Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.

Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here we report that bilirubin (BIL)-dependent cell death in auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediated current (Ih), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at young adult stage in HCN1+/+, but not in HCN1-/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

Conformal immunomodulatory hydrogels for the treatment of otitis media.

Otitis media (OM), a condition stemming from the proliferation of various bacteria within the tympanic cavity (TC), is commonly addressed through the administration of ofloxacin (OFL), a fluoroquinolone antibiotic. Nevertheless, the escalating issue of antibiotic resistance and the challenge of drug leakage underscore the exploration of an alternative, more effective treatment modality in clinical practice. Here, we introduce a simple and easily implementable fluid-regulated strategy aimed at delivering immunomodulatory hydrogels into the TC, ensuring conformal contact with the irregular anatomical surfaces of the middle ear cavity to more effectively eliminate bacteria and treat OM. This innovative strategy exhibits expedited therapeutic process of antibiotic-resistant, acute and chronic OM rats, and significant reductions in the severity of tympanic membrane (TM) inflammation, residual bacteria within the TC (0.12 *105 CFU), and the thickness of TM/TC mucosa (17.63/32.43 µm), as compared to conventional OFL treatment (3.6, 0.76 *105 CFU, 48.70/151.26 µm). The broad-spectrum antibacterial and antibiofilm properties of this strategy against a spectrum of OM pathogens are demonstrated. The strategy is validated to bolster the host's innate immune response through the stimulation of antibacterial protein synthesis, macrophage proliferation and activation, thereby accelerating bacterial eradication and inflammation resolution within the TC. This facile, cost-effective and in vivo degradable technology exhibits promising prospects for future clinical implementation.

HMGB1 accumulation in cytoplasm mediates noise-induced cochlear damage.

Damage-associated molecular pattern molecules (DAMPs) play a critical role in mediating cochlear cell death, which leads to noise-induced hearing loss (NIHL). High-mobility group box 1 (HMGB1), a prototypical DAMP released from cells, has been extensively studied in the context of various diseases. However, whether extracellular HMGB1 contributes to cochlear pathogenesis in NIHL and the potential signals initiating HMGB1 release from cochlear cells are not well understood. Here, through the transfection of the adeno-associated virus with HMGB1-HA-tag, we first investigated early cytoplasmic accumulation of HMGB1 in cochlear hair cells after noise exposure. We found that the cochlear administration of HMGB1-neutralizing antibody immediately after noise exposure significantly alleviated hearing loss and outer hair cells (OHCs) death induced by noise exposure. In addition, activation of signal transducer and activators of transcription 1 (STAT1) and cellular hyperacetylation were verified as potential canonical initiators of HMGB1 cytoplasmic accumulation. These findings reveal the adverse effects of extracellular HMGB1 on the cochlea and the potential signaling events mediating HMGB1 release in hair cells, indicating multiple potential pharmacotherapeutic targets for NIHL.

Effects of obstructive sleep apnea during rapid eye movement sleep on cardiac autonomic dysfunction: Results from the Shanghai sleep health study cohort.

In our large-scale study, the correlation between obstructive sleep apnea (OSA) related to rapid eye movement (REM) sleep and cardiac autonomic dysfunction was assessed by standard polysomnography (PSG). Cardiac autonomic dysfunction was evaluated by the measurement of heart rate variability (HRV). The cardiovascular disease (CVD) risk was determined using the cross-sectional prevalence of CVD and its overall 10 year risk according to the Framingham risk score (FRS). 4152 individuals were included in the study. A higher apnea-hypopnea index during REM sleep (AHIREM ) was correlated with increased CVD risk. The adjusted odds ratios (95% CIs) for CVD prevalence and its high 10 year risk in participants having severe OSA during REM sleep (AHIREM ≥30 events/h) were 1.452 (1.012-2.084) and 1.904 (1.470-2.466) in the demographic adjusted model and 1.175 (0.810-1.704) and 1.716 (1.213-2.427) in the multivariate adjusted model, respectively, compared with the group with a AHIREM of <5 events/h. Fully adjusted multivariate linear regression models showed the independent association between AHIREM and a more elevated ratio of low-frequency and high-frequency (LF/HF) and LF in normalised units [LF (n.u.)] (P = 0.042, P = 0.027 in all participants and P = 0.033, P = 0.029 in participants with AHI during non-REM sleep <5 events/h, respectively). Mediation analysis demonstrated that OSA during REM sleep and CVD risk was significantly mediated by LF/HF and LF (n.u.). OSA during REM sleep may be a marker behind CVD risk because it promotes cardiac autonomic dysfunction.

