Why is tinnitus a problem? A large-scale qualitative evaluation of problems reported by tinnitus patients in mainland China.

Objectives: The lived experience of tinnitus has biopsychosocial characteristics which are influenced by sociocultural factors. The main purpose of this study is to investigate how tinnitus affects people in their everyday life in China. A deductive qualitative analysis examined whether an a priori Western-centric conceptual framework could extend to an Asian context.Design: A large-scale prospective survey collected patient-reported problems associated with tinnitus in 485 adults attending four major ENT clinics in Eastern and Southern mainland China.Results: The evidence suggests that patients in China express a narrower range of problem domains associated with the lived experience of tinnitus. While 13 tinnitus-related problem domains were confirmed, culture-specific adaptations included the addition uncomfortable (a novel concept not previously reported), and the potential exclusion of concepts such as intrusiveness, loss of control, loss of peace and loss of sense of self.Conclusions: The sociocultural context of patients across China plays an important role in defining the vocabulary used to describe the patient-centred impacts of tinnitus. Possible explanatory factors include cultural differences in the meaning and relevance of certain concepts relating to self and in help-seeking behaviour, low health literacy and a different lexicon in Chinese compared to English to describe tinnitus-related problems.

Methyltransferases of gentamicin biosynthesis.

Gentamicin C complex from Micromonospora echinospora remains a globally important antibiotic, and there is revived interest in the semisynthesis of analogs that might show improved therapeutic properties. The complex consists of five components differing in their methylation pattern at one or more sites in the molecule. We show here, using specific gene deletion and chemical complementation, that the gentamicin pathway up to the branch point is defined by the selectivity of the methyltransferases GenN, GenD1, and GenK. Unexpectedly, they comprise a methylation network in which early intermediates are ectopically modified. Using whole-genome sequence, we have also discovered the terminal 6'-N-methyltransfer required to produce gentamicin C2b from C1a or gentamicin C1 from C2, an example of an essential biosynthetic enzyme being located not in the biosynthetic gene cluster but far removed on the chromosome. These findings fully account for the methylation pattern in gentamicins and open the way to production of individual gentamicins by fermentation, as starting materials for semisynthesis.

An automated method for the assessment of the rice grain germination rate.

The germination rate of rice grain is recognized as one of the most significant indicators of seed quality assessment. Currently, grain germination rate is generally determined manually by experienced researchers, which is time-consuming and labor-intensive. In this paper, a new method is proposed for counting the number of grains and germinated grains. In the coarse segmentation process, the k-means clustering algorithm is applied to obtain rough grain-connected regions. We further refine the segmentation results obtained by the k-means algorithm using a one-dimensional Gaussian filter and a fifth-degree polynomial. Next, the optimal single grain area is determined based on the area distribution curve. Accordingly, the number of grains contained in the connected region is equal to the area of the connected region divided by the optimal single grain area. Finally, a novel algorithm is proposed for counting germinated grains. This algorithm is based on the idea that the length of the intersection between the germ and the grain is less than the circumference of the germ. The experimental results show that the mean absolute error of the proposed method for germination rate is 2.7%. And the performance of the proposed method is robust to changes in grain number, grain varieties, scale, illumination, and rotation.

Abnormal Functional Connectivity Within Default Mode Network and Salience Network Related to Tinnitus Severity.

