Melatonin attenuates chronic intermittent hypoxia-induced intestinal barrier dysfunction in mice.

BACKGROUND AND PURPOSE: Chronic intermittent hypoxia (CIH) triggers subclinical intestinal barrier disruption prior to systemic low-grade inflammation. Increasing evidence suggests therapeutic effects of melatonin on systemic inflammation and gut microbiota remodelling. However, whether and how melatonin alleviates CIH-induced intestinal barrier dysfunction remains unclear. EXPERIMENTAL APPROACH: C57BL/6 J mice and Caco-2 cell line were treated. We evaluated gut barrier function spectrophotometrically using fluorescein isothiocyanate (FITC)-labelled dextran. Immunohistochemical and immunofluorescent staining were used to detect morphological changes in the mechanical barrier. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) revealed the expression of tight junctions, signal transducer and activator of transcription 3 (STAT3) levels. 16 S rRNA analysis of the colonic contents microflora. Flow cytometry was used to detect cytokines and Th17 cells with and without melatonin supplementation. KEY RESULTS: We found that CIH could induce colonic mucosal injury, including reduction in the number of goblet cells and decrease the expression of intestinal tight junction proteins. CIH could decrease the abundance of the beneficial genera Clostridium, Akkermansia, and Bacteroides, while increasing the abundance of the pathogenic genera Desulfovibrio and Bifidobacterium. Finally, CIH facilitated Th17 differentiation via the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in vitro and elevated the circulating pro-inflammatory cytokine in vivo. Melatonin supplementation ameliorated CIH-induced intestinal mucosal injury, gut microbiota dysbiosis, enteric Th17 polarization, and systemic low-grade inflammation reactions mentioned-above. CONCLUSION AND IMPLICATIONS: Melatonin attenuated CIH-induced intestinal barrier dysfunction by regulating gut flora dysbiosis, mucosal epithelium integrity, and Th17 polarization via STAT3 signalling.

Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia: a double-blind, randomised clinical trial.

BACKGROUND: The aim of this study was to determine the efficacy of exogenous melatonin supplementation for sleep disturbances in patients with middle-aged primary insomnia. METHODS: This is a randomized double-blind, placebo-controlled parallel study. Participants were recruited from Tianlin community, Xuhui district, Shanghai. Ninety-seven consecutive middle-aged patients with primary insomnia were randomized to receive 3 mg fast-release melatonin (n = 51) or placebo (n = 46) for four-weeks. Objective sleep parameters tested by overnight polysomnography, subjective sleep performance and daytime somnolence obtained from the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) were obtained at baseline and after treatment. Treatment was taken daily 1 h before bedtime. Serious adverse events and side-effects were monitored. RESULTS: Melatonin supplementation significantly decreased early wake time [-30.63min (95% CI, -53.92 to -7.34); P = 0.001] and percentage of N2 sleep [-7.07% (95% CI, -13.47% to -0.68%); P = 0.031]. However, melatonin had no significant effect on other objective sleep parameters including sleep latency, sleep efficiency, wake during the sleep and percent of N1, N3 and REM sleep. Melatonin had no effect on insomnia symptoms and severity on the PSQI [1.53(95% CI, -0.55 to 3.61); p = 0.504]; ISI [0.81 (95% CI, -2.27 to 3.88); p = 0.165] and ESS [-0.83 (95% CI, -3.53 to 1.88); p = 0.147]. No serious adverse events were reported. CONCLUSIONS: Melatonin supplementation over a four-week period is effective and safe in improving some aspects of objective sleep quality such as total sleep time, percentage of rapid eye movement and early morning wake time in middle-aged patients with insomnia. TRIAL REGISTRATION: Identifier: ChiCTR-TRC-13003997; Prospectively registered on 2 December 2013.

Differences in Clinical Characteristics and Brain Activity between Patients with Low- and High-Frequency Tinnitus.