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea.

BACKGROUND: Phosphatidylserine is translocated to the inner leaflet of the phospholipid bilayer membrane by the flippase function of type IV P-tape ATPase (P4-ATPase), which is critical to maintain cellular stability and homeostasis. Transmembrane protein 30A (TMEM30A) is the ß-subunit of P4-ATPase. Loss of P4-ATPase function causes sensorineural hearing loss and visual dysfunction in human. However, the function of TMEM30A in the auditory system is unclear. METHODS: P4-ATPase subtype expression in the cochlea was detected by immunofluorescence staining and quantitative real-time polymerase chain reaction (qRT-PCR) at different developmental stages. Hair cell specific TMEM30A knockout mice and wild-type littermates were used for the following functional and morphological analysis. Auditory function was evaluated by auditory brainstem response. We investigated hair cell and stereocilia morphological changes by immunofluorescence staining. Scanning electron microscopy was applied to observe the stereocilia ultrastructure. Differentially expressed transcriptomes were analyzed based on RNA-sequencing data from knockout and wild-type mouse cochleae. Differentially expressed genes were verified by qRT-PCR. RESULTS: TMEM30A and subtypes of P4-ATPase are expressed in the mouse cochlea in a temporal-dependent pattern. Deletion of TMEM30A in hair cells impaired hearing onset due to progressive hair cell loss. The disrupted kinocilia placement and irregular distribution of spectrin-α in cuticular plate indicated the hair cell planar polarity disruption in TMEM30A deletion hair cells. Hair cell degeneration begins at P7 and finishes around P14. Transcriptional analysis indicates that the focal adhesion pathway and stereocilium tip-related genes changed dramatically. Without the TMEM30A chaperone, excessive ATP8A2 accumulated in the cytoplasm, leading to overwhelming endoplasmic reticulum stress, which eventually contributed to hair cell death. CONCLUSIONS: Deletion of TMEM30A led to disrupted planar polarity and stereocilia bundles, and finally led to hair cell loss and auditory dysfunction. TMEM30A is essential for hair cell polarity maintenance and membrane homeostasis. Our study highlights a pivotal role of TMEM30A in the postnatal development of hair cells and reveals the possible mechanisms underlying P4-ATPase-related genetic hearing loss.

Genome-Wide Association Study of Obstructive Sleep Apnea and Objective Sleep-related Traits Identifies Novel Risk Loci in Han Chinese Individuals.

Rationale: Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. Objectives: To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. Methods: A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. Measurements and Main Results: Two characteristic study-wide significant loci (P < 2.63 × 10-9) for OSA were identified: the PACRG intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89; P = 6.98 × 10-10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter SLC52A3 on 20p13 (OR = 0.83; 95% CI, 0.79-0.88; P = 7.57 × 10-10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. Conclusions: We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that SLC52A3 might be a therapeutic target, whereas riboflavin might be a therapeutic agent.

Prevalence, characteristics, and respiratory arousal threshold of positional obstructive sleep apnea in China: a large scale study from Shanghai Sleep Health Study cohort.

