Harnessing Nanomedicine for Cartilage Repair: Design Considerations and Recent Advances in Biomaterials.

Cartilage injuries are escalating worldwide, particularly in aging society. Given its limited self-healing ability, the repair and regeneration of damaged articular cartilage remain formidable challenges. To address this issue, nanomaterials are leveraged to achieve desirable repair outcomes by enhancing mechanical properties, optimizing drug loading and bioavailability, enabling site-specific and targeted delivery, and orchestrating cell activities at the nanoscale. This review presents a comprehensive survey of recent research in nanomedicine for cartilage repair, with a primary focus on biomaterial design considerations and recent advances. The review commences with an introductory overview of the intricate cartilage microenvironment and further delves into key biomaterial design parameters crucial for treating cartilage damage, including microstructure, surface charge, and active targeting. The focal point of this review lies in recent advances in nano drug delivery systems and nanotechnology-enabled 3D matrices for cartilage repair. We discuss the compositions and properties of these nanomaterials and elucidate how these materials impact the regeneration of damaged cartilage. This review underscores the pivotal role of nanotechnology in improving the efficacy of biomaterials utilized for the treatment of cartilage damage.

Rejuvenating Hyaline Cartilaginous Phenotype of Dedifferentiated Chondrocytes in Collagen II Scaffolds: A Mechanism Study Using Chondrocyte Membrane Nanoaggregates as Antagonists.

Joint cartilage lesions affect the global population in the current aging society. Maintenance and rejuvenation of articular cartilage with hyaline phenotype remains a challenge as the underlying mechanism has not been completely understood. Here, we have designed and performed a mechanism study using scaffolds made of type II collagen (Col2) as the 3D cell cultural platforms, on some of which nanoaggregates comprising extracts of chondrocyte membrane (CCM) were coated as the antagonist of Col2. Dedifferentiated chondrocytes were, respectively, seeded into these Col2 based scaffolds with (antCol2S) or without (Col2S) CCM coating. After 6 weeks, in Col2S, the chondrocytes were rejuvenated to regain hyaline phenotype, whereas this redifferentiation effect was attenuated in antCol2S. Transcriptomic and proteomic profiling indicated that the Wnt/ß-catenin signaling pathway, which is an opponent to maintenance of the hyaline cartilaginous phenotype, was inhibited in Col2S, but it was contrarily upregulated in antCol2S due to the antagonism and shielding against Col2 by the CCM coating. Specifically, in antCol2S, since the coated CCM nanoaggregates contain the same components as those present on the surface of the seeded chondrocytes, the corresponding ligand sites on Col2 had been preoccupied and saturated by CCM coating before exposure to the seeded cells. The results indicated that the ligation between Col2 ligands and integrin α5 receptors on the surface of the seeded chondrocytes in antCol2S was antagonized by the CCM coating, which facilitates the Wnt/ß-catenin signaling toward the loss of hyaline cartilaginous phenotype. This finding reveals the contribution of Col2 for maintenance and rejuvenation of the hyaline cartilaginous phenotype in chondrocytes.

Cartilage Tissue Engineering in Practice: Preclinical Trials, Clinical Applications, and Prospects.

Articular cartilage defects significantly compromise the quality of life in the global population. Although many strategies are needed to repair articular cartilage, including microfracture, autologous osteochondral transplantation, and osteochondral allograft, the therapeutic effects remain suboptimal. In recent years, with the development of cartilage tissue engineering, scientists have continuously improved the formulations of therapeutic cells, biomaterial-based scaffolds, and biological factors, which have opened new avenues for better therapeutics of cartilage lesions. This review focuses on advances in cartilage tissue engineering, particularly in preclinical trials and clinical applications, prospects, and challenges.

Development of artificial bone graft via in vitro endochondral ossification (ECO) strategy for bone repair.

