Aspartoacylase suppresses prostate cancer progression by blocking LYN activation.

BACKGROUND: Globally, despite prostate cancer (PCa) representing second most prevalent malignancy in male, the precise molecular mechanisms implicated in its pathogenesis remain unclear. Consequently, elucidating the key molecular regulators that govern disease progression could substantially contribute to the establishment of novel therapeutic strategies, ultimately advancing the management of PCa. METHODS: A total of 49 PCa tissues and 43 adjacent normal tissues were collected from January 2017 to December 2021 at Zhongnan Hospital of Wuhan University. The advanced transcriptomic methodologies were employed to identify differentially expressed mRNAs in PCa. The expression of aspartoacylase (ASPA) in PCa was thoroughly evaluated using quantitative real-time PCR and Western blotting techniques. To elucidate the inhibitory role of ASPA in PCa cell proliferation and metastasis, a comprehensive set of in vitro and in vivo assays were conducted, including orthotopic and tumor-bearing mouse models (n = 8 for each group). A combination of experimental approaches, such as Western blotting, luciferase assays, immunoprecipitation assays, mass spectrometry, glutathione S-transferase pull-down experiments, and rescue studies, were employed to investigate the underlying molecular mechanisms of ASPA's action in PCa. The Student's t-test was employed to assess the statistical significance between two distinct groups, while one-way analysis of variance was utilized for comparisons involving more than two groups. A two-sided P value of less than 0.05 was deemed to indicate statistical significance. RESULTS: ASPA was identified as a novel inhibitor of PCa progression. The expression of ASPA was found to be significantly down-regulated in PCa tissue samples, and its decreased expression was independently associated with patients' prognosis (HR = 0.60, 95% CI 0.40-0.92, P = 0.018). Our experiments demonstrated that modulation of ASPA activity, either through gain- or loss-of-function, led to the suppression or enhancement of PCa cell proliferation, migration, and invasion, respectively. The inhibitory role of ASPA in PCa was further confirmed using orthotopic and tumor-bearing mouse models. Mechanistically, ASPA was shown to directly interact with the LYN and inhibit the phosphorylation of LYN as well as its downstream targets, JNK1/2 and C-Jun, in both PCa cells and mouse models, in an enzyme-independent manner. Importantly, the inhibition of LYN activation by bafetinib abrogated the promoting effect of ASPA knockdown on PCa progression in both in vitro and in vivo models. Moreover, we observed an inverse relationship between ASPA expression and LYN activity in clinical PCa samples, suggesting a potential regulatory role of ASPA in modulating LYN signaling. CONCLUSION: Our findings provide novel insights into the tumor-suppressive function of ASPA in PCa and highlight its potential as a prognostic biomarker and therapeutic target for the management of this malignancy.

Cognitive impairment and sleep disturbances after minor ischemic stroke.

PURPOSE: Post-stroke cognitive impairment (PSCI) is common among stroke survivors, although its risk factors are not well understood. Here, we assessed cognitive function in patients within 14 days after minor stroke and investigated the risk factors of PSCI, including sleep-related factors. METHODS: Patients with minor acute ischemic stroke (n = 86) were continuously recruited from November 2015 to October 2016. Demographic and clinical data were collected, and cognitive assessment and polysomnography were performed. Based on their cognitive performance, stroke patients were divided into PSCI and no PSCI groups. Age-, sex-, and education-matched participants (n = 36) were included as a healthy control (HC) group. RESULTS: Stroke patients showed impairments in multiple cognitive domains relative to HC participants (p < 0.01). Among stroke patients, the prevalence of PSCI and obstructive sleep apnea was 81.4 and 74.4%, respectively. Impairments in attention and working memory (87.1%) and executive function (84.3%) were the most common among stroke patients. Compared with no PSCI patients, PSCI patients showed a higher prevalence of obstructive sleep apnea (50.0 vs. 80.0%, p = 0.030) and shorter total sleep time (435.1 ± 104.0 vs. 347.3 ± 98.1 min, p = 0.002). Logistic regression analysis showed that education duration, total sleep time, and lowest SaO2 were independent risk factors for PSCI. CONCLUSIONS: The prevalence of PSCI is high after minor ischemic stroke. In particular, attention and working memory and executive function are most commonly impaired. Although the risk factors for PSCI are numerous, shorter total sleep time and degree of hypoxia at night warrant further attention.

