Blood-Labyrinth Barrier in Health and Diseases: Effect of Hormetic Nutrients.

Significance: The stria vascularis, located in the inner ear, consists of three layers, one of which is the blood-labyrinth barrier (BLB). It is formed by endothelial cells, sealed together to prevent the passage of toxic substances from the blood to the inner ear, by pericytes and perivascular-resident macrophage-like melanocyte. Recent Advances: There are various causes that lead to hearing loss, and among these are noise-induced and autoimmune hearing loss, ear disorders related to ototoxic medication, Ménière's disease, and age-related hearing loss. For all of these, major therapeutic interventions include drug-loaded nanoparticles, via intratympanic or intracochlear delivery. Critical Issues: Since many pathologies associated with hearing loss are characterized by a weakening of the BLB, in this review, the molecular mechanisms underlying the response to damage of BLB cellular components have been discussed. In addition, insight into the role of hormetic nutrients against hearing loss pathology is proposed. Future Directions: BLB cellular components of neurovascular cochlear unit play important physiological roles, owing to their impermeable function against all ototoxic substances that can induce damage. Studies are needed to investigate the cross talk occurring between these cellular components to exploit their possible role as novel targets for therapeutic interventions that may unravel future path based on the use of hormetic nutrients. Antioxid. Redox Signal. 40, 542-563.

Redox Modulation of Meniere Disease by Coriolus Versicolor Treatment, a Nutritional Mushroom Approach with Neuroprotective Potential.

BACKGROUND: Meniere's disease (MD) is a cochlear neurodegenerative disease. Hearing loss appears to be triggered by oxidative stress in the ganglion neurons of the inner ear. OBJECTIVE: Here, we confirm the variation of markers of oxidative stress and inflammation in patients with Meniere and hypothesize that chronic treatment with Coriolus mushroom helps in the response to oxidative stress and acts on α-synuclein and on NF-kB-mediated inflammatory processes. METHODS: Markers of oxidative stress and inflammation were evaluated in MD patients with or without Coriolus treatment for 3 or 6 months. RESULTS: MD patients had a small increase in Nrf2, HO-1, γ-GC, Hsp70, Trx and sirtuin-1, which were further increased by Coriolus treatment, especially after 6 months. Increased markers of oxidative damage, such as protein carbonyls, HNE, and ultraweak chemiluminescence, associated with a decrease in plasma GSH/GSSG ratio, were also observed in lymphocytes from MD patients. These parameters were restored to values similar to the baseline in patients treated with Coriolus for both 3 and 6 months. Furthermore, treated MD subjects showed decreased expression of α-synuclein, GFAP and Iba-1 proteins and modulation of the NF-kB pathway, which were impaired in MD patients. These changes were greatest in subjects taking the supplements for 6 months. CONCLUSIONS: Our study suggests MD as a model of cochlear neurodegenerative disease for the identification of potent inducers of the Nrf2-vitagene pathway, able to reduce the deleterious consequences associated with neurodegenerative damage, probably by indirectly acting on α-synuclein expression and on inflammatory processes NF- kB-mediated.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review.

Autosomal dominant non-syndromic hearing loss (HL) typically occurs when only one dominant allele within the disease gene is sufficient to express the phenotype. Therefore, most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history. To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL. DFNA22 (MYO6 gene), DFNA8/12 (TECTA gene), DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), DFNA15 (POU4F3 gene), DFNA2A (KCNQ4 gene), and DFNA10 (EYA4 gene) are some of the most common forms of autosomal dominant non-syndromic HL. The characteristics of autosomal dominant non-syndromic HL are heterogenous. However, in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree). DFNA1 (DIAPH1 gene) and DFNA6/14/38 (WFS1 gene) are the most common forms of autosomal dominant non-syndromic HL affecting low frequencies, while DFNA16 (unknown gene) is characterized by fluctuating HL. A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants.

Universal newborn hearing screening in the Italian Region of Sicily in 2018.

