Emerging pharmacotherapy of tinnitus

Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about 1 in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Because tinnitus is frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social and economic burdens of tinnitus can be enormous. No curative treatments are available. However, tinnitus symptoms can be alleviated to some extent. The most widespread management therapies consist of auditory stimulation and cognitive behavioral treatment, aiming at improving habituation and coping strategies. Available clinical trials vary in methodological rigor and have been performed for a considerable number of different drugs. None of the investigated drugs have demonstrated providing replicable long-term reduction of tinnitus impact in the majority of patients in excess of placebo effects. Accordingly, there are no FDA or European Medicines Agency approved drugs for the treatment of tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing market are desperately needed and even a drug that produces only a small but significant effect would have an enormous therapeutic impact. This review describes current and emerging pharmacotherapies with current difficulties and limitations. In addition, it provides an estimate of the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete knowledge of tinnitus pathophysiology, lack of well-established animal models, heterogeneity of different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and variability in clinical trial methodology. © 2009 Informa UK Ltd.Fil: Langguth, Berthold. Universitat Regensburg; AlemaniaFil: Salvi, Richard. State University of New York; Estados UnidosFil: Elgoyhen, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentin

Head orientation benefit to speech intelligibility in noise for cochlear implant users and in realistic listening conditions

Cochlear implant (CI) users suffer from elevated speech-reception thresholds and may rely on lip reading. Traditional measures of spatial release from masking quantify speech-reception-threshold improvement with azimuthal separation of target speaker and interferers and with the listener facing the target speaker. Substantial benefits of orienting the head away from the target speaker were predicted by a model of spatial release from masking. Audio-only and audio-visual speech-reception thresholds in normal-hearing (NH) listeners and bilateral and unilateral CI users confirmed model predictions of this head-orientation benefit. The benefit ranged 2–5 dB for a modest 30� orientation that did not affect the lip-reading benefit. NH listeners’ and CI users’ lip-reading benefit measured 3 and 5 dB, respectively. A head-orientation benefit of �2 dB was also both predicted and observed in NH listeners in realistic simulations of a restaurant listening environment. Exploiting the benefit of head orientation is thus a robust hearing tactic that would benefit both NH listeners and CI users in noisy listening conditions

Localization of a 64-kDa phosphoprotein in the lumen between the outer and inner envelopes of pea chloroplasts

The identification and localization of a marker protein for the intermembrane space between the outer and inner chloroplast envelopes is described. This 64-kDa protein is very rapidly labeled by [γ-32P]ATP at very low (30 nM) ATP concentrations and the phosphoryl group exhibits a high turnover rate. It was possible to establish the presence of the 64-kDa protein in this plastid compartment by using different chloroplast envelope separation and isolation techniques. In addition comparison of labeling kinetics by intact and hypotonically lysed pea chloroplasts support the localization of the 64-kDa protein in the intermembrane space. The 64-kDa protein was present and could be labeled in mixed envelope membranes isolated from hypotonically lysed plastids. Mixed envelope membranes incorporated high amounts of 32P from [γ-32P]ATP into the 64-kDa protein, whereas separated outer and inner envelope membranes did not show significant phosphorylation of this protein. Water/Triton X-114 phase partitioning demonstrated that the 64-kDa protein is a hydrophilic polypeptide. These findings suggest that the 64-kDa protein is a soluble protein trapped in the space between the inner and outer envelope membranes. After sonication of mixed envelope membranes, the 64-kDa protein was no longer present in the membrane fraction, but could be found in the supernatant after a 110000 × g centrifugation

An overview of the mid-infrared spectro-interferometer MATISSE: science, concept, and current status

