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Background Neuroinflammation with activation of microglia and production of proinflammatory cytokines in the brain plays an active role in epileptic disorders. Brain oxidative stress has also been implicated in the pathogenesis of epilepsy. Damage in the hippocampus is associated with temporal lobe epilepsy, a common form of epilepsy in human. Peripheral inflammation may exacerbate neuroinflammation and brain oxidative stress. This study examined the impact of peripheral inflammation on seizure susceptibility and the involvement of neuroinflammation and oxidative stress in the hippocampus. Results In male, adult Sprague-Dawley rats, peripheral inflammation was induced by the infusion of Escherichia coli lipopolysaccharide (LPS, 2.5 mg/kg/day) into the peritoneal cavity for 7 days via an osmotic minipump. Pharmacological agents were delivered via intracerebroventricular (i.c.v.) infusion with an osmotic minipump. The level of cytokine in plasma or hippocampus was analyzed by ELISA. Redox-related protein expression in hippocampus was evaluated by Western blot. Seizure susceptibility was tested by intraperitoneal (i.p.)  injection of kainic acid (KA, 10 mg/kg). We found that i.p. infusion of LPS for 7 days induced peripheral inflammation characterized by the increases in plasma levels of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). This is associated with a significant increase in number of the activated microglia (Iba-1 + cells), enhanced production of proinflammatory cytokines (including IL-1β, IL-6 and TNF-α), and tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus. These cellular and molecular responses to peripheral inflammation were notably blunted by i.c.v. infusion of a cycloxygenase-2 inhibitor, NS398 (5 μg/μl/h). The i.c.v. infusion of tempol (2.5 μg/μl/h), a reactive oxygen species scavenger, protected the hippocampus from oxidative damage with no apparent effect on microglia activation or cytokine production after peripheral inflammation. In the KA-induced seizure model, i.c.v. infusion of both NS398 and tempol ameliorated the increase in seizure susceptibility in animals succumbed to the LPS-induced peripheral inflammation. Conclusions Together these results indicated that LPS-induced peripheral inflammation evoked neuroinflammation and the subsequent oxidative stress in the hippocampus, resulting in the increase in KA-induced seizure susceptibility. Moreover, protection from neuroinflammation and oxidative stress in the hippocampus exerted beneficial effect on seizure susceptibility following peripheral inflammation.

Patients with chronic obstructive pulmonary disease (COPD) often have exercise intolerance. The prevalence of hypertension in COPD patients ranges from 39-51%, and β-blockers and amlodipine are commonly used drugs for these patients. We aimed to study the impact of β-blockers and amlodipine on cardiopulmonary responses during exercise. A total 81 patients with COPD were included and the patients underwent spirometry, cardiopulmonary exercise tests, and symptoms questionnaires. There were 14 patients who took bisoprolol and 67 patients who did not. Patients with COPD taking ß-blockers had lower blood oxygen concentration (SpO2) and more leg fatigue at peak exercise but similar exercise capacity as compared with patients not taking bisoprolol. There were 18 patients treated with amlodipine and 63 patients without amlodipine. Patients taking amlodipine had higher body weight, lower blood pressure at rest, and lower respiratory rates during peak exercise than those not taking amlodipine. Other cardiopulmonary parameters, such as workload, oxygen consumption at peak exercise, tidal volume at rest or exercise, cardiac index at rest or exercise were not significantly different between patients with or without bisoprolol or amlodipine. Smoking status did not differ between patients with or without bisoprolol or amlodipine. COPD is often accompanied by hypertension, and β-blockers and amlodipine are commonly used antihypertensive drugs for these patients. Patients with COPD taking bisoprolol had lower SpO2 and more leg fatigue during peak exercise. Patients taking amlodipine had lower respiratory rates during exercise than those not taking amlodipine. Exercise capacity, tidal volume, and cardiac index during exercise were similar between patients with and without bisoprolol or amlodipine.

Background Well-being is an important issue in workplace. One of these assessment tools of well-being, Workplace PERMA Profiler, is based on Seligman’s five dimensions well-being. Prolonged fatigue may last for a long time, leading a great impact on both employees and enterprises. However, rare studies about the association between well-being and fatigue had been investigated. Our aim is to establish the Chinese version Profiler, and to discovery the association between workplace well-being and fatigue. Methods The Chinese version was established according to International Society of Pharmacoeconomics and Outcomes Research (ISPOR) task force guidelines. In the study, researchers employed simple random sampling by approaching individuals undergoing health checkups or receiving workplace health services, inviting them to participate in a questionnaire-based interview. Prolonged Fatigue was evaluated by Checklist Individual Strength (CIS). The reliability was evaluated by Cronbach’s alphas, Intra-class Correlation Coefficients (ICCs), and measurement errors. Moreover, confirmatory factor analysis and correlational analyses were assessed for the validity. Results The analyses included 312 Chinese workers. Cronbach’s alphas of the Chinese version ranged from 0.69 to 0.93, while the ICC ranged from 0.70 to 0.92. The 5-factor model of confirmatory factor analysis revealed a nearly appropriate fit (χ 2 (82) = 346.560, Comparative Fit Index [CFI] = 0.887, Tucker-Lewis Index [TLI] = 0.855, Root Mean Square Error of Approximation [RMSEA] = 0.114, Standardized Root Mean Square Residual [SRMR] = 0.060). Moreover, the CIS and its four dimensions were significantly and negatively associated with the Positive Emotion, while they are positively associated with Engagement dimension except CIS-Motivation dimension. Conclusion The Chinese version Workplace PERMA-Profiler indicate nice reliability and validity. Furthermore, all CIS dimensions were negatively influenced by Positive Emotion, while commonly positively associated with Engagement.