OBJECTIVES: We have clarified the role of Universal Neonatal Hearing Screening (UNHS) for both early diagnosis and rapid treatment in order to improve the prognosis of the deaf child and reduce patient management costs. Although in Sicily UNHS has been progressively implemented, there is scarce data in the literature on this matter. Therefore, the main objective was to collect in the year 2018 the following data: number of newborns screened for hearing loss, number of infants "referred" to transiently evoked otoacoustic emissions (TEOAE), number of infants with pathologic auditory brainstem response (ABR) and number of infants affected by permanent hearing loss. METHODS: UNHS monitoring was conducted through the collection of data through a questionnaire, which was analysed evaluating the effectiveness and adherence to the screening program prepared by the Department for Health Activities and the Epidemiological Observatory (DASOE). RESULTS: In 2018, there were 40,243 newborns in Sicily. A total of 37,562 newborns were screened (93.3%). There were 1,328 "referred" infants with TEOAE (3.5%). On the 2nd level, "referred" newborns examined were 1,080 of 1,328 expected (missing 248 "refer" newborns, equal to 18.6%). The number of "referred" infants confirmed with TEOAE was 113 of 1,080, while "referred" infants confirmed with ABR were 71. On the 3rd level, 67 of 71 were infants examined: 28 infants were suffering from monolateral hearing loss (13 slight/mild, 13 moderate, 1 severe and 1 profound) and 39 from bilateral hearing loss (1slight/mild, 19 moderate, 13 severe and 7 profound). Excluding 7 infants from the NICU, 60 of 37,562 infants had hearing loss (1.5%). CONCLUSIONS: The monitoring of the UNHS in Sicily has allowed obtaining the data of individual centres, absent in the literature to date, to verify the effectiveness of the screening, according to JCIH criteria, to highlight some criticalities and, finally, to propose possible solutions.

Effects of hormone therapy containing 2 mg drospirenone and 1 mg 17ß-estradiol on postmenopausal exacerbation of Meniere's disease: Preliminary study.

The present study aimed to evaluate the effects of 2 mg drospirenone (DRSP) and 1 mg 17ß-estradiol (E2) hormone therapy (HT) in combination with rehabilitation therapy for postmenopausal women with Meniere's disease (MD). The combined drug hormone treatment was denoted as DRSP/E2. A total of 65 postmenopausal female patients with MD and severe distress were enrolled in the present prospective study. A total of 31 women comprised the study group (group A), undergoing HT and rehabilitation therapy, whereas 34 women who opted for rehabilitation therapy alone comprised the control group (group B). Vestibular function and distress associated with MD were assessed by stabilometry and the Dizziness Handicap Inventory (DHI) questionnaire, respectively. The data were collected at baseline and during the 3- and 6-month follow-up visits. The areas of the stabilometric ellipses exhibited a higher reduction in group A compared with group B with regard to the baseline values at both follow-up assessments (P<0.001). At baseline, both groups exhibited severe self-perceived discomfort, with similar DHI scores of 72.3±3.7 (group A) and 70.6±3.9 (group B; P=0.07). At the 3-month follow-up, both groups underwent a gradual improvement, which was significantly higher in group A (47.5±3.7) compared with in group B (64.2±3.3; P<0.001). At the 6-month follow-up, the DHI scores were improved in group A (43.4±3.4) compared with in group B (58.5±3.1; P<0.001). Therefore, DRSP/E2 HT was effective in reducing the fluid overload, which is characteristic of MD. The findings of the present study demonstrated that integrated therapy based on the administration of DRSP/E2 HT and rehabilitation may be more effective compared with rehabilitation alone for the management of postmenopausal exacerbation of MD.

A panel of jitter/shimmer may identify functional dysphonia at risk of failure after speech therapy.