This study was aimed at delineating and comparing differences in clinical characteristics and brain activity between patients with low- and high-frequency tinnitus (LFT and HFT, respectively) using high-density electroencephalography (EEG). This study enrolled 3217 patients with subjective tinnitus who were divided into LFT (frequency < 4000 Hz) and HFT (≥4000 Hz) groups. Data regarding medical history, Tinnitus Handicap Inventory, tinnitus matching, and hearing threshold were collected from all patients. Twenty tinnitus patients and 20 volunteers were subjected to 256-channel EEG, and neurophysiological differences were evaluated using standardized low-resolution brain electromagnetic tomography (sLORETA) source-localized EEG recordings. Significant differences in sex (p < 0.001), age (p = 0.022), laterality (p < 0.001), intensity (p < 0.001), tinnitus type (p < 0.001), persistent tinnitus (p = 0.04), average threshold (p < 0.001), and hearing loss (p = 0.028) were observed between LFT and HFT groups. The tinnitus pitch only appeared to be correlated with the threshold of the worst hearing loss in the HFT group. Compared with the controls, the LFT group exhibited increased gamma power (p < 0.05), predominantly in the posterior cingulate cortex (PCC, BA31), whereas the HFT group had significantly decreased alpha1 power (p < 0.05) in the angular gyrus (BA39) and auditory association cortex (BA22). Higher gamma linear connectivity between right BA39 and right BA41 was observed in the HFT group relative to controls (t = 3.637, p = 0.027). Significant changes associated with increased gamma in the LFT group and decreased alpha1 in the HFT group indicate that tinnitus pitch is crucial for matching between the tinnitus and control groups. Differences of band frequency energy in brain activity levels may contribute to the clinical characteristics and internal tinnitus "spectrum" differences.

Role of Zinc Sulphate in Immune Regulation in Artemisia annua Pollen-challenged P815 Mastocytoma Cells.

Objective This study aimed to investigate the role of zinc sulphate in immune regulation in Artemisia annua pollen-challenged P815 mastocytoma cells. Methods P815 mastocytoma cells were treated with various concentrations of zinc sulphate and Artemisia annua pollen. Cell proliferation was measured using the Cell Counting Kit-8. The amount of ST2 and p38 in the cells were measured using Western blotting. The level of interleukins (IL)-33 in the supernatant was determined using the enzyme-linked immunosorbent assay. The levels of IL-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor were measured using the cytometric bead array. Results Artemisia annua pollen at a concentration >0.001 µg/mL induced allergic response in the P815 mastocytoma cells. Expressions of IL-33, IL-4, ST2, and p38 increased along with higher concentrations of Artemisia annua pollen. Zinc sulphate of 50-200 µmol/L promoted the proliferation of P815 mastocytoma cells. Zinc sulphate attenuated the upregulation of IL-33, IL-4, ST2, and p38 caused by Artemisia annua pollen. Conclusion Zinc sulphate can promote the proliferation of P815 mastocytoma cells. It can also attenuate allergic response in the P815 mastocytoma cells induced by Artemisia annua pollen, which might provide a new treatment method for allergic diseases.

The Relative Weight of Temporal Envelope Cues in Different Frequency Regions for Mandarin Sentence Recognition.

Acoustic temporal envelope (E) cues containing speech information are distributed across the frequency spectrum. To investigate the relative weight of E cues in different frequency regions for Mandarin sentence recognition, E information was extracted from 30 contiguous bands across the range of 80-7,562 Hz using Hilbert decomposition and then allocated to five frequency regions. Recognition scores were obtained with acoustic E cues from 1 or 2 random regions from 40 normal-hearing listeners. While the recognition scores ranged from 8.2% to 16.3% when E information from only one region was available, the scores ranged from 57.9% to 87.7% when E information from two frequency regions was presented, suggesting a synergistic effect among the temporal E cues in different frequency regions. Next, the relative contributions of the E information from the five frequency regions to sentence perception were computed using a least-squares approach. The results demonstrated that, for Mandarin Chinese, a tonal language, the temporal E cues of Frequency Region 1 (80-502 Hz) and Region 3 (1,022-1,913 Hz) contributed more to the intelligence of sentence recognition than other regions, particularly the region of 80-502 Hz, which contained fundamental frequency (F0) information.

