Age and sex differences on the association between anxiety disorders and obstructive sleep apnea: A nationwide case-control study in Taiwan.

AIM: The aim of this study was to examine the association between anxiety disorders and obstructive sleep apnea (OSA). METHODS: This is a population-based, retrospective case-control study using Taiwan's nationwide database. We included patients with OSA aged ≥12 years, diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes: 327 and 780. Each enrolled patient with OSA needed to undergo a polysomnography examination within 1 year pre- or post-OSA occurrence. Patients with OSA and controls were selected in a 1:4 ratio. Patients with anxiety disorders (ICD-9-CM code 300) were diagnosed by board-certified psychiatrists and required to visit the outpatient clinic at least three times per year. Multivariate logistic regression and interaction analyses were used to evaluate the objective association. RESULTS: This study enrolled 7987 and 31 948 participants with and without OSA, respectively. A significant difference in anxiety exposure was observed only pre-OSA diagnosis but not post-OSA diagnosis. Compared with patients without anxiety disorders: (i) those with anxiety disorders had an adjusted odds ratio (aOR) of ≈1.864 in OSA comorbidity (aOR = 1.864; 95% confidence interval [CI] = 1.337-2.405); and (ii) subgroup analysis showed a significant interaction that anxiety patients of male sex, aged 18 to 44 years, aged 45 to 64 years, and hypertension had a higher aOR in OSA comorbidity (aOR = 2.104 [95% CI = 1.436-2.589], aOR = 1.942 [95% CI = 1.390-2.503], aOR = 2.179 [95% CI = 1.564-2.811], and aOR = 2.092 [95% CI = 1.497-2.706], respectively). CONCLUSION: The study revealed a higher ratio of previous anxiety exposure in patients with OSA. Compared with those without anxiety, anxiety patients of male sex, aged 18 to 64 years, and with hypertension had a higher risk of OSA comorbidity.

Month of birth and the risk of narcolepsy: a systematic review and meta-analysis.

STUDY OBJECTIVES: The aim of this study is to evaluate the relationship between the month of birth (MOB) and the risk of narcolepsy. METHODS: We conducted a systematic review of the electronic databases PubMed, Embase, and Cochrane CENTRAL from their inception to September 30, 2021. We also added data on narcolepsy from the National Health Insurance Research Database in Taiwan. Then we extracted the relative risk (RR) ratios of narcolepsy in each month of birth to those of the general population and transformed them from MOB to season. A random-effects model was used to calculate pooled RR ratios from the meta-analysis and 95% confidence interval (CI). RESULTS: The meta-analysis analyzed 7 studies and included 3,776 patients from 8 areas (Canada, China, France, Germany, Hong Kong, Netherlands, Taiwan, and United States). The RR ratio was highest in March (1.11; 95% CI, 0.99-1.26) and August (1.11; 95% CI, 0.98-1.26) and lowest in April (0.90; 95% CI, 0.78-1.03). However, none of the MOBs reached statistical significance. Moreover, the narcolepsy risk patterns on the 3 continents (Asia, Europe, and North America) were different. In North America, the highest and lowest significant risks were found in March (1.47; 95% CI, 1.20-1.79) and September (0.75; 95% CI, 0.56-0.99). In Asia, the lowest notable risk was in April (0.80; 95% CI, 0.66-0.97). In Europe, the risk of narcolepsy was not significantly related to any MOB. In terms of seasons, only spring MOBs in North America had a significantly higher risk (1.21; 95% CI, 1.06-1.38). CONCLUSIONS: The findings indicated that the risk of narcolepsy and MOB differed across the 3 continents. This study indicates the important role of environmental factors in narcolepsy. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; Identifier: CRD42020186660. CITATION: Hsu C-W, Tseng P-T, Tu Y-K, et al. Month of birth and the risk of narcolepsy: a systematic review and meta-analysis. J Clin Sleep Med. 2022;18(4):1113-1120.

Prevalence and effects of sleep-disordered breathing on middle-aged patients with sedative-free generalized anxiety disorder: A prospective case-control study.

