Efficacy and preservation of hearing with low-dose gentamicin in unilateral meniere's disease: A clinical symptomatology-based study.

PURPOSE: Meniere's disease (MD), a disorder of the inner ear, presents numerous therapeutic challenges, and intratympanic (IT) gentamicin has been proposed for intractable cases. However, controversy regarding dosage and method persists. The purpose of this study was to assess the efficacy and safety of low-dose IT gentamicin on vertigo attacks in MD using a clinical symptomatology-based method, wherein administration was repeated only if vertigo attacks recurred, with a 2-week interval between injections. MATERIALS AND METHODS: This study included 88 patients with unilateral intractable MD. All patients received one to five IT injections with 0.5 ml of 10 mg of gentamicin (80 mg/2 ml) with an interval of 2 weeks between injections. Vertigo attacks were evaluated before and after therapy and categorized into classes A-F according to the 2015 Equilibrium Committee criteria. Audiovestibular assessments, including Pure Tone Audiometry and Vestibulo-Ocular Reflex evaluations, were performed. RESULTS: Before treatment, patients had an average of 4.4 vertigo attacks/month; after treatment, this average decreased to 0.52. The majority of patients (57 %) reached Class A or B vertigo control with five or fewer gentamicin injections. VOR gain was slightly affected on the healthy side and significantly reduced on the affected side. No hearing deterioration was found in any of the treated patients. CONCLUSIONS: Low-dose IT gentamicin administration based on clinical symptomatology can produce a satisfactory control of vertigo attacks after treatment. This protocol primarily affected the vestibular function, as demonstrated by the significant reduction in VOR gain on the affected side, while avoiding cochlear damage. The lack of adverse events and preservation of hearing underscore the safety and efficacy of this method. These findings have significant clinical implications, suggesting that a low-dose, clinical symptomatology-based gentamicin treatment regimen could be an effective and safe strategy for managing unilateral Meniere's disease in a larger population.

Enhancing the therapeutic potential of intravenous glycerol for Meniere's disease: Robust results from an extensive patient cohort.

INTRODUCTION: Meniere's disease (MD) is an idiopatic condition characterized by recurrent attacks of vertigo, hearing loss, tinnitus, and aural fullness, affecting quality of life. Intravenous glycerol has shown potential as a therapeutic option. This study evaluates its efficacy in a larger patient cohort. MATERIALS AND METHODS: Retrospective study with 168 patients having unilateral MD unresponsive to dietary restrictions. Intravenous 10 % glycerol with 0.9 % sodium chloride was administered for six months. Audio-vestibular assessments and questionnaires were used. RESULTS: Significant improvements in vertigo control observed. 7.1 % achieved complete control, and 58.3 % had substantial control. Quality of life measures improved, and audiometry thresholds remained unchanged. No major adverse events reported. DISCUSSION: Intravenous glycerol effectively controlled vertigo and improved MD patients' quality of life. Limitations include lack of a control group and a relatively short-term follow-up. Future prospects include randomized controlled trials and optimization of treatment protocols. CONCLUSION: Intravenous glycerol shows promise as a therapeutic option for MD, with notable improvements in vertigo control and quality of life. Further research is needed for validation and optimization.

Development of a Magnetoresistive-Based Wearable Eye-Tracking System for Oculomotor Assessment in Neurological and Otoneurological Research-Preliminary In Vivo Tests.

Over the past 20 years, several eye-tracking technologies have been developed. This article aims to present a new type of eye tracker capable of producing detailed information on eye and head movements using an array of magnetoresistive detectors fixed on the patient's head and a small magnet inserted into a contact lens, adapted to the curvature of the cornea of the subject. The software used for data analysis can combine or compare eye and head movements and can represent them as 2D or 3D images. Preliminary data involve an initial patient who was asked to perform several tasks to establish the accuracy, reliability, and tolerance of the magnetic eye tracker and software. The tasks included assessment of saccadic eye movements and pursuit, "drawing" alphabetic shapes or letters, and reading. Finally, a Head Impulse Test (HIT) was performed to estimate the VOR gain, comparing the standard deviation established via vHIT with that established via this magnetic eye tracker (mHIT). This prototypical device is minimally invasive, lightweight, relatively cheap, and tolerable, with a high degree of reliability and precision. All these characteristics could lead to the future use of the magnetic eye tracker in neurological and otoneurological fields.

A Wearable Wireless Magnetic Eye-Tracker, In-Vitro and In-Vivo Tests.

A wireless, wearable magnetic eye tracker is described and characterized. The proposed instrumentation enables simultaneous evaluation of eye and head angular displacements. Such a system can be used to determine the absolute gaze direction as well as to analyze spontaneous eye re-orientation in response to stimuli consisting in head rotations. The latter feature has implications to analyze the vestibulo-ocular reflex and constitutes an interesting opportunity to develop medical (oto-neurological) diagnostics. Details of data analysis are reported together with some results obtained in-vivo or with simple mechanical simulators that enable measurements under controlled conditions.

Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening.

Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome ( https://clinicaltrials.gov , ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials.

Risk of falls, vestibular multimodal processing, and multisensory integration decline in the elderly-Predictive role of the functional head impulse test.

