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Abstract Background The dysregulation of local circadian clock has been implicated in the pathogenesis of a broad spectrum of diseases. However, the pathophysiological role of intrinsic circadian clocks Rev-Erbα in ischemia-reperfusion (IR)-induced acute lung injury (ALI) remains unclear. Methods The IR-ALI model was established by subjecting isolated perfused rat lungs to 40 min of ischemia followed by 60 min of reperfusion. Rats were randomly assigned to one of six groups: control, control + SR9009 (Rev-Erbα agonist, 50 mg/kg), IR, and IR + SR9009 at one of three dosages (12.5, 25, 50 mg/kg). Bronchoalveolar lavage fluids (BALF) and lung tissues were obtained and analyzed. In vitro experiments utilized mouse lung epithelial cells (MLE-12) exposed to hypoxia-reoxygenation (HR) and pretreated with SR9009 (10 µM/L) and Rev-Erbα siRNA. Results SR9009 exhibited a dose-dependent reduction in lung edema in IR-ALI. It significantly inhibited the production of TNF-α, IL-6, and CINC-1 in BALF. Moreover, SR9009 treatment restored suppressed IκB-α levels and reduced nuclear NF-κB p65 levels in lung tissues. In addition, a SR9009 mitigated IR-induced apoptosis and mitogen-activated protein kinase (MAPK) activation in injured lung tissue. Finally, treatment with Rev-Erbα antagonist SR8278 abolished the protective action of SR9009. In vitro analyses showed that SR9009 attenuated NF-κB activation and KC/CXCL-1 levels in MLE-12 cells exposed to HR, and these effects were significantly abrogated by Rev-Erbα siRNA. Conclusions The findings suggest that SR9009 exerts protective effects against IR-ALI in a Rev-Erbα-dependent manner. SR9009 may provide a novel adjuvant therapeutic approach for IR-ALI.

Abstract Tumor burden score (TBS) has been recently introduced to indicate the extent of tumor burden in different cancers, but its role in advanced hepatocellular carcinoma (HCC) is unclear. We aimed to determine the prognostic role of TBS in patients with HCC beyond the Milan criteria receiving surgical resection (SR) or transarterial chemoembolization (TACE). A total of 1303 newly diagnosed HCC patients beyond Milan criteria receiving SR or TACE as the primary therapy were retrospectively analyzed. Independent prognostic predictors were examined by the multivariate Cox proportional hazards model. SR was associated with better overall survival compared with TACE in these patients. Multivariate Cox analysis of the entire cohort revealed that age > 66 years (hazard ratio [HR]: 1.145, 95% confidence interval [CI]: 1.004–1.305, p = 0.043), serum α-fetoprotein > 200 ng/mL (HR: 1.602, 95% CI: 1.402–1.831, p

Abstract Background It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection. Methods VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated. Results Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody. Conclusions Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production.

Protease-activated receptor (PAR)-1 is a thrombin-activated receptor that plays an essential role in ischemia/reperfusion (IR)-induced acute inflammation. PAR-1 antagonists have been shown to alleviate injuries in various IR models. However, the effect of PAR-1 antagonists on IR-induced acute lung injury (ALI) has not yet been elucidated. This study aimed to investigate whether PAR-1 inhibition could attenuate lung IR injury. Lung IR was induced in an isolated perfused rat lung model. Male rats were treated with the specific PAR-1 antagonist SCH530348 (vorapaxar) or vehicle, followed by ischemia for 40 min and reperfusion for 60 min. To examine the role of PAR-1 and the mechanism of SCH530348 in lung IR injury, western blotting and immunohistochemical analysis of lung tissue were performed. In vitro, mouse lung epithelial cells (MLE-12) were treated with SCH530348 or vehicle and subjected to hypoxia-reoxygenation (HR). We found that SCH530348 decreased lung edema and neutrophil infiltration, attenuated thrombin production, reduced inflammatory factors, including cytokine-induced neutrophil chemoattractant-1, interleukin-6 and tumor necrosis factor-α, mitigated lung cell apoptosis, and downregulated the phosphoinositide 3-kinase (PI3K), nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in IR-injured lungs. In addition, SCH530348 prevented HR-induced NF-κB activation and inflammatory chemokine production in MLE12 cells. Our results demonstrate that SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-κB and MAPK pathways. These findings indicate that the PAR-1 antagonist protects against IR-induced ALI and is a potential therapeutic candidate for lung protection following IR injury.

