic transmission at layer 2/3 horizontal connections was significantly reduced in noise-exposed rats compared to normal-hearing animals and, notably, input-output curves of noise-exposed animals subjected to tDCS were similar to those of normal-hearing rats.

Conclusions: Our findings provide novel evidence that anodal tDCS affects structural plasticity in the ACx suggesting that it might be beneficial in treating cortical alterations due to cochlear damage.
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http://dx.doi.org/10.1016/j.brs.2018.05.017DOI Listing
March 2019

Relationship between Subjective Tinnitus Perception and Psychiatric Discomfort.

Int Tinnitus J 2017 Apr 19;20(2):76-82. Epub 2017 Apr 19.

Department Head and Neck Surgery - Institute of Otorhinolaryngology, Catholic University of Sacred Heart. Rome, Italy.

Introduction: Tinnitus patients have higher risk of developing anxiety-depressive disorders and decreased quality of life. The reasons why selected patients are able to cope with chronic tinnitus, whereas it represents a disabling symptom for others remain under discussion.

Objectives: the objective of the study was to determine the tinnitus-related degree of distress along with the prevalence of anxiety-depression disorders in a sample of eighty patients referring for chronic tinnitus at the Department of Otolaryngology of Catholic University of Rome from March to September 2015.

Materials And Methods: We administered to all patients the Italian versions of Tinnitus Handicap Inventory (THI) and Hospital Anxiety and Depression Scale (HADS). Furthermore we investigated the correlation among patient's discomfort, severity of hearing loss and age.

Results: Average THI score was 40.85, meaning moderate degree of discomfort; 57.5% of the patients showed HADS scores consistent with high risk of psychiatric comorbidities. A significant linear correlation between THI and HADS scores was demonstrated.

Conclusion: We suggest that patients with severe tinnitus-related distress are routinely invited to accomplish psychometric questionnaires, to assess the possibility of a neuropsychiatric evaluation and/or specific pharmacological planning. At this purpose we recommend the administration of HADS, as a reliable and quick instrument.
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http://dx.doi.org/10.5935/0946-5448.20160015DOI Listing
April 2017

Nasal lavage levels of granulocyte-macrophage colony-stimulating factor and chronic nasal hypereosinophilia.

Int Forum Allergy Rhinol 2015 Jun 26;5(6):557-62. Epub 2015 Mar 26.

Department of Head and Neck Surgery-Institute of Otorhinolaryngology, Catholic University School of Medicine and Surgery, Rome, Italy.

Background: The aim of the present study was to measure levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) in nasal lavage of patients affected by chronic eosinophilic sinonasal inflammation to clarify the relationship with eosinophilic tissue infiltration and clinical features.

Methods: Between November 2012 and June 2013, we selected 70 patients with chronic eosinophilic inflammation (average age 41.8 years) who were classified into the following groups: persistent allergic rhinitis (group 1), noninfectious non-allergic rhinitis with eosinophilia syndrome (group 2) and chronic rhinosinusitis with polyps (group 3). Finally, we enrolled 20 healthy subjects as controls (group 4). All patients underwent symptoms score questionnaire based on a visual analogue scale, nasal endoscopy and/or computed tomography (CT) scan, and allergy testing. Nasal cytology by scraping of the mucosa and GM-CSF assays in nasal lavage were performed in all subjects.

Results: Detectable levels of GM-CSF were found in 34 of 70 (48.57%) patients, with an average concentration of 2.67 ± 0.8 pg/mL, whereas in controls only 1 of 20 individuals showed detectable GM-CSF levels. Eosinophil infiltration was significantly higher in patients with detectable GM-CSF compared to those with undetectable levels (49.4% vs 39.2%, respectively; p < 0.05). Furthermore, significant weakly-moderate correlation was found between GM-CSF levels and percentage of eosinophil infiltration in tissue (p < 0.05). Correlation between symptom scores and GM-CSF levels was significant only in group 2, which showed higher average concentrations of GM-CSF compared to groups 1 and 3 (2.9 pg/mL vs 1.6 pg/mL and 1.8 pg/mL, respectively; p < 0.05).

Conclusion: Our data confirm that GM-CSF is more frequently detectable in nasal lavages of patients affected by chronic sinonasal eosinophilic inflammation than in controls. Statistical analyses revealed a significant weakly-moderate correlation between GM-CSF levels in nasal lavage of all patients and percentage of eosinophil infiltration of nasal mucosa.
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http://dx.doi.org/10.1002/alr.21519DOI Listing
June 2015

Cochlear injury and adaptive plasticity of the auditory cortex.

