A decrease in integrin α5ß1/FAK is associated with increased apoptosis of aortic smooth muscle cells in acute type a aortic dissection.

BACKGROUND: Acute type A aortic dissection (AAAD) is a devastating disease. Human aortic smooth muscle cells (HASMCs) exhibit decreased proliferation and increased apoptosis, and integrin α5ß1 and FAK are important proangiogenic factors involved in regulating angiogenesis. The aim of this study was to investigate the role of integrin α5ß1 and FAK in patients with AAAD and the potential underlying mechanisms. METHODS: Aortic tissue samples were obtained from 8 patients with AAAD and 4 organ donors at Zhongshan Hospital of Fudan University. The level of apoptosis in the aortic tissues was assessed by immunohistochemical (IHC) staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assays. The expression of integrin α5ß1 and FAK was determined. Integrin α5ß1 was found to be significantly expressed in HASMCs, and its interaction with FAK was assessed via coimmunoprecipitation (Co-IP) analysis. Proliferation and apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assays and flow cytometry after integrin α5ß1 deficiency. RESULTS: The levels of integrin α5ß1 and FAK were both significantly decreased in patients with AAAD. Downregulating the expression of integrin α5ß1-FAK strongly increased apoptosis and decreased proliferation in HASMCs, indicating that integrin α5ß1-FAK might play an important role in the development of AAAD. CONCLUSIONS: Downregulation of integrin α5ß1-FAK is associated with increased apoptosis and decreased proliferation in aortic smooth muscle cells and may be a potential therapeutic strategy for AAAD.

Unleashing the Power of Osmotic Energy: Metal Hydroxide-Organic Framework Membranes for Efficient Conversion.

Osmotic energy, as a renewable clean energy with huge energy density and stable yield, has received widespread attention over the past decades. Reverse electrodialysis (RED) based on ion-exchange membranes is an important method of obtaining osmotic energy from salinity gradients. The preparation of ion-exchange membranes with both high ion selectivity and ion permeability is in constant exploration. In this work, metal hydroxide-organic framework (MHOF) membranes are successfully prepared onto porous anodic aluminum oxide (AAO) membranes by a facile hydrothermal method to form Ni2 (OH)2 @AAO composite membranes, used for osmotic energy conversion. The surface is negatively charged with cation selectivity, and the asymmetric structure and extreme hydrophilicity enhance the ionic flux for effective capture of osmotic energy. The maximum output power density of 5.65 W m-2 at a 50-fold KCl concentration gradient is achieved, which exceeds the commercial benchmark of 5 W m-2 . Meanwhile, the composite membrane can also show good performance in different electrolyte solutions and acid-base environments. This work provides a new avenue for the construction and application of MHOF membranes in efficient osmotic energy conversion.

In Situ Growth of MOF-303 Membranes onto Porous Anodic Aluminum Oxide Substrates for Harvesting Salinity-Gradient Energy.

As an emerging metal-organic framework (MOF) material in recent years, the MOF-303 membrane has shown great potential applications in seawater desalination, dehydration, and atmospheric water harvesting. Herein, we report on a dense and uniform MOF-303 membrane fabricated by a facile in situ hydrothermal synthesis approach in the presence of an anodized aluminum oxide (AAO) channel membrane acting as the only Al source and substrate. Interestingly, the MOF-303 isomer can be obtained due to an insufficient amount of organic ligand caused by the less hydrophilic and larger pore size of the AAO substrate. The MOF-based composite membranes possessed surface-charge-governed ionic transport behavior. Moreover, the MOF-303/AAO membrane yielded an output power density of 1.87 W/m2 under a 50-fold KCl concentration gradient. Under a 50-fold gradient of artificial seawater and river water, a maximum power density of 1.46 W/m2 can be obtained. After 30 days of stability testing, the composite membrane still maintained the power output, and the power density was higher than 1.20 W/m2. This work provides a facile and effective strategy for constructing Al-based MOF composite membranes and boosts their applications in harvesting salinity-gradient energy.

Derivation of a HEAR Pathway for Emergency Department Chest Pain Patients to Safely Avoid a Second Troponin Test.