Endochondral ossification (ECO) is a form of bone formation whereby the newly deposited bone replaces the cartilage template. A decellularized artificial cartilage graft (dLhCG), which is composed of hyaline cartilage matrixes, has been developed in our previous study. Herein, the osteogenesis of bone marrow-derived MSCs in the dLhCG through chondrogenic differentiation, chondrocyte hypertrophy, and subsequent transdifferentiation induction has been investigated by simulating the physiological processes of ECO for repairing critical-sized bone defects. The MSCs were recellularized into dLhCGs and subsequently allowed to undergo a 14-day proliferation period (mrLhCG). Following this, the mrLhCG constructs were subjected to two distinct differentiation induction protocols to achieve osteogenic differentiation: chondrogenic medium followed by chondrocytes culture medium with a high concentration of fetal bovine serum (CGCC group) and canonical osteogenesis inducing medium (OI group). The formation of a newly developed artificial bone graft, ossified dLhCG (OsLhCG), as well as its capability of aiding bone defect reconstruction were characterized by in vitro and in vivo trials, such as mRNA sequencing, quantitative real-time PCR (qPCR), immunohistochemistry, the greater omentum implantation in nude mice, and repair for the critical-sized femoral defects in rats. The results reveal that the differentiation induction of MSCs in the CGCC group can realize in vitro ECO through chondrogenic differentiation, hypertrophy, and transdifferentiation, while the MSCs in the OI group, as expected, realize ossification through direct osteogenic differentiation. The angiogenesis and osteogenesis of OsLhCG were proved by being implanted into the greater omentum of nude mice. Besides, the OsLhCG exhibits the capability to achieve the repair of critical-size femoral defects.

Effect of Combining Sound Therapy with Pharmacotherapy on the Recovery of Hearing Abilities in the Case of Sudden Sensorineural Hearing Loss: A Prospective Study.

INTRODUCTION: This study investigated the effect of sound therapy combined with drug therapy (SDT) on gap detection threshold and speech recognition scores in patients with sudden sensorineural hearing loss (SSNHL). METHODS: Patients with SSNHL were grouped randomly into SDT and drug therapy (DT) groups. All patients received standard drug treatment and patients in the SDT group additionally received sound stimulation for the affected ears for 6 days. Pure tone audiogram, speech recognition scores at normal and time-compressed rates under quiet and noisy conditions, and the gap detection threshold of the SDT and DT groups before treatment and on day 6 and 30 after treatment were compared. RESULTS: There were 20 patients in the SDT group and 24 in the DT group. The pure tone thresholds of affected ears were significantly lower in the SDT group on day 6 after treatment than those in the DT group at 125 and 250 Hz. Significantly lower gap detection thresholds and higher speech recognition scores under noisy conditions were observed at the normal and time-compressed rates in the SDT group than those in the DT group on day 6 and 30 after treatment. Significant correlations were observed between the gap thresholds and speech recognition scores in a noisy environment at normal and time-compressed rates on day 6 and 30. CONCLUSIONS: SDT may improve the recovery of hearing abilities, such as the gap in noise thresholds and speech recognition in noise, in the case of SSNHL. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17012262.

Bletilla striata polysaccharide cryogel scaffold for spatial control of foreign-body reaction.

BACKGROUND: Implantation of a biomaterial may induce the foreign-body reaction to the host tissue that determines the outcome of the integration and the biological performance of the implants. The foreign-body reaction can be modulated by control of the material properties of the implants. METHODS: First, we synthesized methacrylated Bletilla striata Polysaccharide (BSP-MA) and constructed a series of open porous cryogels utilizing this material via the freezing-thawing treatment of solvent-precursors systems. Second, Pore size and modulus were measured to characterize the properties of BSP cryogels. Live/dead staining of cells and CCK-8 were performed to test the cytocompatibility of the scaffolds. In addition, the Real-Time qPCR experiments were carried for the tests. Finally, the BSP scaffolds were implanted subcutaneously to verify the foreign-body reaction between host tissue and materials. RESULTS: Our data demonstrated that cryogels with different pore sizes and modulus can be fabricated by just adjusting the concentration. Besides, the cryogels showed well cytocompatibility in the in vitro experiments and exhibited upregulated expression levels of pro-inflammation-related genes (Tnfa and Il1b) with the increase of pore size. In vivo experiments further proved that with the increase of pore size, more immune cells infiltrated into the inner zone of materials. The foreign-body reaction and the distribution of immune-regulatory cells could be modulated by tuning the material microstructure. CONCLUSIONS: Collectively, our findings revealed Bletilla striata polysaccharide cryogel scaffold with different pore sizes can spatially control foreign-body reaction. The microstructure of cryogels could differentially guide the distribution of inflammatory cells, affect the formation of blood vessels and fibrous capsules, which eventually influence the material-tissue integration. This work demonstrates a practical strategy to regulate foreign body reaction and promote the performance of medical devices.

A phase-transfer catalyst-based nanoreactor for accelerated hydrogen sulfide bio-imaging.