Front Aging Neurosci 2015 5;7. Epub 2015 Feb 5.

Department of Head and Neck Surgery, Medical School, Catholic University of the Sacred Heart , Rome , Italy.

Growing evidence suggests that cochlear stressors as noise exposure and aging can induce homeostatic/maladaptive changes in the central auditory system from the brainstem to the cortex. Studies centered on such changes have revealed several mechanisms that operate in the context of sensory disruption after insult (noise trauma, drug-, or age-related injury). The oxidative stress is central to current theories of induced sensory-neural hearing loss and aging, and interventions to attenuate the hearing loss are based on antioxidant agent. The present review addresses the recent literature on the alterations in hair cells and spiral ganglion neurons due to noise-induced oxidative stress in the cochlea, as well on the impact of cochlear damage on the auditory cortex neurons. The emerging image emphasizes that noise-induced deafferentation and upward spread of cochlear damage is associated with the altered dendritic architecture of auditory pyramidal neurons. The cortical modifications may be reversed by treatment with antioxidants counteracting the cochlear redox imbalance. These findings open new therapeutic approaches to treat the functional consequences of the cortical reorganization following cochlear damage.
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http://dx.doi.org/10.3389/fnagi.2015.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318425PMC
February 2015

Grafting and early expression of growth factors from adipose-derived stem cells transplanted into the cochlea, in a Guinea pig model of acoustic trauma.

Front Cell Neurosci 2014 20;8:334. Epub 2014 Oct 20.

Department of Head and Neck Surgery, Università Cattolica del Sacro Cuore , Rome , Italy.

Noise exposure causes damage of multiple cochlear cell types producing permanent hearing loss with important social consequences. In mammals, no regeneration of either damaged hair cells or auditory neurons has been observed and no successful treatment is available to achieve a functional recovery. Loads of evidence indicate adipose-derived stem cells (ASCs) as promising tools in diversified regenerative medicine applications, due to the high degree of plasticity and trophic features. This study was aimed at identifying the path of in vivo cell migration and expression of trophic growth factors, upon ASCs transplantation into the cochlea, following noise-induced injury. ASCs were isolated in primary culture from the adipose tissue of a guinea pig, transduced using a viral vector to express the green fluorescent protein, and implanted into the scala tympani of deafened animals. Auditory function was assessed 3 and 7 days after surgery. The expression of trophic growth factors was comparatively analyzed using real-time PCR in control and noise-injured cochlear tissues. Immunofluorescence was used to assess the in vivo localization and expression of trophic growth factors in ASCs and cochleae, 3 and 7 days following homologous implantation. ASC implantation did not modify auditory function. ASCs migrated from the perilymphatic to the endolymphatic compartment, during the analyzed time course. Upon noise exposure, the expression of chemokine ligands and receptors related to the PDGF, VEGF, and TGFbeta pathways, increased in the cochlear tissues, possibly guiding in vivo cell migration. Immunofluorescence confirmed the increased expression, which appeared to be further strengthened by ASCs' implantation. These results indicated that ASCs are able to migrate at the site of tissue damage and express trophic factors, upon intracochlear implantation, providing an original proof of principle, which could pave the way for further developments of ASC-based treatments of deafness.
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http://dx.doi.org/10.3389/fncel.2014.00334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202717PMC
November 2014

Nasal fluid release of eotaxin-3 and eotaxin-2 in persistent sinonasal eosinophilic inflammation.

Int Forum Allergy Rhinol 2014 Aug 2;4(8):617-24. Epub 2014 Jul 2.

Department Head and Neck Surgery-Institute of Otorhinolaryngology, Catholic University School of Medicine and Surgery, Rome, Italy.

Background: The aim of the present study was to measure eotaxin-3 (CCL26) and eotaxin-2 (CCL24) in nasal lavage fluid of patients with different forms of chronic sinonasal eosinophilic inflammation to evaluate their role in the pathophysiology of nasal hypereosinophilia.

Methods: The study was an analytic cross-section study, level of evidence 3b. Patients (n = 80) with nasal hypereosinophilia were randomly recruited and grouped in the following categories: persistent allergic rhinitis (AR) (n = 25), nonallergic rhinitis with eosinophilia syndrome (NARES) (n = 30), and chronic rhinosinusitis with polyps (CRSwNP) (n = 25). Non-rhinitic volunteers (n = 20) were recruited as controls. CCL24 and CCL26 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) Quantikine Human Immunoassays (R&D Systems, Minneapolis, MN) in nasal lavage fluids. Differential cell counts were performed by microscopic cytological examination of nasal tissue scraped from the inferior turbinate.

