Protective effect of lutein against acrolein-induced ototoxicity in rats.

BACKGROUND: Acrolein is a reactive aldehyde that forms during burning of wood and other fuels. It is also a product of lipid peroxidation (LPO) reactions and is present in cigarette smoke. Acrolein is known to cause oxidative stress and inflammatory nerve tissue damage. Lutein is a tetraterpenoid molecule with antioxidant and anti-inflammatory properties. There appear to be no studies on the effect of lutein on vestibulocochlear nerve damage induced by acrolein. The aim of this study was to investigate the effect of lutein on vestibulocochlear nerve damage induced by acrolein in rats using biochemical and histopathological methods. METHODS: The rats were divided into three groups (n = 6, for each group) a healthy control group (HG), an acrolein (ACR) group and a lutein and acrolein (LACR) group. In the LACR group, lutein was administered (1 mg/kg) via oral gavage. The ACR and HG groups received saline via oral gavage. Then, 1 h after the administration of lutein and saline, the LACR and ACR groups were treated with 3 mg/kg of acrolein via oral gavage. This procedure was repeated once a day for 30 days. RESULTS: The results of biochemical experiments showed that in the vestibulocochlear nerve tissues of the animals treated with acrolein, the levels of malondialdehyde, total oxidants, nuclear factor kappa b, tumor necrosis factor alpha and interleukin 1 beta significantly increased, whereas the levels of total glutathione and total antioxidants decreased as compared to those in the HG and LACR groups. In addition, severe histopathological damage was observed in vestibulocochlear nerve tissue of the acrolein group, whereas this damage was alleviated in the lutein group. CONCLUSION: Lutein protected vestibulocochlear nerve tissue from acrolein-associated oxidative and proinflammatory damage. This suggests that lutein might be useful in preventing or treating acrolein-induced ototoxicity.

Cranial Nerve Disorders Associated With Immune Checkpoint Inhibitors.

OBJECTIVE: To describe the spectrum, treatment, and outcome of cranial nerve disorders associated with immune checkpoint inhibitor (Cn-ICI). METHODS: This nationwide retrospective cohort study on Cn-ICI (2015-2019) was conducted using the database of the French Refence Center. In addition, a systematic review of the literature (MEDLINE, Scopus, and Web of Science) for records published between 2010 and 2019 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the search terms cranial nerve or neuropathy or palsy and immune checkpoint inhibitors. RESULTS: Among 67 cases with ICI-related neurologic toxicities diagnosed in our reference center, 9 patients with Cn-ICI were identified (7 men, 78%, median age 62 years [range 26-82 years]). Patients were receiving a combination of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death 1 (PD-1)/PD-1 ligand (n = 5, 56%) or anti-PD-1 antibodies alone (n = 4, 44%). Cn-ICI involved optic (n = 3), vestibulocochlear (n = 3), abducens (n = 2), facial (n = 2), and oculomotor (n = 1) nerves. Two patients had involvement of 2 different cranial nerves. Treatment comprised corticosteroids (n = 8, 89%), ICI permanent discontinuation (n = 7, 78%), plasma exchange (n = 2, 22%), and IV immunoglobulin (n = 1, 11%). Median follow-up was 11 months (range 1-41 months). In 3 cases (33%), neurologic deficit persisted/worsened despite treatment: 2 optic and 1 vestibulocochlear. Among cases from the literature and the present series combined (n = 39), the most commonly affected cranial nerves were facial (n = 13, 33%), vestibulocochlear (n = 8, 21%), optic (n = 7, 18%), and abducens (n = 4, 10%). Trigeminal, oculomotor, and glossopharyngeal nerves were less frequently affected (total n = 7). CONCLUSION: Cranial nerve disorders can complicate treatment with ICIs. Approximately one-third of the patients had persisting deficits, most frequently involving hearing and vision loss.

Contributions of Mouse and Human Hematopoietic Cells to Remodeling of the Adult Auditory Nerve After Neuron Loss.