Hydrogen sulfide (H2S) is an important signaling molecule in various biological processes; however, its real-time monitoring in living cells is hampered by long detection time for current fluorescent probes. To overcome this challenge, we designed a phase-transfer catalyst (PTC) approach to accelerate the reaction between the probe and the analyte by conjugating common fluorescent probes - mostly hydrophobic small molecules - with an amphiphilic PEG-PPG-PEG polymer, enabling the controllable assembly of H2S nanoprobes in an aqueous solution. The PEG block helps to establish a PTC microenvironment that endows the assembled nanoprobes with a significantly reduced detection time (3-10 min; versus 20-60 min for small-molecule probes). Based on this approach, we synthesised two nanoprobes of different wavelengths, DS-Blue-nano and DN-Green-nano, which can sensitively detect H2S in living macrophage cells with bright fluorescence starting at as early as 7 min and reaching stability at 15 min. These data suggest PTC-based nanoprobes as a new and generic approach for constructing sensitive fluorescent probes for the real-time imaging of H2S, and perhaps other molecules in future, under biological conditions.

Biomaterial-based physical regulation of macrophage behaviour.

Macrophages play a critical role in regulating immune reactions induced by implanted biomaterials. They are highly plastic and in response to diverse stimuli in the microenvironment can exhibit a spectrum of phenotypes and functions. In addition to biochemical signals, the physical properties of biomaterials are becoming increasingly appreciated for their significant impact on macrophage behaviour, and the underlying mechanisms deserve more in-depth investigations. This review first summarises the effects of key physical cues - including stiffness, topography, physical confinement and applied force - on macrophage behaviour. Then, it reviews the current knowledge of cellular sensing and transduction of physical cues into intracellular signals. Finally, it discusses the major challenges in understanding mechanical regulation that could provide insights for biomaterial design.

Switching Tinnitus-On: Maps and source localization of spontaneous EEG.

OBJECTIVE: To identify the spectrotemporal changes and sources in patients that could "turn on" tinnitus with multichannel electroencephalography (EEG) system. METHODS: Multichannel EEG was recorded from six patients during the Tinnitus-On and Tinnitus-Off states. The EEG power spectrum and eLORETA-based sources were measured. RESULTS: There was a global increase in delta and theta during Tinnitus-On plus large changes in alpha 1 and alpha 2. During the Tinnitus-On state, many new sources in delta, theta, alpha 1 and gamma bands emerged in the opposite hemisphere in the inferior temporal gyrus (Brodmann area, BA 20), middle temporal gyrus (BA 21), lateral perirhinal cortex (BA 36), ventral entorhinal cortex (BA 28) and anterior pole of the temporal gyrus (BA 38). CONCLUSIONS: The emergence of new delta, theta and gamma band sources in the inferior temporal gyrus (BA 20), middle temporal gyrus (BA 21) and lateral perirhinal cortex (BA 36) plus the appearance of new delta and theta sources in the ventral entorhinal cortex (BA28) and anterior pole of the temporal lobe (BA 38) may comprise a network capable of evoking the phantom sound of tinnitus by simultaneously engaging brain regions involved in memory, sound recognition, and distress which together contribute to tinnitus severity. SIGNIFICANCE: The sudden appearance of new sources of activity in the opposite hemisphere within the inferior temporal gyrus, middle temporal gyrus and perirhinal cortex may initiate the perception of tinnitus perception.

Enhanced Near-Infrared Emission from Carbon Dots by Surface Deprotonation.

Carbon dots (CDs) with efficient excitation and emission in deep-red/near-infrared (NIR) spectral range are important for bioimaging applications. Herein, we develop a simple and effective method to significantly enhance both the absorption and emission of CDs in deep-red/NIR by suppressing nonradiative charge recombination via deprotonation of the CD surface. As compared to aqueous solutions at room temperature, NIR emission of CDs in N,N-dimethylformamide and glycerol experience a 50- and 70-fold increase at -20 °C, respectively, due to enhanced deprotonation ability and viscosity. On the basis of the adjustable NIR fluorescence intensity of CDs, multilevel data encryption in the NIR region is realized by controlling the humidity and the temperature of a CD-ink stamped paper.

Coagulation States in Patients With Sudden Sensorineural Hearing Loss Evaluated by Thromboelastography.

