Deep resequencing of the voltage-gated potassium channel subunit KCNE3 gene in chronic tinnitus

Membrane-stabilizing drugs have long been used for the treatment of chronic tinnitus, suggesting an underlying disturbance of sensory excitability due to changes in ion conductance. The present study addresses the potassium channel subunit gene KCNE3 as a potential candidate for tinnitus susceptibility. 288 Caucasian outpatients with a diagnosis of chronic tinnitus were systematically screened for mutations in the KCNE3 open reading frame and in the adjacent region by direct sequencing. Allele frequencies were determined for 11 known variants of which two (F66F and R83H) were polymorphic but were not associated with the disorder. No novel variants were identified and only three carriers of R83H were noted. However, owing to a lack of power, our study can neither rule out effects of KCNE3 on the risk for developing chronic tinnitus, nor can it exclude a role in predicting the severity of tinnitus. More extensive investigations are invited, including tests for possible effects of variation in this ion channel protein on the response to treatment

Bioequivalence of Oral Products and the Biopharmaceutics Classification System: Science, Regulation, and Public Policy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109935/1/cptclpt2011109.pd

Phase diagram of the lattice SU(2) Higgs model

We perform a detailed study of the phase diagram of the lattice Higgs SU(2) model with fixed Higgs field length. Consistently with previsions based on the Fradkin Shenker theorem we find a first order transition line with an endpoint whose position we determined. The diagram also shows cross-over lines: the cross-over corresponding to the pure SU(2) bulk is also present at nonzero coupling with the Higgs field and merges with the one that continues the line of first order transition beyond the critical endpoint. At high temperature the first order line becomes a crossover, whose position moves by varying the temperature.Comment: 18 pages, 15 figure

Resequencing of the auxiliary GABAB receptor subunit gene KCTD12 in chronic tinnitus

Tinnitus is a common and often incapacitating hearing disorder marked by the perception of phantom sounds. Susceptibility factors remain largely unknown but GABAB receptor signaling has long been implicated in the response to treatment and, putatively, in the etiology of the disorder. We hypothesized that variation in KCTD12, the gene encoding an auxiliary subunit of GABAB receptors, could help to predict the risk of developing tinnitus. Ninety-five Caucasian outpatients with a diagnosis of chronic tinnitus were systematically screened for mutations in the KCTD12 open reading frame and the adjacent 3′ untranslated region by Sanger sequencing. Allele frequencies were determined for 14 known variants of which three (rs73237446, rs34544607, and rs41287030) were polymorphic. When allele frequencies were compared to data from a large reference population of European ancestry, rs34544607 was associated with tinnitus (p = 0.04). However, KCTD12 genotype did not predict tinnitus severity (p = 0.52) and the association with rs34544607 was weakened after screening 50 additional cases (p = 0.07). Pending replication in a larger cohort, KCTD12 may act as a risk modifier in chronic tinnitus. Issues that are yet to be addressed include the effects of neighboring variants, e.g., in the KCTD12 gene regulatory region, plus interactions with variants of GABAB1 and GABAB2

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

Paired Associative Stimulation of the Auditory System: A Proof-Of-Principle Study

Background Paired associative stimulation (PAS) consisting of repeated application of transcranial magnetic stimulation (TMS) pulses and contingent exteroceptive stimuli has been shown to induce neuroplastic effects in the motor and somatosensory system. The objective was to investigate whether the auditory system can be modulated by PAS. Methods Acoustic stimuli (4 kHz) were paired with TMS of the auditory cortex with intervals of either 45 ms (PAS(45 ms)) or 10 ms (PAS(10 ms)). Two-hundred paired stimuli were applied at 0.1 Hz and effects were compared with low frequency repetitive TMS (rTMS) at 0.1 Hz (200 stimuli) and 1 Hz (1000 stimuli) in eleven healthy students. Auditory cortex excitability was measured before and after the interventions by long latency auditory evoked potentials (AEPs) for the tone (4 kHz) used in the pairing, and a control tone (1 kHz) in a within subjects design. Results Amplitudes of the N1-P2 complex were reduced for the 4 kHz tone after both PAS(45 ms) and PAS(10 ms), but not after the 0.1 Hz and 1 Hz rTMS protocols with more pronounced effects for PAS(45 ms). Similar, but less pronounced effects were observed for the 1 kHz control tone. Conclusion These findings indicate that paired associative stimulation may induce tonotopically specific and also tone unspecific human auditory cortex plasticity

A microscopic semiclassical confining field equation for U(1)U(1) lattice gauge theory in 2+1 dimensions

We present a semiclassical nonlinear field equation for the confining field in 2+1--dimensional $U(1)$ lattice gauge theory (compact QED). The equation is derived directly from the underlying microscopic quantum Hamiltonian by means of truncation. Its nonlinearities express the dynamic creation of magnetic monopole currents leading to the confinement of the electric field between two static electric charges. We solve the equation numerically and show that it can be interpreted as a London relation in a dual superconductor.Comment: 21 pages, epsf postscript figures included, full postscript available at ftp://ftp.th.physik.uni-frankfurt.de/pub/cbest/micro.ps.Z or http://www.th.physik.uni-frankfurt.de/~cbest/pub.htm

HPC-oriented Canonical Workflows for Machine Learning Applications in Climate and Weather Prediction

Machine learning (ML) applications in weather and climate are gaining momentum as big data and the immense increase in High-performance computing (HPC) power are paving the way. Ensuring FAIR data and reproducible ML practices are significant challenges for Earth system researchers. Even though the FAIR principle is well known to many scientists, research communities are slow to adopt them. Canonical Workflow Framework for Research (CWFR) provides a platform to ensure the FAIRness and reproducibility of these practices without overwhelming researchers. This conceptual paper envisions a holistic CWFR approach towards ML applications in weather and climate, focusing on HPC and big data. Specifically, we discuss Fair Digital Object (FDO) and Research Object (RO) in the DeepRain project to achieve granular reproducibility. DeepRain is a project that aims to improve precipitation forecast in Germany by using ML. Our concept envisages the raster datacube to provide data harmonization and fast and scalable data access. We suggest the Juypter notebook as a single reproducible experiment. In addition, we envision JuypterHub as a scalable and distributed central platform that connects all these elements and the HPC resources to the researchers via an easy-to-use graphical interface

Risk Attitudes and Birth Order

Risk attitudes play important roles in health behavior and everyday decision making. It is unclear, however, whether these attitudes can be predicted from birth order. We investigated 200 mostly male volunteers from two distinct settings. After correcting for multiple comparisons, for the number of siblings and for confounding by gender, ordinal position predicted perception of health-related risks among participants in extreme sports (p < .01). However, the direction of the effect contradicted Adlerian theory. Except for alcohol consumption, these findings extended to self-reported risk behavior. Together, the data call for a cautious stand on the impact of birth order on risk attitudes