VSSP-activated macrophages mediate senescence and tumor inhibition in a preclinical model of advanced prostate cancer.

Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Ptenpc-/-; Trp53pc-/- tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Ptenpc-/-; Trp53pc-/- tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Video abstract.

Alcohol binge-drinking damage on the vestibulo-oculomotor reflex.

PURPOSE: Binge drinking is associated with several adverse effects in multiple organs. This study aimed at evaluating the effects of a binge-like-drinking on the vestibulo-oculomotor reflex (VOR) using the video Head Impulse Test (vHIT) and the functional Head Impulse Test (fHIT). METHODS: Eleven healthy men (age range 32-35 years) with moderate drinking habits and no history of vestibular dysfunction were enrolled. A preliminary assessment of breath alcohol concentration (BrAC) to check for zero alcohol value and a pre-intake evaluation of VOR using the vHIT and the fHIT were carried on. Then, the subjects were asked to take drinks with different alcohol content (8-40% ethanol by volume) according to their choice, consuming at least 5 standard drinks. Volunteers stopped drinking after 3 h. After a further 30 min, post-intake BrAC measurements and VOR analysis were repeated. RESULTS: After alcohol intake, vHIT recorded an overall significant reduction of VOR gain (0.82 ± 0.07 on both sides) although the outcomes were below the normal range only in the four subjects with the highest blood alcohol levels. The post-intake fHIT outcomes were substandard in 9 participants, with a significant deterioration in performance (% of exact answers = 84.54 ± 11.05% on the left, 83.18 ± 14.53 on the right). CONCLUSIONS: Binge drinking severely affects VOR; fHIT seems more sensitive than vHIT in the assessment of VOR function for complex vestibular lesions, such as those determined by ethanol, suggesting that fHIT could support vHIT in vestibular dysfunction assessment.

Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives.

Ocular fibrosis leads to severe visual impairment and blindness worldwide, being a major area of unmet need in ophthalmology and medicine. To date, the only available treatments are antimetabolite drugs that have significant potentially blinding side effects, such as tissue damage and infection. There is thus an urgent need to identify novel targets to prevent/treat scarring and postsurgical fibrosis in the eye. In this review, the latest progress in biological mechanisms underlying ocular fibrosis are discussed. We also summarize the current knowledge on preclinical studies based on viral and non-viral gene therapy, as well as chemical inhibitors, for targeting TGFß or downstream effectors in fibrotic disorders of the eye. Moreover, the role of angiogenetic and biomechanical factors in ocular fibrosis is discussed, focusing on related preclinical treatment approaches. Moreover, we describe available evidence on clinical studies investigating the use of therapies targeting TGFß-dependent pathways, angiogenetic factors, and biomechanical factors, alone or in combination with other strategies, in ocular tissue fibrosis. Finally, the recent progress in cell-based therapies for treating fibrotic eye disorders is discussed. The increasing knowledge of these disorders in the eye and the promising results from testing of novel targeted therapies could offer viable perspectives for translation into clinical use.

Does cervical range of motion affect the outcomes of canalith repositioning procedures for posterior canal benign positional paroxysmal vertigo?

PURPOSE: Canalith repositioning procedure (CRP) for posterior canal benign positional paroxysmal vertigo (BPPV), also known as Epley maneuver, is a common procedure for the treatment of BPPV. This maneuver entails flexion, extension and rotation of the patient's neck. This study aims to investigate the impact of cervical range of motion (C-ROM) on CRP efficacy. MATERIALS AND METHODS: The study included 47 patients with posterior canal BPPV treated by CRP. The procedure was considered successful if vertigo and nystagmus disappeared at the post-treatment evaluation. If CRP resulted ineffective, it was repeated up to three times per session. C-ROM was measured at BPPV diagnosis before treatment. Patients were followed up for 30 days. RESULTS: The first CRP was successful in 29 patients (61.7%), while it was ineffective in 18 patients (38.3%) requiring multiple repositioning maneuvers. Patients who needed two or more CRP showed lower C-ROM in extension (p = .003) and flexion (p = .042), and earlier recurrences (p = .006). Univariate regression analysis showed that lower cervical extension was significantly associated with the failure of the first CRP (OR: 0.899, 95% CI 0.831-0.973, p = .008). CONCLUSIONS: Our data suggest that a reduced C-ROM can require multiple CRPs to successfully treat BPPV and increase the risk of early recurrences.