Objective: Generalized anxiety disorder (GAD) and sleep-disordered breathing (SDB) share similar symptoms, such as poor sleep quality, irritability, and poor concentration during daily activities. This study aims to investigate the proportion of undiagnosed SDB and its impacts on anxiety severity and autonomic function in newly diagnosed, sedative-free GAD patients. Methods: This prospective case-control study included newly diagnosed GAD patients and control participants with matched age, sex, and body mass index (BMI) in Taiwan. All participants completed questionnaires for sleep and mood symptoms and a resting 5-min heart rate variability (HRV) examination during enrollment. The participants also used a home sleep apnea test to detect SDB. An oxygen desaturation index (ODI) ≥ 5 was considered indicative of SDB. Results: In total, 56 controls and 47 newly diagnosed GAD participants (mean age 55.31 ± 12.36 years, mean BMI 23.41 ± 3.42 kg/m2) were included. There was no significant difference in the proportion of undiagnosed SDB in the control and sedative-free GAD groups (46.43 vs. 51.06%). Sedative-free GAD patients with SDB scored significantly higher on Beck Anxiety Inventory (23.83 ± 11.54) than those without SDB (16.52 ± 10.61) (p < 0.001). Both control and sedative-free GAD groups with SDB had worse global autonomic function than the control group without SDB, as evidenced by the HRV results (p < 0.05 for all). Conclusion: Average age 55 years and mean BMI 23 kg/m2 patients with GAD and matched controls had an undiagnosed SDB prevalence of approximately 50%. SDB correlated with worsening anxiety severity and reduced cardiac autonomic function. Moreover, age and BMI were considered major risk factors for predicting undiagnosed SDB.

The Association Between Asthma and Narcolepsy: A Nationwide Case-Control Study in Taiwan.

PURPOSE: Asthma, which is caused by inflammation of the airways, affects the sensitivity of nerve endings. Narcolepsy is a chronic sleep disorder that may be caused by autoimmunity. Recent studies have reported a positive association between narcolepsy and asthma. We aimed to examine the association between asthma and narcolepsy and determine the effects of therapeutic corticosteroid or bronchodilator use. MATERIALS AND METHODS: We conducted a nationwide population-based, nested case-control study using Taiwan's National Health Insurance Research Database (NHIRD) between 2000 and 2013. Subjects with narcolepsy (ICD-9-CM code 347) were enrolled, with 1:3 estimated propensity score-matched controls based on sex, age, and index year. The association between narcolepsy and asthma was assessed using multiple logistic regression analyses. The covariates included sex, age, monthly insurance premiums, geographical area of residence, urbanization level of residence, level of care, and presence of diseases related to immune response and central nervous system. The effects of corticosteroid and bronchodilator use were also analyzed. RESULTS: Overall, 2008 subjects were identified from the NHIRD (502 patients with narcolepsy and 1506 controls). The participants with narcolepsy had almost three times the level of previous asthma diagnosis than controls. Compared to those without asthma, patients with asthma had an adjusted odds ratio (OR) of 3.181 for narcolepsy comorbidity (95% confidence interval [CI]: 2.048-4.941, p<0.001). The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity, with an adjusted OR of 0.465 (95% CI, 0.250-0.634; p<0.001), in patients with asthma when compared to those without treatment. CONCLUSION: This study demonstrated a significantly higher level of previous asthma diagnosis in patients with narcolepsy. The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity in asthma patients, compared to those without treatment.

Selective ß2-AR Blockage Suppresses Colorectal Cancer Growth Through Regulation of EGFR-Akt/ERK1/2 Signaling, G1-Phase Arrest, and Apoptosis.

