A novel role of sesamol in inhibiting NF-κB-mediated signaling in platelet activation

<p>Abstract</p> <p>Background</p> <p>Platelet activation is relevant to a variety of coronary heart diseases. Our previous studies revealed that sesamol possesses potent antiplatelet activity through increasing cyclic AMP formation. Although platelets are anucleated cells, they also express the transcription factor, NF-κB, that may exert non-genomic functions in platelet activation. Therefore, we further investigated the inhibitory roles of sesamol in NF-κB-mediated platelet function.</p> <p>Methods</p> <p>Platelet aggregation, Fura 2-AM fluorescence, and immunoblotting analysis were used in this study.</p> <p>Results</p> <p>NF-κB signaling events, including IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation, were markedly activated by collagen (1 μg/ml) in washed human platelets, and these signaling events were attenuated by sesamol (2.5~25 μM). Furthermore, SQ22536 and ODQ, inhibitors of adenylate cyclase and guanylate cyclase, respectively, strongly reversed the sesamol (25 μM)-mediated inhibitory effects of IKKβ phosphorylation, IκBα degradation, and p65 phosphorylation stimulated by collagen. The protein kinase A (PKA) inhibitor, H89, also reversed sesamol-mediated inhibition of IκBα degradation. Moreover, BAY11-7082, an NF-κB inhibitor, abolished IκBα degradation, phospholipase C (PLC)γ2 phosphorylation, protein kinase C (PKC) activation, [Ca²⁺]i mobilization, and platelet aggregation stimulated by collagen. Preincubation of platelets with the inhibitors, SQ22536 and H89, both strongly reversed sesamol-mediated inhibition of platelet aggregation and [Ca²⁺]i mobilization.</p> <p>Conclusions</p> <p>Sesamol activates cAMP-PKA signaling, followed by inhibition of the NF-κB-PLC-PKC cascade, thereby leading to inhibition of [Ca²⁺]i mobilization and platelet aggregation. Because platelet activation is not only linked to hemostasis, but also has a relevant role in inflammation and metastasis, our data demonstrating that inhibition of NF-κB interferes with platelet function may have a great impact when these types of drugs are considered for the treatment of cancer and various inflammatory diseases.</p

The Clinical COPD Questionnaire Correlated with BODE Index-A Cross-Sectional Study

The Global initiative for Chronic Obstructive Lung Disease (GOLD) staging has widely used in the stratification of the severity of COPD, while BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index was proven superior to FEV1 in predicting mortality, exacerbation and disease severity in patients with COPD. Clinical COPD Questionnaire (CCQ), a questionnaire with ten items categorized into three domains (symptoms, functional state and mental state) was developed to measure health status of COPD patients. However, little is known about the relationship between CCQ score and BODE index. We performed a prospective study with the inclusion of 89 patients who were clinically stable after a 6-week-therapy for COPD symptoms comparing their health status assessed by CCQ, BODE index and GOLD staging. We found that the total CCQ score was correlated with BODE score (P < 0.001) and GOLD staging (P < 0.001); of three CCQ domains, the functional status correlated the most with BODE index (rS = 0.670) and GOLD staging (rS = 0.531), followed by symptoms (rS = 0.482; rS = 0.346, respectively), and mental status (rS = 0.340; rS = 0.236, respectively). Our data suggest that CCQ is a reliable and convenient alternative tool to evaluate the severity of COPD

Bacteremic pneumonia caused by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: Appropriateness of empirical treatment matters

BackgroundClinical information about bacteremic pneumonia caused by extended-spectrum beta-lactamase (ESBL)-producing organism is limited.MethodsA retrospective study was conducted at two medical centers in Taiwan. From May 2002 to August 2010, clinical information and outcome of adults with bacteremic pneumonia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae were analyzed. The primary outcome is the 30-day mortality.ResultsA total of 111 patients with bacteremic pneumonia caused by E. coli (37 patients, 33.3%) and K. pneumoniae (74, 66.7%) were identified. Their mean age was 69.2 years and 51.4% were male patients. Fifty-seven (51.3%) episodes were classified as hospital-acquired infections, 19 (17.1%) as health-care-associated infections, and four (3.6%) as community-acquired infections. Fifty-one (45.9%) patients received appropriate empiric antimicrobial therapy. The 30-day mortality rate was 40.5% (45 patients). In the multivariate analysis, several independent risk factors, including rapidly fatal underlying disease [odds ratio (OR), 5.75; 95% confidence interval (CI), 1.54–21.48; p = 0.009], severe sepsis (OR, 4.84; 95% CI, 1.55–15.14; p = 0.007), critical illness (OR, 4.28; 95% CI, 1.35–13.57; p = 0.013), and receipt of appropriate empirical therapy (OR, 0.19; 95% CI, 0.07–0.55; p = 0.002), were associated with 30-day mortality. The survival analysis consistently found that individuals with appropriate empiric therapy had a higher survival rate (log-rank test, p < 0.001).ConclusionESBL-producing bacteremic pneumonia, especially health-care-associated infections, often occurred in adults with comorbidities. Appropriate empirical therapy was associated with a favorable outcome