OBJECTIVE: The state of coagulation is controversial in patients with sudden sensorineural hearing loss (SSNHL). We used thromboelastography (TEG) to explore the relationships between blood coagulation parameters and SSNHL pathogenesis and recovery. STUDY DESIGN: Prospective study. SETTING: Affiliated Sixth People's Hospital, Shanghai Jiao Tong University. METHODS: A total of 104 newly diagnosed patients with SSNHL and 29 matched healthy controls were recruited. Hearing assessments, TEG, and conventional coagulation tests (CCTs) were performed, followed by standard treatments and follow-up. RESULTS: The TEG parameters of patients with SSNHL were in the normal range, but the group exhibited a significantly prolonged kinetic time (K; P = .004) and a smaller angle (P = .003) as compared with the controls. After grouping the patients with SSNHL according to audiograms and comparing them in pairs, we found that the differences were significant only when controls were compared with patients with low-frequency SSNHL (K, P = .023; angle, P = .04) and flat-type SSNHL (K, P = .017; angle, P = .014). Logistic regression analysis showed that neither TEG nor CCT parameters significantly affected hearing improvement after SSNHL treatment. CONCLUSIONS: Although the K value and angle were significantly increased and significantly reduced, respectively, in the test group as compared with the control group, the state of coagulation in patients with SSNHL was still within the normal range. No CCT or TEG coagulation parameters (except the angle) differed significantly among patients in each group according to hearing recovery status, which suggested that the coagulation status does not determine the prognosis of patients with SSNHL.

Glucocorticoid and Breviscapine Combination Therapy Versus Glucocorticoid Alone on Sudden Sensorineural Hearing Loss in Patients with Different Audiometric Curves.

INTRODUCTION: We aimed to retrospectively analyze the therapeutic outcomes of using glucocorticoid combined with a vasodilator, breviscapine, versus glucocorticoid alone in patients with sudden sensorineural hearing loss (SSNHL) and to explore the impact on different audiometric curves. METHODS: Data from 154 patients were collected between January 2017 and December 2018. Patients received treatments of either glucocorticoid combined with breviscapine (GC + Bre) or glucocorticoid alone (GC). These two groups were stratified into low frequencies SSNHL (LF-SSNHL), high frequencies SSNHL (HF-SSNHL), all frequencies SSNHL (AF-SSNHL), and total deafness SSNHL (TD-SSNHL) subgroups according to their corresponding audiograms. The hearing level was evaluated by pure tone audiometry, and hearing recovery was calculated by comparing the pure tone average (PTA) at pretreatment and 4 weeks after therapy. RESULTS: Hearing recovery was significantly greater for GC + Bre than GC-only treatment in the AF-SSNHL and TD-SSNHL subgroups (P < 0.05) and to a lesser extent in the LF-SSNHL and HF-SSNHL subgroups (P > 0.05). Logistic regression analysis also showed a favorable outcome for SSNHL in the GC + Bre group (odds ratio 2.848, P < 0.05). CONCLUSION: Treating SSNHL using glucocorticoid combined with breviscapine could be more beneficial than using glucocorticoid alone, especially for patients with AF-SSNHL and TD-SSNHL. TRIAL REGISTRATION NUMBER: ChiCTR18000170072.

A New Proposal for Severity Evaluation of Menière's Disease by Using the Evidence From a Comprehensive Battery of Auditory and Vestibular Tests.

To date, no widely accepted criteria exist to quantify the severity of Menière's disease (MD) by using vestibular tests. This study aimed to compare association of hearing loss and vertigo severity with association of accurate assessments of vestibular function and the vertigo severity. The severity of vertigo was documented by a comprehensive medical history with number of vertigo attacks in the past 6 months and a Dizziness Handicap Inventory (DHI) questionnaire. The involvement of vestibular organs was verified by audio-vestibular tests in 80 definite MD patients. Correlations between DHI scores, number of vertigo attacks in the past 6 months, audio-vestibular function, and the number of involved vestibular end organs were evaluated. We show that there are no significant differences in either severity of vertigo or laboratory results across the degree of hearing loss. Furthermore, the number of involved vestibular end organs was significantly correlated with vestibulo-ocular reflex gain in anterior and posterior canal video head impulse test (vHIT), interaural asymmetry ratio in vestibular-evoked myogenic potentials (VEMPs), and number of vertigo attacks in the past 6 months and DHI score. The vestibulo-ocular reflex gain in the rotatory chair test (RCT) was significantly correlated with the DHI Physical scores and number of involved vestibular end organs at 0.08 Hz. These results indicate that hearing loss is a poor indicator of vertigo severity in MD whereas the number of involved vestibular end organs may serve as an objective measure for MD progress. A battery of vestibular tests targeting different sensor organs is a complementary method for evaluating inner ear deficits and may aid in "grading" the severity of MD.