Increased Serum Cystatin C in Early Parkinson's Disease with Objective Sleep Disturbances.

BACKGROUND: Sleep disturbance is one of the major non-motor symptoms which cause the disability of Parkinson's disease (PD) patients. Cystatin C (CysC) is a more sensitive biomarker than serum creatinine or estimated glomerular filtration rate. Previous studies have reported altered CysC levels in neurodegenerative disorders and sleep disorders. This study aimed to explore the correlations of serum CysC levels and objective sleep disturbances in early PD. METHODS: We recruited 106 early PD patients and 146 age- and sex-matched controls. All participants underwent clinical investigation and video-polysomnography. Sleep parameters and serum levels of CysC were measured. Then, we investigated the relationships between CysC and clinical variables and objective sleep disturbances in early PD patients. RESULTS: The mean serum level of CysC was significantly higher in patients with early PD (1.03 ± 0.19 mg/L) compared to controls (0.96 ± 0.15 mg/L, P = 0.009). There were significantly positive correlations between serum CysC levels and age (r = 0.334, P < 0.001), gender (r = 0.264, P = 0.013), and creatinine levels (r = 0.302, P = 0.018) in early PD patients. Increased serum CysC levels in early PD patients were significantly associated with higher apnea and hypopnea index (AHI) (r = 0.231, P = 0.017), especially hypopnea index (r = 0.333, P < 0.001). In early PD patients, elevated serum CysC levels were positively correlated with oxygen desaturation index (r = 0.223, P = 0.021), percentage of time spent at oxygen saturation (SaO2) <90% (r = 0.644, P < 0.001), arousal with respiratory event during sleep (r = 0.247, P = 0.013). On the contrary, the elevated serum CysC levels were negatively correlated with mean and minimal SaO2(r = -0.323, -0.315, both P = 0.001) in PD patients. CONCLUSIONS: The level of serum CysC was higher in early PD patients. PD patients with elevated serum CysC levels had more respiratory events and more severe oxygen desaturation. Therefore, the serum CysC levels may predict the severities of sleep-disordered breathing problems in early PD patients.

Two polysomnographic features of REM sleep behavior disorder: Clinical variations insight for Parkinson's disease.

INTRODUCTION: Loss of REM sleep muscle atonia (RWA) and dream-enactment behavior (DEB) are two associated features of REM sleep behavior disorder (RBD), which is frequently associated with Parkinson's disease (PD). Few studies have examined both DEB and RWA simultaneously in patients with PD. This study aimed to evaluate relationships between RWA, DEB and clinical characteristics of PD. METHODS: We conducted overnight polysomnography in 145 patients with PD. DEB (motor behaviors and/or vocalizations during REM) and increased RWA (IRWA; tonic and phasic chin EMG density ≥ 30% and ≥15%, respectively) were identified. Patients were categorized as clinical RBD (DEB and IRWA), sub-DEB positive (DEB only), subclinical RBD (IRWA only), or normal REM sleep. RESULTS: Patients with DEB had higher Hoehn and Yahr (H&Y) stage, Unified Parkinson's Disease Rating Scale (UPDRS) III score, levodopa equivalent dose(LEDs), and worse cognition. RWA was associated with H&Y stage, LEDs, cognition, and sleep structure in all patients. PD duration was associated with RWA, but not DEB. The PD patients who exhibited clinical or subclinical RBD, compared to sub-DEB positive, had higher H&Y stage, UPDRS III score and LEDs, lower cognitive score, worse sleep structure than the PD + cREM group. CONCLUSION: Both DEB and RWA were associated with severity of PD illness. Subclinical RBD might have different disease progression from sub-DEB positive. DEB symptoms may fluctuate or disappear whereas RWA may continue to develop as PD progresses. Differences in the course of DEB and RWA may reflect the difference in the degeneration process of neurodegenerative disorders.