BACKGROUND: Previous studies have demonstrated that tinnitus is associated with neural changes in the cerebral cortex. This study is aimed at investigating the central nervous characteristics of tinnitus patients with different severity by using a rs-EEG. PARTICIPANTS AND METHODS: rs-EEG was recorded in fifty-seven patients with chronic tinnitus and twenty-seven healthy controls. Tinnitus patients were divided into moderate-to-severe tinnitus group and slight-to-mild tinnitus group based on their Tinnitus Handicap Inventory (THI) scores. Source localization and functional connectivity analyses were used to measure the changes in central levels and examine the altered network patterns. The correlation between functional connectivity and tinnitus severity was analyzed. RESULT: Compared to the healthy controls, all tinnitus patients showed significant activation in the auditory cortex (middle temporal lobe, BA 21), while moderate-to-severe tinnitus group showed enhanced connectivity between the parahippocampus and posterior cingulate gyrus. Moreover, the moderate-to-severe tinnitus group had enhanced functional connectivity between auditory cortex and insula compared to the slight-to-mild tinnitus group. The connections between the insula and the parahippocampal and posterior cingulate gyrus were positively correlated with THI scores. CONCLUSION: The current study reveals that patients with moderate-to-severe tinnitus demonstrate greater changes in the central brain areas, including the auditory cortex, insula, parahippocampus and posterior cingulate gyrus. In addition, enhanced connections were found between the insula and the auditory cortex, as well as the posterior cingulate gyrus and the parahippocampus, which suggests abnormality in the auditory network, salience network, and default mode network. Specifically, the insula is the core region of the neural pathway that is composed of the auditory cortex, insula, and parahippocampus/posterior cingulate gyrus. This suggests that the severity of tinnitus is affected by multiple brain regions.

The Acceptability and Influencing Factors of an Internet-Based Tinnitus Multivariate Integrated Sound Therapy for Patients With Tinnitus.

OBJECTIVE: To explore the acceptability and influencing factors of an Internet-based Tinnitus Multivariate Integrated Sound Therapy (iT-MIST). The individually tailored sound therapy used narrowband noise centered on the patient's tinnitus frequency in combination with natural sounds and relaxing music. DESIGN: Patients with tinnitus were given a 1-week trial of iT-MIST. Semistructured interviews were then carried out and a thematic analysis used to analyze, identify, organize, and report factors discovered in the data. STUDY SAMPLE: Semistructured interviews were carried out with 11 participants, 2 women and 9 men, mean age 39.82 years. RESULTS: The first theme identified from patient interview analysis was their motivation to undertake and expectations of iT-MIST. Nearly half of the participants indicated that advice from the physician was considered very important and professional. Benefits acknowledged by most participants from their iT-MIST experience were accessibility, convenience, time- and cost-effectiveness, and emotional benefit. However, a few participants with poor understanding of tinnitus and iT-MIST showed a negative acceptability with doubtful thoughts and complaints about technical issues such as being easily interrupted by messages and phone calls. CONCLUSION: Patients with tinnitus in this study were not universally accepting of the iT-MIST therapy. Concerns about their tinnitus and ability to comply with doctor's recommendations were the main influencing factors. Attitude or willingness to explore new therapies facilitated its use. Emotional benefits, for example, relaxation and comfort, were seen to sustain motivation, while doubtful thoughts and technical problems negatively affected acceptability.

Missed hearing loss in tinnitus patients with normal audiograms.

The prevalence of tinnitus is positively correlated with hearing loss, although, tinnitus can also present alongside clinically normal pure-tone thresholds. As standard pure tone audiograms (PTA) only sample at octave or inter-octaves, they potentially can miss lesions between the tested frequencies. Here we investigate if tinnitus patients with normal audiograms have hearing loss missed by standard PTA testing, referred as "missed hearing loss" in the paper. Hearing thresholds in 106 tinnitus patients who have a normal PTA were tested using fine frequency resolution (1/24 octave step) audiometry, referred as precision PTA (P-PTA), at ±1/3 octave band centered at their tinnitus frequencies. Tinnitus pitch, loudness and residual inhibition were evaluated based on the result of P-PTA. DPOAEs were also tested to evaluate the function of outer hair cells (OHC). Using the P-PTA test, we found that 49% (52 out of 106) of tinnitus patients with normal audiograms showed sharply notched hearing loss and most of the notches were at their tinnitus frequencies. Using a fine frequency step (1/24 octave) to assess tinnitus pitch, the successful matching rate increased to 84%, significantly higher than the rate measured in traditional method (51%, Fisher's test, P < 0.0001, n = 106). The number of patients whose tinnitus loudness was less than 5 dB SL increased from 26% to 55% after the loudness reassessment based on the tinnitus pitch match (n = 106, Chi-Square test, P < 0.01). The percentage of patients who showed positive residual inhibition of tinnitus also increased from 31% to 54% (Chi-Square test, P < 0.05). DPOAEs revealed significantly reduced OAE amplitude in the tinnitus patients, suggesting that OHC dysfunction may contribute to their notched hearing loss. However, in 13 out of 31 patients with notched hearing loss, their DPOAE did not show any reduction which suggests that their notched hearing loss may be induced by the dysfunction of the inner hair cells or afferent synapses (synaptopathy). Our study confirmed hidden cochlear impairments in tinnitus patients with seemingly normal audiograms. We conclude that P-PTA can help identify a mild hearing impairment that may otherwise be missed by conventional PTA and that P-PTA can also improve tinnitus evaluation accuracy.