BACKGROUND: There are no reliable outcome predictors for functional dysphonia (FD) patients. OBJECTIVES: To investigate if any clinical or phoniatric characteristics could identify FD patients at risk of negative outcome after speech therapy. METHODS: We retrospectively reviewed the results of 78 FD patients treated with the proprioceptive elastic method. Before and one-month after therapy, patients underwent endoscopy, acoustic analysis with Multi-Dimensional Voice Program, and Voice Handicap Index-10 questionnaire (VHI-10). Negative outcome was the persistence of VHI-10 ≥ 13. RESULTS: 26 FD patients had negative outcome (i.e. VHI-10 ≥ 13) after speech therapy. At univariate analysis, clinical variables (i.e. sex, age, comorbidities, dysphonia duration, and professional voice use) were not associated with the outcome. Elevated Jitter% (Jitt; p = 0.03), Shimmer% (Shim; statistical trend, p = 0.06), and Noise to Harmonics Ratio (statistical trend, p = 0.06) were found in patients with poor results. At multivariate analysis, higher Jitt was an independent negative prognostic factor (p = 0.02), while a statically trend was identified for Shim (p = 0.06). A panel of Jitt >1.5 and Shim >5.1 showed an acceptable discriminatory power (AUC [ROC] = 0.76) according to Hosmer and Lemeshow scale. CONCLUSION: A panel of two acoustic analysis parameters could help in identifying FD patients at risk of speech therapy failure. Further studies in these patients are needed to evaluate the most efficient treatment protocol.

Current management of arytenoid sub-luxation and dislocation.

PURPOSE: To review the current management of arytenoid subluxation/dislocation (AS/AD) focusing on diagnostic, therapeutic, and prognostic controversies. METHODS: The international literature of the last 20 years has been considered. After the application of inclusion criteria, 20 studies were selected (471 AS/AD cases in total). RESULTS: All the included investigations were retrospective case series. AS/AD was often iatrogenic occurring at least in 0.01% of patients undergone endo-tracheal intubation. The most common symptom was persistent hoarseness. The diagnosis was made by video-laryngoscopy and neck computed tomography in most reports, while some used also laryngeal electromyography. Laryngeal electromyography was fundamental to rule out unilateral vocal fold paralysis, the main differential diagnosis. The surgical relocation of AS/AD under general or local anesthesia was achieved in about 80% of patients. CONCLUSION: AS/AD is a mechanical disorder of the larynx that can be successfully treated if promptly diagnosed. Clinical trials and multi-centric studies are necessary to set management guidelines.

Hericium Erinaceus Prevents DEHP-Induced Mitochondrial Dysfunction and Apoptosis in PC12 Cells.

Hericium Erinaceus (HE) is a medicinal plant known to possess anticarcinogenic, antibiotic, and antioxidant activities. It has been shown to have a protective effect against ischemia-injury-induced neuronal cell death in rats. As an extending study, here we examined in pheochromocytoma 12 (PC12) cells, whether HE could exert a protective effect against oxidative stress and apoptosis induced by di(2-ethylhexyl)phthalate (DEHP), a plasticizer known to cause neurotoxicity. We demonstrated that pretreatment with HE significantly attenuated DEHP induced cell death. This protective effect may be attributed to its ability to reduce intracellular reactive oxygen species levels, preserving the activity of respiratory complexes and stabilizing the mitochondrial membrane potential. Additionally, HE pretreatment significantly modulated Nrf2 and Nrf2-dependent vitagenes expression, preventing the increase of pro-apoptotic and the decrease of anti-apoptotic markers. Collectively, our data provide evidence of new preventive nutritional strategy using HE against DEHP-induced apoptosis in PC12 cells.

Curcumin, Hormesis and the Nervous System.

Curcumin is a polyphenol compound extracted from the rhizome of Curcuma longa Linn (family Zingiberaceae) commonly used as a spice to color and flavor food. Several preclinical studies have suggested beneficial roles for curcumin as an adjuvant therapy in free radical-based diseases, mainly neurodegenerative disorders. Indeed, curcumin belongs to the family of hormetins and the enhancement of the cell stress response, mainly the heme oxygenase-1 system, is actually considered the common denominator for this dual response. However, evidence-based medicine has clearly demonstrated the lack of any therapeutic effect of curcumin to contrast the onset or progression of neurodegeneration and related diseases. Finally, the curcumin safety profile imposes a careful analysis of the risk/benefit balance prior to proposing chronic supplementation with curcumin.