The neurotransmitter Norepinephrine (NE) has been implicated in coding surprise during decision making. Here, the authors demonstrate that this extends to sensory processing: NE release is specific to unexpected events even on extremely rapid time scales and without explicit tracking of probability.

Background: Poloxamer 188 (P188) possesses anti-inflammatory properties and can help to maintain plasma membrane function. P188 has been reported to exert beneficial effects in the treatment of various disorders. However, the effects of P188 in ischemia/reperfusion (IR)-induced acute lung injury have not been examined.Methods: We investigated the ability of P188 to attenuate IR-induced acute lung injury in rats and hypoxia/reoxygenation (HR) injury in murine epithelial cells. Isolated perfused rat lungs were exposed to 40 min ischemia followed by 60 min reperfusion to induce IR injury.Results: IR led to lung edema, increased pulmonary arterial pressure, promoted lung tissue inflammation and oxidative stress, and upregulated the levels of TNF-α, IL-6 and CINC-1, and increased Lactic dehydrogenase (LDH) activity in bronchoalveolar lavage fluid. IR also downregulated the levels of inhibitor of κB (IκB-α), upregulated nuclear factor (NF)-κB (NF-κB), and promoted apoptosis in lung tissues. P188 significantly suppressed all these effects. In vitro, P188 also exerted a similar effect in murine lung epithelial cells exposed to HR. Furthermore, P188 reduced the number of propidium iodide-positive cells, maintained cell membrane integrity, and enhanced cell membrane repair following HR.Conclusion: We conclude that P188 protects against lung IR injury by suppressing multiple signaling pathways and maintaining cell membrane integrity.

Endoplasmic reticulum (ER) stress that disrupts ER function can occur in response to a wide variety of cellular stress factors leads to the accumulation of unfolded and misfolded proteins in the ER. Many studies have shown that ER stress amplified inflammatory reactions and was involved in various inflammatory diseases. However, little is known regarding the role of ER stress in hyperoxia-induced acute lung injury (HALI). This study investigated the influence of ER stress inhibitor, 4-phenyl butyric acid (4-PBA), in mice with HALI. Treatment with 4-PBA in the hyperoxia groups significantly prolonged the survival, decreased lung edema, and reduced the levels of inflammatory mediators, lactate dehydrogenase, and protein in bronchoalveolar lavage fluid, and increased claudin-4 protein expression in lung tissue. Moreover, 4-PBA reduced the ER stress-related protein expression, NF-κB activation, and apoptosis in the lung tissue. In in vitro study, 4-PBA also exerted a similar effect in hyperoxia-exposed mouse lung epithelial cells (MLE-12). However, when claudin-4 siRNA was administrated in mice and MLE-12 cells, the protective effect of 4-PBA was abrogated. These results suggested that 4-PBA protected against hyperoxia-induced ALI via enhancing claudin-4 expression.