Effects of Various Extents of High-Frequency Hearing Loss on Speech Recognition and Gap Detection at Low Frequencies in Patients with Sensorineural Hearing Loss.

This study explored whether the time-compressed speech perception varied with the degree of hearing loss in high-frequency sensorineural hearing loss (HF SNHL) individuals. 65 HF SNHL individuals with different cutoff frequencies were recruited and further divided into mildly, moderately, and/or severely affected subgroups in terms of the averaged thresholds of all frequencies exhibiting hearing loss. Time-compressed speech recognition scores under both quiet and noisy conditions and gap detection thresholds within low frequencies that had normal thresholds were obtained from all patients and compared with data from 11 age-matched individuals with normal hearing threshold at all frequencies. Correlations of the time-compressed speech recognition scores with the extents of HF SNHL and with the 1 kHz gap detection thresholds were studied across all participants. We found that the time-compressed speech recognition scores were significantly affected by and correlated with the extents of HF SNHL. The time-compressed speech recognition scores also correlated with the 1 kHz gap detection thresholds except when the compression ratio of speech was 0.8 under quiet condition. Above all, the extents of HF SNHL were significantly correlated with the 1 kHz gap thresholds.

Effects of steep high-frequency hearing loss on speech recognition using temporal fine structure in low-frequency region.

The present study examined the effects of steep high-frequency sensorineural hearing loss (SHF-SNHL) on speech recognition using acoustic temporal fine structure (TFS) in the low-frequency region where the absolute thresholds appeared to be normal. In total, 28 participants with SHF-SNHL were assigned to 3 groups according to the cut-off frequency (1, 2, and 4 kHz, respectively) of their pure-tone absolute thresholds. Fourteen age-matched normal-hearing (NH) individuals were enrolled as controls. For each Mandarin sentence, the acoustic TFS in 10 frequency bands (each 3-ERB wide) was extracted using the Hilbert transform and was further lowpass filtered at 1, 2, and 4 kHz. Speech recognition scores were compared among the NH and 1-, 2-, and 4-kHz SHF-SNHL groups using stimuli with varying bandwidths. Results showed that speech recognition with the same TFS-speech stimulus bandwidth differed significantly in groups and filtering conditions. Sentence recognition in quiet conditions was better than that in noise. Compared with the NH participants, nearly all the SHF-SNHL participants showed significantly poorer sentence recognition within their frequency regions with "normal hearing" (defined clinically by normal absolute thresholds) in both quiet and noisy conditions. These may result from disrupted auditory nerve function in the "normal hearing" low-frequency regions.

Comparative study of the efficacy of the canalith repositioning procedure versus the vertigo treatment and rehabilitation chair.

CONCLUSION: Vertigo treatment and rehabilitation chair (TRV) may be suggested as the first choice for patients with posterior canal benign paroxysmal positional vertigo (p-BPPV). OBJECTIVE: To investigate the short- and long-term treatment efficacy of the canalith repositioning procedure (CRP) versus TRV for patients with p-BPPV. METHODS: A total of 165 patients with unilateral p-BPPV were assigned to either the CRP group or the TRV group. Patients were assessed at 1 week, 4 weeks, 3 months, and 6 months after their first treatment. The numbers of treatment sessions required for successful repositioning in both groups at 4 weeks, 3 months, and 6 months were recorded. RESULTS: Treatment efficacy of patients in the TRV group was significantly better than that of patients in the CRP group 1 week after the first treatment. The number of treatment sessions needed for successful repositioning was significantly lower in the TRV group than in the CRP group at 4 weeks and 3 months after the first treatment.

Delayed diagnosis and treatment of benign paroxysmal positional vertigo associated with current practice.

