Logistic Regression Analysis of Factors Influencing the Effectiveness of Intensive Sound Masking Therapy in Patients with Tinnitus

Objectives: To investigate factors influencing the effectiveness intensive sound masking therapy on tinnitus using Logistic Regression Analysis. Design: The study used a retrospective cross-section analysis. Participants: 102 patients with tinnitus were recruited at the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, China. Intervention: Intensive sound masking therapy was used as an intervention approach for patients with tinnitus. Primary and secondary outcome measures: participants underwent audiological investigations and tinnitus pitch and loudness matching measurements, followed by intensive sound masking therapy. The Tinnitus Handicap Inventory (THI) was used as the outcome measure pre- and post-treatment. Multivariate logistic regression was performed to investigate the association of demographic and audiological factors with effective therapy. Results: According to the THI score changes pre-and post-sound masking intervention, fifty-one participants were categorised into an effective group, the remaining 51 participants were placed in a non-effective group. Those in the effective group were significantly younger than those in the non-effective group (p=0.012). Significantly more participants had flat audiogram configurations in the effective group (p=0.04). Multivariable logistic regression analysis showed that age (OR=0.96, 95% CI: 0.93, 0.99, p=0.007), audiometric configuration (p=0.027) and THI score pre-treatment (OR=1.04, 95% CI: 1.02, 1.07, p<0.001) were significantly associated with therapeutic effectiveness. Further analysis showed that patients with flat audiometric configurations were 5.45 times more likely to respond to intervention than those with high-frequency steeply sloping audiograms (OR=5.45, 95% CI: 1.67, 17.86, p=0.005). Conclusion: Audiometric configuration, age and THI scores appear to be predictive for the effectiveness of sound masking treatment. Gender, tinnitus characteristics and hearing threshold measures seem not to be related to treatment effectiveness. Further randomized control study is needed to provide further evidence of the effectiveness of prognostic factors in tinnitus interventions

2-All­yloxy-5-nitro­benzoic acid

The mol­ecule of the title compound, C10H9NO5, is approximately planar, with the mean planes of the nitro, carboxyl and all­yloxy groups rotated by 8.1 (3), 7.9 (3) and 4.52 (18)°, respectively, from the plane of the benzene ring. Bond lengths in the aromatic ring are influenced by both electronic effects and strain induced by ortho-substitution. In the crystal structure, centrosymmetrically related mol­ecules are paired into dimers through strong O—H⋯O hydrogen bonds

The effect of symmetrical and asymmetrical hearing impairment on the music quality perception

The purpose of this study was to investigate the effect of symmetrical, asymmetrical and unilateral hearing impairment on music quality perception. Six validated music pieces in the categories of classical music, folk music and pop music were used to assess music quality in terms of its ‘pleasantness’, ‘naturalness’, ‘fullness’, ‘roughness’ and ‘sharpness’. 58 participants with sensorineural hearing loss [20 with unilateral hearing loss (UHL), 20 with bilateral symmetrical hearing loss (BSHL) and 18 with bilateral asymmetrical hearing loss (BAHL)] and 29 normal hearing (NH) subjects participated in the present study. Hearing impaired (HI) participants had greater difficulty in overall music quality perception than NH participants. Participants with BSHL rated music pleasantness and naturalness to be higher than participants with BAHL. Moreover, the hearing thresholds of the better ears from BSHL and BAHL participants as well as the hearing thresholds of the worse ears from BSHL participants were negatively correlated to the pleasantness and naturalness perception. HI participants rated the familiar music pieces higher than unfamiliar music pieces in the three music categories. Music quality perception in participants with hearing impairment appeared to be affected by symmetry of hearing loss, degree of hearing loss and music familiarity when they were assessed using the music quality rating test (MQRT). This indicates that binaural symmetrical hearing is important to achieve a high level of music quality perception in HI listeners. This emphasizes the importance of provision of bilateral hearing assistive devices for people with asymmetrical hearing impairment