Background: 2-Methoxyestradiol (2ME), a natural 17-β estradiol metabolite, is a potent anti-inflammatory agent, but its effect on ischemia/reperfusion (IR)-induced acute lung inflammation remains unknown. Annexin A1 (AnxA1), a glucocorticoid-regulated protein, is effective at inhibiting neutrophil transendothelial migration by binding the formyl peptide receptors (FPRs). We aimed to investigate whether 2ME upregulates the expression of AnxA1 and protects against IR-induced lung damage.Methods: IR-mediated acute lung inflammation was induced by ischemia for 40 min followed by reperfusion for 60 min in an isolated, perfused rat lung model. The rat lungs were randomly treated with vehicle or 2ME, and the functional relevance of AnxA1 was determined using an anti-AnxA1 antibody or BOC2 (a pan-receptor antagonist of the FPR). In vitro, human primary alveolar epithelial cells (HPAECs) and rat neutrophils were pretreated with 2ME and an AnxA1 siRNA or anti-AnxA1 antibody and subjected to hypoxia-reoxygenation (HR).Results: 2ME significantly decreased all lung edema parameters, neutrophil infiltration, oxidative stress, proinflammatory cytokine production, lung cell apoptosis, tight junction protein disruption, and lung tissue injury in the IR-induced acute lung inflammation model. 2ME also increased the expression of the AnxA1 mRNA and protein and suppressed the activation of nuclear factor-κB (NF-κB). In vitro, 2ME attenuated HR-triggered NF-κB activation and interleukin-8 production in HPAECs, decreased transendothelial migration, tumor necrosis factor-α production, and increased apoptosis in neutrophils exposed to HR. These protective effects of 2ME were significantly abrogated by BOC2, the anti-AnxA1 antibody, or AnxA1 siRNA.Conclusions: 2ME ameliorates IR-induced acute lung inflammation by increasing AnxA1 expression. Based on these results, 2ME may be a promising agent for attenuating IR-induced lung injury.

Hakka has been the lingua franca used among various Chinese groups in Sabah, Malaysia, since the 1950s. Economic development and de-emphasis on ethnic identity within Chinese communities throughout Malaysia is now forcing Sabah Hakkas to confront external pressures on their language and culture. Language shift from Hakka is in progress as young Hakkas prefer speaking Mandarin, while their parents feel responsible for maintaining Hakka. This article presents a case study of family language policies in four Hakka families in Sabah. Whether a particular language is used in the family and passed down to the next generation is one of the significant points of enquiry in studying language shift. In this study, parents’ ethnic identity, children’s language choices, and the factors affecting family language policy are examined. The findings show that the quintessence of Hakka culture in Sabah is the Hakka language, and this helps to keep the language alive at home. However, concern for children’s education and wider social factors such as globalisation, economic changes and the media are influencing language practices in Hakka families.

Background: Ulcerative colitis (UC) is an immune-mediated inflammatory disease that is associated with an increased incidence of cardiovascular events. Several inflammatory mechanisms associated with the pathogenesis of UC are involved in the initiation and progression of aortic aneurysms (AAs). We aimed to evaluate whether patients with UC have an increased risk of AA. Methods: We conducted a retrospective cohort study using data extracted from Taiwan's National Health Insurance Research Database. All medical conditions for each case and control subject were categorized using the International Classification of Diseases, 9th Revision. Hazard ratios and 95% confidence intervals for associations between UC and AA were estimated using the Cox regression adjusted for comorbidities. Results: Our analyses included 7256 UC patients and propensity score-matched controls. Compared to the controls, UC patients exhibited a significantly increased risk of developing an AA (adjusted odds ratio = 3.154, P < 0.001). Conclusion: UC patients have an increased risk of developing an AA, and healthcare professionals should be aware of this risk when treating UC patients. Aortic surveillance may be required for UC patients.

In this work, we fabricated indium gallium zinc oxide (IGTO) metal-semiconductor-metal (MSM) photodetectors (PDs) with different oxygen flow ratios and investigated and discussed their characteristics. 0% PDs show a high responsivity of 25.75 A/W, but their dark current is very high and their switching time is low. 10% PDs exhibit the highest performance. They show a high photo/dark current ratio of 1.05 × 105 with a low dark current of 1.19 × 10-11 A. Their responsivity is 0.12 A/W and their rejection ratio is 9.38 × 105, which is sufficiently high to ensure the accuracy of distinguishing between UV and visible ranges. Their rising time is 206 s and their falling time is 58 s. It was observed that the response time shortened as the oxygen flow ratio was increased. [ABSTRACT FROM AUTHOR]