Tonic Electromyogram Density in Multiple System Atrophy with Predominant Parkinsonism and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) have associated sleep disorders related to the underlying neurodegenerative pathology. Clinically, MSA with predominant parkinsonism (MSA-P) resembles PD in the manifestation of prominent parkinsonism. Whether the amount of rapid eye movement (REM) sleep without atonia could be a potential marker for differentiating MSA-P from PD has not been thoroughly investigated. This study aimed to examine whether sleep parameters could provide a method for differentiating MSA-P from PD. METHODS: This study comprised 24 MSA-P patients and 30 PD patients, and they were of similar age, gender, and REM sleep behavior disorder (RBD) prevalence. All patients underwent clinical evaluation and one night of video-polysomnography recording. The tonic and phasic chin electromyogram (EMG) activity was manually quantified during REM sleep of each patient. We divided both groups in terms of whether they had RBD to make subgroup analysis. RESULTS: No significant difference between MSA-P group and PD group had been found in clinical characteristics and sleep architecture. However, MSA-P patients had higher apnea-hypopnea index (AHI; 1.15 [0.00, 8.73]/h vs. 0.00 [0.00, 0.55]/h, P = 0.024) and higher tonic chin EMG density (34.02 [18.48, 57.18]% vs. 8.40 [3.11, 13.06]%, P < 0.001) as compared to PD patients. Subgroup analysis found that tonic EMG density in MSA + RBD subgroup was higher than that in PD + RBD subgroup (55.04 [26.81, 69.62]% vs. 11.40 [8.51, 20.41]%, P < 0.001). Furthermore, no evidence of any difference in tonic EMG density emerged between PD + RBD and MSA - RBD subgroups (P > 0.05). Both disease duration (P = 0.056) and AHI (P = 0.051) showed no significant differences during subgroup analysis although there was a trend toward longer disease duration in PD + RBD subgroup and higher AHI in MSA - RBD subgroup. Stepwise multiple linear regression analysis identified the presence of MSA-P (ß = 0.552, P < 0.001) and RBD (ß = 0.433, P < 0.001) as predictors of higher tonic EMG density. CONCLUSION: Tonic chin EMG density could be a potential marker for differentiating MSA-P from PD.

Retinal nerve fiber layer thinning: a window into rapid eye movement sleep behavior disorders in Parkinson's disease.

PURPOSE: Retinal nerve fiber layer (RNFL) thinning occurs in Parkinson's disease (PD) and other neurodegenerative diseases. Idiopathic RBD (iRBD) is a well-established prodromal hallmark of synucleinopathies and occurs secondary to many neurodegenerative diseases, including PD. The aim of this study is to determine whether or not retinal structures are altered with the onset of rapid eye movement (REM) sleep behavior disorders (RBD). METHODS: In all, a total of 63 patients with PD, 14 patients with idiopathic RBD, and 26 sex- and age-matched healthy controls were enrolled and underwent optical coherence tomography measurements (HD-OCT (Zeiss) ) for the average and every quadrant of RNFL thickness. The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was used to classify PD patients with clinically probable RBD (PD + pRBD) or without probable RBD (PD - pRBD). Patients with iRBD were identified by polysomnography. RESULTS: For patients with RBD (idiopathic or secondary to PD), we found a significant decrease in RNFL thickness compared with groups without RBD (PD - pRBD and healthy controls) (all p < 0.05). Average RNFL thickness in patients with iRBD is significantly thinner than in healthy controls (p < 0.05). In PD, the average RNFL thickness was dramatically thinner in the PD + pRBD group than the PD - pRBD group (p < 0.005). Compared with healthy controls, RNFL thickness was slightly thinner in the drug-naive PD group but not the PD group with drug treatment. Multiple linear regression analysis showed that RBDSQ score was negatively associated with average and inferior RNFL variation in PD (all p < 0.005). CONCLUSIONS: The findings show that RNFL was slightly but significantly thinner in idiopathic RBD. In PD, RNFL thickness may vary depending on the presence of RBD.