The study aims to develop a decision pathway based on HEAR score and 0 h high-sensitivity cardiac troponin T (hs-cTnT) to safely avoid a second troponin test for suspected non-ST elevation myocardial infarction (NSTEMI) in emergency departments. A HEAR score consists of history, electrocardiogram, age, and risk factors. A HEAR pathway is established using a Bayesian approach based on a predefined safety threshold of NSTEMI prevalence in the rule-out group. In total, 7131 patients were retrospectively enrolled, 582 (8.2%) with index visit NSTEMI and 940 (13.2%) with 180-day major adverse cardiovascular events (MACE). For patients with a low-risk HEAR score (0 to 2) and low 0 h hs-cTnT (<14 ng/L), the HEAR pathway recommends early discharge without further testing. After the HEAR pathway had been applied to rule out NSTEMI, the negative predictive value of index visit NSTEMI was 100.0% (95% CI, 99.8% to 100.0%) and false-negative rate of 180-day MACE was 0.40% (95% CI, 0.18% to 0.87%). Compared with the 0 h hs-cTnT < limit of detection (LoD) strategy (<5 ng/L), the HEAR pathway could correctly reclassify 1298 patients without MACE as low risk and lead to a 18.2% decrease (95% CI, 17.4-19.1%) in the need for a second troponin test. The HEAR pathway may lead to a substantial and safe reduction in repeated troponin test for emergency department patients with suspected NSTEMI.

Simple Death Risk Models to Predict In-hospital Outcomes in Acute Aortic Dissection in Emergency Department.

Objective: We sought to find a bedside prognosis prediction model based on clinical and image parameters to determine the in-hospital outcomes of acute aortic dissection (AAD) in the emergency department. Methods: Patients who presented with AAD from January 2010 to December 2019 were retrospectively recruited in our derivation cohort. Then we prospectively collected patients with AAD from January 2020 to December 2021 as the validation cohort. We collected the demographics, medical history, treatment options, and in-hospital outcomes. All enrolled patients underwent computed tomography angiography. The image data were systematically reviewed for anatomic criteria in a retrospective fashion by three professional radiologists. A series of radiological parameters, including the extent of dissection, the site of the intimal tear, entry tear diameter, aortic diameter at each level, maximum false lumen diameter, and presence of pericardial effusion were collected. Results: Of the 449 patients in the derivation cohort, 345 (76.8%) were male, the mean age was 61 years, and 298 (66.4%) had a history of hypertension. Surgical repair was performed in 327 (72.8%) cases in the derivation cohort, and the overall crude in-hospital mortality of AAD was 10.9%. Multivariate logistic regression analysis showed that predictors of in-hospital mortality in AAD included age, Marfan syndrome, type A aortic dissection, surgical repair, and maximum false lumen diameter. A final prognostic model incorporating these five predictors showed good calibration and discrimination in the derivation and validation cohorts. As for type A aortic dissection, 3-level type A aortic dissection clinical prognosis score (3ADPS) including 5 clinical and image variables scored from -2 to 5 was established: (1) moderate risk of death if 3ADPS is <0; (2) high risk of death if 3ADPS is 1-2; (3) very high risk of death if 3ADPS is more than 3. The area under the receiver operator characteristic curves in the validation cohorts was 0.833 (95% CI, 0.700-0.967). Conclusion: Age, Marfan syndrome, type A aortic dissection, surgical repair, and maximum false lumen diameter can significantly affect the in-hospital outcomes of AAD. And 3ADPS contributes to the prediction of in-hospital prognosis of type A aortic dissection rapidly and effectively. As multivariable risk prediction tools, the risk models were readily available for emergency doctors to predict in-hospital mortality of patients with AAD in extreme clinical risk.

Diagnosis of sepsis with inflammatory biomarkers, cytokines, endothelial functional markers from SIRS patients.

BACKGROUND: Sepsis is a life-threatening illness with a challenging diagnosis. Rapid detection is the key to successful treatment of sepsis. To investigate diagnostic value, the plasma protein profiles of inflammatory biomarkers, cytokines, and endothelial functional markers were compared between healthy controls, SIRS, and septic patients. METHODS: The plasma protein profiles were performed by Luminex Assay in a cohort of 50 SIRS patients, 82 septic patients and 25 healthy controls. Fourteen plasma proteins were analyzed in the same cohort: IL-1ß, IL-6, IL-8, IL-10, CCL-2, VEGF, VEGF-C, VEGFR2, CD62E, CD62P, MFG-E8, ICAM-1, TFPI, Urokinase. RESULT: IL-2R, IL-6, IL-8, IL-10, CCL-2, ICAM-1, and Urokinase were significantly higher in sepsis patients than SIRS patients. VEGF, IL-1ß, CD62E, CD62P, MFG-E8, and TFPI have no statistical difference. VEGF-C, VEGFR2 were significantly different in SIRS patients than sepsis patients. Urokinase, ICAM-1, and VEGFR2 were significantly different between sepsis group and SIRS group. The AUCs of Urokinase, ICAM-1, and VEGFR2 and the combination for the diagnosis of sepsis were 0.650, 0.688, 0.643, and 0.741, respectively. CONCLUSIONS: Most patients have the higher level of several cytokines and developed endothelial cell injury in the initial phase of sepsis, Urokinase, ICAM-1, and VEGFR2 may be useful to evaluate severity and prognosis of sepsis patients.

