Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1.

The Mre11/Rad50/NBS1 (MRN) complex is thought to be a critical sensor that detects damaged DNA and recruits ATM to DNA foci for activation. However, it remains to be established how the MRN complex regulates ATM recruitment to the DNA foci during DNA double-strand breaks (DSBs). Here we show that Skp2 E3 ligase is a key component for the MRN complex-mediated ATM activation in response to DSBs. Skp2 interacts with NBS1 and triggers K63-linked ubiquitination of NBS1 upon DSBs, which is critical for the interaction of NBS1 with ATM, thereby facilitating ATM recruitment to the DNA foci for activation. Finally, we show that Skp2 deficiency exhibits a defect in homologous recombination (HR) repair, thereby increasing IR sensitivity. Our results provide molecular insights into how Skp2 and the MRN complex coordinate to activate ATM, and identify Skp2-mediatetd NBS1 ubiquitination as a vital event for ATM activation in response to DNA damage.

A review of EPAP nasal device therapy for obstructive sleep apnea syndrome.

BACKGROUND: Expiratory positive airway pressure (EPAP) nasal devices provide a new therapeutic option for obstructive sleep apnea (OSA). METHODS: Here, we review the literature about treatment of OSA with EPAP, which has been shown to reduce the apnea/hypopnea index (AHI) and daytime sleepiness. RESULTS: Patients generally prefer EPAP to continuous positive airway pressure (CPAP), and there are no serious adverse effects from its use. Although CPAP more effectively improves sleep apnea, a recent study showed similar outcomes in symptom improvement using EPAP. Patients with mild to moderate OSA who do not tolerate CPAP are appropriate candidates for EPAP. However, there are few well-designed clinical trials that evaluate efficacy. CONCLUSIONS: More studies are needed to assess the efficacy of and compliance with EPAP nasal devices, to define which patients will benefit from EPAP therapy, and to compare EPAP to other alternative OSA therapies.

Adequate continuous positive airway pressure therapy reduces mortality in Chinese patients with obstructive sleep apnea.

BACKGROUND: Severe obstructive sleep apnea (OSA) is a risk factor for mortality. The ability of continuous positive airway pressure (CPAP) therapy to mitigate this increased risk of death has not been studied in Chinese adults. The objective of our study was to compare mortality in Chinese patients with simple snoring, untreated OSA, and OSA treated with CPAP. METHODS: We recruited adults with OSA or simple snoring from our sleep medicine clinic. OSA was diagnosed using standard polysomnography. Subjects were followed at least annually for a mean of 8.9 years (SD 1.9). CPAP compliance was checked with the built-in meter. We then assessed all-cause mortality. RESULTS: Five hundred fifty simple snorers, 257 with untreated mild OSA, 316 with untreated moderate OSA, 457 with untreated severe OSA, and 235 with mild to severe OSA treated with CPAP were included. Simple snorers had a much lower mortality rate (2.98 per 1000 person-years [95% CI, 2.93 to 3.02]) than the untreated severe OSA group (11.07 per 1000 person-years [95%CI, 10.86 to 11.29]; P < 0.0001). Compared with simple snorers, fully adjusted mortality was highest in the untreated, severe OSA group (hazard ratio [HR], 3.51 [95%CI, 1.93 to 6.39]). Treatment of severe OSA patients with CPAP eliminated this increase in mortality (HR, 0.81[95%CI, 0.36-1.86]). CONCLUSIONS: Severe OSA significantly markedly increases the risk of death in Chinese patients and CPAP treatment with adequate compliance reduces this risk.

Sleep-Disordered Breathing Is Associated With Impaired Odor Identification in Older U.S. Adults.