Discovering rare-earth-free magnetic materials through the development of a database

We develop an open-access database that provides a large array of datasets specialized for magnetic compounds as well as magnetic clusters. Our focus is on rare-earth-free magnets. Available datasets include (i) crystallography, (ii) thermodynamic properties, such as the formation energy, and (iii) magnetic properties that are essential for magnetic-material design. Our database features a large number of stable and metastable structures discovered through our adaptive genetic algorithm (AGA) searches. Many of these AGA structures have better magnetic properties when compared to those of the existing rare-earth-free magnets and the theoretical structures in other databases. Our database places particular emphasis on site-specific magnetic data, which are obtained by high-throughput first-principles calculations. Such site-resolved data are indispensable for machine-learning modeling. We illustrate how our data-intensive methods promote efficiency of the experimental discovery of new magnetic materials. Our database provides massive datasets that will facilitate an efficient computational screening, machine-learning-assisted design, and the experimental fabrication of new promising magnets

Aptamer modified Zr-based porphyrinic nanoscale metal-organic frameworks for active-targeted chemo-photodynamic therapy of tumors

Active-targeted nanoplatforms could specifically target tumors compared to normal cells, making them a promising therapeutic agent. The aptamer is a kind of short DNA or RNA sequence that can specifically bind to target molecules, and could be widely used as the active targeting agents of nanoplatforms to achieve active-targeted therapy of tumors. Herein, an aptamer modified nanoplatform DOX@PCN@Apt-M was designed for active-targeted chemo-photodynamic therapy of tumors. Zr-based porphyrinic nanoscale metal organic framework PCN-224 was synthesized through a one-pot reaction, which could produce cytotoxic 1O2 for efficient treatment of tumor cells. To improve the therapeutic effect of the tumor, the anticancer drug doxorubicin (DOX) was loaded into PCN-224 to form DOX@PCN-224 for tumor combination therapy. Active-targeted combination therapy achieved by modifying the MUC1 aptamer (Apt-M) onto DOX@PCN-224 surface can not only further reduce the dosage of therapeutic agents, but also reduce their toxic and side effects on normal tissues. In vitro, experimental results indicated that DOX@PCN@Apt-M exhibited enhanced combined therapeutic effect and active targeting efficiency under 808 nm laser irradiation for MCF-7 tumor cells. Based on PCN-224 nanocarriers and aptamer MUC1, this work provides a novel strategy for precisely targeting MCF-7 tumor cells

Sirtuin 1 and Autophagy Attenuate Cisplatin-Induced Hair Cell Death in the Mouse Cochlea and Zebrafish Lateral Line

Cisplatin-induced ototoxicity is one of the major adverse effects in cisplatin chemotherapy, and hearing protective approaches are unavailable in clinical practice. Recent work unveiled a critical role of autophagy in cell survival in various types of hearing loss. Since the excessive activation of autophagy can contribute to apoptotic cell death, whether the activation of autophagy increases or decreases the rate of cell death in CDDP ototoxicity is still being debated. In this study, we showed that CDDP induced activation of autophagy in the auditory cell HEI-OC1 at the early stage. We then used rapamycin, an autophagy activator, to increase the autophagy activity, and found that the cell death significantly decreased after CDDP injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) significantly increased cell death. In accordance with in vitro results, rapamycin alleviated CDDP-induced death of hair cells in zebrafish lateral line and cochlear hair cells in mice. Notably, we found that CDDP-induced increase of Sirtuin 1 (SIRT1) in the HEI-OC1 cells modulated the autophagy function. The specific SIRT1 activator SRT1720 could successfully protect against CDDP-induced cell loss in HEI-OC1 cells, zebrafish lateral line, and mice cochlea. These findings suggest that SIRT1 and autophagy activation can be suggested as potential therapeutic strategies for the treatment of CDDP-induced ototoxicity

Biochemistry and modeling of human Dicer, a key protein involved in RNA interference

