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Bisphenol A (BPA) is an environmental contaminant widely suspected to be a neurological toxicant. Epidemiological studies have demonstrated close links between BPA exposure, pathogenetic brain degeneration, and altered neurobehaviors, considering BPA a risk factor for cognitive dysfunction. However, the mechanisms of BPA resulting in neurodegeneration remain unclear. Herein, cultured N2a neurons were subjected to BPA treatment, and neurotoxicity was assessed using neuronal viability and differentiation assays. Signaling cascades related to cellular self-degradation were also evaluated. BPA decreased cell viability and axon outgrowth (e.g., by down-regulating MAP2 and GAP43), thus confirming its role as a neurotoxicant. BPA induced neurotoxicity by down-regulating Bcl-2 and initiating apoptosis and autophagy flux inhibition (featured by nuclear translocation of apoptosis-inducing factor (AIF), light chain 3B (LC3B) aggregation, and p62 accumulation). Both heme oxygenase (HO)-1 and AMP-activated protein kinase (AMPK) up-regulated/activated by BPA mediated the molecular signalings involved in apoptosis and autophagy. HO-1 inhibition or AIF silencing effectively reduced BPA-induced neuronal death. Although BPA elicited intracellular oxygen free radical production, ROS scavenger NAC exerted no effect against BPA insults. These results suggest that BPA induces N2a neurotoxicity characterized by AIF-dependent apoptosis and p62-related autophagy defects via HO-1 up-regulation and AMPK activation, thereby resulting in neuronal degeneration.

Diabetes mellitus is associated with an increased risk of Alzheimer’s dementia and cognitive decline. The cause of neurodegeneration in chronic diabetic patients remains unclear. Changes in brain microglial activity due to glycemic fluctuations may be an etiological factor. Here, we examined the impact of acute ambient glucose fluctuations on BV-2 microglial activity. Biochemical parameters were assayed and showed that the shift from normal glucose (NG; 5.5 mM) to high glucose (HG; 25 mM) promoted cell growth and induced oxidative/inflammatory stress and microglial activation, as evidenced by increased MTT reduction, elevated pro-inflammatory factor secretion (i.e., TNF-α and oxygen free radicals), and upregulated expression of stress/inflammatory proteins (i.e., HSP70, HO-1, iNOS, and COX-2). Also, LPS-induced inflammation was enlarged by an NG-to-HG shift. In contrast, the HG-to-NG shift trapped microglia in a state of metabolic stress, which led to apoptosis and autophagy, as evidenced by decreased Bcl-2 and increased cleaved caspase-3, TUNEL staining, and LC3B-II expression. These stress episodes were primarily mediated through MAPKs, PI3K/Akt, and NF-κB cascades. Our study demonstrates that acute glucose fluctuation forms the stress that alters microglial activity (e.g., inflammatory activation or self-degradation), representing a novel pathogenic mechanism for the continued deterioration of neurological function in diabetic patients.

Patients with diabetes mellitus can experience hyperglycemia, which affects brain function and produces cognitive impairment or neurodegeneration. Neuroinflammation is an important cause of cognitive dysfunction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic agents that reportedly possess anti-inflammatory properties and may produce beneficial cognitive effects. We hypothesized that SGLT2 inhibitors alleviate hyperglycemia-related inflammation in brain immune cells. Cultured BV-2 microglia were exposed to high glucose (HG) in the absence or presence of SGLT2 inhibitors including canagliflozin (Cana), dapagliflozin (Dapa), empagliflozin (Empa), and ertugliflozin (Ertu). Afterward, we evaluated the cytotoxic and inflammatory responses by specific biochemical assays. Treatments with non-toxic Cana or Dapa, but not Empa or Ertu, inhibited proliferation without cell death. Only Cana rescued BV-2 microglia from HG-induced cytotoxicity, including apoptosis or autophagic degradation. None of SGLT2 inhibitors affected the HG-stimulated induction of stress proteins HO-1 and HSP70. Also, compared to the other three SGLT2 inhibitors, Cana was better at inhibiting HG-induced oxidative/inflammatory stress, as evidenced by its ability to repress proinflammatory factors (e.g., oxygen free radicals, iNOS, NLRP3, IL-1β, and TNF-α) other than COX-2. Cana’s action to alleviate HG insults was mediated not by altering SGLT2 protein expression, but by reducing HG-stimulated signaling activities of NFκB, JNK, p38, and PI3K/Akt pathways. Particularly, Cana imitated the effects of NFκB inhibitor on HG-induced iNOS and COX-2. Of the four SGLT2 inhibitors, Cana provided BV-2 microglia with the best protection against HG-induced inflammatory toxicity. Thus, Cana may help to reduce innate neuroimmune damage caused by hyperglycemia.