Nutritional Mushroom Treatment in Meniere's Disease with Coriolus versicolor: A Rationale for Therapeutic Intervention in Neuroinflammation and Antineurodegeneration.

Meniere's disease (MD) represents a clinical syndrome characterized by episodes of spontaneous vertigo, associated with fluctuating, low to medium frequencies sensorineural hearing loss (SNHL), tinnitus, and aural fullness affecting one or both ears. To date, the cause of MD remains substantially unknown, despite increasing evidence suggesting that oxidative stress and neuroinflammation may be central to the development of endolymphatic hydrops and consequent otholitic degeneration and displacement in the reuniting duct, thus originating the otolithic crisis from vestibular otolithic organs utricle or saccule. As a starting point to withstand pathological consequences, cellular pathways conferring protection against oxidative stress, such as vitagenes, are also induced, but at a level not sufficient to prevent full neuroprotection, which can be reinforced by exogenous nutritional approaches. One emerging strategy is supplementation with mushrooms. Mushroom preparations, used in traditional medicine for thousands of years, are endowed with various biological actions, including antioxidant, immunostimulatory, hepatoprotective, anticancer, as well as antiviral effects. For example, therapeutic polysaccharopeptides obtained from Coriolus versicolor are commercially well established. In this study, we examined the hypothesis that neurotoxic insult represents a critical primary mediator operating in MD pathogenesis, reflected by quantitative increases of markers of oxidative stress and cellular stress response in the peripheral blood of MD patients. We evaluated systemic oxidative stress and cellular stress response in MD patients in the absence and in the presence of treatment with a biomass preparation from Coriolus. Systemic oxidative stress was estimated by measuring, in plasma, protein carbonyls, hydroxynonenals (HNE), and ultraweak luminescence, as well as by lipidomics analysis of active biolipids, such as lipoxin A4 and F2-isoprostanes, whereas in lymphocytes we determined heat shock proteins 70 (Hsp72), heme oxygenase-1 (HO-1), thioredoxin (Trx), and γ-GC liase to evaluate the systemic cellular stress response. Increased levels of carbonyls, HNE, luminescence, and F2-isoprostanes were found in MD patients with respect to the MD plus Coriolus-treated group. This was paralleled by a significant (p < 0.01) induction, after Coriolus treatment, of vitagenes such as HO-1, Hsp70, Trx, sirtuin-1, and γ-GC liase in lymphocyte and by a significant (p < 0.05) increase in the plasma ratio-reduced glutathione (GSH) vs. oxidized glutathione (GSSG). In conclusion, patients affected by MD are under conditions of systemic oxidative stress, and the induction of vitagenes after mushroom supplementation indicates a maintained response to counteract intracellular pro-oxidant status. The present study also highlights the importance of investigating MD as a convenient model of cochlear neurodegenerative disease. Thus, searching innovative and more potent inducers of the vitagene system can allow the development of pharmacological strategies capable of enhancing the intrinsic reserve of vulnerable neurons, such as ganglion cells to maximize antidegenerative stress responses and thus providing neuroprotection.

Effects of combined oral contraception containing drospirenone on premenstrual exacerbation of Meniere's disease: Preliminary study.