PURPOSE: To evaluate the prevalence, characteristics, and respiratory arousal threshold (ArTH) of Chinese patients with positional obstructive sleep apnea (POSA) according to the Cartwright Classification (CC) and Amsterdam Positional Obstructive Sleep Apnea Classification (APOC). METHODS: A large-scale cross-sectional study was conducted in our sleep center from 2007 to 2018 to analyze the clinical and polysomnography (PSG) data of Chinese POSA patients. Low ArTH was defined based on PSG indices. RESULTS: Of 5,748 OSA patients, 36.80% met the CC criteria, and 42.88% the APOC criteria, for POSA. The prevalence of POSA was significantly higher in women than men (40.21% and 46.52% vs. 36.13% and 42.18% for CC and APOC, respectively). Chinese POSA patients had a lower apnea hypopnea index (AHI) and lower oxygen desaturation index, shorter duration of oxygen saturation (SaO2) < 90%, and a higher mean SaO2 and higher lowest SaO2 value compared to subjects with non-positional OSA (NPOSA). More than 40% of the POSA patients had a low ArTH; the proportion was extremely high in the supine-isolated-POSA (si-POSA) group and APOC I group. In multivariate logistic regression analyses, higher mean SaO2 and lower AHI during sleep were positive predictors of POSA. CONCLUSIONS: According to the CC and APOC criteria, more than 1/3 of our Chinese subjects with OSA had POSA. Chinese POSA patients had less severe OSA and nocturnal hypoxia. Compared to NPOSA patients, significantly more patients with POSA had a low ArTH. A low ArTH may be an important endotype in the pathogenesis of POSA, especially in patients with si-POSA and APOC I. Further studies are necessary to develop personalized management strategies for POSA patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry; URL: http://www.chictr.org.cn ; No. ChiCTR1900025714 (retrospectively registered).

Risk factors for non-positional obstructive sleep apnea-hypopnea syndrome.

OBJECTIVE: To explore the main risk factors for non-positional obstructive sleep apnea (NPOSA). METHODS: A total of 560 patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) were divided into non-positional obstructive sleep apnea (NPOSA) and positional obstructive sleep apnea (POSA) groups. All patients were assessed by the Friedman staging system and anthropometry before overnight polysomnography. Blood tests were performed to determine the fasting blood glucose level and lipid profile. Forward logistic regression analysis was performed to evaluate the effects of all parameters on positional dependency. RESULTS: The study sample consisted of 318 NPOSA patients and 242 POSA patients (88% and 85% were men, respectively). The mean apnea-hypopnea index (AHI) was 57.0 events/h in the NPOSA group, compared with 25.7 events/h in the POSA group. The POSA group had a significantly smaller neck circumference (NC), waist circumference (WC), hip circumference (HC), lower body mass index (BMI), AHI, fasting blood glucose, and apolipoprotein-B (apoB) levels than did the NPOSA group (all, P < 0.01). The minimal nocturnal oxyhemoglobin saturation (minSpO2) and apoB/apoA ratio were higher in the POSA group than in the NPOSA group (both, P < 0.001). The AHI, minSpO2, WC, and fasting blood glucose level were included in the logistic regression models. CONCLUSION: The AHI, WC, minSpO2, and fasting blood glucose level are the main independent risk factors for NPOSA.

LncRNA FAM230B promotes the metastasis of papillary thyroid cancer by sponging the miR-378a-3p/WNT5A axis.

Emerging evidence indicates that the dysregulation of long non-coding RNAs (lncRNAs) plays critical roles in the progression of papillary thyroid cancer (PTC). In this study, we found consistently elevated expression levels of the lncRNA FAM230B in PTC tissues, both in newly generated RNA-seq data and in datasets from the GEO and TCGA databases. We demonstrated that the expression of FAM230B can be used for the diagnosis of PTC and is also strongly associated with lymph node metastasis. The potential biological functions of FAM230B and molecular mechanisms by which it regulates PTC progression were investigated. Functionally, FAM230B promoted the migration and invasion of PTC cells in vitro and in vivo. Mechanistically, FAM230B sponged miR-378a-3p and showed competitive binding to the 3'-UTR of WNT5A. FAM230B overexpression resulted in elevated WNT5A expression and thereby regulated the epithelial-mesenchymal transition in PTC cells. Finally, we verified that both miR-378a-3p overexpression and WNT5A silencing effectively offset the impacts of FAM230B on PTC cell migration and invasion. In conclusion, our study demonstrated the oncogenic function of the lncRNA FAM230B in PTC cells, providing a novel target for PTC diagnosis and therapy.