Correction to: Is there a relation between sudden sensorineural hearing loss and white matter lesions?

In the original publication, fifth author's surname was incorrectly published as "Diacinto". The correct surname should read as "Diacinti".

Is there a relation between sudden sensorineural hearing loss and white matter lesions?

PURPOSE: Sudden sensorineural hearing loss (SSNHL) has similarities to conditions with vascular etiologies such as myocardial infarction and cerebral stroke. Thus, it could be considered as an early sign of a vascular disease and not only a specific local condition. Chronic hypoperfusion in the brain districts leads to a chronic ischemic damage, called cerebral small vessel disease (CSVD), detectable with brain magnetic resonance imaging (MRI). METHODS: The authors used CSVD to establish the presence of vascular risk factors in individuals with SSNHL and used the Fazekas score scale to classify them. RESULTS: Our study showed that individuals with SSNHL aged between 48 and 60 years have 26% more probability to have a Fazekas score higher than 1 compared to the general population. Individuals younger than 28 years showed a statistically significant negative correlation to have a Fazekas score higher than 0. The higher is the Fazekas score, the less is the probability of hearing recovery. The medium hearing-recovery probability is 46%. This decreases by 16% for every increase of score in the Fazekas scale. In the present study, the recovery probability decreased from 80% in individuals younger than 48 years with a score of 0 to 14% in individuals with a Fazekas scores of 3 and 4. CONCLUSIONS: The authors assessed a higher prevalence of CSVD compared to the general population in patients aged between 48 and 60 years with SSNHL. Moreover, they assessed that the presence of CSVD is related to a decreased probability of recovery, as it has already been demonstrated for stroke.

Assistance Dogs for Persons with Hearing Impairment: A Review.

The use of dogs to help people with disabilities has been known for a long time. Assistance dogs carry out a variety of practical tasks for disabled people with appropriate and targeted training, including assisting deaf persons or people with profound hearing loss. The benefits of assistance dogs for persons with hearing impairment (hearing dogs) include a) improved ability to carry out daily tasks through the codified reporting of sounds proper of everyday life and/or of dangerous situations and b) psychosocial aspects such as companionship and sense of protection. The benefits derived from the use of assistance dogs for persons with hearing impairment are less studied compared to those of assistance dogs employed for other disabilities. Moreover, the role of hearing dogs may appear rather controversial considering technological advances in the field of surgical or prosthetic rehabilitation for people with hearing impairment. This article aims to review features and training of hearing dogs, the effects of their employment and legislative aspects for their owners.

The Prevalence of Chronic Cerebrospinal Venous Insufficiency in Meniere Disease: 24-Month Follow-up after Angioplasty.

PURPOSE: To evaluate relationship between Meniere disease (MD) and chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound, magnetic resonance (MR) imaging, and venography and to evaluate the effectiveness of angioplasty of the internal jugular vein (IJV) and azygos vein (AV) in reducing symptoms of MD. MATERIALS AND METHODS: Patients with a confirmed diagnosis of MD unresponsive to standard treatment underwent duplex ultrasound and MR imaging to diagnose CCSVI. Healthy volunteers were also studied to evaluate CCSVI in asymptomatic subjects. Patients with CCSVI and MD underwent venography and percutaneous transluminal angioplasty (PTA) of IJV and AV. RESULTS: There were 182 patients with no clinical benefit from standard treatments evaluated. CCSVI was diagnosed in 175 (87.5%) patients with MD. Venography was performed in 69 patients to confirm the diagnosis of CCSVI. In 80% of these patients, PTA of the IJV and/or AV was effective for treating signs and symptoms of MD. In the healthy cohort, CCSVI was observed in only 12% of subjects. CONCLUSIONS: These results suggest a possible etiologic relationship between CCSVI and MD that warrants further investigation.

Low-frequency pitch perception in children with cochlear implants in comparison to normal hearing peers.