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.

Cytochrome P450 1A2 Is Incapable of Oxidizing Bilirubin Under Physiological Conditions.

Background: Bilirubin (BR) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) through glucuronidation in the liver. Some studies have shown that several subtypes of cytochrome P450 (CYP) enzymes, including CYP1A2, are upregulated by inducers and proposed to be alternative BR degradation enzymes. However, no information is available on the BR degradation ability of CYP in normal rats without manipulation by CYP inducers. Methods: Quantitative real-time polymerase chain reaction (QRT-PCR), western blot, immunofluorescence, and confocal microscopy were used to find expression of CYP1A2 in the brain and the liver. BR metabolites in microsomal fractions during development were examined by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (LC-MS/MS). Results: In the present study, we observed that CYP1A2 mRNA levels increased at postnatal days (P)14 and P30 with respect to the level at P7 both in liver and brain, this increment was especially pronounced in the brain at P14. The expression of CYP1A2 in the brainstem (BS) was higher than that in the cerebellum (CLL) and cortex (COR). Meanwhile, the CYP1A2 protein level was significantly higher in the COR than in the brainstem and CLL at P14. The levels of BR and its metabolites (m/z values 301, 315, 333 and biliverdin) were statistically unaltered by incubation with liver and brain microsomal fractions. Conclusion: Our results indicated that the region-specific expression of CYP1A2 increased during development, but CYP family enzymes were physiologically incapable of metabolizing BR. The ability of CYPs to oxidize BR may be triggered by CYP inducers.

Neuroimaging consequences of cerebral small vessel disease in patients with obstructive sleep apnea-hypopnea syndrome.

OBJECTIVE: This study aimed to investigate the association between severity of obstructive sleep apnea-hypopnea syndrome (OSAHS) and the neuroimaging consequences of cerebral small vessel disease (SVD). METHODS: Patients with OSAHS and age- and gender-matched healthy control subjects completed the mini-mental state examination and underwent an evoked-related potential study and overnight polysomnographic monitoring. Magnetic resonance imaging (MRI) was performed to detect markers of silent cerebral SVD, including Virchow-Robin spaces (VRS) rated on a five-point scale, white matter lesions, lacunar infarcts, and deep microbleeds. Multinomial logistic regression models were used to examine the associations of the apnea-hypopnea index (AHI) and arousal index (AI) values, mean oxyhemoglobin saturation, the duration of snoring history, and MRI markers of small vessel disease with the incidence of enlarged VRS. RESULTS: The study included 72 patients with severe OSAHS and 53 volunteers without OSAHS. The duration of snoring history ranged from 5 to 22 years in the OSAHS group. Smaller P3 amplitudes at Cz were found in OSAHS patients than control subjects (p < .05), which is associated with neurocognitive impairment. Enlarged VRS were more prevalent in the basal ganglia and centrum semiovale of patients with OSAHS than in the control group. No significant between-group differences were observed in the number of white matter lesions, lacunar infarcts, and deep microbleeds. Enlarged VRS were positively correlated with AHI and AI values in the OSAHS group (r = .63, p < .001; r = .55, p < .001, respectively). CONCLUSIONS: Silent cerebral SVD was more prevalent in patients with OSAHS than in the controls. Enlarged VRS observed in the basal ganglia and centrum semiovale were positively correlated with severity of OSAHS, which may contribute to cognitive impairment.

Excessive daytime sleepiness and metabolic syndrome in men with obstructive sleep apnea: a large cross-sectional study.

PURPOSE: Excessive daytime sleepiness is a common symptom in obstructive sleep apnea (OSA). Previous studies have showed that excessive daytime sleepiness is associated with some individual components of metabolic syndrome. We performed a large cross-sectional study to explore the relationship between excessive daytime sleepiness and metabolic syndrome in male OSA patients. METHODS: A total of 2241 suspected male OSA patients were consecutively recruited from 2007 to 2013. Subjective daytime sleepiness was assessed using the Epworth sleepiness scale. Anthropometric, metabolic, and polysomnographic parameters were measured. Metabolic score was used to evaluate the severity of metabolic syndrome. RESULTS: Among the male OSA patients, most metabolic parameters varied by excessive daytime sleepiness. In the severe group, male OSA patients with excessive daytime sleepiness were more obese, with higher blood pressure, more severe insulin resistance and dyslipidemia than non-sleepy patients. Patients with metabolic syndrome also had a higher prevalence of excessive daytime sleepiness and scored higher on the Epworth sleepiness scale. Excessive daytime sleepiness was independently associated with an increased risk of metabolic syndrome (odds ratio =1.242, 95% confidence interval: 1.019-1.512). No substantial interaction was observed between excessive daytime sleepiness and OSA/ obesity. CONCLUSIONS: Excessive daytime sleepiness was related to metabolic disorders and independently associated with an increased risk of metabolic syndrome in men with OSA. Excessive daytime sleepiness should be taken into consideration for OSA patients, as it may be a simple and useful clinical indicator for evaluating the risk of metabolic syndrome.