Sea level nocturnal minimal oxygen saturation can accurately detect the presence of obstructive sleep apnea in a population with high pretest probability.

PURPOSE: To evaluate whether a predictive model based on nocturnal minimal oxygen saturation (SpO2) alone can accurately detect the presence of obstructive sleep apnea (OSA) in a population with suspected OSA. METHODS: A total of 4297 participants with suspected OSA were enrolled in this study, and laboratory-based polysomnography (PSG) tests were performed at sea level in all subjects. Nocturnal minimal SpO2 was obtained automatically as part of the PSG test. Stratified sampling was used to divide the participants' data into the training set (75%) and the test set (25%). An OSA detection model based on minimal SpO2 alone was created using the training set data and its performance was evaluated using the independent test set data ("hold-out" evaluation). Gender-specific models, and models based on minimal SpO2 in combination with other predictive factors (age, body mass index, waist-to-hip ratio, snoring grade, Epworth Sleepiness Scale score, and comorbidities), were also created and compared in terms of OSA detection performance. RESULTS: The prevalence of OSA was 85.6% in our study population. The models including multiple predictors, and the gender-specific models, failed to outperform the model based solely on minimal SpO2, which showed good predictive performance (C statistic, 0.922) having an overall accuracy rate of 0.86, sensitivity of 0.87, specificity of 0.84, positive predictive value of 0.97, and positive likelihood ratio of 5.34. In addition, the model based on minimal SpO2 alone could also accurately predict the presence of moderate-to-severe OSA and severe OSA, with C statistics of 0.914 and 0.900, respectively. CONCLUSIONS: A predictive model based on nocturnal minimal SpO2 alone may be an alternative option to detect the presence of OSA in a high-risk population when standard diagnostic tests are unavailable.

The association between obesity indices and obstructive sleep apnea is modified by age in a sex-specific manner.

BACKGROUND: The beneficial effects of weight reduction on obstructive sleep apnea (OSA) are highly variable. Whether or not the variability is associated with the effects of age and sex remains unclear. This study examined this issue with large cross-sectional data. METHOD: Anthropometric measurements, polysomnographic variables, biochemical indicators, and medical history were collected for each participant. Multivariable linear regression with interaction terms was used to estimate the modification effect of age on the associations between OSA severity (assessed by apnea-hypopnea index, AHI) with obesity indices (body mass index, BMI; neck circumference, NC; waist circumference, WC; waist-to-hip ratio, WHR) in a sex-specific manner, and vice versa. To facilitate interpretation of the results, participants were further classified into six subpopulations according to both sex and age, and population-specific beta-coefficients were calculated and compared. RESULTS: A total of 5756 adults (4600 men) with suspected OSA were included in the study. BMI, NC, WC, and WHR were all positively correlated with AHI after adjusting for potential confounders in all populations. In men, these associations were much stronger and more significant in younger than older individuals (P for interaction < 0.001). For example, a 10% increase in BMI was independently associated with a 32% increase in AHI for men < 40 years old, whereas the corresponding increases were 21% and 17% for men 40-60 and > 60 years old, respectively. By contrast, no modification effect of age was observed in women (P for interaction > 0.05). A 10% increase in BMI was associated with 26%, 27%, and 24% increases in AHI for women < 40, 40-60, and > 60 years old, respectively. CONCLUSIONS: Age modifies the associations between obesity indices and OSA severity in a sex-specific manner. These findings may broaden the understanding of age- and sex-related heterogeneities in the pathogenic role of obesity in OSA, and may be beneficial for individualized risk evaluation and treatment management for patients with OSA.

Transcriptomic Analysis Reveals an Altered Hcy Metabolism in the Stria Vascularis of the Pendred Syndrome Mouse Model.