Five years ago, an unexpected discovery opened a whole new paradigm of biology – RNA interference (RNAi). From the simple notion that dsRNA, when introduced into various organisms, can specificly inhibit expression of homologous endogenous gene, the RNA interference has expanded into a wide range of gene regulatory pathways of great biological importance. At the same time, RNAi started to be widely used as powerful experimental tool for probing gene function in almost any organism. The research on RNAi is moving forward at high speed, both at the mechanistic level and as a tool. Genetic and biochemical studies in various systems have revealed much information about the mechanism of RNAi. It is now well established that dsRNAs is processed by a nuclease Dicer into short dsRNAs varing in length from 21 to 25 nt, named siRNAs, which in turn are incorporated into the RNA induced silencing complex (RISC) to target mRNA degradation. Identification of siRNAs led to the discovery of a whole new class of regulatory small RNAs of similar size, named microRNAs (miRNAs), which have diverse biological functions. Hundreds of miRNAs were cloned, and their functions are being investigated. The single stranded miRNAs are also processed by Dicer from miRNA precursors and incorporated into a complex similar, if not identical, to RISC. In animals, miRNAs imperfectly base-pair with mRNA leading to translational repression. Dicer, a central protein of the RNAi and miRNA pathways is a focus of the study presented in this thesis. A full length human Dicer cDNA was cloned and protein overexpressed in the baculovirus system and purified. Its processing activity was demonstrated using both dsRNA and pre-miRNAs as substrates. Detailed study of the RNase III-like activity of Dicer, its biochemical properties and a model of its function are described in two experimental chapters of this thesis. This thesis is divided into three major chapters followed by a short general discussion. Chaptercontains a general introduction to RNA interference. It describes a history of RNAi discovery, summarizes what is known about the RNAi mechanism in general, and also about the species-specific differences. The mechanistic aspects of the miRNA pathway are also described. An overview of all important proteins involved in RNAi is presented. Finally, a summary of RNAi as a tool for reverse genetics is provided. Chapterdescribes the characterization of the purified recombinant human Dicer protein. In vitro experiments showed that the purified protein cleaves dsRNAs into ~22 nucleotide siRNAs. This was a first direct evidence that Dicer indeed has RNase III-like nuclease activity. Accumulation of processing intermediates of discrete sizes, and experiments performed with substrates containing modified ends, indicated that Dicer preferentially cleaves dsRNAs at their termini. Binding of the enzyme to the substrate could be uncoupled from the cleavage step by omitting Mg2+ or performing the reaction at 4oC. Activity of the recombinant Dicer, and of the endogenous protein present in mammalian cells extracts, was stimulated by limited proteolysis, and the proteolysed enzyme became active at 4oC. Cleavage of dsRNA by purified Dicer and the endogenous enzyme was ATP independent, in contrast to results obtained in Drosophila and C. elegans. Additional experiments suggested that if ATP participates in the Dicer reaction in mammalian cells, it might be involved in the product release needed for the multiple turnover of the enzyme. Chapter 3 describes the mutagenesis study of the human Dicer RNase III domains, which revealed that Dicer contains a single compound catalytic center. Both RNase III domains in Dicer contribute to the dsRNA cleavage reaction. The Dicer mutagenesis study was initiated whether a model of dsRNA cleavage originating from an X-ray structural study of the Aquifex aeolicus RNase III also applies to Dicer. Mutants containing changes in residues implicated in the catalysis in both Dicer RNase III domains were prepared to study their effect on RNA processing. Our results were in conflict with the bacterial Rnase III model and all speculated Dicer model. We have further mutated the catalytic residues of the E. coli RNase III and tested their effect on processing of different substrates. The results are consistent with those obtained with Dicer mutants. More specifically, our results indicate that instead the two catalytic centers proposed previously, both enzymes contain only one catalytic center, generating products with 2-nt 3’ overhangs. Together with other data, a new model was proposed according to which Dicer functions as an intramolecular dimer of its two RNase III domains, assisted by the flanking RNA binding domains, PAZ and dsRBD