The peripheral auditory nerve (AN) carries sound information from sensory hair cells to the brain. The present study investigated the contribution of mouse and human hematopoietic stem cells (HSCs) to cellular diversity in the AN following the destruction of neuron cell bodies, also known as spiral ganglion neurons (SGNs). Exposure of the adult mouse cochlea to ouabain selectively killed type I SGNs and disrupted the blood-labyrinth barrier. This procedure also resulted in the upregulation of genes associated with hematopoietic cell homing and differentiation, and provided an environment conducive to the tissue engraftment of circulating stem/progenitor cells into the AN. Experiments were performed using both a mouse-mouse bone marrow transplantation model and a severely immune-incompetent mouse model transplanted with human CD34+ cord blood cells. Quantitative immunohistochemical analysis of recipient mice demonstrated that ouabain injury promoted an increase in the number of both HSC-derived macrophages and HSC-derived nonmacrophages in the AN. Although rare, a few HSC-derived cells in the injured AN exhibited glial-like qualities. These results suggest that human hematopoietic cells participate in remodeling of the AN after neuron cell body loss and that hematopoietic cells can be an important resource for promoting AN repair/regeneration in the adult inner ear.

Hearing and Vestibular Function After Preoperative Intratympanic Gentamicin Therapy for Vestibular Schwanomma as Part of Vestibular Prehab.

OBJECTIVE: To evaluate auditory and vestibular function after presurgical treatment with gentamicin in schwannoma patients. BACKGROUND: The vestibular PREHAB protocol aims at diminishing the remaining vestibular function before vestibular schwannoma surgery, to ensure less acute symptoms from surgery, and initiate a more efficient vestibular rehabilitation already before surgery. However, the potential cochleotoxicity of gentamicin is a concern, since modern schwannoma surgery strives to preserve hearing. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Seventeen patients diagnosed with vestibular schwannoma between 2004 and 2011, and took part in vestibular PREHAB program. The patients were of age 21 to 66 years (mean 48.8), 9 females and 8 males. INTERVENTION: Intratympanic gentamicin installations before surgery as part of the vestibular PREHAB. MAIN OUTCOME MEASURES: Hearing thresholds, word recognition score, caloric response, subjective visual vertical and horizontal, cVEMP, and vestibular impulse tests. RESULTS: Combined analysis of frequency and hearing threshold showed a significant decrease after gentamicin therapy (p < 0.001). Pure-tone average decreased with 7.1 ± 8.5 dB (p = 0.004), and speech recognition with 10%. The treatment resulted in unilateral vestibular deafferentation with no notable reaction to bithermal caloric irrigation (reduction 64%, p < 0.001), loss of the vestibulo-ocular response measured by the head-impulse test, and deviation of subjective horizontal/vertical to the side of the lesion (+2.2 degrees, p = 0.010). CONCLUSIONS: Intratympanic installations of gentamicin, as part of the vestibular PREHAB, result in unilateral vestibular deafferentation, but constitute a definite risk for high-frequency hearing loss. The hearing results are in line with those reported upon when treating Menière's disease.

Influence of smoking on audiological characteristics of hearing function.

Cigarette smoking and related diseases are global problem of health. Discussion regarding influence of smoking on hearing function has been continued about 20 years. The aim of our study was estimation of relation between smoking and development of cochlear neuritis. Research was conducted at Ltd. National Centre of ENT - Japaridze-Kevanishvili clinic and Ltd.Audiology National Center. The data were collected from September 2011 to December 2013. Cross- sectional observational study was carried out. 600 persons (mean age - 45.4±10.4) were enrolled in the research. After filling the informed consent persons were divided into two groups: smokers (300 smokers, apparently healthy persons, mean age 44.3±10.6 years) and control group (300 healthy non-smoker persons, mean age 46.5±10.2 years). All persons completed a questionnaire, which includes questions about smoking status too. The inclusion criterion in smokers group was a smoking habit during 5 years at least 10 cigarettes per day. Otoscopy and Acoustic impedance test (timpanometry, reflexometry, testing for Eustachian tube conductivity) were used for verification of outer and middle-ear normality. Pure Tone Audiometry was performed for hearing measure and identifies hearing nerve condition. Obtained results were statistically treated by the student's t-distribution. For minimal level of significance was taken p<0,05. In smokers group hearing loss was proved in 31.33% (94 persons) and in control group - in 17.34% (52 persons). Hearing-loss vs. normal-hearing ratio amounted hence to 0.46 (P<0.01) in the smokers group and to 0.21 (P<0.01) in the nonsmokers'. Hearing loss in smokers may be provided by different pathological mechanisms.

Ototoxicity of gentian violet on the guinea pig cochlea.