Purpose: Slc26a4-/- mice exhibit severer defects in the development of the cochlea and develop deafness, while the underlying mechanisms responsible for these effects remain unclear. Our study was to investigate the potential mechanism linking SLC26A4 deficiency to hearing loss. Materials and Methods: RNA sequencing was applied to analyze the differential gene expression of the stria vascularis (SV) from wildtype and Slc26a4-/- mice. GO and KEGG pathway analysis were performed. Quantitative RT-PCR was applied to validate the expression of candidate genes affected by Slc26a4. ELISA and immunofluorescence technique were used to detect the homocysteine (Hcy) level in serum, brain, and SV, respectively. Results: 183 upregulated genes and 63 downregulated genes were identified in the SV associated with Slc26a4 depletion. Transcriptomic profiling revealed that Slc26a4 deficiency significantly affected the expression of genes associated with cell adhesion, transmembrane transport, and the biogenesis of multicellular organisms. The SV from Slc26a4-/- mice exhibited a higher expression of Bhmt mRNAs, as well as altered homocysteine (Hcy) metabolism. Conclusions: The altered expression of Bhmt results in a dramatic change in multiple biochemical reactions and a disruption of nutrient homeostasis in the endolymph which may contribute to hearing loss of Slc26a4 knockout mouse.

Interaction between obstructive sleep apnea and short sleep duration on insulin resistance: a large-scale study : OSA, short sleep duration and insulin resistance.

OBJECTIVES: Both short sleep duration and obstructive sleep apnea (OSA) seem to be associated with insulin resistance. We aimed to explore whether short sleep duration modifies the relationship between OSA and insulin resistance. METHODS: Participants were consecutively enrolled from our sleep center during the period from 2007 to 2017. The index of homeostasis model assessment insulin resistance (HOMA-IR) was calculated from insulin and glucose. Sleep duration was determined by standard polysomnography. The associations between sleep duration and insulin resistance were estimated by logistic regression analyses. RESULTS: A total of 5447 participants (4507 OSA and 940 primary snorers) were included in the study. OSA was independently correlated with insulin resistance after adjusting for all potential confounders (OR, 1.319; 95% CI, 1.088-1.599), but not short sleep duration. In stratified analysis by sleep duration, compared with primary snorers, in the OSA group only extremely short sleep duration (< 5 h) was significantly associated with insulin resistance after adjusting for all covariates (OR, 2.229; 95% CI, 1.283-3.874). Rapid eye movement predominant OSA was significantly associated with insulin resistance (OR = 1.355, 95% CI: 1.019-1.802) after adjustment for confounding factors including age, sex and body mass index. CONCLUSIONS: OSA, but not short sleep duration, was independently associated with insulin resistance. It is worth noting that OSA combined with extremely short sleep duration showed a greater detrimental effect than OSA itself with regard to insulin resistance.

Contrast-Enhanced MRI Combined With the Glycerol Test Reveals the Heterogeneous Dynamics of Endolymphatic Hydrops in Patients With Menière's Disease.

BACKGROUND: The sensitivity of endolymphatic hydrops (EH) to the glycerol test varies in patients with Menière's disease (MD). PURPOSE: To explore the features of EH and its glycerol-induced dynamics in MD. STUDY TYPE: Case-control study. POPULATION: Twenty patients with MD (24 affected ears) were included. FIELD STRENGTH/SEQUENCE: 3.0T 3D-FLAIR (fluid-attenuated inversion recovery) MRI and late gadolinium enhancement. ASSESSMENT: Intratympanic gadolinium-enhanced MRI was performed in the MD-affected ears before and after the glycerol test. The borders of the endolymphatic and total lymphatic space were contoured on the axial MRI slices to evaluate the volume of hydrops in both the cochlear and vestibular regions. STATISTICAL TESTS: Paired and unpaired t-tests, the Mann-Whitney U-test, linear discriminant analysis, Pearson's correlation, and linear regression. RESULTS: After glycerol ingestion, vestibular EH decreased in all patients, whereas cochlear EH significantly decreased only in patients with positive glycerol test results (all P < 0.01). At baseline, cochlear EH in the positive result group was greater than in the negative result group (P = 0.007). Unexpectedly, in the positive result group a drastic glycerol-induced dehydrating effect was observed in patients whose pretest cochlear EH ratio was >16% (P = 0.011). Moreover, the dehydrating role of glycerol was positively correlated with the baseline cochlear hydrops level (r = 0.7691, P < 0.001). DATA CONCLUSION: MRI provides evidence that glycerol administration improves the hearing threshold via dehydrating the EH. In the cochlear region, the baseline level of cochlear EH is a closely related factor for the validity of the glycerol test, whereas EH is consistently dehydrated in the vestibular component. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:1066-1073.