The aim of the present study was to investigate the application of two new pitch perception tests in children with cochlear implants (CI) and to compare CI outcomes to normal hearing (NH) children, as well as investigating the effect of chronological age on performance. The tests were believed to be linked to the availability of Temporal Fine Structure (TFS) cues. 20 profoundly deaf children with CI (5-17 years) and 31 NH peers participated in the study. Harmonic Intonation (HI) and Disharmonic Intonation (DI) tests were used to measure low-frequency pitch perception. HI/DI outcomes were found poorer in children with CI. CI and NH groups showed a statistically significant difference (p < 0.001). HI scores were better than those of DI test (p < 0.001). Chronological age had a significant effect on DI performance in NH group (p < 0.05); children under the age of 8.5 years showed larger inter-subject-variability; however, the majority of NH children showed outcomes that were considered normal at adult-level. For the DI test, bimodal listeners had better performance than when listening with CI alone. HI/DI tests were applicable as clinical tools in the pediatric population. The majority of CI users showed abnormal outcomes on both tests confirming poor TFS processing in the hearing-impaired population. Findings indicated that the DI test provided more differential low-frequency pitch perception outcomes in that it reflected phase locking and TFS processing capacities of the ear, whereas HI test provided information of its place coding capacity as well.

Early collection of saliva specimens from Bell's palsy patients: quantitative analysis of HHV-6, HSV-1, and VZV.

Bell's palsy is the most common cause of facial paralysis. Although it has been associated with diabetes mellitus, hypertension, pregnancy, and preeclampsia, the etiology of Bell's palsy remains unknown. The reactivation of latent herpes simplex virus (HSV) or varicella-zoster virus (VZV) with subsequent inflammation and entrapment of the facial nerve in the narrow labyrinthine segment has been implicated as a cause of facial paralysis, but the active role of these viruses in Bell's palsy is still discussed. This study quantified HSV-1 DNA, VZV DNA, and HHV-6 DNA in 95 saliva samples collected from patients within 48 hr from the onset of paralysis. HSV-1, VZV, and HHV-6 were detected in 13%, 3%, and 61% of patients, respectively. The detection rate did not differ significantly between patients and a control group of healthy donors. Interestingly, however, the value of HHV-6 DNA copies was significantly higher than that detected in healthy donors. In addition, the mean value of HHV-6 DNA recorded in patients who had at least a one grade improvement of palsy at the first visit was significantly lower than that detected in patients who showed no change in facial palsy grade or an increase of at least one grade. These findings call into question the role of HSV-1 and VZV in the etiology of Bell's palsy, and suggest that HHV-6 may be involved in the development of the disease or that the underlying disease mechanism might predispose patients to HHV-6 reactivation.

Oral versus short-term intratympanic prednisolone therapy for idiopathic sudden hearing loss.

OBJECTIVES: To assess the therapeutic effectiveness of an intratympanic (IT) steroid protocol compared to a systemic steroid protocol. METHODS: A total of 265 consecutive patients presenting unilateral idiopathic sudden sensorineural hearing loss were divided into 2 groups. One group comprised 131 patients enrolled between May 2009 and May 2010, and the other consisted of 134 patients enrolled between June 2010 and June 2011; a total of 48 patients were excluded among the 2 groups. The first group received oral prednisone for 8 days in tapering doses; the second group had IT prednisolone at a dose of 62.5 mg/ml once a day for 3 consecutive days. Audiological examinations were performed at study entry and 30 days after the beginning of therapy. Mean pure tone audiometry (PTA) of both groups and hearing outcomes following the criteria of Furuhashi et al. [Clin Otolaryngol 2002;27:458-463] and Siegel [Otolaryngol Clin North Am 1975;8:467-473] were investigated. RESULTS: The strong efficacy of steroid therapy was evident in both groups, observing both PTA and hearing threshold improvement. The evaluation of the hearing outcomes shows a significantly better result for the short-term IT protocol; this result is ascribable to two types of audiometric curves: down- and up-sloping. CONCLUSION: The results show a significant efficacy of both steroid therapeutic approaches. There was no significant difference in PTA improvement between the 2 study groups; the short-term IT protocol led to better results in the evaluation of the hearing outcomes (following the criteria of Siegel and Furuhashi et al.) for up- and down-sloping audiometric curves.

Bell's palsy: symptoms preceding and accompanying the facial paresis.