This study was conducted to investigate the clinical significance, manifestations, microbiological characteristics and outcomes of carbapenem-resistant Enterobacteriaceae (CRE) isolates, and compare the clinical features of community- and healthcare-acquired CRE isolates. A total of 78 patients were identified to have CRE. Klebsiella pneumoniae was the most common pathogens (n = 42, 53.8%), followed by Enterobacter cloacae (n = 24, 30.8%), and Escherichia coli (n = 11, 14.1%). Most of the patients acquired CRE from healthcare settings (n = 55, 70.5%), and other cases got CRE from community settings (n = 23, 29.5%). Nine cases (11.5%) were classified as CRE colonization. Among the remaining 69 cases of CRE infections, pneumonia (n = 28, 40.6%) was the most common type of infections, followed by urinary tract infection (n = 24, 34.8%), and intra-abdominal infection (n = 16, 23.2%). The patients acquired CRE from community settings were more likely to be elderly, female, and had more urinary tract infections than from healthcare settings. In contrast, the patients acquired CRE from healthcare settings had more intra-abdominal infections, intra-abdominal surgery, and presence of indwelling device than from community settings. In conclusion, community-acquired CRE are not rare, and their associated clinical presentations are different from healthcare-acquired CRE.

Abstract Study Objectives Epilepsy is characterized by disrupted sleep architecture. Studies on sleep macro- and microstructure revealed that patients with epilepsy experience disturbed rapid eye movement (REM) sleep; however, no consensus has been reached on non-REM (NREM) sleep changes. Cyclic alternating pattern (CAP) is a marker of sleep instability that occurs only during NREM sleep. This meta-analysis investigated CAP differences between patients with epilepsy and healthy controls. Methods This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines in searching PubMed, Embase, and Cochrane Central database for studies comparing polysomnographic sleep microstructures between patients with epilepsy and healthy controls. A meta-analysis using a random-effects model was performed. We compared CAP rates, percentages of phase A1, A2, A3 subtypes, and phase B durations between patients with epilepsy and healthy controls. Results A total of 11 studies, including 209 patients with epilepsy and 197 healthy controls, fulfilled the eligibility criteria. Compared with healthy controls, patients with epilepsy had significantly increased CAP rates and decreased A1 subtype percentages, and patients with sleep-related epilepsy had increased A3 subtype percentages. Subgroup analyses revealed that antiseizure medications (ASMs) decreased CAP rates and increased phase B durations but did not affect the microstates of phase A in patients with sleep-related epilepsy. Conclusions This meta-analysis detected statistically significant differences in CAP parameters between patients with epilepsy and healthy controls. Our findings suggest patients with epilepsy experience NREM sleep instability. ASMs treatment may decrease NREM instability but did not alter the microstates of phase A.