Abstract Background Emerging evidence reveals that nicotinamide phosphoribosyltransferase (NAMPT) has a significant role in the pathophysiology of the inflammatory process. NAMPT inhibition has a beneficial effect in the treatment of a variety of inflammatory diseases. However, it remains unclear whether NAMPT inhibition has an impact on ischemia-reperfusion (I/R)-induced acute lung injury. In this study, we examined whether NAMPT inhibition provided protection against I/R lung injury in rats. Methods Isolated perfused rat lungs were subjected to 40 min of ischemia followed by 60 min of reperfusion. The rats were randomly allotted to the control, control + FK866 (NAMPT inhibitor, 10 mg/kg), I/R, or I/R + FK866 groups (n = 6 per group). The effects of FK866 on human alveolar epithelial cells exposed to hypoxia-reoxygenation (H/R) were also investigated. Results Treatment with FK866 significantly attenuated the increases in lung edema, pulmonary arterial pressure, lung injury scores, and TNF-α, CINC-1, and IL-6 concentrations in bronchoalveolar lavage fluid in the I/R group. Malondialdehyde levels, carbonyl contents and MPO-positive cells in lung tissue were also significantly reduced by FK866. Additionally, FK866 mitigated I/R-stimulated degradation of IκB-α, nuclear translocation of NF-κB, Akt phosphorylation, activation of mitogen-activated protein kinase, and downregulated MKP-1 activity in the injured lung tissue. Furthermore, FK866 increased Bcl-2 and decreased caspase-3 activity in the I/R rat lungs. Comparably, the in vitro experiments showed that FK866 also inhibited IL-8 production and NF-κB activation in human alveolar epithelial cells exposed to H/R. Conclusions Our findings suggest that NAMPT inhibition may be a novel therapeutic approach for I/R-induced lung injury. The protective effects involve the suppression of multiple signal pathways.

BackgroundPrevious investigations reveal that BTP2, a store-operated calcium channel blocker, has protective and anti-inflammatory properties in multiple inflammatory diseases. This study investigates whether BTP2 can protect against decompression sickness (DCS) in a rat model.MethodsBTP2 (2 mg/kg) was administered to male Sprague–Dawley rats 30 min before subjecting them to hyperbaric pressure. Control rats were not treated. After decompression, signs of DCS were examined, and samples of bronchoalveolar lavage fluid and lung tissue were obtained for evaluation.ResultsThe incidence and mortality of DCS were decreased significantly in rats treated with BTP2 compared to those treated with dimethyl sulfoxide. BTP2 significantly attenuated DCS-induced lung edema, histological evidence of lung inflammation, necroptosis, and apoptosis, while it decreased levels of tumor necrosis factor alpha, interleukin-6, and cytokine-induced neutrophil chemoattractant-1 in bronchoalveolar lavage fluid. In addition, BTP2 reduced the expression of nuclear factor of activated T cells and early growth response protein 3 in lung tissue. BTP2 also significantly increased the levels of inhibitor kappa B alpha and suppressed the levels of nuclear factor kappa B in lung tissue.ConclusionThe results suggest that BTP2 may has potential as a prophylactic therapy to attenuate DCS-induced injury.