PURPOSE: Gentian violet (GV) is an antimicrobial and antifungal agent that has been used widely to treat intractable discharge in the ear. The purpose of this report is to warn clinicians about the ototoxic effect of GV in the middle ear. MATERIALS AND METHODS: GV ototoxicity was evaluated by measuring compound action potentials (CAPs) in the VIIIth nerve in adult Hartley guinea pigs. The middle ear cavities of the animals were filled with GV solution (0.5% or 0.13%), and CAPs were measured after intervals of 5 and 30 minutes and 1, 2, 6, and 24 hours. After all measurements were completed, the temporal bones were harvested for histopathologic evaluation. Celloidin-embedded specimens were cut into 20-µm slices and examined using light microscopy. The bacteriostatic activity of GV was evaluated using a disk-diffusion assay. RESULTS: A 0.5% GV solution produced a mild elevation in the CAP threshold at 30 minutes, a greater reduction at 1 hour, and complete abolishment of CAP at 24 hours. A 0.13% GV solution caused mild elevation in the CAP threshold at 2 hours and severe elevation at 6 hours. Massive new bone formation was found in the middle ear cavity at 6 weeks. GV concentrations of 0.13% and 0.06% were effective against all bacteria tested, with the exception of Pseudomonas aeruginosa. CONCLUSIONS: Although GV has marked antibacterial and antifungal activities, its use should be limited to the external ear canal. GV exerts an ototoxic effect in a concentration- and time-dependent manner, and so the use of this drug in the middle ear cavity is not recommended.

Drop attacks and vertical vertigo after transtympanic gentamicin: diagnosis and management.

Drop attacks represent a significant problem during the natural course of Meniere's disease. They are characterized by a sudden fall to the ground without loss of consciousness. Diagnosis is clinical and based on the typical description of the patient. Involvement of vertical canal is possible during Meniere's disease and also after gentamicin application. Treatment of drop attacks is still a matter of discussion; most cases have a benign course with spontaneous remission and no treatment is necessary. In severe cases, aggressive treatment (surgical or pharmacological) is necessary. A case of drop attack associated with vertical vertigo is presented. Vestibular tests were performed in order to assess the involvement of inner ear. Caloric test and ice water test reveal no response. Vestibular Evoked Myogenic Potentials are present even after high doses of gentamicin. Drop attacks and vertical vertigo can occur after transtympanic gentamicin and can be well managed with high doses of local gentamicin.

Systemic ototoxicity: a review.

BACKGROUND: Systemic ototoxicity is a significant cause of vestibulocochlear morbidity in sub-Saharan Africa. It may result in permanent hearing impairment and/or balance problems. OBJECTIVES: To review the literature pertaining to the ototoxic potential of three frequently prescribed systemic medications in the sub-Saharan setting; quinine, furosemide and aminoglycoside antibiotics. The pathophysiology, clinical manifestations and risk factors and risk minimisation strategies regarding the ototoxicity associated with these drugs are presented in order to highlight this problem and reduce the incidence of adverse outcomes. DATA SOURCES: The biomedical literature was systematically reviewed. This included a search of the National Library of Medicine's PubMed database (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=PubMed). The search was limited to the English language literature and used the following search terms: ototoxicity; aminoglycosides; quinine; furosemide; gentamicin; vestibular toxicity; auditory toxicity; and Africa. STUDY SELECTION: Studies and reviews directly addressing clinical ototoxicity, experimental studies and studies regarding ototoxicity in sub-Saharan Africa were reviewed. The authors formed a consensus opinion regarding the most relevant articles considering factors including evidence level. DATA EXTRACTION: Systematic data extraction was undertaken from relevant studies. CONCLUSIONS: Quinine, furosemide and aminoglycosides are potentially ototoxic. High doses, prolonged treatment and intravenous administration increase this risk. The clinical condition of the patient may further predispose patients to ototoxic damage. Lack of monitoring facilities and efficacious, cost effective alternatives increase the risks of ototoxicity in the African setting. Clinicians must be aware of these risks and those patients at increased risk, and be vigilant in recognising their clinical manifestations.

[Frequency, pattern, and diagnosis of adverse reactions in patients with pulmonary tuberculosis during chemotherapy with leading drugs]. / Chastota, kharakter i diagnostika pobochnykh reaktsii u bol'nykh tuberkulezom legkikh pri khimioterapii osnovnymi preparatami.