MATISSE is the second-generation mid-infrared spectrograph and imager for the Very Large Telescope Interferometer (VLTI) at Paranal. This new interferometric instrument will allow significant advances by opening new avenues in various fundamental research fields: studying the planet-forming region of disks around young stellar objects, understanding the surface structures and mass loss phenomena affecting evolved stars, and probing the environments of black holes in active galactic nuclei. As a first breakthrough, MATISSE will enlarge the spectral domain of current optical interferometers by offering the L and M bands in addition to the N band. This will open a wide wavelength domain, ranging from 2.8 to 13 um, exploring angular scales as small as 3 mas (L band) / 10 mas (N band). As a second breakthrough, MATISSE will allow mid-infrared imaging - closure-phase aperture-synthesis imaging - with up to four Unit Telescopes (UT) or Auxiliary Telescopes (AT) of the VLTI. Moreover, MATISSE will offer a spectral resolution range from R ~ 30 to R ~ 5000. Here, we present one of the main science objectives, the study of protoplanetary disks, that has driven the instrument design and motivated several VLTI upgrades (GRA4MAT and NAOMI). We introduce the physical concept of MATISSE including a description of the signal on the detectors and an evaluation of the expected performances. We also discuss the current status of the MATISSE instrument, which is entering its testing phase, and the foreseen schedule for the next two years that will lead to the first light at Paranal.Comment: SPIE Astronomical Telescopes and Instrumentation conference, June 2016, 11 pages, 6 Figure

Control of Reflexive Saccades following Hemispherectomy

Individuals who have undergone hemispherectomy for treatment of intractable epilepsy offer a rare and valuable opportunity to examine the ability of a single cortical hemisphere to control oculomotor performance. We used peripheral auditory events to trigger saccades, thereby circumventing dense postsurgical hemianopia. In an antisaccade task, patients generated numerous unintended short-latency saccades toward contralesional auditory events, indicating pronounced limitations in the ability of a single hemicortex to exert normal inhibitory control over ipsilateral (i.e., contralesional) reflexive saccade generation. Despite reflexive errors, patients retained an ability to generate correct antisaccades in both directions. The prosaccade task revealed numerous contralesional express saccades, a robust contralesional gap effect, but the absence of both effects for ipsilesional saccades. These results indicate limits to the saccadic control capabilities following hemispherectomy: A single hemicortex can mediate antisaccades in both directions, but plasticity does not extend fully to the bilateral inhibition of reflexive saccades. We posit that these effects are due to altered control dynamics that reduce the responsivity of the superior colliculus on the intact side and facilitate the release of an auditory-evoked ocular grasp reflex into the blind hemifield that the intact hemicortex has difficulty suppressing

The minimum monitoring signal-to-noise ratio for off-axis signals and its implications for directional hearing aids

The signal-to-noise ratio (SNR) benefit of hearing aid directional microphones is dependent on the angle of the listener relative to the target, something that can change drastically and dynamically in a typical group conversation. When a new target signal is significantly off-axis, directional microphones lead to slower target orientation, more complex movements, and more reversals. This raises the question of whether there is an optimal design for directional microphones. In principle an ideal microphone would provide the user with sufficient directionality to help with speech understanding, but not attenuate off-axis signals so strongly that orienting to new signals was difficult or impossible. We investigated the latter part of this question. In order to measure the minimal monitoring SNR for reliable orientation to off-axis signals, we measured head-orienting behaviour towards targets of varying SNRs and locations for listeners with mild to moderate bilateral symmetrical hearing loss. Listeners were required to turn and face a female talker in background noise and movements were tracked using a head-mounted crown and infrared system that recorded yaw in a ring of loudspeakers. The target appeared randomly at ± 45, 90 or 135° from the start point. The results showed that as the target SNR decreased from 0 dB to −18 dB, first movement duration and initial misorientation count increased, then fixation error, and finally reversals increased. Increasing the target angle increased movement duration at all SNRs, decreased reversals (above −12 dB target SNR), and had little to no effect on initial misorientations. These results suggest that listeners experience some difficulty orienting towards sources as the target SNR drops below −6 dB, and that if one intends to make a directional microphone that is usable in a moving conversation, then off-axis attenuation should be no more than 12 dB

Interobserver reliability of classification and characterization of proximal humeral fractures: a comparison of two and three-dimensional CT