[Prognostic risk factors of patients with sepsis and the clinical characteristics of patients with septic myocardial injury].

OBJECTIVE: To analyze the prognostic risk factors of patients with sepsis and the clinical characteristics of patients with septic myocardial injury. METHODS: A retrospective study was conducted. The clinical data of 300 patients with sepsis admitted to emergency department of Zhongshan Hospital of Fudan University from September 2017 to June 2020 were enrolled, including basic information, blood test indicators and auxiliary inspection indicators. The patients were grouped according to myocardial injury and the clinical characteristics of patients with septic myocardial injury were analyzed. According to 28-day prognosis, they were divided into survival group and non-survival group. The differences in various indicators between the two groups were compared, and binary Logistic regression was used to explore independent risk factors for death in patients with sepsis. RESULTS: In 300 patients, 47 patients were excluded for previous heart disease or lack of the main inspections, and 253 patients were enrolled finally. (1) Myocardial injury occurred in 136 out of 253 patients (53.8%), and 117 without myocardial injury. Compared with the non-myocardial injury group, the myocardial injury group had higher blood white blood cell count [WBC (×109/L): 9.7 (6.7, 13.4) vs. 8.3 (5.4, 12.2)] and procalcitonin [PCT (µg/L): 0.61 (0.18, 4.63) vs. 0.23 (0.09, 0.99)] at admission, and more Staphylococcal infections (17.6% vs. 2.6%), more arrhythmia (sinus tachycardia: 30.9% vs. 23.1%), more ST-T changes (26.5% vs. 23.1%), lower left ventricular ejection fraction [LVEF: 0.60 (0.54, 0.65) vs. 0.62 (0.60, 0.66)], higher pulmonary artery systolic pressure [PASP (mmHg, 1 mmHg = 0.133 kPa): 38.0 (32.2, 46.0) vs. 33.0 (30.0, 40.2)], and worse prognosis (28-day mortality: 44.1% vs. 6.0%, all P < 0.05). Logistic regression analysis showed that PCT increased [odds ratio (OR) = 1.039, 95% confidence interval (95%CI) was 1.018-1.060, P < 0.01], LVEF decreased (OR = 0.828, 95%CI was 0.729-0.941, P < 0.01) and sinus tachycardia (OR = 3.512, 95%CI was 1.417-8.702, P < 0.01) were clinical characteristics of septic patients with myocardial injury. (2) A total of 186 of the 253 patients survived, and 67 died with 28-day mortality of 26.5%. Compared with the survival group, non-survival group had higher myocardial markers and inflammation markers at admission [cardiac troponin T (cTnT, µg/L): 0.06 (0.02, 0.17) vs. 0.02 (0.01, 0.05), N-terminal pro-brain natriuretic peptide (NT-proBNP, ng/L): 3 037.0 (1 308.7, 12 033.7) vs. 893.9 (272.8, 2 825.5), creatine kinase (CK, U/L): 144.5 (57.5, 660.8) vs. 89.5 (47.8, 201.0), WBC (×109/L): 10.5 (6.7, 14.6) vs. 8.6 (6.0, 12.0), C-reactive protein (CRP, mg/L): 89.2 (54.8, 128.5) vs. 63.8 (19.3, 105.6), PCT (µg/L): 2.13 (0.31, 11.79) vs. 0.28 (0.10, 1.25), all P < 0.05], and more sinus tachycardia and atrial arrhythmia (41.8% vs. 22.0%, 29.9% vs. 17.7%, both P < 0.05). Logistic regression analysis showed that cTnT increased (OR = 2.115, 95%CI was 1.189-5.459, P < 0.05), sinus tachycardia (OR = 2.557, 95%CI was 1.103-5.929, P < 0.05) and atrial arrhythmia (OR = 2.474, 95%CI was 1.025-5.969, P < 0.05) were independent risk factors for 28-day death in patients with sepsis. CONCLUSIONS: Myocardial injury is an independent risk factor for death in patients with sepsis. PCT elevation, LVEF decreased and sinus tachycardia are main characteristics of patients with septic myocardial injury, which should attract clinical attention.

TMT-Based Quantitative Proteomic Analysis Identification of Integrin Alpha 3 and Integrin Alpha 5 as Novel Biomarkers in Pathogenesis of Acute Aortic Dissection.