OBJECTIVES: Meniere's disease is caused by an augmented endolymph pressure in the inner ear; symptoms are vertigo, fluctuating hearing loss and tinnitus. Exacerbations has been noted during premenstrual phase. The study aims to evaluate the effects of a 20 µm Ethinylestradiol (EE) and 3 mg Drospirenone (DRSP) oral contraceptive (20 µmEE/3mgDRSP) in continuous regimen, associated with rehabilitation therapy on Meniere's disease. STUDY DESIGN: This non-randomized controlled study was performed from October 2015 to October 2017. Forty-two premenopausal women affected by MD with severe distress in the premenstrual phase were enrolled. Sixteen women constituted the study group (Group A), and twenty women constituted the control group (Group B). Group A underwent EE/DRSP therapy and rehabilitation and Group B underwent rehabilitation therapy alone. Stabilometry and the Dizziness Handicap Inventory questionnaire were used to measure vestibular function and distress related to the disease, respectively, at baseline (T0), 3 months (T1) and 6 months (T2). RESULTS: At T0, both groups had large, similar areas of stabilometric ellipses (p = NS) that reduced more in Group A than in Group B, at T1 and T2 (p < 0.001). High scores of the DHI (cut-off ≤54) were observed at T0 in both groups (A 66.8 ±â€¯2.8 vs B 65.5 ±â€¯3.6; p = NS). At T1, a gradual improvement in both groups was observed, manly in Group A (A 45.1 ±â€¯3.6 vs B 62.4 ±â€¯4.1; p < 0.001). At T2, the DHI scores were significantly lower in Group A (39.2 ±â€¯3.8) compared to Group B (68.8 ±â€¯3.6) (p < 0.001). CONCLUSIONS: DRSP could be effective in reducing the fluid overload typical of the premenstrual phase, improving symptoms of MD. The results support the efficacy of EE/DRSP usage associated with rehabilitation therapy on premenstrual exacerbation of MD.

Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer's disease and Alzheimer-linked pathologies: modulation by nutritional mushrooms.

Human life develops and expands not only in time and space, but also in the retrograde permanent recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered or lost under pathological conditions such as Alzheimer's disease, including recently associated oxidant pathologies, such as ocular neural degeneration occurring in glaucoma or neurosensorial degeneration occurring in Menière's disease. Oxidative stress and altered antioxidant systems have been suggested to play a role in the aetiology of major neurodegenerative disorders, and altered expression of genes sensing oxidative stress, as well as decreased cellular stress response mechanisms could synergistically contribute to the course of these oxidant disorders. Thus, the theory that low levels of stress can produce protective responses against the pathogenic processes is a frontier area of neurobiological research focal to understanding and developing therapeutic approaches to neurodegenerative disorders. Herein, we discuss cellular mechanisms underlying AD neuroinflammatory pathogenesis that are contributory to Alzheimer's disease. We describe endogenous cellular defence mechanism modulation and neurohormesis as a potentially innovative approach to therapeutics for AD and other neurodegenerative conditions that are associated with mitochondrial dysfunction and neuroinflammation. Particularly, we consider the emerging role of the inflammasome as an important component of the neuroprotective network, as well as the importance of Coriolus and Hericium nutritional mushrooms in redox stress responsive mechanisms and neuroprotection.

Multicenter research into the quality of life of patients with advanced oropharyngeal carcinoma with long-term survival associated with human papilloma virus.

The treatment of advanced-stage oropharyngeal squamous cell carcinoma may utilize various modes, including combining surgery with chemoradiotherapy (CTRT), or primary CTRT followed by rescue surgery. In previous literature it has been revealed how patients treated with combined modes report a low quality of life (QoL) and severe consequences following surgery, radiotherapy and chemotherapy, in the short and in the long-term. The decrease in the QoL of patients treated with high-intensity multi-modal strategies highlights the necessity of modifying treatments, particularly for young HPV-positive patients, where an increased survival rate has already been reported. The modified treatment for HPV-positive tumors in the tonsils and at the base of the tongue is based on the deintensification of therapies aiming to reduce toxicity and thereby improve QoL in the long term, whilst still maintaining therapeutic effectiveness. The aim of the present study was to evaluate the QoL in patients with a long-term survival, who were treated with combined therapy for squamous cell tumors in the tonsils and at the base of the tongue, and to compare the results observed in HPV-positive and HPV-negative patients. According to statistical analysis, differences in the general QoL and in the single scales of the European Organization for the Research and Treatment of Cancer questionnaires were not correlated with the type of therapy selected for the particular patient. QoL considered the presence of HPV, the type of treatment, the subregion of the tonsils vs. the base of the tongue and the disease stage at the time of diagnosis, and was determined to be non-influential with regard to these specific variables.

