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

Locomotor hyperactivity in 14-3-3Zeta KO mice is associated with dopamine transporter dysfunction

Dopamine (DA) neurotransmission requires a complex series of enzymatic reactions that are tightly linked to catecholamine exocytosis and receptor interactions on pre- and postsynaptic neurons. Regulation of dopaminergic signalling is primarily achieved through reuptake of extracellular DA by the DA transporter (DAT) on presynaptic neurons. Aberrant regulation of DA signalling, and in particular hyperactivation, has been proposed as a key insult in the presentation of schizophrenia and related neuropsychiatric disorders. We recently identified 14-3-3ζ as an essential component of neurodevelopment and a central risk factor in the schizophrenia protein interaction network. Our analysis of 14-3-3ζ-deficient mice now shows that baseline hyperactivity of knockout (KO) mice is rescued by the antipsychotic drug clozapine. 14-3-3ζ KO mice displayed enhanced locomotor hyperactivity induced by the DA releaser amphetamine. Consistent with 14-3-3ζ having a role in DA signalling, we found increased levels of DA in the striatum of 14-3-3ζ KO mice. Although 14-3-3ζ is proposed to modulate activity of the rate-limiting DA biosynthesis enzyme, tyrosine hydroxylase (TH), we were unable to identify any differences in total TH levels, TH localization or TH activation in 14-3-3ζ KO mice. Rather, our analysis identified significantly reduced levels of DAT in the absence of notable differences in RNA or protein levels of DA receptors D1–D5. Providing insight into the mechanisms by which 14-3-3ζ controls DAT stability, we found a physical association between 14-3-3ζ and DAT by co-immunoprecipitation. Taken together, our results identify a novel role for 14-3-3ζ in DA neurotransmission and provide support to the hyperdopaminergic basis of pathologies associated with schizophrenia and related disorders.H Ramshaw, X Xu, EJ Jaehne, P McCarthy, Z Greenberg, E Saleh, B McClure, J Woodcock, S Kabbara, S Wiszniak, Ting-Yi Wang, C Parish, M van den Buuse, BT Baune, A Lopez and Q Schwar

Developments in the Photonic Theory of Fluorescence

Conventional fluorescence commonly arises when excited molecules relax to their ground electronic state, and most of the surplus energy dissipates in the form of photon emission. The consolidation and full development of theory based on this concept has paved the way for the discovery of several mechanistic variants that can come into play with the involvement of laser input – most notably the phenomenon of multiphoton-induced fluorescence. However, other effects can become apparent when off-resonant laser input is applied during the lifetime of the initial excited state. Examples include a recently identified scheme for laser-controlled fluorescence. Other systems of interest are those in which fluorescence is emitted from a set of two or more coupled nanoemitters. This chapter develops a quantum theoretical outlook to identify and describe these processes, leading to a discussion of potential applications ranging from all-optical switching to the generation of optical vortices

Buber, educational technology, and the expansion of dialogic space

Buber’s distinction between the ‘I-It’ mode and the ‘I-Thou’ mode is seminal for dialogic education. While Buber introduces the idea of dialogic space, an idea which has proved useful for the analysis of dialogic education with technology, his account fails to engage adequately with the role of technology. This paper offers an introduction to the significance of the I-It/I-Thou duality of technology in relation to opening dialogic space. This is followed by a short schematic history of educational technology which reveals the role technology plays, not only in opening dialogic space, but also in expanding dialogic space. The expansion of dialogic space is an expansion of what it means to be ‘us’ as dialogic engagement facilitates the incorporation, into our shared sense of identity, of aspects of reality that are initially experienced as alien or ‘other’. Augmenting Buber with an alternative understanding of dialogic space enables us to see how dialogue mediated by technology, as well as dialogue with monologised fragments of technology (robots), can, through education, lead to an expansion of what it means to be human

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

Study of the Decays B0 --> D(*)+D(*)-

The decays B0 --> D*+D*-, B0 --> D*+D- and B0 --> D+D- are studied in 9.7 million Y(4S) --> BBbar decays accumulated with the CLEO detector. We determine Br(B0 --> D*+D*-) = (9.9+4.2-3.3+-1.2)e-4 and limit Br(B0 --> D*+D-) < 6.3e-4 and Br(B0 --> D+D-) < 9.4e-4 at 90% confidence level (CL). We also perform the first angular analysis of the B0 --> D*+D*- decay and determine that the CP-even fraction of the final state is greater than 0.11 at 90% CL. Future measurements of the time dependence of these decays may be useful for the investigation of CP violation in neutral B meson decays.Comment: 21 pages, 5 figures, submitted to Phys. Rev.

Understanding the Interplay Among Regulatory Self-Efficacy, Moral Disengagement, and Academic Cheating Behaviour During Vocational Education: A Three-Wave Study

The literature has suggested that to understand the diffusion of unethical conduct in the workplace, it is important to investigate the underlying processes sustaining engagement in misbehaviour and to study what occurs during vocational education. Drawing on social-cognitive theory, in this study, we longitudinally examined the role of two opposite dimensions of the self-regulatory moral system, regulatory self-efficacy and moral disengagement, in influencing academic cheating behaviour. In addition, in line with the theories highlighting the bidirectional relationship between cognitive processes and behaviour, we aimed to also examine the reciprocal influence of behaviour on these dimensions over time. Overall, no previous studies have examined the longitudinal interplay between these variables. The sample included 866 (62.8% female) nursing students who were assessed three times annually from the beginning of their vocational education. The findings from a cross-lagged model confirmed that regulatory self-efficacy and moral disengagement have opposite influences on cheating behaviour, that regulatory self-efficacy negatively influences not only the engagement in misconduct but also the justification mechanisms that allow the divorce between moral standards and action, and that moral disengagement and cheating behaviour reciprocally support each other over time. Specifically, not only did moral disengagement influence cheating behaviour even when controlling for its prior levels, but also cheating behaviour affected moral disengagement one year later, controlling for its prior levels. These findings suggest that recourse to wrongdoing could gradually lead to further normalising this kind of behaviour and morally desensitising individuals to misconduct

Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia

Peer reviewe

Measurement of B(/\c->pKpi)

The /\c->pKpi yield has been measured in a sample of two-jet continuum events containing a both an anticharm tag (Dbar) as well as an antiproton (e+e- -> Dbar pbar X), with the antiproton in the hemisphere opposite the Dbar. Under the hypothesis that such selection criteria tag e+e- -> Dbar pbar (/\c) X events, the /\c->pkpi branching fraction can be determined by measuring the pkpi yield in the same hemisphere as the antiprotons in our Dbar pbar X sample. Combining our results from three independent types of anticharm tags, we obtain B(/\c->pKpi)=(5.0+/-0.5+/-1.2)