Sonographic Alteration of Basal Ganglia in Different Forms of Primary Focal Dystonia: A Cross-sectional Study.

BACKGROUND: Few studies have addressed whether abnormalities in the lenticular nucleus (LN) are characteristic transcranial sonography (TCS) echo features in patients with primary dystonia. This study aimed to explore alterations in the basal ganglia in different forms of primary focal dystonia. METHODS: cross-sectional observational study was performed between December 2013 and December 2014 in 80 patients with different forms of primary focal dystonia and 55 neurologically normal control subjects. TCS was performed in patients and control subjects. Multiple comparisons of multiple rates were used to compare LN hyperechogenicity ratios between control and patient groups. RESULTS: Thirteen individuals were excluded due to poor temporal bone windows, and two subjects were excluded due to disagreement in evaluation by sonologists. Totally, 70 patients (cervical dystonia, n = 30; blepharospasm, n = 30; oromandibular dystonia, n = 10) and 50 normal controls were included in the final analysis. LN hyperechogenicity was observed in 51% (36/70) of patients with primary focal dystonia, compared with 12% (6/50) of controls (P < 0.001). Substantia nigra hyperechogenicity did not differ between the two groups. LN hyperechogenicity was observed in 73% (22/30) of patients with cervical dystonia, a greater prevalence than in patients with blepharospasm (33%, 10/30, P = 0.002) and oromandibular dystonia (40%, 4/10, P = 0.126). LN hyperechogenicity was more frequently observed in patients with cervical dystonia compared with controls (73% vs. 12%, P < 0.001); however, no significant difference was detected in patients with blepharospasm (33% vs. 12%, P = 0.021) or oromandibular dystonia (40% vs. 12%, P = 0.088). CONCLUSIONS: LN hyperechogenicity is more frequently observed in patients with primary focal dystonia than in controls. It does not appear to be a characteristic TCS echo feature in patients with blepharospasm or oromandibular dystonia.

Alteration of brainstem raphe measured by transcranial sonography in depression patients with or without Parkinson's disease.

The purpose of our study was to assess the alteration of the brainstem raphe (BR) on transcranial sonography (TCS) in depression patients with or without Parkinson's disease (PD) and to explore whether the different changes of BR could reflect an increasing impairment of raphe structures. TCS was performed in patients with PD, depression with PD, depression only, and controls. Using the red nucleus as an internal standard, the BR was rated semi-quantitatively from grades 1-4 with grades 1-3 determined as abnormal. The rate of abnormal BR (≤grade 3) was found to be only 10 % in patients with PD (4/40) and 5 % in control patients (2/40). The rate of abnormal raphe was significantly higher (p < 0.05) in patients with both depression and PD (85 %, 34/40) or patients with depression only (87.5 %, 35/40). TCS of the raphe in most patients with mild depression scored grade 3, while those with moderate depression scored grade 2-3, and those with severe depression scored grade 1. The different BR echogenicity score reflected an increasing impairment of raphe structures in depression patients with or without PD (p < 0.05). TCS provides a good tool for assessing depression, more severe depressive symptoms were associated with different aspects in TCS studies.

Elevated Serum Liver Enzymes in Patients with Obstructive Sleep Apnea-hypopnea Syndrome.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAS) is associated with elevated liver enzymes and fatty liver. The purpose of this study was to measure serum liver enzyme levels in patients evaluated by polysomnography (PSG) and the factors associated with liver injury in OSAS patients. METHODS: All patients referred to PSG for evaluation of sleep apnea symptoms between June 2011 and November 2014 were included in this study. Demographic data and PSG parameters were recorded. Serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were systematically measured. OSAS patients were divided into mild, moderate, and severe groups according to the apnea-hypopnea index (AHI) values of 5-14 events/h, 15-29 events/h, and ≥30 events/h. RESULTS: A total of 540 patients were enrolled in this study; among these patients, 386 were male. Elevated liver enzymes were present in 42.3% of OSAS patients (32.4% in mild/moderate group; 51.0% in severe group) and 28.1% patients without OSAS. Patients with OSAS had higher body mass index (BMI) (P < 0.01). In the bivariate correlation, the liver enzymes level was negatively correlated with age and the lowest arterial oxygen saturation (SaO 2 ), and was positively correlated with BMI, oxygen desaturation index, percent of total time with oxygen saturation level <90% (TS90%), AHI, total cholesterol (TC), and triglyceride (TG). In logistic regression analysis, Age, BMI, TS90%, TC, and TG were included in the regression equation. CONCLUSIONS: Our data suggest that OSAS is a risk factor for elevated liver enzymes. The severity of OSAS is correlated with liver enzyme levels; we hypothesize that hypoxia is one of main causes of liver damage in patients with OSAS.