This individual prospective cohort study aims to report and analyze the symptoms preceding and accompanying the facial paresis in Bell's palsy (BP). Two hundred sixty-nine patients affected by BP with a maximum delay of 48 hours from the onset were enrolled in the study. The evolution of the facial paresis expressed as House-Brackmann grade in the first 10 days and its correlation with symptoms were analyzed. At the onset, 136 patients presented postauricular pain, 114 were affected by dry eye, and 94 reported dysgeusia. Dry mouth was present in 54 patients (19.7%), facial pain, hyperlacrimation, aural fullness, and hyperacusis represented a smaller percentage of the reported symptoms. After 10 days, 39.9% of the group had a severe paresis while 10.2% reached a complete recovery. Dry mouth at the onset was correlated with severe grade of palsy and was prognostic for poor recovery in the early period. These outcomes lead to the deduction that the nervus intermedius plays an important role in the presentation of the BP and it might be responsible for most of the accompanying symptomatology of the paresis. Our findings could be of important interest to early address a BP patient to further examinations and subsequent therapy.

Bridging the Gap between Psychophysiological and Audiological Factors in the Assessment of Tinnitus: An EEG Investigation in the Beta Band.

BACKGROUND: Despite substantial progress in investigating its psychophysical complexity, tinnitus remains a scientific and clinical enigma. The present study, through an ecological and multidisciplinary approach, aims to identify associations between electroencephalographic (EEG) and psycho-audiological variables. METHODS: EEG beta activity, often related to stress and anxiety, was acquired from 12 tinnitus patients (TIN group) and 7 controls (CONT group) during an audio cognitive task and at rest. We also investigated psychological (SCL-90-R; STAI-Y; BFI-10) and audiological (THI; TQ12-I; Hyperacusis) variables using non-parametric statistics to assess differences and relationships between and within groups. RESULTS: In the TIN group, frontal beta activity positively correlated with hyperacusis, parietal activity, and trait anxiety; the latter is also associated with depression in CONT. Significant differences in paranoid ideation and openness were found between groups. CONCLUSIONS: The connection between anxiety trait, beta activity in the fronto-parietal cortices and hyperacusis provides insights into brain functioning in tinnitus patients, offering quantitative descriptions for clinicians and new multidisciplinary treatment hypotheses.

Sleep architecture variation in chronic tinnitus patients.

OBJECTIVES: The aim of the study was to evaluate the sleep architecture and its possible alterations in chronic tinnitus patients, and investigate any possible correlation between sleep architecture modifications and tinnitus perception, adaptation, and the degree of discomfort in these patients. DESIGN: In a prospective, case-control, nonrandomized study, 18 patients affected by chronic tinnitus were compared with a homogeneous control group consisting of 15 healthy subjects. The experimental group was enrolled at the Tinnitus ambulatory at Policlinico Umberto I Department of Sensory Organs, and the control group was composed of voluntary subjects. A full overnight polysomnography was performed on both groups. Tinnitus patients answered two questionnaires: the tinnitus handicap inventory (THI) and a questionnaire concerning their subjective sleep quality, tinnitus intensity before bedtime, tinnitus intensity at remembered nocturnal wake-up periods, and tinnitus intensity at morning wake-up. Controls completed only the sleep quality questionnaire. RESULTS: All tinnitus patients had a statistically significant alteration in sleep stages. Average percentage of stage 1 + stage 2 was 85.4% ± 6.3, whereas, in the control group, the average percentage of stage 1 + stage 2 was 54.9 ± 11.2 (p < 0.001). Stages 3 and 4 and rapid eye movement (REM) sleep was lacking in all tinnitus patients with an average percentage of 6.4 ± 4.9 of REM sleep, and 6.4 ± 4.9 of stages 3 + 4. The control group showed an average percentage of 21.5 ± 3.6 of REM sleep and 21.5 ± 3.6 of stages 3 + 4 (p < 0.001). No correlation was found between the decrease of REM and the increase of the THI score in the tinnitus group (r = 0.04). However, a mild correlation was found between the increase of light sleep (stage 1 + stage 2) and the THI score reported by the tinnitus group. Therefore, patients with light sleep report a higher THI score (r = 0.4). CONCLUSIONS: The significant alteration of sleep parameters assessed in tinnitus patients underlines the necessity to consider an adequate therapy that could improve patients' sleep quality and also opens avenues for further investigations.

A 9-year-old boy with atypical retroauricular pain: a case report.

Idiopathic causes of retroauricular pain are rarely seen in clinical practice. We present a 9-year-old child who suffered from atypical retroauricular pain resistant to conventional treatment. After excluding any other cause of retroauricular pain, a nerve block was performed with a 0.3 ml lidocaine 1% injection into the trigger point. We believe that this case report is important because in the literature there are no similar cases described in children.