Age-related degeneration of the vestibular system, also known as presbyastasis, leads to unstable gait and higher risk of falls. These conditions affect lifestyle and may have non-negligible social repercussions due to fear-related states of anxiety and depression. In order to develop a model for predicting risk of falls, we assessed vestibulo-ocular function by video and functional Head Impulse Tests (vHIT and fHIT) and their possible correlations with Tinetti Balance Test score. Thirty-one patients over 65 years of age admitted with trauma due to falls were recruited. Vestibular evaluation (complete otoneurological assessment, vHIT, fHIT), cognitive tests (Mini Mental State Examination), anxiety and depression evaluation and Tinetti Balance Test were performed. The possibility of a correlation between the head impulse tests (vHIT, fHIT) and the Tinetti Balance Test was investigated by logistic regression analysis (Nagelkerke r 2 and Wald test). A linear correlation was found between the Tinetti Balance Test score and fHIT, whereas no correlation was found for vHIT. Functional HIT is an effective test for predicting the risk of falls in elderly patients.

An innovative eye-tracker: Main features and demonstrative tests.

We present a set of results obtained with an innovative eye-tracker based on magnetic dipole localization by means of an array of magnetoresistive sensors. The system tracks both head and eye movements with a high rate (100-200 Sa/s) and in real time. A simple setup is arranged to simulate head and eye motions and to test the tracker performance under realistic conditions. Multimedia material is provided to substantiate and exemplify the results. A comparison with other available technologies for eye-tracking is drawn, discussing advantages (e.g., precision) and disadvantages (e.g., invasivity) of the diverse approaches, with the presented method standing out for low cost, robustness, and relatively low invasivity.

The Human Spleen in Malaria: Filter or Shelter?

The human spleen is an immune sentinel and controls red blood cell (RBC) quality. By mechanically retaining subsets of infected RBCs, the spleen may reduce the pace at which the parasite biomass increases before the adaptive immune response operates. Conversely, the spleen may contribute to malaria pathogenesis, particularly anemia that is associated with splenomegaly. Large spleens may also shelter parasites in chronic carriers. Upon treatment with artemisinins, the spleen clears circulating parasites by pitting and releases 'once-infected' RBCs in circulation. This triggers postartesunate delayed hemolysis and explains the long post-treatment positivity of histidine-rich protein 2 (HRP2)-based dipsticks. Importantly, splenic retention of RBCs also applies to gametocytes, the clearance of which may be enhanced by stiffening them with drugs, a potential way to block malaria transmission.

High-throughput microsphiltration to assess red blood cell deformability and screen for malaria transmission-blocking drugs.

The mechanical retention of rigid erythrocytes in the spleen is central in major hematological diseases such as hereditary spherocytosis, sickle-cell disease and malaria. Here, we describe the use of microsphiltration (microsphere filtration) to assess erythrocyte deformability in hundreds to thousands of samples in parallel, by filtering them through microsphere layers in 384-well plates adapted for the discovery of compounds that stiffen Plasmodium falciparum gametocytes, with the aim of interrupting malaria transmission. Compound-exposed gametocytes are loaded into microsphiltration plates, filtered and then transferred to imaging plates for analysis. High-content imaging detects viable gametocytes upstream and downstream from filters and quantifies spleen-like retention. This screening assay takes 3-4 d. Unlike currently available methods used to assess red blood cell (RBC) deformability, microsphiltration enables high-throughput pharmacological screening (tens of thousands of compounds tested in a matter of months) and involves a cell mechanical challenge that induces a physiologically relevant dumbbell-shape deformation. It therefore directly assesses the ability of RBCs to cross inter-endothelial splenic slits in vivo. This protocol has potential applications in quality control for transfusion and in determination of phenotypic markers of erythrocytes in hematological diseases.

Picomolar Inhibition of Plasmepsin V, an Essential Malaria Protease, Achieved Exploiting the Prime Region.

Malaria is an infectious disease caused by Plasmodium parasites. It results in an annual death-toll of ~ 600,000. Resistance to all medications currently in use exists, and novel antimalarial drugs are urgently needed. Plasmepsin V (PmV) is an essential Plasmodium protease and a highly promising antimalarial target, which still lacks molecular characterization and drug-like inhibitors. PmV, cleaving the PExEl motif, is the key enzyme for PExEl-secretion, an indispensable parasitic process for virulence and infection. Here, we describe the accessibility of PmV catalytic pockets to inhibitors and propose a novel strategy for PmV inhibition. We also provide molecular and structural data suitable for future drug development. Using high-throughput platforms, we identified a novel scaffold that interferes with PmV in-vitro at picomolar ranges (~ 1,000-fold more active than available compounds). Via systematic replacement of P and P' regions, we assayed the physico-chemical requirements for PmV inhibition, achieving an unprecedented IC50 of ~20 pM. The hydroxyethylamine moiety, the hydrogen acceptor group in P2', the lipophilic groups upstream to P3, the arginine and other possible substitutions in position P3 proved to be critically important elements in achieving potent inhibition. In-silico analyses provided essential QSAR information and model validation. Our inhibitors act 'on-target', confirmed by cellular interference of PmV function and biochemical interaction with inhibitors. Our inhibitors are poorly performing against parasite growth, possibly due to poor stability of their peptidic component and trans-membrane permeability. The lowest IC50 for parasite growth inhibition was ~ 15 µM. Analysis of inhibitor internalization revealed important pharmacokinetic features for PExEl-based molecules. Our work disclosed novel pursuable drug design strategies for highly efficient PmV inhibition highlighting novel molecular elements necessary for picomolar activity against PmV. All the presented data are discussed in respect to human aspartic proteases and previously reported inhibitors, highlighting differences and proposing new strategies for drug development.