Comparison of Acute Lobar Nephronia and Acute Pyelonephritis in Children: A Single-Center Clinical Analysis in Southern Taiwan

BackgroundPatients with acute lobar nephronia (ALN) require a longer duration of antimicrobial treatment than those with acute pyelonephritis (APN), and ALN is associated with renal scarring. The aim of this study was to provide an understanding of ALN by comparing the clinical features of pediatric patients with ALN and APN.MethodsWe enrolled all of the patients with ALN (confirmed by computed tomography) admitted to our hospital from 1999 to 2012 in the ALN group. In addition, each patient diagnosed with APN who was matched for sex, age, and admission date to each ALN patient was enrolled in the APN group. The medical charts of patients in these two groups were retrospectively reviewed and analyzed for comparison.ResultsThe fever duration after hospitalization in the ALN group and the APN group were 4.85 ± 2.33 days and 2.30 ± 1.47 days respectively. The microbiological distributions and the majority of susceptibilities were similar in the ALN and APN groups. The majority of clinical manifestations are nonspecific and unreliable for the differentiation of ALN and APN. The patients with ALN were febrile for longer after antimicrobial treatment, had more nausea/vomiting symptoms, higher neutrophil count, bandemia, and C-reactive protein (CRP) levels, and lower platelet count (all p < 0.05). In multivariate analysis, initial CRP levels, nausea/vomiting symptoms, and fever duration after admission were independent variables with statistical significance to predict ALN. Severe nephromegaly occurred significantly more in the ALN group than in the APN group (p = 0.022).ConclusionThe majority of clinical manifestations, laboratory findings, and microbiological features are similar between patients with ALN and APN. Clinicians should keep a high index of suspicion regarding ALN, particularly for those with ultrasonographic nephromegaly, initial higher CRP, nausea/vomiting, and fever for > 5 days after antimicrobial treatment

Improved Breath Phase and Continuous Adventitious Sound Detection in Lung and Tracheal Sound Using Mixed Set Training and Domain Adaptation

Previously, we established a lung sound database, HF_Lung_V2 and proposed convolutional bidirectional gated recurrent unit (CNN-BiGRU) models with adequate ability for inhalation, exhalation, continuous adventitious sound (CAS), and discontinuous adventitious sound detection in the lung sound. In this study, we proceeded to build a tracheal sound database, HF_Tracheal_V1, containing 11107 of 15-second tracheal sound recordings, 23087 inhalation labels, 16728 exhalation labels, and 6874 CAS labels. The tracheal sound in HF_Tracheal_V1 and the lung sound in HF_Lung_V2 were either combined or used alone to train the CNN-BiGRU models for respective lung and tracheal sound analysis. Different training strategies were investigated and compared: (1) using full training (training from scratch) to train the lung sound models using lung sound alone and train the tracheal sound models using tracheal sound alone, (2) using a mixed set that contains both the lung and tracheal sound to train the models, and (3) using domain adaptation that finetuned the pre-trained lung sound models with the tracheal sound data and vice versa. Results showed that the models trained only by lung sound performed poorly in the tracheal sound analysis and vice versa. However, the mixed set training and domain adaptation can improve the performance of exhalation and CAS detection in the lung sound, and inhalation, exhalation, and CAS detection in the tracheal sound compared to positive controls (lung models trained only by lung sound and vice versa). Especially, a model derived from the mixed set training prevails in the situation of killing two birds with one stone.Comment: To be submitted, 31 pages, 6 figures, 5 table

Effects of Extract from Solid-State Fermented Cordyceps sinensis on Type 2 Diabetes Mellitus