Dynamic activation of basilar membrane macrophages in response to chronic sensory cell degeneration in aging mouse cochleae.

In the sensory epithelium, macrophages have been identified on the scala tympani side of the basilar membrane. These basilar membrane macrophages are the spatially closest immune cells to sensory cells and are able to directly respond to and influence sensory cell pathogenesis. While basilar membrane macrophages have been studied in acute cochlear stresses, their behavior in response to chronic sensory cell degeneration is largely unknown. Here we report a systematic observation of the variance in phenotypes, the changes in morphology and distribution of basilar membrane tissue macrophages in different age groups of C57BL/6J mice, a mouse model of age-related sensory cell degeneration. This study reveals that mature, fully differentiated tissue macrophages, not recently infiltrated monocytes, are the major macrophage population for immune responses to chronic sensory cell death. These macrophages display dynamic changes in their numbers and morphologies as age increases, and the changes are related to the phases of sensory cell degeneration. Notably, macrophage activation precedes sensory cell pathogenesis, and strong macrophage activity is maintained until sensory cell degradation is complete. Collectively, these findings suggest that mature tissue macrophages on the basilar membrane are a dynamic group of cells that are capable of vigorous adaptation to changes in the local sensory epithelium environment influenced by sensory cell status.

Hyperexcitability of inferior colliculus and acoustic startle reflex with age-related hearing loss.

Chronic tinnitus and hyperacusis often develop with age-related hearing loss presumably due to aberrant neural activity in the central auditory system (CAS) induced by cochlear pathologies. However, the full spectrum of physiological changes that occur in the CAS as a result age-related hearing loss are still poorly understood. To address this issue, neurophysiological measures were obtained from the cochlea and the inferior colliculus (IC) of 2, 6 and 12 month old C57BL/6J mice, a mouse model for early age-related hearing loss. Thresholds of the compound action potentials (CAP) in 6 and 12 month old mice were significantly higher than in 2 month old mice. The sound driven and spontaneous firing rates of IC neurons, recorded with 16 channel electrodes, revealed mean IC thresholds of 22.8 ± 6.5 dB (n = 167) at 2 months, 37.9 ± 6.2 dB (n = 132) at 6 months and 47.1 ± 15.3 dB (n = 151) at 12 months of age consistent with the rise in CAP thresholds. The characteristic frequencies (CF) of IC neurons ranged from 3 to 32 kHz in 2 month old mice; the upper CF ranged decreased to 26 kHz and 16 kHz in 6 and 12 month old mice respectively. The percentage of IC neurons with CFs between 8 and 12 kHz increased from 36.5% in 2 month old mice, to 48.8% and 76.2% in 6 and 12 month old mice, respectively, suggesting a downshift of IC CFs due to the high-frequency hearing loss. The average spontaneous firing rate (SFRs) of all recorded neurons in 2 month old mice was 3.2 ± 2.5 Hz (n = 167). For 6 and 12 month old mice, the SFRs of low CF neurons (<8 kHz) was maintained at 3-6 spikes/s; whereas SFRs of IC neurons with CFs > 8 kHz increased to 13.0 ± 15.4 (n = 68) Hz at 6 months of age and then declined to 4.8 ± 7.4 (n = 110) spikes/s at 12 months of age. In addition, sound-evoked activity at suprathreshold levels at 6 months of age was much higher than at 2 and 12 months of age. To evaluate the behavioral consequences of sound evoked hyperactivity in the IC, the amplitude of the acoustic startle reflex was measured at 4, 8 and 16 kHz using narrow band noise bursts. Acoustic startle reflex amplitudes in 6 and 12 month old mice (n = 4) were significantly larger than 2 month old mice (n = 4) at 4 and 8 kHz, but not 16 kHz. The enhanced reflex amplitudes suggest that high-intensity, low-frequency sounds are perceived as louder than normal in 6 and 12 month old mice compared to 2 month olds. The increased spontaneous activity, particularly at 6 months, may be related to tinnitus whereas the increase in sound-evoked activity and startle reflex amplitudes may be related to hyperacusis.