Pneumolabyrinth after intratympanic steroid injection in patient with prosthesis of the stapes: a case report.

The aim of this study is to present a patient who developed a pneumolabyrinth following intratympanic steroid injection performed one year after stapes surgery. The patient started a medical treatment but since no improvement of his symptoms occurred, 10 days after the intratympanic injection a surgical treatment was proposed. An exploratory tympanotomy showed a displacement of the stapes prosthesis from the platinotomy, a dislocation of the incus long process, a fracture of the footplate and a depression into the vestibule. The fragment of the broken footplate was removed, a new prosthesis was located. Nausea, vertigo and nystagmus resolved immediately following surgery with a hearing threshold unchanged. In the present case report, the pathogenesis of pneumolabyrinth may be connected to an IT steroid injection proposed to the patient for the onset of sudden sensorineural hearing loss. To our knowledge, no case of a pneumolabyrinth provoked by intratympanic steroid injection has been previously described.

Listening Effort in Tinnitus: A Pilot Study Employing a Light EEG Headset and Skin Conductance Assessment during the Listening to a Continuous Speech Stimulus under Different SNR Conditions.

Background noise elicits listening effort. What else is tinnitus if not an endogenous background noise? From such reasoning, we hypothesized the occurrence of increased listening effort in tinnitus patients during listening tasks. Such a hypothesis was tested by investigating some indices of listening effort through electroencephalographic and skin conductance, particularly parietal and frontal alpha and electrodermal activity (EDA). Furthermore, tinnitus distress questionnaires (THI and TQ12-I) were employed. Parietal alpha values were positively correlated to TQ12-I scores, and both were negatively correlated to EDA; Pre-stimulus frontal alpha correlated with the THI score in our pilot study; finally, results showed a general trend of increased frontal alpha activity in the tinnitus group in comparison to the control group. Parietal alpha during the listening to stimuli, positively correlated to the TQ12-I, appears to reflect a higher listening effort in tinnitus patients and the perception of tinnitus symptoms. The negative correlation between both listening effort (parietal alpha) and tinnitus symptoms perception (TQ12-I scores) with EDA levels could be explained by a less responsive sympathetic nervous system to prepare the body to expend increased energy during the "fight or flight" response, due to pauperization of energy from tinnitus perception.

Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer.

Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. Senescent-like neutrophils express the triggering receptor expressed on myeloid cells 2 (TREM2) and are more immunosuppressive and tumor-promoting than canonical immunosuppressive neutrophils. Genetic and pharmacological elimination of senescent-like neutrophils decreases tumor progression in different mouse models of prostate cancer. Mechanistically, we have found that apolipoprotein E (APOE) secreted by prostate tumor cells binds TREM2 on neutrophils, promoting their senescence. APOE and TREM2 expression increases in prostate cancers and correlates with poor prognosis. Collectively, these results reveal an alternative mechanism of tumor immune evasion and support the development of immune senolytics targeting senescent-like neutrophils for cancer therapy.

The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells.

Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs. Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.

An electrophysiological approach to tinnitus interpretation.

INTRODUCTION: Serotonin seems to play a central role in tinnitus. The intensity dependence of auditory evoked potential (IDAP) is considered an index of central serotonergic activity in the auditory cortex. The higher the steepness of the N1/P2 component amplitude-stimulus function slope (N1/P2 ASF slope as calculated by IDAP), the lower the central serotonergic activity. Similarly, the N1 amplitude-stimulus function slope (N1 ASF slope) was investigated. Auditory brainstem responses (ABR) examine the auditory system functionality from the periphery and through the brainstem, where serotonergic projections have been identified. OBJECTIVES: Assessing whether tinnitus perception neurotransmitters activity inbalance could be investigated by an electrophysiological approach. MATERIALS AND METHODS: Ten normoacousic tinnitus patients and 14 healthy controls were included in the study. Subjects underwent EEG (IDAP) recording, ABR recording and psychometric questionnaires administration. RESULTS: N1/P2 ASF slope and N1ASF slope tended to have a greater steepness in patients. N1ASF slope was significantly correlated with ABR wave V and interpeak III-V latencies in patients. ABR wave V and interpeak III-V latencies were significantly longer in patients than in controls. CONCLUSION: N1/P2 ASF slope, N1 ASF slope and ABR components appear to be useful electrophysiologic methods to study possible functional alterations related to the serotonergic activity.