BACKGROUND: Sleep-disordered breathing (SDB) is a common, underdiagnosed condition in older adults with major health consequences, including disrupted central nervous system functioning. Whether SDB may affect sensory function is unclear. We sought to address this question by comparing 2 forms of olfactory testing which measure peripheral and central olfactory processing. METHODS: We assessed SDB (survey-reported snoring frequency, nighttime apneic events, or diagnosis of sleep apnea) in the National Social Life, Health, and Aging Project, a nationally representative sample of older U.S. adults. Odor sensitivity (peripheral) and odor identification (central) were assessed with validated instruments. Logistic regression was used to test the relationship between SDB and olfaction, accounting for relevant covariates, including demographics, cognition, and comorbidity. RESULTS: Twenty-nine percent of older U.S. adults reported symptoms of SDB (apneic events or nightly snoring). Of these, only 32% had been diagnosed with sleep apnea. Older adults with SDB (those who reported symptoms or have been diagnosed with sleep apnea) were significantly more likely to have impaired odor identification (odds ratio 2.13, 95% confidence interval 1.19-3.83, p = .012) in analyses that accounted for age, gender, race/ethnicity, education, cognition, comorbidities (including depression), and body mass index. Presence of SDB was not associated with impaired odor sensitivity (odds ratio 1.03, 95% confidence interval 0.75-1.43, p = .84). CONCLUSION: SDB is highly prevalent but underdiagnosed in older U.S. adults and is associated with impaired odor identification but not odor sensitivity. These data support the concept that SDB affects pathways in the central nervous system which involve chemosensory processing.

Rare Mutations in AHDC1 in Patients with Obstructive Sleep Apnea.

OBJECTIVES: Obstructive sleep apnea (OSA) is a common disorder influenced by genetic and environmental factors. Mutations of AT-hook DNA-binding motif containing 1 (AHDC1) gene have been implicated which could cause rare syndromes presenting OSA. This study aims to investigate some rare mutations of AHDC1 in Chinese Han individuals with OSA. PATIENTS AND METHODS: Three hundred and seventy-five patients with OSA and one hundred and nine control individuals underwent polysomnography. A targeted sequencing experiment was taken in 100 patients with moderate-to-severe OSA, and genotyping was taken in 157 moderate-to-severe OSA and 100 control individuals. The effect of mutations was validated by the luciferase reporter assay. RESULTS: One rare missense mutation (AHDC1: p.G1484D) and two mutations (c.-88C>T; c.-781C>G) in 5'-untranslated region (UTR) of AHDC1 were identified. The rare mutation (c.-781C>G) in 5'-UTR that was identified in several patients presenting more severe clinical manifestations affects expression of AHDC1. Conclusions. Our results revealed three rare mutations of AHDC1 in patients with OSA in Chinese Hanindividuals.

Olfactory cortex and Olfactory bulb volume alterations in patients with post-infectious Olfactory loss.

Upper respiratory tract infection (URI) is one of the most common etiology of olfactory loss. Previous studies demonstrated that both olfactory bulb (OB) volume and sulcus (OS) depth decreased in patients with post-infectious olfactory loss (PIOL) compared to normal controls. The aim of our study was to observe alterations of central olfactory pathways in patients with PIOL. T1 weighted magnetic resonance images were acquired in 19 PIOL patients and 19 age- and sex-matched control subjects on a 3 T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. We also analyzed OB volume in coronal T2-weighted images. Whole-brain analysis revealed a significant gray matter volume loss in the right orbitofrontal cortex (OFC) in patients group. Further analysis with region of interest exhibited a significant negative correlation between gray matter volume in right OFC as well as OB volume and the duration of olfactory loss in these patients (r = -0.566 and r = -0.535 both P < 0.05, respectively). In conclusion, the morphological alterations in the right OFC and OB might contribute to the pathogenic mechanism of olfactory dysfunction after upper respiratory tract infection.

The Relationship Between Obstructive Sleep Apnea Hypopnea Syndrome and Inflammatory Markers and Quality of Life in Subjects With Acute Coronary Syndrome.