Neurovegetative disorders of perimenopausal women treated with docosahexaenoic acid (DHA, 625 mg).

The study evaluated the effect of DHA 625 mg in women who experience menopausal symptoms, on sexuality and quality of life (QoL), and on the auditory brainstem response (ABR). Forty-two perimenopausal women were enrolled. The Kupperman Index (KI) was used to evaluate menopause symptoms. The Short Form-36 (SF-36), Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS) were used to assess QoL, sexual function, and sexual distress, respectively. Auditory evoked potentials to measure the ABR. The study had one follow-up at 6 months. The women reported an improvement in the KI total score (p < .001). Moreover, women reported QoL improvements in all the psychological categories (p < .001), but not in physical categories (p = NS). FSFI and FSDS total scores increased (p < .01) and the FSDS score decreased (p < .01), mainly due to arousal (p < .03) and lubrication (p < .05) sexual aspects. The ABR wave latencies were lower than the baseline values (p < .05). DHA could be effective in modulating some perimenopausal symptoms in women and, consequently could contribute to improve their QoL and sexual life. Finally, DHA seems to have a direct activity on the neuronal conduction time into the audiological system.

The watch-pat in pediatrics sleep disordered breathing: Pilot study on children with negative nocturnal pulse oximetry.

OBJECTIVES: The main purpose of this study was to determine the efficacy of Watch-PAT in Pediatric Sleep Disordered Breathing (PSDB) diagnosis in children with symptoms suggestive of PSDB, in which the nocturnal pulse oximetry was negative according to the Brouilette criteria. METHODS: We enrolled 28 patients aged between 5 and 12 years (mean age: 7.75 ± 1.69), who underwent the registration with Watch-PAT, that utilizes the Peripheral Arterial Tone (PAT), AHI, RDI, body position, snoring, pulse oximetry and actigraphy. RESULTS: Recording Watch-PAT was indicative of PSDB in 10/28 (35.7%) patients; when it was placed the threshold of AHI > 1 the number of positive patients for PSDB increased to 17/28 (60.7%). Exists a positive correlation between pat-RDI (rho = 0.798, p = 0.005) and the snoring > 40% of the time (rho = 0.656, p < 0.001) were correlated with the pat-AHI values. CONCLUSION: The recording Watch-PAT appears to permit the defection of a certain number of SDB that might escape to the clinical evaluation and pulse oximetry only.

Expression pattern of estroprogestinic receptors in sinonasal inverted papilloma.

Inverted papilloma (IP) is a locally destructive, benign neoplasm of the nose and paranasal sinuses with a high tendency for recurrence, a significant potential for malignancy, and an etiology that today is still uncertain. The expression of hormonal receptors in neoplastic tissues has been the focus of intensive research for its potential diagnostic, prognostic, and therapeutic significance. The aim of this study was to assess the potential estroprogestinic receptor expression in patients undergoing sinus surgery for IP. A retrospective study was carried out, on surgical specimens of 73 patients who underwent endoscopic sinus surgery for first manifestation of sinonasal IP (primitive IP group) and in 21 subjects who had developed a recurrence (relapsed IP group). The results of the immunohistochemical analysis of the first group showed the absence of receptor expression for PGR in all cases analyzed and the presence of a low positivity for ER in 11 cases (P > 0.082). Similarly, in the second group the results showed a low presence of ER receptors in 3 of the 21 cases (P > 0.068), while there was no evidence of PGR receptors in the examined samples. In addition, in 11 of the cases only 3 were considered positive (27.2%) showing a recurrence during follow-up (P > 0.068).Our results suggest that the sinonasal IP is a benign tumor independent of estrogen and progesterone, and the receptors for these hormones are therefore unsuitable as predictors of relapse or possible prognostic indicators and therapeutic targets.