The frequency and pattern of adverse reactions to essential antituberculous agents were studied in 480 patients with first diagnosed and recurrent pulmonary tuberculosis. Adverse reactions were found to occur in 16.9% of cases and to be mainly associated with concomitant diseases of different organs and systems wherein they occurred 15.6 times more frequently, rather than with the number (3-4-5) of used drugs. Adverse reactions were generally caused by an individual drug and predominantly streptomycin. At the same time no significant difference was established in the frequency of toxic (45.5%) and allergic (37%) reactions, but with a rather low frequency of mixed reactions (17.3%). The firstly performed cytochemical and immunological studies of lymphocytes and eosinophils provided new evidence for the pathogenesis of different patterns of adverse reactions. Lymphocytes from patients with toxic reactions showed significant intracellular structural and metabolic disturbances that led to a higher apoptosis of these cells. In patients with lymphocytic allergic reactions, on the contrary, displayed activated processes of anaerobic oxidation and their cytotoxic activity. In both types of adverse reactions, eosinophils exhibited severe intracellular metabolic disturbances that result in destruction and increased apoptosis, which determined the allergic component in virtually all types of side effects. Rational pathogenetic therapy using hormonal, vitamin, and metabolic agents and plasmapheresis could show a 2-fold reduction in the number of patients with adverse reactions without changing the routine chemotherapy regimen and only in 5.6% of cases, the reactions were intractable, which made a specific drug be discontinued and therapy used on an individual basis.

Comparison of cis- and trans-crotononitrile effects in the rat reveals specificity in the neurotoxic properties of nitrile isomers.

The neurotoxic compound crotononitrile has two isomeric forms, cis and trans. We compared the effects of these two isomers isolated by distillation from the commercially available mixture. Adult male Long-Evans rats were administered vehicle control, cis-crotononitrile (80, 100, and 120 mg/kg/day), or trans-crotononitrile (250 mg/kg/day) for 3 days and the changes in corneal transparency and vestibular function were assessed. Surface preparations of the vestibular sensory epithelia and the organ of Corti were examined for hair cell loss by scanning electron microscopy. Concentrations in retina and brain regions of glial fibrillary acidic protein, a marker for reactive gliosis, were also determined in rats exposed to cis-crotononitrile. In a dose-dependent manner, cis-crotononitrile induced vestibular dysfunction, corneal opacity, and hair cell loss in both vestibular epithelia and organ of Corti, and gliosis in retina, olfactory bulb, superior colliculus, inferior colliculus, hypothalamus, hippocampus, and cingulate cortex, but not in cerebellum or striatum. This neurotoxic pattern is similar to that caused by 3,3'-iminodipropionitrile and allylnitrile. In contrast, trans-crotononitrile triggered rearing deficits but not vestibular dysfunction, hair cell loss, or corneal opacity. The isomeric specificity of crotononitrile isomers shows that the neurotoxic effects of nitriles depend on strict structural requirements, suggesting that they act through interaction with specific molecular targets.

Ouabain application to the round window of the gerbil cochlea: a model of auditory neuropathy and apoptosis.

The physiological and morphological changes resulting from acute and chronic infusion of ouabain onto the intact round-window (RW) membrane were examined in the gerbil cochlea. Osmotic pumps fitted with cannulas allowed chronic (0.5-8 days) infusions of ouabain. Acute and short-term applications of ouabain (1-24 h) induced an increase in auditory-nerve compound action potential (CAP) thresholds at high frequencies with lower frequencies unaffected. The resulting threshold shifts were basically all (no response) or none (normal thresholds), with a sharp demarcation between high and low frequencies. Survival times of 2 days or greater after ouabain exposure resulted in complete auditory neuropathy with no CAP response present at any frequency. Distortion product otoacoustic emissions (DPOAEs) and the endocochlear potential (EP) were largely unaffected by the ouabain indicating normal function of the outer hair cells (OHC) and stria vascularis. One to 3 days after short-term applications, apoptosis was evident among the spiral ganglion neurons assessed both morphologically and with TdT-mediated dUTP-biotin nick end labeling (TUNEL). With 4-8 day survival times, most spiral ganglion cells were absent; however, a few cell bodies remained intact in many ganglia profiles. These surviving neurons had many of the characteristics of type II afferents. Our working hypothesis is that the ouabain induces a spreading depression among the type I ganglion cells by blocking the Na,K-ATPase pump. Because of the constant spike activity of these cells, the ouabain rapidly alters potassium concentrations within ([K+]i) and external to ([K+]o) the ganglion cells, thereby initiating an apoptotic cascade.

Expression of BDNF and TrkB mRNAs in the crista neurosensory epithelium and vestibular ganglia following ototoxic damage.