The stress-upregulated catecholamines-activated ß1- and ß2-adrenergic receptors (ß1/2-ARs) have been shown to accelerate the progression of cancers such as colorectal cancer (CRC). We investigated the underlying mechanism of the inhibition of ß1/2-ARs signaling for the treatment of CRC and elucidated the significance of ß2-AR expression in CRC in vitro and in clinical samples. The impacts of ß1/2-AR antagonists in CRC in vitro and CRC-xenograft in vivo were examined. We found that repression of ß2-AR but not ß1-AR signaling selectively suppressed cell viability, induced G1-phase cell cycle arrest, caused both intrinsic and extrinsic pathways-mediated apoptosis of specific CRC cells and inhibited CRC-xenograft growth in vivo. Moreover, the expression of ß2-AR was not consistent with the progression of CRC in vitro or in clinical samples. Our data evidence that the expression profiles, signaling, and blockage of ß2-AR have a unique pattern in CRC comparing to other cancers. ß2-AR antagonism selectively suppresses the growth of CRC accompanying active ß2-AR signaling, which potentially carries wild-type KRAS, in vitro and in vivo via the inhibition of ß2-AR transactivated EFGR-Akt/ERK1/2 signaling pathway. Thus, ß2-AR blockage might be a potential therapeutic strategy for combating the progressions of ß2-AR-dependent CRC.

WW domain-containing oxidoreductase is involved in upregulation of matrix metalloproteinase 9 by Epstein-Barr virus latent membrane protein 2A.

WW domain-containing oxidoreductase (WOX1) participates in tumor suppression and many other biologic functions, but its molecular and functional interactions with viral proteins remain largely unknown. This study reveals that WOX1 is physically associated with latent membrane protein 2A (LMP2A), an oncoprotein of Epstein-Barr virus. The molecular interaction involves the tyrosine residue 33 of WOX1 and the proline-rich motifs of LMP2A. Interestingly, endogenous WOX1 is required for some LMP2A-triggered, cancer-promoting effects, including activation of extracellular signal-regulated kinase-1/2, upregulation of matrix metalloproteinase 9 (MMP9) and promotion of cell invasion. Upon knockdown of endogenous WOX1, LMP2A-triggered MMP9 induction is restored by exogenous wild-type WOX1, but not by a WOX1 mutant defective in LMP2A binding. These results indicate that, through interaction with LMP2A, WOX1 is involved in MMP9 induction, suggesting a novel role of WOX1 in Epstein-Barr virus-associated cancer progression.

Epstein-Barr virus Zta upregulates matrix metalloproteinases 3 and 9 that synergistically promote cell invasion in vitro.

Zta is a lytic transactivator of Epstein-Barr virus (EBV) and has been shown to promote migration and invasion of epithelial cells. Although previous studies indicate that Zta induces expression of matrix metalloproteinase (MMP) 9 and MMP1, direct evidence linking the MMPs to Zta-induced cell migration and invasion is still lacking. Here we performed a series of in vitro studies to re-examine the expression profile and biologic functions of Zta-induced MMPs in epithelial cells derived from nasopharyngeal carcinoma. We found that, in addition to MMP9, MMP3 was a new target gene upregulated by Zta. Ectopic Zta expression in EBV-negative cells increased both mRNA and protein production of MMP3. Endogenous Zta also contributed to induction of MMP3 expression, migration and invasion of EBV-infected cells. Zta activated the MMP3 promoter through three AP-1 elements, and its DNA-binding domain was required for the promoter binding and MMP3 induction. We further tested the effects of MMP3 and MMP9 on cell motility and invasiveness in vitro. Zta-promoted cell migration required MMP3 but not MMP9. On the other hand, both MMP3 and MMP9 were essential for Zta-induced cell invasion, and co-expression of the two MMPs synergistically increased cell invasiveness. Therefore, this study provides integrated evidence demonstrating that, at least in the in vitro cell models, Zta drives cell migration and invasion through MMPs.