Clinical correlates of rapid eye movement sleep without atonia in Parkinson's disease.

OBJECTIVE: The aim of the present study was to investigate the relationship between rapid eye movement (REM) sleep without atonia (RWA) and Parkinson's disease (PD) progression. METHODS: We quantified tonic and phasic RWA by performing polysomnography in 198 PD patients. We then correlated the extent of RWA with clinical patient characteristics. RESULTS: PD patients were categorized into quartiles of tonic and phasic RWA. We found that patients with more RWA tended to be older and have longer PD duration, a greater likelihood of REM sleep behavior disorder (RBD), more advanced Hoehn & Yahr (H&Y) stage, a higher dose of parkinsonian medication, poorer cognitive performance, worse quality of life, and more severe sleep disturbance. After adjusting for age, sex, and PD duration, patients in the highest two RWA quartile were more likely to have severe PD (H&Y stage ⩾ 3.0) than those in the lowest RWA quartile. CONCLUSIONS: These findings provide evidence that RWA, especially with regard to tonic muscle activity, is associated with PD severity. SIGNIFICANCE: Further studies are warranted to determine the importance and utility of assessing RWA to evaluate sleep in PD patients.

Parkinson's disease patients with pain suffer from more severe non-motor symptoms.

Non-motor symptoms, including pain, depression, sleep disorder, and olfactory dysfunction, occur frequently in patients with Parkinson's disease (PD), even before the onset of motor symptoms. Although studies have examined the correlation between pain and depression or sleep disorder in PD, few studies have investigated the correlation between pain and a range of other non-motor symptoms of PD. PD patients (n = 142) with or without pain were included in the study. PD severity was evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H/Y) staging scale. Pain severity was analyzed with the Visual Analog Scale. The Hamilton Rating Scale for Depression (HRSD; 24 items), Montreal Cognitive Assessment Beijing Version (MoCA), and non-motor questionnaire (NMSQT) measured symptoms of depression, cognitive function, and non-motor symptoms. The incidence of pain was 47.9% in patients with PD, most of whom had moderate pain levels. Patients with pain showed higher HRSD, UPDRS, H/Y, and NMSQT scores and lower MoCA scores compared to those of patients without pain. HRSD and NMSQT scores were closely related with pain (P < 0.001). Non-motor symptoms were more prominent in patients with pain compared to that of controls and PD patients without pain.

Validation study of REM sleep behavior disorder questionnaire-Hong Kong (RBDQ-HK) in east China.

OBJECTIVE: To validate the REM Sleep Behavior Disorder (RBD) Questionnaire-Hong Kong (RBDQ-HK) in polysomnography (PSG)-confirmed RBD and non-RBD subjects, and to evaluate its usefulness in different clinical populations. METHODS: In total, 325 subjects (115 RBD and 210 controls) from East China were enrolled. After patients had finished the structured interview, and completed the RBDQ-HK and video-PSG test, we evaluated the reliability of RBDQ-HK (areas under the curves (AUC), the best cut-off values, factor 2 of RBDQ-HK, and overall scale) and validated the usefulness of RBDQ-HK between the Parkinson disease (PD) and obstructive sleep apnea (OSA) groups. RESULTS: The best cut-off values for factor 2 of RBDQ-HK were located at 7/8 with a sensitivity of 90% and specificity of 82% (AUC=0.911), and for RBDQ-HK overall scale were located at 17 with a sensitivity of 85% and specificity of 81% (AUC=0.892) in all subjects. Both factor 2 and overall scale of RBDQ-HK are valid in all subjects (PD and OSA patients), with a higher accuracy given by factor 2 of RBDQ-HK. CONCLUSIONS: RBDQ-HK and its factor 2 are useful and validated RBD screening instruments, and could be used as a tool for screening RBD in patients with PD and OSA.