Following ototoxic lesion with the aminoglycoside gentamicin, the vestibular neurosensory epithelia undergo degeneration and then limited spontaneous regeneration. The spatio-temporal expression of brain-derived neurotrophic factor (BDNF) and of its high affinity receptor (trkB) mRNA was investigated in the vestibular end organs and ganglia of chinchillas following gentamicin ototoxicity. In the vestibular ganglia of untreated chinchillas, the level of expression of BDNF mRNA is low. At 1 and 2 weeks after intraotic treatment with gentamicin, BDNF mRNA levels in the vestibular ganglia were elevated significantly compared to untreated chinchillas and chinchillas 4 weeks after treatment. At 4 weeks after gentamicin treatment, BDNF mRNA levels were at intact levels of expression. In the crista ampullaris, high levels of BDNF transcripts were found in the untreated chinchillas. At 1 and 2 weeks after treatment, when only supporting cells are present in the crista, BDNF mRNA was undetectable. Four weeks after aminoglycoside treatment BDNF mRNA was present in the epithelium but at lower levels than in the intact epithelium. In contrast to its ligand, high levels of trkB mRNA hybridization were present in the vestibular ganglia of untreated chinchillas and trkB mRNA levels did not change following gentamicin treatment. In the vestibular epithelia, trkB mRNA was not detected either in the intact epithelium or after gentamicin ototoxicity. These data suggest that BDNF may be involved in the maintenance of the vestibular ganglia and contribute to neurite outgrowth to new and repaired hair cells following ototoxic damage.

Glutamate toxicity induced degeneration of outer hair cells with a temporal increase of nitric oxide production in the guinea pig cochlea.

The aim of this study was to examine the roles of glutamate (GLU) toxicity and involvement of nitric oxide (NO) in the pathogenesis of cochlear degeneration. We examined guinea pig cochleae following chronic exposure to GLU. Trypan blue extrusion and transmission electron microscopy were performed to evaluate degeneration in the organ of Corti. In parallel, nitric oxide synthase (NOS) activity was demonstrated by histochemical staining of NADPH diapholase. GLU treatment caused time-dependent degeneration of outer hair cells (OHCs) in conjunction with a temporal increase of NOS activity in the organ of Corti. This suggests that GLU may be involved in OHC degeneration under toxic conditions, with NO production possibly playing a role in this process.

[Effect of industrial noise and ototoxic antibiotics on ear function in man]. / Vliianie proizvodstvennogo shuma i ototoksicheskikh antibiotikov na sostoianie slukhovoi funktsii cheloveka.

Fifty workers of the 166 ones examined were occupationally exposed to noise; 26 of them were treated with ototoxic antibiotics. Workers of treated with antibiotics most often (69.2%) developed deterioration of acoustic function.

[The vestibular system and cerebellum in organic mercury intoxication; an otolaryngological and neuropathological investigation on 14 autopsy cases in Niigata].

The vestibular system consisting of vestibular ganglion, nerve and inferior, medial, lateral and superior nuclei and fastigial nucleus, cerebellar vermis, flocculus and hemisphere in 14 autopsy cases of methyl mercury intoxication in Niigata and 12 age-matched controls were examined neuropathologically. The findings were evaluated semiquantitatively, that is, -; normal, +/-; gliosis alone, +; loss of neurons or myelinated fibers less than about 40%, ++; loss of neurons from about 41 to 80%, ; loss of neurons more than about 81%. The results were compared to the records of the equilibrium function of those patients. The examinations on the equilibrium function revealed positive findings in the optokinetic and positional nystagmus, eye tracking, Mann or Stepping test in many of the patients. There were no remarkable histological alterations in the vestibular ganglion and nerve of the patients. Moderate and diffuse gliosis with slight shrinkage of neurons were observed in the vestibular and fastigial nuclei of all the patients. Slight loss of neurons in various vestibular nuclei was examined in only 4 patients. The fastigial nucleus showed no evident loss of neurons. In contrast, the cerebellum showed diffuse loss of Purkinje and granule cells, the degree of which was higher in the vermis than in the hemisphere and the flocculus. In the controls, the vestibular nerve and nuclei showed no remarkable alteration even in eight decade subjects. However, the Purkinje cells in the vermis seemed to have a tendency to decrease in aging. The dysequilibrium in the patient of methyl mercury intoxication did not seem to be correspond to the degeneration of the vestibular ganglion, nerve or nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)