Results: Mean CCL26 levels were significantly higher (p < 0.05) in AR and in NARES (132.0 pg/mL and 187.63 pg/mL, respectively) than in the control group (13.5 pg/mL); in patients with CRSwNP, CCL26 values were increased compared to controls even though the difference was not statistically significant (58.9 pg/mL vs 16.5 pg/mL). Mean CCL24 levels measured in AR, NARES, and CRSwNP were significantly increased (p < 0.05) compared to controls (96.7 pg/mL, 135.4 pg/mL, and 107.0 pg/mL, respectively, vs 32.2 pg/mL). Moreover, we observed a significant correlation between CCL24 and CCL26 levels, evaluating them intraindividually by Spearman's rank correlation test. Finally, a significant correlation was found between CCL24 and CCL26 levels and the percentage of eosinophilic infiltration of nasal mucosa.

Conclusion: Our data suggest that CCL26 and CCL24 are likely involved in the pathogenesis of chronic nasal hypereosinophilia, with a complex cooperation and different involvement of the various members of eotaxin family. Further studies are necessary to better understand the actual physiopathologic mechanism, possible clinical relevance, and therapeutic implications.
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http://dx.doi.org/10.1002/alr.21348DOI Listing
August 2014

Time evolution of noise induced oxidation in outer hair cells: role of NAD(P)H and plasma membrane fluidity.

Biochim Biophys Acta 2014 Jul 13;1840(7):2192-202. Epub 2014 Apr 13.

Dipartimento di Scienze Chirurgiche per le patologie della testa e del collo, Università Cattolica (UCSC), Roma, Italy.

Background: Noise exposure impairs outer hair cells (OHCs). The common basis for OHC dysfunction and loss by acoustic over-stimulation is represented by reactive oxygen species (ROS) overload that may affect the membrane structural organization through generation of lipid peroxidation.

Methods: Here we investigated in OHC different functional zones the mechanisms linking metabolic functional state (NAD(P)H intracellular distribution) to the generation of lipid peroxides and to the physical state of membranes by two photon fluorescence microscopy.

Results: In OHCs of control animals, a more oxidized NAD(P)H redox state is associated to a less fluid plasma membrane structure. Acoustic trauma induces a topologically differentiated NAD(P)H oxidation in OHC rows, which is damped between 1 and 6h. Peroxidation occurs after ~4h from noise insult, while ROS are produced in the first 0.2h and damage cells for a period of time after noise exposure has ended (~7.5h) when a decrease of fluidity of OHC plasma membrane occurs. OHCs belonging to inner rows, characterized by a lower metabolic activity with respect to other rows, show less severe metabolic impairment.

Conclusions: Our data indicate that plasma membrane fluidity is related to NAD(P)H redox state and lipid peroxidation in hair cells.

General Significance: Our results could pave the way for therapeutic intervention targeting the onset of redox umbalance.
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http://dx.doi.org/10.1016/j.bbagen.2014.04.005DOI Listing
July 2014

Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense.

J Neurosci 2013 Feb;33(9):4011-23

Institute of Otolaryngology, Catholic University School of Medicine, I-00168 Rome, Italy.

This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.
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http://dx.doi.org/10.1523/JNEUROSCI.2282-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619303PMC
February 2013

Efficacy of different routes of administration for Coenzyme Q10 formulation in noise-induced hearing loss: systemic versus transtympanic modality.

Acta Otolaryngol 2012 Apr;132(4):391-9

Institute of Otolaryngology, Catholic University, Italy.

Conclusion: The effectiveness of a coenzyme Q10 formulation, Q-ter, given via transtympanic injection is interesting for the future application of this minimally invasive procedure in the treatment of reactive oxygen species (ROS)-induced hearing loss.

Objective: We focused on antioxidant therapy in noise-induced hearing loss (NIHL). Our study was designed to evaluate the effectiveness of Q-ter for different schedules of drug administration to establish the best modality for treatment.

Methods: Rats were exposed to acoustic trauma (10 kHz at 120 dB for 60 min) and received Q-ter according to two modalities: systemic (Q-ter 100 mg/kg for 4 days 1 h before and 3 days post noise exposure) and transtympanic (Q-ter 20 and 40% concentration 1 h before noise exposure). Auditory brainstem response (ABR), immunohistochemical and morphological studies were performed.