Early age noise exposure increases loudness perception - A novel animal model of hyperacusis.

The neural mechanisms that give rise to hyperacusis, a reduction in loudness tolerance, are largely unknown. Some reports suggest that hyperacusis is linked to childhood hearing loss. However, the evidence for this is largely circumstantial. In order to rigorously test this hypothesis, we studied loudness changes in rats caused by intense noise exposure (12 kHz narrow band noise, 115 dB SPL, 4 h) at postnatal 16 days. Rats without noise exposure were used as controls. The exposed noise group (n = 7) showed a mean 40-50 dB hearing loss compared to the control group (n = 8) at high frequencies (>= 8 kHz) and less hearing loss at lower frequencies. Loudness was evaluated using sound reaction time and loudness response functions in an operant conditioning-based behavioral task using narrow-band noise (40-110 dB SPL, centered at 2, 4 and 12 kHz). Interestingly, the sound reaction time of the noise group was significantly shorter than the control group at supra-threshold levels. The average reaction time was less than 100 ms in the noise group at 100 dB SPL, which was three times shorter than the control group. Our results indicate that early noise-induced hearing loss leads to a significant increase of loudness, a behavior indicative of hyperacusis. Our results are consistent with clinical reports suggesting that hearing loss at an early age is a significant risk factor for hyperacusis.

Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea.

Sestrin 2 (SESN2) is a stress-inducible protein that protects tissues from oxidative stress and delays the aging process. However, its role in maintaining the functional and structural integrity of the cochlea is largely unknown. Here, we report the expression of SESN2 protein in the sensory epithelium, particularly in hair cells. Using C57BL/6J mice, a mouse model of age-related cochlear degeneration, we observed a significant age-related reduction in SESN2 expression in cochlear tissues that was associated with early onset hearing loss and accelerated age-related sensory cell degeneration that progressed from the base toward the apex of the cochlea. Hair cell death occurred by caspase-8 mediated apoptosis. Compared to C57BL/6J control mice, Sesn2 KO mice displayed enhanced expression of proinflammatory genes and activation of basilar membrane macrophages, suggesting that loss of SESN2 function provokes the immune response. Together, these results suggest that Sesn2 plays an important role in cochlear homeostasis and immune responses to stress.

Apical hair cell degeneration causes the increase in the amplitude of summating potential.

CONCLUSION: This study indicates that the lesion of hair cells in the apical turn of the cochlea can cause the change in the summating potential (SP)/Compound potential (CAP) ratio. OBJECTIVES: Electrocochleography is a valuable clinic test for diagnosis of cochlear pathologies and the ratio of SP to CAP has been used to identify Meniere's disease. However, it remains controversial whether the increase of the SP/CAP ratio represents exclusively the endolymphatic hydrops. METHOD: This study measured the SP and CAP in mice that displayed outer hair cell (OHC) degeneration in the apical section of the cochlea as their age increased. RESULTS: As compared with the mice aged 8-10 months, the 24-month old mice displayed a significant increase in the amplitude of SP at 12-16 kHz. This result suggests that the degeneration of OHCs in the apical turn leads to the increase of the + SP at the middle frequencies. In contrast, the aging mice did not have a significant change in the CAP amplitude at super-threshold levels.