Autoimmune Ear Disease: Clinical and Diagnostic Relevance in Cogan's Sydrome.

The autoimmune inner ear disease is a clinical syndrome with uncertain pathogenesis that is often associated to rapidly progressive hearing loss that, especially at the early stages of disease, may be at monoaural localization, although more often it is at binaural localization. It usually occurs as a sudden deafness, or a rapidly progressive sensorineural hearing loss. In this study a particular form of autoimmune inner ear disease is described, Cogan's syndrome. Cogan's syndrome is a chronic inflammatory disorder that most commonly affects young adults. Clinical hallmarks are interstitial keratitis, vestibular and auditory dysfunction. Associations between Cogan's syndrome and systemic vasculitis, as well as aortitis, also exist. We report a case of a young woman who presented audiological and systemic characteristics attributable to Cogan's syndrome. In the description of the case we illustrate how the appearance and evolution of the disease presented.

A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas.

BACKGROUND: The INI1/SMARCB1 gene protein product has been implicated in the direct pathogenesis of schwannomas from patients with one form of schwannomatosis [SWNTS1; MIM # 162091] showing a mosaic pattern of loss of protein expression by immunohistochemistry [93% in familial vs. 55% in sporadic cases]. AIM OF STUDY: To verify whether such INI1/SMARCB1 mosaic pattern could be extended to all schwannomas arising in the sporadic and familial schwannomatoses [i.e. to SMARCB1-related (SWNTS1) or LZTR1-related (SWNTS2) schwannomatosis or to SMARCB1/LZTR1-negative schwannomatosis] and whether it could be involved in classical NF2 or solitary peripheral schwannomas METHODS: We blindly analysed schwannoma samples obtained from a total of 22 patients including (a) 2 patients (2 males; aged 38 and 55 years) affected by non-familial SMARCB1-associated schwannomatosis (SWTNS1); (b) 1 patient (1 female; aged 33 years) affected by familial schwannomatosis (SWTNS1/ SMARCB1 germ line mutations); (c) 5 patients (3 males, 2 females; aged 33 to 35 years) affected by non-familial (sporadic) LZTR1-associated schwannomatosis (SWNTS2); (d) 3 patients (3 males; aged 35 to 47 years) affected by familial schwannomatosis (SWTNS2/ LZTR1 germ line mutations); (e) 2 patients (1 male, 1 female; aged 63 and 49 years, respectively) affected by non-familial schwannomatosis (SWTNS, negative for SMARCB1, LZTR1 and NF2 gene mutations); (f) 4 patients (3 males, 1 females; aged 15 to 24 years) affected by classical NF2 (NF2: harbouring NF2 germ line mutations; and (g) 5 patients (3 males, 2 females; aged 33 to 68 years) who had solitary schwannomas. [follow-up = 15-30 years; negative for constitutional/somatic mutation analysis for the SMARCB1, LZTR1 and NF2 genes] were (blindly) analyzed. The INI1/SMARCB1 immunostaining pattern was regarded as (1) diffuse positive nuclear staining [= retained expression] or (2) mosaic pattern [mixed positive/negative nuclei = loss of expression in a subset of tumour cells]. RESULTS: All solitary peripheral schwannomas and NF2-associated vestibular schwannomas showed diffuse nuclear INI1/SMARCB1 staining in 97-100% of neoplastic cells; schwannomas obtained from all cases of non-familial and familial schwannomatosis and NF2-associated non-vestibular schwannomas showed a mosaic pattern ranging from 10 to 70% of INI1/SMARCB1-positive expression. We did not record a complete lack of nuclear staining. CONCLUSIONS: The present data suggests that (a) mosaic loss of immunohistochemical INI1/SMARCB1 expression, despite the interlesional variability, is a reliable marker of schwannomatosis regardless of the involved gene and it might help in the differential diagnosis of schwannomatosis vs. solitary schwannomas and (b) INI1/SMARCB1 expression is not useful in the differential with mosaic NF2, since NF2-associated peripheral schwannomas show the same immunohistochemical pattern.