Results: Q-ter administration significantly decreased NIHL at day 21 from noise exposure. The improvement of auditory function by Q-ter was paralleled by a significant reduction in oxidative stress. The transtympanic and systemic routes of drug administration showed a similar degree of protection.
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http://dx.doi.org/10.3109/00016489.2011.652307DOI Listing
April 2012

A new oral otoprotective agent. Part 1: Electrophysiology data from protection against noise-induced hearing loss.

Med Sci Monit 2012 Jan;18(1):BR1-8

Center of Bioacoustics, University of Ferrara, Ferrara, Italy.

Background: Data from animal studies show that antioxidants can compensate against noise-induced stress and sensory hair cell death. The aim of this study was to evaluate the otoprotection efficacy of various versions of orally administered Acuval 400 against noise damage in a rat animal model.

Material/methods: Fifty-five Sprague Dawley rats were divided into 4 groups: A) noise-exposed animals; B) animals exposed to noise and treated with the Acuval; C) animals exposed to noise and treated with a combination of Coenzyme Q10 and Acuval; D) animals treated only with Acuval and Coenzyme Q10 and with no exposure to noise. All solutions were administered orally 5 times: 24 and 2 hrs prior to noise exposure, and then daily for 3 days. The auditory function was assessed by measuring auditory brainstem responses (ABR) in the range from 2 to 32 kHz at times =1, 7, 14 and 21 days after noise exposure.

Results: At low frequencies (click and 4 kHz) animals from both A and B groups showed significant threshold shifts in the majority of the tested frequencies and tested times. For the same frequencies, animals from group C presented threshold levels similar to those from group D. At frequencies ≥ 8 kHz the protective performance of the 2 Acuval groups is more clearly distinguished from the noise group A. At 32 kHz the 2 Acuval groups perform equally well in terms of otoprotection. Animals in Group D did not show any significant differences in the hearing threshold during the experiment.

Conclusions: The data of this study suggest that a solution containing Coenzyme Q10 and Acuval 400, administered orally, protects from noise-induced hearing loss.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560681PMC
http://dx.doi.org/10.12659/msm.882180DOI Listing
January 2012

Post-processing analysis of transient-evoked otoacoustic emissions to detect 4 kHz-notch hearing impairment--a pilot study.

Med Sci Monit 2011 Jun;17(6):MT41-9

Institute of Otolaryngology, Catholic University School of Medicine, Rome, Italy.

Background: To identify a parameter to distinguish normal hearing from hearing impairment in the early stages. The parameter was obtained from transient-evoked otoacoustic emissions (TEOAEs), overcoming the limitations of the usually adopted waveform descriptive parameters which may fail in standard clinical screenings.

Material/methods: Audiometric examinations and TEOAE analysis were conducted on 15 normal ears and on 14 hearing-impaired ears that exhibited an audiometric notch around 4 kHz. TEOAE signals were analyzed through a multivariate technique to filter out the individual variability and to highlight the dynamic structure of the signals. The new parameter (named radius 2-dimension--RAD2D) was defined and evaluated for simulated TEOAE signals modeling a different amount of hearing impairment.

Results: Audiometric examinations indicated 14 ears as impaired-hearing (IH), while the TEOAE ILO92 whole reproducibility parameter (WWR) indicated as IH 7 signals out of 14 (50%). The proposed new parameter indicated as IH 9 signals out of 14 (64%), reducing the number of false negative cases of WWR.

Conclusions: In this preliminary study there is evidence that the new parameter RAD2D defines the topology and the quantification of the damage in the inner ear. The proposed protocol can be useful in hearing screenings to identify hearing impairments much earlier than conventional pure tone audiometry and TEOAE pass/fail test.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539534PMC
http://dx.doi.org/10.12659/msm.881793DOI Listing
June 2011

Undifferentiated human adipose tissue-derived stromal cells induce mandibular bone healing in rats.

Arch Otolaryngol Head Neck Surg 2011 May;137(5):463-70

Department of Otolaryngology, Università Cattolica del Sacro Cuore, School of Medicine A. Gemelli, Rome, Italy.

Objective: To test the osteo-regenerative potential of adipose tissue-derived stromal cells (ATSCs), an attractive human source for tissue engineering, in a rat model of mandibular defect. Human dermal fibroblasts (HDFs) were used as a differentiated cellular control in the study.

Design: The ATSCs and HDFs were isolated from human lipoaspirate and skin biopsy specimens, respectively. Cells were characterized in vitro and then adsorbed on an osteo-conductive scaffold to be transplanted in a mandibular defect of immunosuppressed rats. Naked unseeded scaffold was used as a negative control.