Prevalence and Predictors of Atherogenic Serum Lipoprotein Dyslipidemia in Women with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is associated with dyslipidemia. However, no study has focused on dyslipidemia in women with OSA. The aim of this study was to determine the prevalence and risk factors for dyslipidemia in women with OSA. Between 2007 and 2013, 570 eligible female patients with suspected OSA were consecutively recruited. The analyzed data consisted of polysomnography parameters, biochemical indicators, and anthropometric measurements. Serum lipid levels and dyslipidemia were compared. Binary logistic regression and multivariate linear regression models were used to determine the independent risk factors influencing serum lipids. After multivariate adjustment, there were essentially no major differences in serum lipid levels among patients with no to mild, moderate, and severe OSA nor did serum lipid levels change with OSA severity. Dyslipidemia in total cholesterol, triglycerides, low-density lipoprotein cholesterol, apolipoproteins(apo) B and apoE increased with OSA severity, but only in non-obese subjects and those <55 years of age. Age, body mass index, waist to hip ratio, glucose and insulin were major risk factors for most serum lipids after multivariate adjustments. Our results indicate that, in women with OSA, age, obesity/central obesity, and insulin resistance are major determinants of dyslipidemia.

The effect of bilirubin on the excitability of mitral cells in the olfactory bulb of the rat.

Olfactory dysfunction is a common clinical phenomenon observed in various liver diseases. Previous studies have shown a correlation between smell disorders and bilirubin levels in patients with hepatic diseases. Bilirubin is a well-known neurotoxin; however, its effect on neurons in the main olfactory bulb (MOB), the first relay in the olfactory system, has not been examined. We investigated the effect of bilirubin (>3 µM) on mitral cells (MCs), the principal output neurons of the MOB. Bilirubin increased the frequency of spontaneous firing and the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). TTX completely blocked sEPSCs in almost all of the cells tested. Bilirubin activity was partially blocked by N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid (AMPA) receptor antagonists. Furthermore, we found that bilirubin increased the frequency of intrinsic firing independent of synaptic transmission in MCs. Our findings suggest that bilirubin enhances glutamatergic transmission and strengthens intrinsic firing independent of synaptic transmission, all of which cause hyperexcitability in MCs. Our findings provide the basis for further investigation into the mechanisms underlying olfactory dysfunction that are often observed in patients with severe liver disease.

Independent Association between Sleep Fragmentation and Dyslipidemia in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is independently associated with dyslipidemia. Previous studies have demonstrated that sleep fragmentation can impair lipid metabolism. The present study aimed to identify whether sleep fragmentation is independently associated with dyslipidemia, in a large-scale, clinic-based consecutive OSA sample. This cross-sectional study was conducted among 2,686 patients who underwent polysomnography (PSG) for suspicion of OSA from January 2008 to January 2013 at the sleep laboratory. Multivariate regression analyses were performed to evaluate the independent associations between the microarousal index (MAI) and lipid profiles adjusting for potential confounders, including metabolic syndrome components and nocturnal intermittent hypoxia. The adjusted odds ratios (ORs) for various types of dyslipidemia according to MAI quartiles, as determined by logistic regression were also evaluated. MAI was found positively associated with low-density lipoprotein cholesterol (LDL-c) but not with total cholesterol (TC), triglyceride (TG) or high-density lipoprotein cholesterol (HDL-c). Furthermore, the adjusted ORs (95% confidence interval) for hyper-LDL cholesterolemia increased across MAI quartiles, as follows: 1 (reference), 1.3 (1.1-1.7), 1.6 (1.2-2.0), and 1.6 (1.2-2.1) (p = 0.001, linear trend). Sleep fragmentation in OSA is independently associated with hyper-LDL cholesterolemia, which may predispose patients with OSA to a higher risk of cardiovascular disease.