The purposes of this study were to demonstrate the current status of benign paroxysmal positional vertigo (BPPV) management and the advantages of repositioning maneuvers as well as to facilitate the accurate and efficient diagnosis and management of BPPV. Of 131 participants with severe dizziness/vertigo who were examined and treated, 31 (23.7%) fulfilled the diagnostic criteria for BPPV. All patients in the study had a diagnosis of BPPV confirmed by their history, typical subjective symptom reports, and characteristic positional nystagmus during the Dix-Hallpike test and/or roll test. All participants were comprehensively interviewed regarding their medical history, characteristics of the first attack of vertigo, associated symptoms, previous financial costs, and number of hospital visits. The average duration from the appearance of the first symptoms until a final diagnostic positional maneuver was >70 months. On average, patients visited hospitals more than eight times before the final diagnosis due to initial visits to inappropriate departments, including neurology, emergency, orthopaedic surgery, and Traditional Chinese Medicine, with a corresponding average financial cost of more than 5,000 RMB. The canalith repositioning procedure (CRP) was effective in 80.65% of patients after the first repositioning maneuver. Our data demonstrated that despite the significant prevalence of BPPV, delays in diagnosis and treatment frequently occur, which have both cost and quality-of-life impacts on both patients and their caregivers. The CRP is very effective for patients with BPPV. It is important for patients to pay more attention to the impact of BPPV on their lives and recognize its nature to ensure compliant follow-up in otolaryngology.

Mitochondrial dysfunction disrupts trafficking of Kir4.1 in spiral ganglion satellite cells.

The inward-rectifier K(+) channel Kir4.1 is responsible for maintaining cochlear homeostasis and restoring neural excitability. The large-conductance calcium-activated K(+) channel (BK(Ca)) plays a key role in phase locking signals in the mammalian inner ear. To evaluate the influence of mitochondrial dysfunction on the expression and subcellular localization of these channels, 3-nitropropionic acid (3-NP) was administered to rat round window membranes for 30 min. Auditory brainstem response was measured both before and 2 hr after 3-NP administration. Immunofluorescent confocal microscopy was used to measure the expression and subcellular localization of Kir4.1 and BK(Ca). Alexa Fluor 568-labeled bovine serum albumin (BSA) was applied to round window membranes as a tracer to explore the cochlear distribution of drug delivery and was detected in the lateral wall, spiral ganglion, cochlear nerve, and organ of Corti. Hearing loss of 23 (+/-4.4 SE) and 58 (+/-6.7 SE) dB developed in rats treated with 0.3 and 0.5 mol/liter of 3-NP, respectively. BK(Ca) was visualized in the cellular membrane and cytoplasm in the upper and middle region of inner hair cells, and it was not affected by 3-NP. Kir4.1 was detected in intermediate cells of the stria, Deiter's cells, and spiral ganglion satellite cells. Kir4.1 failed to reach the perineural cytoplasm of the satellite cells after 3-NP treatment. The results of this study suggest that mitochondrial dysfunction disrupts trafficking of Kir4.1 in spiral ganglion satellite cells.

The effect of noise-induced sloping high-frequency hearing loss on the gap-response in the inferior colliculus and auditory cortex of guinea pigs.

Gap detection has been used as an evaluation tool for temporal processing in subjects with sensorineural hearing loss (SNHL). However, the results from other reports are varied making it difficult to clearly define the impact of SNHL on the temporal processing ability of the auditory system. Specifically, we do not know if and how a high-frequency hearing loss impacts, presumably through off-channel interaction, the temporal processing in low-frequency channels where hearing sensitivity is virtually normal. In this experiment, gap-evoked responses in a low-frequency band (0.5-8 kHz) were recorded in the inferior colliculus (IC) and auditory cortex (AC) of guinea pigs through implanted electrodes, before and after a slopping high-frequency hearing loss, which was induced by over-stimulation using a 12-kHz-tone. The results showed that the gap thresholds in the low-frequency region increased gradually and became significantly higher 8 weeks after the induced high-frequency hearing loss. In addition, the response latency was slightly increased in the IC but this was not true for the AC. These results strongly indicate that a high-frequency hearing loss exerted an off-channel impact on temporal processing in the low-frequency region of the auditory system.