Clinical manifestations of Parkinson disease and the onset of rapid eye movement sleep behavior disorder.

OBJECTIVE: To identify whether the presence and/or timing of rapid eye movement (REM) sleep behavior disorder (RBD) onset were associated with differences in clinical features and sleep parameters of Parkinson disease (PD). METHODS: In all, 112 PD patients were enrolled and all underwent extensive clinical evaluations and video-polysomnography (PSG). Clinical features and PSG parameters were compared in PD patients with (PD+RBD) or without (PD-RBD) RBD, RBD preceding (RBD>PD), or not (PD⩾RBD) PD onset. RESULTS: Sixty-three of the 112 PD patients were affected by RBD. Adjusted for age, gender, education, body mass index (BMI), levodopa equivalent daily dose (LED) and PD duration, PD+RBD patients had higher Hoehn & Yahr stage, higher scores for UPDRS parts I, II and III, more dyskinesia, higher ratio of axial/limb manifestations, and more hallucinations. Their cognitive and quality-of-life status was significantly lower (all P<0.05). For PSG, PD+RBD patients exhibited higher percentages of phasic and tonic EMG activities, lower apnea hypopnea (AHI) and oxygen desaturation index (ODI), and less time in arterial oxygen saturation (SaO2) <90% during REM sleep (all P<0.05). PD⩾RBD (n=22) patients did not significantly differ from RBD>PD (n=41) patients in clinical manifestations, whereas the PD⩾RBD subgroup had significantly higher UPDRS part I score, lower PDQ score and lower AHI during REM than the PD-RBD group (all P<0.05), but not RBD>PD subgroup. Correlation analysis showed that worse cognition was associated with shorter interval of RBD preceding PD onset (r=0.297, P=0.018), but not RBD duration (P=0.202). CONCLUSIONS: Clinical manifestations of PD may vary depending on the presence and timing of RBD onset. These findings are compatible with the hypothesis that RBD may be a marker of complex subtypes of PD.

[Clinical characteristics in Parkinson's disease patients with cognitive impairment and effects of cognitive impairment on sleep].

OBJECTIVE: To analyze the clinical characteristics, correlation factors and clinical heterogeneities in Parkinson's disease (PD) patients with cognitive impairment and identify whether cognitive impairment could influence the aspect of sleep. METHODS: A total of 130 PD outpatients and inpatients of sleep center at our hospital were eligible for participation. According to Montreal cognitive assessment (MOCA), they were divided into cognitive normal group (MOCA ≥ 26) (n = 51) and cognitive impairment group (MOCA < 26) (n = 79). Their clinical characteristics were mainly evaluated by unified Parkinson's disease rating scale (UPDRS) , Hoehn-Yahr (H-Y) stage, Hamilton depression scale (HAMD-24 item) and Epworth sleepiness scale (ESS). And all of them underwent video-polysomnography (PSG). RESULTS: The proportion of cognitive impairment (MOCA < 26) was 60.76%. Compared to those without cognitive impairment, the PD patients with cognitive impairment had significantly higher score of HAMD (10 ± 7 vs 7 ± 4), increased incidence of hallucinations (40.50% vs 19.60%) and REM behavior disorders (RBD) (63.29% vs 39.21%), significantly higher H-Y stage [2.5(2.0-3.0) vs 2.0 (2.0-2.5)] , United Kingdom Parkinson Disease Society (UPDRS) part III (22 ± 10 vs 19 ± 10) and levodopa-equivalent daily dose (LED) (511 ± 302vs 380 ± 272) (all P < 0.05). However, no significant differences existed in the subscores of MOCA between PD patients with different sides of onset and motor subtypes of onset (all P > 0.05). Non-conditional Logistic regression analysis showed that PD duration, score of HAMD and H-Y stage were the major influencing factors of cognition. On PSG, significantly decreased sleep efficiency (57% ± 21% vs 66% ± 17%), higher percentage of non-REM sleep stage 1 (NREMS1) (37% ± 21% vs 27% ± 13%), lower percentage of NREMS2 (40% ± 17% vs 46% ± 13%) and REM sleep (39% ± 28% vs 54% ± 36%) were found for PD patients with cognitive impairment (all P < 0.05). CONCLUSION: The PD patients with cognitive impairment have more severe disease and partial nonmotor symptoms. And the severity of disease and depression is closely associated with cognitive impairment. Cognitive impairment may also affect sleep to cause decreased sleep efficiency and severe sleep structure disorder.