Main Outcome Measures: Bone healing was studied by computerized tomography and histologic analysis after 4, 8, and 12 weeks.

Results: Computed tomography showed that undifferentiated ATSCs induced successful bone healing of the mandible defect when transplanted in animals, compared with HDFs and negative controls. Histologic analysis demonstrated that the newly formed tissue in the surgical defect retained the features of compact bone.

Conclusion: Undifferentiated human ATSCs are suitable for cell-based treatment of mandibular defects, even in the absence of previous osteogenic induction in vitro.
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http://dx.doi.org/10.1001/archoto.2011.61DOI Listing
May 2011

Therapeutic window for ferulic acid protection against noise-induced hearing loss in the guinea pig.

Acta Otolaryngol 2011 Apr 3;131(4):419-27. Epub 2011 Jan 3.

Institutes of Otolaryngology, School of Medicine, Catholic University, Rome, Italy.

Conclusion: Our results are in agreement with the general idea that natural antioxidants achieve their best cytoprotective capacity if given before and soon after the stressor.

Objective: We focused on ferulic acid (FA, 4-hydroxy 3-methoxycinnamic acid), a phenolic compound that is known to exhibit antioxidant properties. Our study was designed to evaluate the effectiveness of FA for different schedules of treatment to establish the 'therapeutic window' for FA protection.

Methods: Guinea pigs were exposed to acoustic trauma (6 kHz at 120 dB for 60 min) and received a total dose of 600 mg/kg of FA. Group I, noise control; group II, noise + FA (150 mg/kg) for 4 days starting 24 h post exposure; group III, noise + FA (60 mg/kg) 1 h before and 9 days post exposure; group IV, noise + FA (60 mg/kg) given 3 days before and 7 days post exposure; group V, noise + FA (150 mg/kg) 1 h before and 3 days post noise exposure. Auditory brainstem response (ABR) test and immunohistochemical and morphological studies were performed.

Results: Group V had significantly decreased noise-induced hearing loss at day 21 from noise exposure. The improvement of auditory function by FA was paralleled by a significant reduction in oxidative stress marker. The other schedules of drug administration showed a minor degree of protection.
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http://dx.doi.org/10.3109/00016489.2010.539263DOI Listing
April 2011

Comparison of salicylate- and quinine-induced tinnitus in rats: development, time course, and evaluation of audiologic correlates.

Otol Neurotol 2010 Jul;31(5):823-31

Center for Hearing and Deafness, Department of Communicative Disorders and Sciences, University at Buffalo, Buffalo, New York, USA.

Background: Salicylate and quinine have been shown to reliably induce short-term tinnitus when administered at high doses. The present study compared salicylate and quinine-induced tinnitus in rats using the gap prepulse inhibition of acoustic startle (GPIAS).

Methods: Twenty-four rats were divided into 2 groups; the first group (n = 12) was injected with salicylate (300 mg kg d), whereas the second (n = 12) was treated with quinine orally at a dose of 200 mg kg d. Animals were treated daily for 4 consecutive days. All rats were tested for tinnitus and hearing loss before and 2, 24, 48, 72, and 96 hours after the first drug administration. Tinnitus was assessed using GPIAS; hearing function was measured with distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response.

Results: Salicylate treatment induced transient tinnitus with a pitch near 16 kHz starting 2 hours posttreatment, persisting over the 4-day treatment period and disappearing 24 hours later. Animals in the quinine group showed GPIAS changes at a higher pitch (20 kHz); however, changes were more variable among animals, and the mean data were not statistically significant. Hearing function varied across treatments. In the salicylate group, high-level DPOAEs were slightly affected; most changes occurred 2 hours posttreatment. Low-level DPOAEs were affected at all frequencies with a progressive dose-dependent effect. In the quinine group, only high-level DPOAEs were affected, mainly at 16 kHz.

Conclusion: The present study highlights the similarities and differences in the frequency and the time course of tinnitus and hypoacusis induced by salicylate and quinine. Transient tinnitus was reliably induced pharmacologically with salicylate, whereas hearing loss remained subclinical with only minor changes in DPOAEs.
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http://dx.doi.org/10.1097/MAO.0b013e3181de4662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893285PMC
July 2010

Noise induced hearing loss and vestibular dysfunction in the guinea pig.

Int J Audiol 2009 Nov;48(11):804-10

Institute of Otolaryngology, Catholic University, Rome, Italy.