Background The number of people aged greater than 65 years is growing in many countries. Taiwan will be a superaged society in 2026, and health care utilization will increase considerably. Our study aimed to evaluate the efficacy of the geriatric integrated outpatient clinic model for reducing health care utilization by older people. Methods This was a retrospective case-control study. Patients aged greater than 65 years seen at the geriatric outpatient clinic (Geri-OPD) and non-geriatric outpatient clinic (non-Geri-OPD) at a single medical centre were age and sex matched. Data on the number of outpatient clinic visits, emergency department visits, hospitalizations and medical expenditures were collected during the first and second years. A subgroup analysis by Charlson comorbidity index (CCI) and older age (age≧80 years) was performed, and the results were compared between the Geri-OPD and non-Geri-OPD groups. Results A total of 6723 patients were included (3796 women and 2927 men). The mean age was 80.42 ± 6.39 years. There were 1291 (19.2%) patients in the Geri-OPD group and 5432 (80.8%) patients in the non-Geri-OPD group. After one year of regular follow-up, the Geri-OPD patients showed a significant reduction in the types of drugs included in each prescription (5.62 ± 10.85) and the number of clinic visits per year (18.18 ± 48.85) ( P  < 0.01). After a two-year follow-up, the number of clinic visits, emergency department visits, and hospitalizations and the annual medical costs were still decreased in the Geri-OPD patients. The Geri-OPD patients had more comorbidities and a higher rate of health care utilization than the non-Geri-OPD patients. In the subgroup analysis, patients with more comorbidities (CCI≧2) and an older age (≧80 years) in the Geri-OPD group showed a significant reduction in health care utilization. The Geri-OPD patients also showed a significant decrease in medical utilization in the second year compared with the non-Geri-POD patients. Conclusion The Geri-OPD reduced medical costs, the number of drugs prescribed, and the frequency of outpatient clinic visits, emergency department visits and hospitalizations in older patients with complicated conditions. The effect was even better in the second year.

PurposeThis study investigated the basal autonomic regulation in patients with obstructive sleep apnea (OSA) showing periodic limb movements in sleep (PLMS) emerging after therapy with continuous positive airway pressure (CPAP).MethodsData of patients with OSA undergoing a first polysomnography for diagnosis and a second polysomnography for therapy with CPAP were reviewed. Patients with OSA showing PLMS on the first polysomnography were excluded. By using heart rate variability analysis, epochs without any sleep events and continuous effects from the second polysomnography were retrospectively analyzed.ResultsOf 125 eligible patients, 30 with PLMS after therapy with CPAP (PLMS group) and 30 not showing PLMS on both polysomnography (non-PLMS group) were randomly selected for the analysis. No significant differences in the demographic characteristics and variables of polysomnographies were identified between the groups. Although one trend of low root mean square of successive differences (RMSSD) between intervals of adjacent normal heart beats (NN intervals) in the PLMS group was observed, patients in the PLMS group had significantly low normalized high-frequency (n-HF) and high-frequency (HF) values, but high normalized low frequency (n-LF) and high ratio of LF to HF (LF/HF ratio). After adjustment for confounding variables, PLMS on the second polysomnography was significantly associated with RMSSD (β = − 6.7587, p = 0.0338), n-LF (β = 0.0907, p = 0.0148), n-HF (β = − 0.0895, p = 0.0163), log LF/HF ratio (β = 0.4923, p = 0.0090), and log HF (β = − 0.6134, p = 0.0199).ConclusionsPatients with OSA showing PLMS emerging after therapy with CPAP may have a basal sympathetic predominance with potential negative cardiovascular effects.