Background: Increasing evidence suggests that Fbxo3 signaling has an important impact on the pathophysiology of the inflammatory process. Fbxo3 protein inhibition has reduced cytokine-driven inflammation and improved disease severity in animal model of Pseudomonas-induced lung injury. However, it remains unclear whether inhibition of Fbxo3 protein provides protection in acute lung injury induced by ischemia-reperfusion (I/R). In this study, we investigated the protective effects of BC-1215 administration, a Fbxo3 inhibitor, on acute lung injury induced by I/R in rats.Methods: Lung I/R injury was induced by ischemia (40 min) followed by reperfusion (60 min). The rats were randomly assigned into one of six experimental groups (n = 6 rats/group): the control group, control + BC-1215 (Fbxo3 inhibitor, 0.5 mg/kg) group, I/R group, or I/R + BC-1215 (0.1, 0.25, 0.5 mg/kg) groups. The effects of BC-1215 on human alveolar epithelial cells subjected to hypoxia-reoxygenation (H/R) were also examined.Results: BC-1215 significantly attenuated I/R-induced lung edema, indicated by a reduced vascular filtration coefficient, wet/dry weight ratio, lung injury scores, and protein levels in bronchoalveolar lavage fluid (BALF). Oxidative stress and the level of inflammatory cytokines in BALF were also significantly reduced following administration of BC-1215. Additionally, BC-1215 mitigated I/R-stimulated apoptosis, NF-κB, and mitogen-activated protein kinase activation in the injured lung tissue. BC-1215 increased Fbxl2 protein expression and suppressed Fbxo3 and TNFR associated factor (TRAF)1–6 protein expression. BC-1215 also inhibited IL-8 production and NF-κB activation in vitro in experiments with alveolar epithelial cells exposed to H/R.Conclusions: Our findings demonstrated that Fbxo3 inhibition may represent a novel therapeutic approach for I/R-induced lung injury, with beneficial effects due to destabilizing TRAF proteins.

To quantify damage to reinforced concrete (RC) column members after an earthquake, an engineer needs to know the maximum applied force that was generated by the earthquake. Therefore, in this work, piezoceramic transducers were used to detect the applied force on an RC column member under dynamic loading. To investigate the use of post-embedded piezoceramic sensors in detecting the force that is applied to RC columns, eight full-size RC column specimens with various failure modes were tested under specific earthquake loadings. Post-embedded piezoceramic sensors were installed at a range of depths (70–80 mm) beneath the surface of a column specimen to examine the relationship between the signals that were obtained from them and the force applied by the dynamic actuator. The signals that were generated by the post-embedded piezoceramic sensors, which correlate with the applied force, are presented. These results indicate that the post-embedded piezoceramic sensors have great potential as tools for measuring the maximum applied force on an RC column in an earthquake. In other words, signals that are obtained from post-embedded piezoceramic sensors on an RC column in an earthquake can be used to determine the applied force and corresponding damage or residual seismic capacity.

BACKGROUND:Diabetes is the most common comorbidity of necrotizing fasciitis (NF), but the effect of stress-induced hyperglycemia (SIH) on diabetic patients with NF has never been investigated. The aim of this study was to assess whether SIH, as determined by the glycemic gap between admission glucose levels and A1C-derived average glucose levels, predicts adverse outcomes in diabetic patients hospitalized with NF. METHODS:We retrospectively reviewed the glycemic gap and clinical outcomes in 252 diabetic patients hospitalized due to NF from 2011 to 2018 in a single medical center in Taiwan. A receiver operating characteristic (ROC) curve was used to analyze the optimal cutoff values for predicting adverse outcomes. Univariate and multivariate logistic regression analyses were employed to identify significant predictors of adverse outcomes. RESULTS:In total, 194 diabetic NF patients were enrolled. Compared with patients without adverse outcomes, patients with adverse outcomes had significantly higher glycemic gaps, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and C-reactive protein (CRP) levels; lower albumin and hemoglobin levels; greater incidence of limb loss; and longer hospital and intensive care unit stays. The glycemic gap positively correlates with the laboratory risk indicator for NF scores, APACHE II scores and CRP levels. A glycemic gap of 146 mg/dL was the optimal cutoff value for predicting adverse outcomes using the ROC curve. Compared with patients with glycemic gaps ≤146 mg/dL, those with glycemic gaps >146 mg/dL had higher APACHE II scores and incidence rates of adverse outcomes, especially bacteremia and acute kidney injury. Multivariate analysis revealed that a glycemic gap >146 mg/dL and APACHE II score >15 were independent predictors of adverse outcomes, while the presence of hyperglycemia at admission was not. CONCLUSIONS:An elevated glycemic gap was significantly independently associated with adverse outcomes in diabetic NF patients. Further prospective studies are warranted to validate the role of the glycemic gap in NF patients with diabetes.