Bone marrow-derived mesenchymal stem cells differentiate into nerve-like cells in vitro after transfection with brain-derived neurotrophic factor gene.

Bone marrow-derived mesenchymal stem cells can differentiate into a variety of adult cells. Brain-derived neurotrophic factor (BDNF) is briefly active during differentiation and induces mesenchymal stem cells to differentiate into nerve cells. In this study, we cloned human BDNF to generate a recombinant pcDNA3.1(-)-BDNF vector and transfected the vector into bone marrow-derived mesenchymal stem cells. We selected these cells with Geneticin-418 to obtain BDNF-BMSCs, which were induced with retinoic acid to obtain induced BDNF-BMSCs. The transfected cells displayed the typical morphology and surface antigen profile of fibroblasts and were observed to express clusters of differentiation 29, 44, and 90 (observed in matrix and stromal cells), but not clusters of differentiation 31, 34, and 45 (observed in red blood cells and endothelial cells), via flow cytometry. Enzyme-linked immunosorbent assays showed that transfected bone marrow-derived mesenchymal stem cells secreted more BDNF than non-transfected bone marrow-derived mesenchymal stem cells. Immunocytochemistry and real-time reverse transcription polymerase chain reaction analysis showed that non-induced BDNF-BMSCs maintained a higher proliferative capacity and expressed higher amounts of brain-derived neurotrophic factor, nestin, neuron-specific enolase, and glial fibrillary acid protein than non-transfected bone marrow-derived mesenchymal stem cells. An additional increase was observed in the induced BDNF-BMSCs compared to the non-induced BDNF-BMSCs. This expression profile is characteristic of neurocytes. Our data demonstrate that bone marrow-derived mesenchymal stem cells transfected with the BDNF gene can differentiate into nerve-like cells in vitro, which may enable the generation of sufficient quantities of nerve-like cells for treatment of neuronal diseases.

[The principal component analysis of clinical symptoms in patients with Meniere's disease during acute phase].

OBJECTIVE: To explore the severity index of Meniere's disease during acute phase by a statistical method of principal component analysis (PCA). METHOD: Ninety-five patients with Meniere's disease in the acute phase who saw the doctor with 24 hours after onset were included in this study and their clinical data were analyzed retrospectively. The subjective symptoms of hearing loss (X1) and ear stuffy plug (X4) were evaluated by VAS scoring system, and the impact of vertigo (X2) and tinnitus (X3) on the patients were evaluated by DHI and THI score. The principal component analysis (PCA) method was used to analyze the quantified data and construct a synthetic evaluate function of subjective symptoms. RESULT: (1) The quantitative results of subjective symptoms in patients with Meniere's disease were as follow: VAS score (X1) of hearing loss was 0-91 points, with an average of 46.23 ± 18.80, DHI score (X2) of vertigo was 8-98 points, with an average of 49.66 ± 15.67, THI score (X3) of tinnitus was 10-100 points, with an average of 47.53 ± 17.44, and ear VAS score (X4) of stuffy plug feeling was 0-82 points, with an average of 21.55 ± 27.54. (2) The eigenvalue of principal components Z1, Z2 and Z3 were 1.876, 0.984 and 0.703 respectively, and the variance contribution were 46.898%, 24.592% and 17.574% respectively. (3) The constructed synthetic evaluate function of the disease was as follow: The Meniere's disease severity index ƒ = 0.213ZX1 + 0.398ZX2 + 0.370ZX3 + 0.455ZX4. CONCLUSION: The method of PCA for the subjective evaluation of symptoms in Meniere's disease can be constructed as a model of comprehensive evaluation system, which may provide relatively comprehensive information of clinical original variables included in the four main symptoms, reflecting the severity of the disease.