Background Porphyrias are a group of rare, genetic disorders of heme biosynthesis in which reduced activity of any of the eight pathway enzymes leads to accumulation of intermediates and distinct clinical syndromes. These disorders are heterogeneous—not a single polymorphic condition—and are associated with impaired quality of life and increased mortality. Global epidemiological data, particularly from Asia, remain limited. This study analyzes population-based data from Taiwan to provide real-world evidence. Methods This study utilized the Taiwan National Health Insurance Research Database (~ 23 million population), which is linked with the Cause of Death Database and the Registry for National Health Insurance Catastrophic Illness Card database. Cases were validated through the rare disease registry of the Health Promotion Administration. The annual case numbers (2002–2022) were analyzed, with follow-up data on survival and causes of death. Outpatient and inpatient visits by specialty (2001–2022) and the average annual number of medical visits per person (2001–2022), including outpatient, inpatient and emergency visits, were assessed. Results Among 126 patients with porphyria, 77.0% were female, with a mean age at diagnosis of 35.12 years. The annual incidence ranges from 0.04 to 0.62 per million, with a prevalence of 5.15 per million in 2022. The neurology, family medicine, and otolaryngology departments accounted for the most outpatient visits, whereas hospitalizations were common in the pediatrics, neurology, and gastroenterology departments. The mortality rate was 1543.4 per 100,000 people, and healthcare utilization was significantly 2-fold and above than that in the general population. Conclusions The incidence and prevalence of porphyria in Taiwan are lower than those reported in previous studies. The high mortality rate and diverse clinical manifestations emphasize the need for early diagnosis and timely management to reduce the disease burden.

Background Decreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS). Methods Systemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25–0.8 Hz) and high-frequency (HF; 0.8–2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump. Results The suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline. Conclusion These results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.

Excessive fructose intake presents the major risk factor for metabolic cardiovascular disease. Perivascular adipose tissue (PVAT) is a metabolic tissue and possesses a paracrine function in regulating aortic reactivity. However, whether and how PVAT alters vascular function under fructose overconsumption remains largely unknown. In this study, male Sprague-Dawley rats (8 weeks old) were fed a 60% high fructose diet (HFD) for 12 weeks. Fasting blood sugar, insulin, and triglycerides were significantly increased by HFD intake. Plasma adiponectin was significantly enhanced in the HFD group. The expression of uncoupling protein 1 (UCP1) and mitochondrial mass were reduced in the aortic PVAT of the HFD group. Concurrently, the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and mitochondrial transcription factor A (TFAM) were suppressed. Furthermore, decreased fusion proteins (OPA1, MFN1, and MFN2) were accompanied by increased fission proteins (FIS1 and phospho-DRP1). Notably, the upregulated α-smooth muscle actin (α-SMA) and osteocalcin in the PVAT were concurrent with the impaired reactivity of aortic contraction and relaxation. Coenzyme Q 10 (Q, 10 mg/100 mL, 4 weeks) effectively reversed the aforementioned events induced by HFD. Together, these results suggested that the dysregulation of mitochondrial dynamics mediated HFD-triggered PVAT whitening to impair aortic reactivity. Fortunately, coenzyme Q 10 treatment reversed HFD-induced PVAT whitening and aortic reactivity.

PurposeThe association between secondhand smoke (SHS) and peripheral arterial disease (PAD) was inconsistent and the studies were relatively scarce, hence, we conducted a meta-analysis of the association between SHS and PAD.Materials and methodsWe systematically searched three electronic databases (PubMed, EMBASE, and Web of Science), and calculated the pooled prevalence risk ratio (RR) and estimated standard error by random effect model from the meta-analysis. Furthermore, we performed a subgroup meta-analysis according to the location of SHS exposure.ResultsWe initially identified 502 articles from the electronic database, and 6 articles, cross-sectional data from 4 cross-sectional studies and 2 prospective cohort studies, were included in the meta-analysis. Among these six articles, two studies showed a significant correlation between SHS exposure and PAD, whereas no study showed a negative correlation between SHS exposure and PAD. In the meta-analysis, pooled prevalence showed a significant association between SHS exposure and PAD (RR = 1.23; 95% confidence interval [CI] 1.08–1.41; z = 3.02, p = 0.003). In the subgroup analysis based on location of SHS exposure, the prevalence RR of PAD at home was 1.30 (95% CI 1.14–1.49, Z-3.99, p < 0.0001). The prevalence RR in the subgroup of SHS exposure at work was not significant (RR = 0.89; 95% CI 0.55–1.44; z = 0.48, p = 0.63).ConclusionExposure to SHS was significantly and positively associated with PAD. Moreover, we found a significant association between exposure to SHS and PAD at home, but the association was not significant at work.