This study aimed to identify the trends in the incidence of thymic cancer, i.e., thymoma, thymic carcinoma, and thymic neuroendocrine tumor, in the United States. Data from the United States Cancer Statistics (USCS) database (2001-2015) and those from the Surveillance, Epidemiology, and End Results (SEER) database (SEER 9 [1973-2015], SEER 13 [1992-2015], and SEER 18 [2000-2015]) were used in this study. All incidences were per 100,000 population at risk. The trends in incidence were described as annual percent change (APC) using the Joinpoint regression program. Data from the USCS (2001-2015) database showed an increase in thymic cancer diagnosis with an APC of 4.89% from 2001 to 2006, which is mainly attributed to the significant increase in the incidence of thymoma and thymic carcinoma particularly in women. The incidence of thymic cancer did not increase from 2006 to 2015, which may be attributed to the increase in the diagnosis of thymic carcinoma from 2004 to 2015, with a concomitant decrease in thymoma from 2008 to 2015. Before declining, the age-specific incidence of thymic cancer peaked at ages 70-74 years, with a peak incidence at 1.06 per 100,000 population, and decreased in older age groups. The incidence of thymic cancer was higher in men than in women. Asian/Pacific Islanders had the highest incidence of thymoma, followed by black and then white people. The incidence of thymic carcinoma increased from 2004 to 2015, with a concomitant decrease in thymoma from 2008 to 2015. Asian/Pacific Islanders had the highest incidence of thymoma than other races.

There are indications that the pupillary dilation response (PDR) reflects surprising moments in an auditory sequence such as the appearance of a deviant noise against repetitively presented pure tones (Liao, Yoneya, Kidani, Kashino, & Furukawa, 2016), and salient and loud sounds that are evaluated by human participants subjectively (Liao, Kidani, Yoneya, Kashino, & Furukawa, 2016). In the current study, we further examined whether the reflection of PDR in auditory surprise can be accumulated and revealed in complex and yet structured auditory stimuli, i.e., music, and when the surprise is defined subjectively. Participants listened to 15 excerpts of music while their pupillary responses were recorded. In the surprise-rating session, participants rated how surprising an instance in the excerpt was, i.e., rich in variation versus monotonous, while they listened to it. In the passive-listening session, they listened to the same 15 excerpts again but were not involved in any task. The pupil diameter data obtained from both sessions were time-aligned to the rating data obtained from the surprise-rating session. Results showed that in both sessions, mean pupil diameter was larger at moments rated more surprising than unsurprising. The result suggests that the PDR reflects surprise in music automatically.

Introduction: Maintaining immobilization to minimize skull motion is important during frameless radiosurgery. This study aimed to compare the intrafractional skull motions between two head supports.Methods: With 6D skull tracking system, 4,075 image records from 45 patients receiving radiosurgery by CyberKnife were obtained. Twenty-three patients used TIMO head supports (CIVCO) (Group A) and twenty-two patients used Silverman head supports (CIVCO) with MoldCare cushions (ALCARE) (Group B). The skull motions in X (superior-inferior), Y (right-left), Z (anterior-posterior) axes, 3D (three-dimensional) vector, Roll, Pitch and Yaw between the two groups were compared and the margins of planning target volume were estimated.Results: The translational motions in Group A were similar in three axes at initial but became different after 10 min, and those in Group B were less prominent in the Y axis. The rotational errors in Group A were most obvious in Yaw, but those in Group B were stationary in three axes. The motions in the X axis, 3D vector, Pitch and Yaw in Group B were significantly smaller than those in Group A; conversely, the motions in the Z axis in Group B were larger. To cover the 95% confidence intervals, margins of 0.77, 0.79, and 0.40 mm in the X, Y, and Z axes, respectively, were needed in Group A, and 0.69, 0.50, and 0.51 mm were needed in Group B.Conclusions: Both head supports could provide good immobilization during the frameless radiosurgery. Silverman head support with MoldCare cushion was better than TIMO head support in the superior-inferior direction, 3D vector, Pitch and Yaw axes, but worse in the anterior-posterior direction.