Diabetes mellitus is the most common chronic disease in the world, and a wide range of drugs, including Chinese herbs, have been evaluated for the treatment of associated metabolic disorders. This study investigated the potential hypoglycemic and renoprotective effects of an extract from the solid-state fermented mycelium of Cordyceps sinensis (CS). We employed the KK/HIJ diabetic mouse model, in which the mice were provided with a high-fat diet for 8 weeks to induce hyperglycemia, followed by the administration of CS or rosiglitazone for 4 consecutive weeks. Several parameters were evaluated, including changes in body weight, plasma lipid profiles, oral glucose tolerance tests, insulin tolerance tests, and plasma insulin concentrations. Our results show that the CS extract significantly elevated HDL/LDL ratios at 4 weeks and decreased body weight gain at 8 weeks. Interestingly, CS treatment did not lead to obvious improvements in hyperglycemia or resistance to insulin, while in vitro MTT assays indicated that CS protects pancreatic beta cells against the toxic effects of STZ. CS also enhanced renal NKA activity and reduced the accumulation of mesangial matrix and collagen deposition. In conclusion, CS extract can potentially preserve β-cell function and offer renoprotection, which may afford a promising therapy for DM

A Novel Design of Grooved Fibers for Fiber-Optic Localized Plasmon Resonance Biosensors

Bio-molecular recognition is detected by the unique optical properties of self-assembled gold nanoparticles on the unclad portions of an optical fiber whose surfaces have been modified with a receptor. To enhance the performance of the sensing platform, the sensing element is integrated with a microfluidic chip to reduce sample and reagent volume, to shorten response time and analysis time, as well as to increase sensitivity. The main purpose of the present study is to design grooves on the optical fiber for the FO-LPR microfluidic chip and investigate the effect of the groove geometry on the biochemical binding kinetics through simulations. The optical fiber is designed and termed as U-type or D-type based on the shape of the grooves. The numerical results indicate that the design of the D-type fiber exhibits efficient performance on biochemical binding. The grooves designed on the optical fiber also induce chaotic advection to enhance the mixing in the microchannel. The mixing patterns indicate that D-type grooves enhance the mixing more effectively than U-type grooves. D-type fiber with six grooves is the optimum design according to the numerical results. The experimental results show that the D-type fiber could sustain larger elongation than the U-type fiber. Furthermore, this study successfully demonstrates the feasibility of fabricating the grooved optical fibers by the femtosecond laser, and making a transmission-based FO-LPR probe for chemical sensing. The sensor resolution of the sensor implementing the D-type fiber modified by gold nanoparticles was 4.1 × 10−7 RIU, which is much more sensitive than that of U-type optical fiber (1.8 × 10−3 RIU)

Multilaboratory assessment of Epstein-Barr virus serologic assays: the case for standardization

IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations

Benchmarking of eight recurrent neural network variants for breath phase and adventitious sound detection on a self-developed open-access lung sound database-HF_Lung_V1

A reliable, remote, and continuous real-time respiratory sound monitor with automated respiratory sound analysis ability is urgently required in many clinical scenarios-such as in monitoring disease progression of coronavirus disease 2019-to replace conventional auscultation with a handheld stethoscope. However, a robust computerized respiratory sound analysis algorithm has not yet been validated in practical applications. In this study, we developed a lung sound database (HF_Lung_V1) comprising 9,765 audio files of lung sounds (duration of 15 s each), 34,095 inhalation labels, 18,349 exhalation labels, 13,883 continuous adventitious sound (CAS) labels (comprising 8,457 wheeze labels, 686 stridor labels, and 4,740 rhonchi labels), and 15,606 discontinuous adventitious sound labels (all crackles). We conducted benchmark tests for long short-term memory (LSTM), gated recurrent unit (GRU), bidirectional LSTM (BiLSTM), bidirectional GRU (BiGRU), convolutional neural network (CNN)-LSTM, CNN-GRU, CNN-BiLSTM, and CNN-BiGRU models for breath phase detection and adventitious sound detection. We also conducted a performance comparison between the LSTM-based and GRU-based models, between unidirectional and bidirectional models, and between models with and without a CNN. The results revealed that these models exhibited adequate performance in lung sound analysis. The GRU-based models outperformed, in terms of F1 scores and areas under the receiver operating characteristic curves, the LSTM-based models in most of the defined tasks. Furthermore, all bidirectional models outperformed their unidirectional counterparts. Finally, the addition of a CNN improved the accuracy of lung sound analysis, especially in the CAS detection tasks.Comment: 48 pages, 8 figures. To be submitte