BACKGROUND: The objective of this work was to examine the relationship between obstructive sleep apnea (OSA) and inflammatory markers and quality of life in patients with acute coronary syndrome, especially undergoing percutaneous coronary intervention. METHODS: One hundred eighteen subjects were admitted with acute coronary syndrome over 1 y who had symptoms of OSA and positive polysomnography on admission. Of these subjects, 53 underwent primary percutaneous coronary intervention during their admission, and 65 had medical management. We then compared inflammatory markers by OSA status. We also assessed cardiac symptoms using the Seattle Angina Questionnaire and sleep symptoms using the Epworth Sleepiness Scale. RESULTS: Subjects in the percutaneous coronary intervention group had a higher oxygen desaturation index (ODI) (P = .02) and apnea-hypopnea index (AHI) (P = .048) compared with those in the medical management group. In percutaneous coronary intervention subjects, the moderate-severe OSA group (AHI ≥ 15/h) had a higher hematocrit (P = .047), homocysteine (P = .01), and high-sensitivity C-reactive protein (P = .045) compared with those with no or mild OSA (AHI < 15/h). There was a significant correlation between high-sensitivity C-reactive protein and both AHI (r = 0.46, P = .001) and ODI (r = 0.47, P < .001). Those with moderate-severe OSA had higher Epworth Sleepiness Scale (P = .002), greater physical limitation (P = .01), and lower treatment satisfaction and disease perception (P = .007), as judged by subscales of the Seattle Angina Questionnaire, compared with those with no or mild OSA. Finally, subjects undergoing percutaneous coronary intervention with lower AHI (r = 0.48, P < .001) and ODI (r = 0.49, P < .001) reported higher treatment satisfaction. CONCLUSIONS: Subjects with acute coronary syndrome undergoing percutaneous coronary intervention who had moderate-severe OSA showed higher levels of inflammatory mediators and lower treatment satisfaction and disease perception. These factors may increase the risk of adverse sequelae by increasing the systemic inflammatory response.

Predictors of facial palsy after surgery for benign parotid disease: multivariate analysis of 626 operations.

BACKGROUND: The objective was to identify the risk factors for, and incidence of, facial palsy following conservative parotidectomy. METHODS: Conservative parotidectomies for benign diseases (N = 626) were studied retrospectively. The risk factors for postoperative facial palsy were determined by univariate and multivariate analyses of variables related to patient demographics, comorbid illnesses, and characteristics of the operation. RESULTS: The rate of transient facial palsies was 23.16% following parotidectomy. Significant risk factors for transient facial palsy were diabetic mellitus (odds ratio [OR] 1.727 [95% CI: 1.062-2.810]) and extended surgery (OR 3.049 [95% CI: 2.058-4.515]). Only the type of surgery was found to have a statistically significant causal relation with permanent facial palsy (p = .017). CONCLUSIONS: Comorbid diabetes, and more extensive as opposed to partial superficial parotidectomy, may be associated with transient facial palsy following operation for benign parotid disease. The incidence of permanent facial palsy may be higher when a more extensive parotidectomy is performed.

[In vitro study of directional inducible differentiation of inner ear hair cells from human adipose-derived mesenchymal stem cells].

OBJECTIVE: To explore the feasibility of directionally inducing human adipose-derived mesenchymal stem cells (hAD-MSCs) towards inner ear hair cells. METHODS: Mesenchymal stem cells from human adipose tissue were isolated, purified and cultured in vitro. hAD-MSCs were induced to neural stem/progenitor-like cell, and then co-cultured with embryonic chick otic vesicle cells. Processed hAD-MSCs were tested by immunostaining to ascertain whether they expressed characteristic hair cell markers. RESULTS: Morphologically, hAD-MSCs were induced to differentiate into neural stem/progenitor cells and expressed specific neural markers. After being co-cultured with embryonic chick otic vesicle cells, hAD-MSCs expressed specific surface markers of inner ear hair cells. CONCLUSIONS: hAD-MSCs can be directionally induced to differentiate towards hair cell-like cells in vitro.

[Quality of life survey on patients with chronic rhinosinusitis by using Chinese version of the 22-item sinonasal outcome test (SNOT-22)].

OBJECTIVE: To explore the health-related quality of life (QOL) status of patients with chronic rhinosinusitis. METHODS: Sixty four patients with chronic rhinosinusitis and twenty healthy volunteers were enrolled, and their QOL scores were assessed by using SF-36 questionnaire (Chinese version) and SNOT-22 questionnaire translated into Chinese. RESULTS: The feasibility, reliability, validity, and responsibility of Chinese version of SNOT-22 questionnaire all passed the test. It showed that by Chinese version of SNOT-22 questionnaire the most five important items affecting health status were nasal obstruction, runny nose, loss of smell or taste, dizziness and post-nasal discharge respectively. The coefficient of correlation was 0. 233 between the SNOT-22 questionnaire and the Lund-MacKay CT score of patients with chronic rhinosinusitis. CONCLUSIONS: Chinese version of SNOT-22 questionnaire can effectively assess the QOL status of patients with chronic rhinosinusitis. It showed less correlation between the SNOT-22 questionnaire and the Lund-MacKay CT score of patients with chronic rhinosinusitis.