Epstein-Barr virus latent membrane protein 2A promotes invasion of nasopharyngeal carcinoma cells through ERK/Fra-1-mediated induction of matrix metalloproteinase 9.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is highly metastatic, and this malignant feature may be promoted by an EBV oncoprotein, latent membrane protein 2A (LMP2A). Acting as a signal regulator, LMP2A can enhance invasiveness and motility of epithelial cells. Downstream from the LMP2A-triggered signaling events, it is largely unknown what key effector proteins are induced and essentially promote cell invasion. In the present study, we found that in NPC cells, LMP2A upregulated matrix metalloproteinase 9 (MMP9), a metastasis-associated protease. LMP2A increased MMP9 expression at both the mRNA and protein levels. It also activated the MMP9 promoter, in which two AP-1 elements were required for the promoter activation. Among AP-1 transcription factors, Fra-1 was induced by LMP2A and is essential for LMP2A-triggered MMP9 expression. Induction of Fra-1 was dependent on the LMP2A-activated ERK1/2 pathway, and induction of the ERK1/2-Fra-1-MMP9 axis required PY motifs in the amino-terminal domain of LMP2A. Notably, LMP2A-promoted invasion of NPC cells was blocked when MMP9 expression, Fra-1 induction, or ERK1/2 activation was inhibited. In addition, we found an association of LMP2A with MMP9 expression in NPC tumor biopsy specimens, where Fra-1 was a major mediation factor. This study reveals an underlying mechanism of LMP2A-induced cell invasion, from signal transduction to upregulation of a critical protease. Considering that MMP9 can also be upregulated by another EBV oncoprotein, LMP1, this protease may be a pivotal effector at which the EBV-induced, invasion-promoting mechanisms converge, serving as an attractive therapeutic target for NPC treatment.

Epstein-Barr virus Zta-induced immunomodulators from nasopharyngeal carcinoma cells upregulate interleukin-10 production from monocytes.

During lytic infection with Epstein-Barr virus (EBV), several viral lytic proteins function to evade immune recognition or to actively suppress immune cells. An EBV lytic transactivator, Zta, induces an immunosuppressive cytokine interleukin 10 (IL-10) in B cells, but whether it regulates IL-10 in the context of epithelial cells is unclear. In this study, we tested nasopharyngeal carcinoma (NPC) cell lines and found that Zta did not induce IL-10 in these epithelial cells. Interestingly, the conditioned medium of Zta-expressing NPC cells enhanced IL-10 production from monocytes. We further revealed that the IL-10-inducing effect involved at least two immunomodulators that were upregulated by Zta and secreted from NPC cells: granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostaglandin E(2) (PGE(2)). Zta was recruited to and activated the GM-CSF promoter, thus upregulating GM-CSF expression. Zta also activated the promoter of cyclooxygenase-2 (COX-2), and Zta-induced COX-2 increased downstream PGE(2) production. Cotreatment with GM-CSF and PGE(2) synergistically induced IL-10 production from monocytes. The IL-10-inducing effect of the Zta-conditioned medium was reduced when GM-CSF or the COX-2/PGE(2) pathway was blocked. The conditioned medium of NPC cells with EBV lytic infection showed a similar increase of GM-CSF and PGE(2) levels as well as the IL-10-inducing effect on monocytes, and knockdown of Zta abolished all the effects. Therefore, through Zta-induced immunomodulators, EBV lytic infection in NPC cells can direct bystander monocytes to produce IL-10, which may be a novel way of EBV to promote local immunosuppression.

Endogenous latent membrane protein 1 in Epstein-Barr virus-infected nasopharyngeal carcinoma cells attracts T lymphocytes through upregulation of multiple chemokines.

Tumor-infiltrating T lymphocytes are considered to facilitate development of Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC), but how EBV in NPC tumor cells directs T cell infiltration remains unclear. Here we compare EBV-infected NPC cells with and without spontaneous expression of viral latent membrane protein 1 (LMP1) and find that culture supernatants of LMP1-positive NPC cells exert enhanced chemoattraction to primary T cells. Knockdown of endogenous LMP1 in the cells suppresses the chemotactic activity. Endogenous LMP1 in NPC cells upregulates multiple chemokines, among which MIP-1alpha, MIP-1beta and IL-8 contribute to T cell chemotaxis. We further reveal that LMP1-induced production of MIP-1alpha and MIP-1beta in NPC cells requires not only two carboxyl-terminal activation regions of LMP1 but also their downstream NF-kappaB and JNK pathways. This study corroborates that endogenous LMP1 in EBV-infected NPC cells induces multiple chemokines to promote T cell recruitment and perhaps other pathogenic events in NPC.