This study analysed the acoustic and vestibular functional and morphological modifications in guinea pigs after acoustic trauma. Animals were exposed to noise (6 kHz, at 120 dB SPL for 60 minutes) and then auditory brainstem responses (ABR) and vestibuloocular reflex (VOR) were measured at 6 hours, 1 day, 3, 7, and 21 days after noise. Western blotting and immunostaining for 4-hydroxy-2-noneal (4-HNE) and vascular endothelial growth factor (VEGF) were performed in the cochlear and vestibular regions at 1 and 7 days after noise exposure. A significant decrease of VOR gain was observed on day 1 and the recovery was completed at day 21. ABR threshold values reached a level of 80 dB at day 1 after trauma reaching a value of about 50 dB SPL on day 21. 4-HNE expression, a marker of lipid peroxidation was strongly increased in the cochlea. In the vestibule, 4-HNE immunoreactivity was faint. However, VEGF was up-regulated both in the cochlea and vestibule. In conclusion, the expression of VEGF in both cochlear and vestibular structures suggests a reparative role with potentially therapeutic implications.
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http://dx.doi.org/10.3109/14992020903023140DOI Listing
November 2009

The monitoring role of otoacoustic emissions and oxidative stress markers in the protective effects of antioxidant administration in noise-exposed subjects: a pilot study.

Med Sci Monit 2009 Nov;15(11):PR1-8

Institute of Otolaryngology, Catholic University of Rome, Rome, Italy.

Background: Oxidative stress has been recently identified as the pivotal pathway of cochlear damage. The aims of this study were to evaluate whether distortion product otoacoustic emissions (DPOAEs) can discriminate normal subjects with a risk of damage induced by sound exposure, the effectiveness of OAEs in monitoring the protective effects of Coenzyme Q10 terclatrate (QTer), and the role of blood parameters in monitoring preventive therapies.

Material/methods: Twenty volunteers were randomized to two groups: the first (n=10) was treated with Q-Ter (200 mg orally once daily) for 7 days before noise exposure and the second group was treated with placebo using the same schedule. All participants were exposed to white noise of 90 dB HL for 15 minutes. DPOAEs and pure-tone audiometry (PTA) were measured before and 1 h, 16 h, and 7 and 21 days after exposure. Inflammatory and oxidative stress parameters were measured before and 2 and 24 h after exposure.

Results: In the placebo group, DPOAE amplitudes were reduced 1 and 16 h after exposure compared with the baseline values (p<0.05). In the Q-Ter group, DPOAEs did not show any significant difference between baseline and post-exposure (p>0.1). PTA threshold values in the Q-Ter and placebo groups did not differ before and after exposure. No significantly different levels of the inflammatory markers were observed in the Q-Ter and placebo groups at the different time points.

Conclusions: This pilot study confirms that DPOAEs represent a sensitive test for monitoring the effects of noise in preclinical conditions and pharmacological treatment.
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November 2009

Ex vivo gene therapy using autologous dermal fibroblasts expressing hLMP3 for rat mandibular bone regeneration.

Head Neck 2010 Mar;32(3):310-8

Department of Otolaryngology, School of Medicine, Catholic University of Sacred Heart, Rome, Italy.

Background: Implantation of autologous skin fibroblasts transduced ex vivo with a replication-defective adenoviral vector, carrying the LIM mineralization protein-3 (Ad-LMP-3), and adsorbed on a hydroxyapatite/collagen (HA/COL) scaffold.

Methods: Twenty-seven Wistar rats were used. A 5- x 5-mm full-thickness defect was created in the exposed mandible. All animals were randomized into 3 experimental groups: (1) autologous dermal fibroblasts transduced with Ad-LMP-3 and adsorbed on the HA/COL; (2) nontransduced dermal fibroblasts adsorbed on the HA/COL scaffold; and (3) HA/COL scaffold without cells. Three-dimensional micro-CT (3DmicroCT or 3DmuCT) and histological analysis were performed.

Results: Efficient neoosteogenesis was observed in animals treated with LMP-3-expressing cells (group 1) as soon as 4 weeks after surgery. Conversely, nonsignificant bone formation was detected in control animals (groups 2 and 3) at all time points tested.

Conclusion: These results suggest that the experimental approach based on transplantation of genetically modified autologous cells could provide an alternative treatment for cranio-maxillo-facial defects. Nonetheless, additional data from the study on larger bone defects must follow to foresee a clinical application in the near future.
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http://dx.doi.org/10.1002/hed.21185DOI Listing
March 2010