Correlation of Epworth Sleepiness Scale with multiple sleep latency test and its diagnostic accuracy in assessing excessive daytime sleepiness in patients with obstructive sleep apnea hypopnea syndrome.

BACKGROUND: Excessive daytime sleepiness (EDS) is often associated with obstructive sleep apnea hypopnea syndrome (OSAHS) and contributes to a number of comorbidities in these patients. Therefore, early detection of EDS is critical in disease management. We examined the association between Epworth Sleepiness Scale (ESS) and multiple sleep latency test (MSLT) and diagnostic accuracy of ESS in assessing EDS in OSAHS patients. METHODS: The ESS, MSLT and overnight polysomnography were administered to 107 Chinese patients to assess EDS and its correlations with polysomnographic parameters. The diagnostic accuracy of ESS in classifying EDS (mean sleep latency (MSL) ≤ 10 minutes) was evaluated by calculating the area under ROC curve. RESULTS: As the severity of OSAHS increased, MSL decreased with increase in ESS score. Conversely, patients with worsening EDS (shorter MSL) were characterized by advanced nocturnal hypoxaemia and sleep disruption compared to those with normal MSL, suggesting EDS is associated with more severe OSAHS. There was a negative correlation between ESS score and MSL and both moderately correlated with some polysomnographic nocturnal hypoxaemic parameters. The area under ROC curve of ESS for identifying EDS was 0.80 (95% CI: 0.71 to 0.88) and ESS score ≥ 12 provided the best predictive value with a sensitivity of 80% and specificity of 69%. CONCLUSION: The ESS score moderately correlates with MSL and our ROC study supports ESS as a screening strategy for assessing EDS in OSAHS.

Autophagic impairment contributes to systemic inflammation-induced dopaminergic neuron loss in the midbrain.

BACKGROUND: Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown. RESULTS: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells. CONCLUSION: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.

Application and interpretation of current autophagy inhibitors and activators.

Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

[Association between serum adipocyte fatty acid binding protein level and dyslipidemia in patients with obstructive sleep apnea syndrome].

OBJECTIVE: To explore the association between serum adipocyte fatty acid binding protein (A-FABP) levels and dyslipidemia in patients with obstructive sleep apnea syndromes (OSAS). METHODS: Eighty snoring patients were monitored by overnight polysomnography (PSG) in Second Affiliated Hospital of Soochow University from November 2010 to May 2011. There were 63 males and 17 females with a mean age of (48 ± 14) years (range: 22 - 77 years). Based on the results of apnea-hypopnea index (AHI), they were divided into 3 groups: primary snoring group (AHI < 5/h, n = 19), mild-moderate OSAS group (5/h ≤ AHI ≤ 40/h, n = 22) and severe OSAS group (AHI > 40/h, n = 39). The levels of A-FABP, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured and compared between the primary snoring group and OSAS patients of different severities. And the correlations between serum A-FABP and plasma lipid as well as PSG parameters were further evaluated by partial correlation analysis. RESULTS: Compared with the primary snoring group ((15.7 ± 3.3) µg/L) and mild-moderate group ((17.3 ± 4.3) µg/L), there was a significant elevation of serum A-FABP level in the severe OSAS group ((20.4 ± 4.6) µg/L) (P = 0.001, P = 0.026). Additionally, after adjustment for body mass index and age, the serum A-FABP level showed significant positive correlations with TC, TG and LDL-C (r = 0.469, P = 0.000; r = 0.239, P = 0.035 and r = 0.366, P = 0.001). Serum A-FABP level was positively correlated with AHI and the time of oxygen saturation (SaO2) < 90% (r = 0.231, P = 0.042 and r = 0.226, P = 0.047). Nevertheless, the serum A-FABP level showed significant negative correlations with the lowest SaO2 and the mean SaO2 (r = -0.234, P = 0.039 and r = -0.270, P = 0.017). CONCLUSION: Dyslipidemia and elevated level of serum A-FABP are common in OSAS patients.