Interobserver reliability for the classification of proximal humeral fractures is limited. The aim of this study was to test the null hypothesis that interobserver reliability of the AO classification of proximal humeral fractures, the preferred treatment, and fracture characteristics is the same for two-dimensional (2-D) and three-dimensional (3-D) computed tomography (CT). Members of the Science of Variation Group--fully trained practicing orthopaedic and trauma surgeons from around the world--were randomized to evaluate radiographs and either 2-D CT or 3-D CT images of fifteen proximal humeral fractures via a web-based survey and respond to the following four questions: (1) Is the greater tuberosity displaced? (2) Is the humeral head split? (3) Is the arterial supply compromised? (4) Is the glenohumeral joint dislocated? They also classified the fracture according to the AO system and indicated their preferred treatment of the fracture (operative or nonoperative). Agreement among observers was assessed with use of the multirater kappa (κ) measure. Interobserver reliability of the AO classification, fracture characteristics, and preferred treatment generally ranged from "slight" to "fair." A few small but statistically significant differences were found. Observers randomized to the 2-D CT group had slightly but significantly better agreement on displacement of the greater tuberosity (κ = 0.35 compared with 0.30, p < 0.001) and on the AO classification (κ = 0.18 compared with 0.17, p = 0.018). A subgroup analysis of the AO classification results revealed that shoulder and elbow surgeons, orthopaedic trauma surgeons, and surgeons in the United States had slightly greater reliability on 2-D CT, whereas surgeons in practice for ten years or less and surgeons from other subspecialties had slightly greater reliability on 3-D CT. Proximal humeral fracture classifications may be helpful conceptually, but they have poor interobserver reliability even when 3-D rather than 2-D CT is utilized. This may contribute to the similarly poor interobserver reliability that was observed for selection of the treatment for proximal humeral fractures. The lack of a reliable classification confounds efforts to compare the outcomes of treatment methods among different clinical trials and reports

eTRIKS Analytical Environment: A Modular High Performance Framework for Medical Data Analysis

Translational research is quickly becoming a science driven by big data. Improving patient care, developing personalized therapies and new drugs depend increasingly on an organization's ability to rapidly and intelligently leverage complex molecular and clinical data from a variety of large-scale partner and public sources. As analysing these large-scale datasets becomes computationally increasingly expensive, traditional analytical engines are struggling to provide a timely answer to the questions that biomedical scientists are asking. Designing such a framework is developing for a moving target as the very nature of biomedical research based on big data requires an environment capable of adapting quickly and efficiently in response to evolving questions. The resulting framework consequently must be scalable in face of large amounts of data, flexible, efficient and resilient to failure. In this paper we design the eTRIKS Analytical Environment (eAE), a scalable and modular framework for the efficient management and analysis of large scale medical data, in particular the massive amounts of data produced by high-throughput technologies. We particularly discuss how we design the eAE as a modular and efficient framework enabling us to add new components or replace old ones easily. We further elaborate on its use for a set of challenging big data use cases in medicine and drug discovery

The future of metabolomics in ELIXIR.

Metabolomics, the youngest of the major omics technologies, is supported by an active community of researchers and infrastructure developers across Europe. To coordinate and focus efforts around infrastructure building for metabolomics within Europe, a workshop on the "Future of metabolomics in ELIXIR" was organised at Frankfurt Airport in Germany. This one-day strategic workshop involved representatives of ELIXIR Nodes, members of the PhenoMeNal consortium developing an e-infrastructure that supports workflow-based metabolomics analysis pipelines, and experts from the international metabolomics community. The workshop established metabolite identification as the critical area, where a maximal impact of computational metabolomics and data management on other fields could be achieved. In particular, the existing four ELIXIR Use Cases, where the metabolomics community - both industry and academia - would benefit most, and which could be exhaustively mapped onto the current five ELIXIR Platforms were discussed. This opinion article is a call for support for a new ELIXIR metabolomics Use Case, which aligns with and complements the existing and planned ELIXIR Platforms and Use Cases