Background Nucleic acid amplification tests (NAAT) have been used as a diagnostic tool for pulmonary tuberculosis (PTB) in Taiwan for many years. In accordance with Taiwanese legislation, health care personnel are required to notify the Centers for Disease Control and Prevention (CDC) in case of suspected PTB. This study aimed to investigate the impact of NAAT(Gen-Probe) on the notification system for PTB and anti-tuberculosis treatments in Taiwan. Methods A retrospective study on the impact of NAAT (Enhanced Amplified Mycobacterium tuberculosis Direct Test [E-MTD], Gen-Probe, San Diego, CA, USA) [NAAT(Gen-Probe)] was carried out at Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation from March 2011 to December 2017. During the study period, microscopic acid-fast-bacilli smears and mycobacterial cultures were available for PTB diagnosis. NAAT(Gen-Probe) was first introduced at the hospital in January 2014 for use as a diagnostic method for PTB. Positive sputum culture was considered as the gold standard for PTB diagnosis. We excluded clinically-diagnosed PTB cases. Results When NAAT(Gen-Probe) was applied, the rate of error notification to CDC decreased from 64.3 to 7.0% ( P  < 0.001), and unnecessary anti-TB treatments administered to suspected cases decreased from 14.9 to 6.5% ( P  = 0.005). In the non-PTB group, the mean duration of unnecessary anti-TB treatments changed from 38.9 ± 38.3 days to 37.0 ± 37.9 days ( P  = 0.874). In the PTB group, the mean time from notifying CDC to initiating treatment decreased from 3.05 ± 6.95 days to 1.48 ± 1.99 days ( P  = 0.004). The sensitivity, specificity, positive predictive value, and negative predictive value of NAAT(Gen-Probe) were 99.0, 92.3, 99.0, and 92.3%, respectively. Conclusions Use of NAAT(Gen-Probe) led to decrease in the rate of error notification of suspected PTB cases to the CDC, avoidance of unnecessary use of anti-TB treatments, and accelerated initiation of appropriate treatments.

Background Colorectal cancer (CRC) poses a significant clinical challenge because of drug resistance, which can adversely impact patient outcomes. Recent research has shown that abnormalities within the tumor microenvironment, especially hyperglycemia, play a crucial role in promoting metastasis and chemoresistance, and thereby determine the overall prognosis of patients with advanced CRC. Methods This study employs data mining and consensus molecular subtype (CMS) techniques to identify pitavastatin and atorvastatin as potential agents for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained under either low or high glucose conditions were established and utilized to assess the cytotoxic effects of pitavastatin and atorvastatin, both with and without 5-fluorouracil (5-FU). CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of pitavastatin and atorvastatin. Results A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. The CMS4 CRC cell line SW480 (SW480-HG) was established and cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. Pitavastatin and atorvastatin could inhibit cell proliferation and 3D spheroid formation of CMS4 CRC cells under high glucose conditions. In addition, both pitavastatin and atorvastatin can synergistically promote the 5-FU-mediated cytotoxic effect and inhibit the growth of 5-FU-resistant CRC cells. Mechanistically, pitavastatin and atorvastatin can induce apoptosis and synergistically promote the 5-FU-mediated cytotoxic effect by activating autophagy, as well as the PERK/ATF4/CHOP signaling pathway while decreasing YAP expression. Conclusion This study highlights the biomarker-guided precision medicine strategy for drug repurposing. Pitavastatin and atorvastatin could be used to assist in the treatment of advanced CRC, particularly with CMS4 subtype CRC patients who also suffer from hyperglycemia. Pitavastatin, with an achievable dosage used for clinical interventions, is highly recommended for a novel CRC therapeutic strategy.

Automatic speech and music activity detection (SMAD) is an enabling task that can help segment, index, and pre-process audio content in radio broadcast and TV programs. However, due to copyright concerns and the cost of manual annotation, the limited availability of diverse and sizeable datasets hinders the progress of state-of-the-art (SOTA) data-driven approaches. We address this challenge by presenting a large-scale dataset containing Mel spectrogram, VGGish, and MFCCs features extracted from around 1600 h of professionally produced audio tracks and their corresponding noisy labels indicating the approximate location of speech and music segments. The labels are several sources such as subtitles and cuesheet. A test set curated by human annotators is also included as a subset for evaluation. To validate the generalizability of the proposed dataset, we conduct several experiments comparing various model architectures and their variants under different conditions. The results suggest that our proposed dataset is able to serve as a reliable training resource and leads to SOTA performances on various public datasets. To the best of our knowledge, this dataset is the first large-scale, open-sourced dataset that contains features extracted from professionally produced audio tracks and their corresponding frame-level speech and music annotations.