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.

Interrelationships among common predictors of cardiovascular diseases in patients of OSA: A large-scale observational study.

BACKGROUND AND AIMS: The apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) and insulin resistance has been recognized as common cardiovascular diseases (CVD) risk factors. However, whether they were biomarkers for 10-year CVD risk in obstructive sleep apnea (OSA) had been rarely studied. Besides, interrelationships between the ApoB/ApoA-I, insulin resistance and OSA remain unclear. METHODS AND RESULTS: A total of 4010 subjects were finally included. Anthropometric, fasting biochemical, and polysomnographic parameters were collected. 10-year Framingham CVD risk score (FRS) was calculated for each subjects. The relationships between insulin resistance, OSA risk and the ApoB/ApoA-I was evaluated through logistic regressions analysis, restricted cubic spline (RCS) analysis and mediation analysis. ApoB/ApoA-I, HOMA-IR and AHI were all risk factors for high10-year CVD risk as assessed by FRS (odds ratios (OR) = 5.365, 1.094, 1.010, respectively, all P < 0.001)). The fully adjusted OR (95% confidence intervals) for both OSA [1 (reference), 1.308 (1.027-1.665), 1.517 (1.178-1.953), and 1.803 (1.371-2.372)] and insulin resistance [1 (reference), 1.457 (1.173-1.711), 1.701 (1.369-2.113), 2.051(1.645-2.558)] increased from the first to the fourth quartiles of the ApoB/ApoA-I. The RCS mapped a nonlinear dose-effect relationship between the ApoB/ApoA-I and risk of insulin resistance and OSA. Mediation analyses showed HOMA-IR explain 9.7%, 4.7% and 10.8% of the association between apnea-hypopnea index, oxygen desaturation index, micro-arousal index and ApoB/ApoA-I, respectively. CONCLUSIONS: Our study revealed that ApoB/ApoA-I, insulin resistance and OSA were risk factors for CVD. Insulin resistance may serve as a potential mediator in OSA-related lipoprotein disorders and further increase CVD risk.

The use of visceral adiposity variables in the prediction of obstructive sleep apnea: evidence from a large cross-sectional study.

PURPOSE: The purposes of this study were to evaluate the ability of visceral adiposity variables [the lipid accumulation product (LAP), the visceral adiposity index (VAI), and the triglyceride-glucose index (TyG)] in predicting obstructive sleep apnea hypopnea syndrome (OSAHS) and to determine the effect of sex on the prediction. METHODS: A total of 5539 subjects admitted to the sleep center for suspected OSAHS were consecutively recruited from 2007 to 2016. Anthropometric measurements, biological indicators, Epworth sleepiness scale score, and polysomnographic variables were collected. Prediction models for diagnosing OSAHS were established in the test group by logistic regression and verified in the validation group by receiver operating characteristic (ROC) curves. RESULTS: A total of 4703 patients were included in total. LAP and TyG were of moderate diagnostic accuracy for OSAHS, with the diagnostic efficiency differing between men and women. A prediction model was developed that combined visceral adiposity indicators with waist circumstance and the lowest SpO2. The sensitivity of those indicators were both 84% in men and women, respectively, and their specificity were both 90%. In addition, the model was confirmed in the validation group with a sensitivity and specificity of 83% and 85% in men and 85% and 84% in women. CONCLUSIONS: LAP and TyG were of moderate efficiency in screening for OSAHS. The prediction model provides a simple and practical screening tool for OSAHS.

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.