Background Perceived sleep quality may play an important role in diagnosis and therapy for obstructive sleep apnea (OSA). However, few studies have assessed factors that are associated with perceived sleep quality in OSA patients. Hypoxemia depresses the central nervous system and attenuates the perceived respiratory load in asthmatic patients. This study aimed to investigate the factors related to perceived sleep quality, focusing on the role of hypoxemia. Methods Polysomnography studies of 156 OSA patients were reviewed. Traditional polysomnographic parameters, including parameters of oxy-hemoglobin saturation (SpO2), were calculated, and the sleep questionnaire and scales were used. Considering the possible pitfalls of absolute values of SpO2 and individualized responses to hypoxemia, the amplitude of desaturation was further computed as “median SpO2 minus lowest 5 % SpO2 “and “highest 5 % SpO2 minus median 5 % SpO2”. Correlations between these parameters and perceived sleep quality, represented as the Pittsburgh sleep quality index (PSQI), were performed. Multiple linear regression analysis was also conducted to investigate the factors associated with the PSQI. Results Although the PSQI was not correlated with the apnea-hypopnea index (r = −0.113, p  = 0.162) and oxygen desaturation index (r = −0.085, p  = 0.291), the PSQI was negatively correlated with “median SpO2 minus lowest 5 % SpO2” (r = −0.161, p  = 0.045). After adjusting for age, total sleep time, the periodic limb movements index, tendency of depression, and the lowest 5 % SpO2, the “median SpO2 minus lowest SpO2” was still a significant predictor for a lower PSQI (β = −0.357, p  = 0.015). Conclusions More severe hypoxemia is associated with better perceived sleep quality among OSA patients. This paradox may be associated with hypoxemia-related impairment of perception. The effect of hypoxemia did not appear to be significant in relatively mild hypoxemia but become significant in severe hypoxemia.” Median SpO2 minus lowest 5 % SpO2” may also be a better predictor of perceived sleep quality than the apnea-hypopnea index because of the disproportionate effects of hypoxemia. Additionally, further studies are necessary to confirm the role of hypoxemia on perceived sleep quality and identify the possible threshold of hypoxemia in OSA patients.

Obstructive sleep apnea (OSA) can cause sleep fragmentation and intermittent hypoxemia, which are linked to oxidative stress. White matter changes (WMCs) representing cerebrovascular burden and are at risk factor for oxidative ischemic injury. The current study explores the mutual relationships between OSA and WMCs. We performed a systematic review of electronic databases for clinical studies investigating OSA and WMCs. Random-effects models were used for pooled estimates calculation. A total of 22 studies were included in the meta-analysis. The results revealed a significantly higher prevalence rate of WMCs [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.52–2.80, p < 0.001] and significantly higher severity of WMCs (Hedges’ g = 0.23, 95% CI 0.06–0.40, p = 0.009) in the patients with OSA than in controls. Furthermore, the results revealed a significantly higher apnea–hypopnea index (Hedges’ g = 0.54, 95% CI 0.31–0.78, p < 0.001) and significantly higher prevalence rate of moderate-to-severe OSA (OR 2.86, 95% CI 1.44–5.66, p = 0.003) in the patients with WMCs than in controls, however there was no significant difference in the prevalence rate of mild OSA between the patients with WMCs and controls (OR 0.71, 95% CI 0.20–2.54, p = 0.603). OSA was associated with a higher prevalence and more severe WMCs, and the patients with WMCs had an increased association with moderate-to-severe OSA. Future large-scale randomized controlled trials with a longitudinal design are essential to further evaluate treatment in patients with OSA.

Obstructive sleep apnea (OSA) has been considered as one of the risk factors for ischemic stroke, but the impact of OSA on wake-up stroke (WUS) is not well studied. We aimed to determine the relationship between OSA and WUS. We prospectively recruited 71 patients with mild to moderate ischemic stroke during hospitalization. Patients were classified into WUS and non-WUS. A full-night sleep respiratory study was performed between 3 and 14 days after stroke onset. Demographic data, sleep respiratory data, heart rate variability, stroke risk factors, stroke classification and sleep-related scales were recorded. We compared the differences in the variables between the two groups and determined the independent variables associated with WUS. Of the 71 patients, 26 (36.6%) had WUS. The patients with WUS had a significantly higher apnea-hypopnea index (23.1 ± 19.4 vs. 12.5 ± 11.9, p  = 0.016), obstructive apnea index (7.8 ± 9.7 vs. 3.0 ± 4.0, p  = 0.021) and lower mean blood oxygen saturation (95.1 ± 1.5 vs. 95.8 ± 1.3, p  = 0.046) than the non-WUS patients. There were no significant differences in demographic data, stroke risk factors, sleep-related scales or heart rate variability. Logistic regression revealed that severe sleep-disordered breathing (apnea-hypopnea index ≥30) was the only independent variable associated with WUS (OR 6.065, 95% CI 1.451–25.350; p  = 0.014). We conclude that in patients with mild to moderate ischemic stroke, OSA is the only risk factor associated with WUS, which cannot be distinguished clinically from non-WUS.