Neurocognitive impairment in Chinese patients with obstructive sleep apnoea hypopnoea syndrome.

BACKGROUND AND OBJECTIVE: Sleep-disordered breathing is known to be associated with impairment in cognitive function. The aim of this study was to characterize neurocognitive impairment in a cohort of Chinese patients with varying severities of obstructive sleep apnoea hypopnoea syndrome (OSAHS), and to develop a sensitive instrument for routine screening of cognitive impairment. METHODS: Eligible patients (n = 394) were categorized into a primary snoring group, and mild, moderate and severe OSAHS groups, based on assessment of AHI. The Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) questionnaires were administered to assess cognitive function, and the correlations between questionnaire scores and clinical and polysomnographic parameters were further evaluated by stepwise multivariate regression. RESULTS: MoCA scores decreased progressively across the spectrum from primary snoring to severe OSAHS. Importantly, mild neurocognitive impairment as defined by a MoCA score <26 was more common in the moderate (38.6%) and severe (41.4%) OSAHS groups than in the mild OSAHS (25.0%) and primary snoring (15.2%) groups. In contrast, MMSE scores were largely normal and comparable among all four groups. Evaluation of MoCA subdomains further revealed selective reduction in memory/delayed recall, visuospatial and executive function, and attention span in the severe OSAHS group compared with the other groups. Stepwise multivariate regression analysis demonstrated that MoCA scores correlated significantly with lowest oxygen saturation (L-SaO(2) ) and years of education. CONCLUSIONS: Neurocognitive impairment is common in patients with OSAHS. The MoCA is a brief and sensitive tool for the assessment of cognitive impairment in OSAHS patients, whose performance on the MMSE is in the normal range.

Daytime sleepiness and its determining factors in Chinese obstructive sleep apnea patients.

OBJECTIVE: The aim of this study was to characterize excessive daytime sleepiness (EDS) in a large cohort of Chinese patients with various severity of obstructive sleep apnea-hypopnea syndrome (OSAHS), and investigate its correlations with clinical/polysomnographic variables. MATERIALS AND METHODS: A total of 1,035 consecutive Chinese patients with snoring (mean age ± SD 45 ± 15 years, BMI 26.6 ± 4.3 kg/m(2)) were examined by overnight polysomnography, and subjective EDS was assessed using the Epworth Sleepiness Scale (ESS). RESULTS: The 1,035 patients were compared according to severity of sleep-disordered breathing: AHI <5 (primary snoring group or normal overall AHI) (24.1%), AHI 5-20 (mild OSAHS, 21.7%), AHI >20-40 (moderate OSAHS 16.5%), and AHI >40 (severe OSAHS 37.7%). ESS score progressively increased as the severity of OSAHS aggravated among these patients. More severe OSAHS patients were characterized by EDS, nocturnal hypoxemia, and disruption of sleep structure. Progressive worsening of nocturnal hypoxemia was observed from mild to severe OSAHS patients with a strong correlation with ESS score. The stepwise multiple regression analysis performed to evaluate the correlations of individual clinical and polysomnographic variables with the ESS score revealed that the ESS score significantly correlated with the oxygen desaturation index (ODI), apnea-hypopnea index (AHI), and body mass index (BMI), and ODI was the strongest determinant of ESS score. CONCLUSION: EDS is correlated with the severity of OSAHS. More severe patients are characterized by higher ESS score, higher BMI, and progressive worsening of nocturnal hypoxemia. Nocturnal hypoxemia is a major determinant of EDS in Chinese OSAHS patients.