BACKGROUND: Acute aortic dissection (AAD) is a devastating cardiovascular disease with a high rate of disability and mortality. This disease often rapidly progresses to fatal multiple organ hypoperfusion, and the incidence has been increasing in recent years. However, the molecular mechanisms have yet to be clarified. This study is aimed at identifying the differential abundance proteins (DAPs) of aortic arch tissues in patients with AAD by proteomics and select possible proteins involved in AAD pathogenesis. METHODS: The fresh aortic arch tissues obtained from 5 AAD patients and 1 healthy donor were analyzed by amine-reactive tandem mass tag (TMT) labelling and mass spectrometry; then, the pathological sections of another 10 healthy donors and 20 AAD patients were chosen to verify the proteomic results by immunohistochemistry. RESULTS: Of 809 proteins identified by proteomic analysis, 132 differential abundance proteins (DAPs) were screened, of which 100 proteins were significantly downregulated while 32 upregulated. Among 100 downregulated proteins, two proteins with known function, integrin alpha 3 (ITGA-3) and ITGA-5, were selected as target proteins involved in AAD pathogenesis. Two target DAPs were verified by immunohistochemisty, and the results showed that the integrated option density (IOD) of ITGA-3 and ITGA-5 in AAD patients was significantly lower than that in healthy donors, which were consistent with the proteomic results (P < 0.001). CONCLUSION: ITGA-3 and ITGA-5 represent novel biomarkers for the pathogenesis of AAD and might be a therapeutic target in the future.

miR-21 enhances the protective effect of loperamide on rat cardiomyocytes against hypoxia/reoxygenation, reactive oxygen species production and apoptosis via regulating Akap8 and Bard1 expression.

Effective therapies to reduce ischemia/reperfusion and hypoxia/reoxygenation injury are currently lacking. Furthermore, the effects of loperamide and microRNA (miR)-21 on hypoxia/reoxygenation injury of cardiomyocytes have remained to be elucidated. Therefore, the present study aimed to investigate the effect of loperamide and miR-21 on cardiomyocytes during hypoxia/reoxygenation injury, and to explore the underlying molecular mechanisms. H9c2 rat cardiomyocytes were pre-treated with loperamide prior to hypoxia/reoxygenation. The viability of H9c2 cells was measured with a cell counting kit 8 and apoptosis was detected with an Annexin V-phycoerythrin/7-aminoactinomycin D apoptosis kit. Furthermore, reactive oxygen species were detected with a specific kit. Genes regulated by miR-21 were screened with an mRNA chip and confirmed using reverse-transcription quantitative polymerase chain reaction analysis. The direct targeting relationship of miR-21 with certain mRNAs was then confirmed using a Dual-Luciferase Reporter Assay system. The results indicated that the apoptotic rate and reactive oxygen species levels in rat cardiomyocytes were markedly increased after hypoxia/reoxygenation treatment. Pre-treatment with loperamide significantly protected H9c2 cells against apoptosis and reactive oxygen species production after hypoxia/reoxygenation. The protection was markedly decreased by miR-21 inhibitor and enhanced by miR-21 mimics. Screening for genes associated with cardiomyocyte apoptosis revealed that the relative expression of A-kinase anchoring protein 8 (Akap8) and BRCA1 associated RING domain 1 (Bard1) was consistent with the experimental results on apoptosis and reactive oxygen species. Compared with the group treated by hypoxia/reoxygenation alone, pre-treatment with loperamide markedly decreased the expression of BRCA1-interacting protein C-terminal helicase 1, Akap8 and Bard1 after hypoxia/reoxygenation. The decrease in the expression of Akap8 and Bard1 was markedly attenuated by miR-21 inhibitor and enhanced by miR-21 mimics. miR-21 mimics directly targeted the 3'-untranslated region (UTR) of Akap8 and Bard1 mRNA to thereby decrease their expression. In conclusion, the protection of rat cardiomyocytes against hypoxia/reoxygenation-induced apoptosis and reactive oxygen species production by loperamide was markedly enhanced by miR-21. miR-21 directly targets the 3'-UTR of Akap8 and Bard1 mRNA and enhances the inhibitory effects of loperamide on Akap8 and Bard1 expression in rat cardiomyocytes after hypoxia/reoxygenation.

Identification of Lysophosphatidylcholines and Sphingolipids as Potential Biomarkers for Acute Aortic Dissection via Serum Metabolomics.

OBJECTIVES: Acute aortic dissection (AAD) is a severe clinical emergency with a high mortality, and is easily misdiagnosed in its early stage. This study aimed at discovering serum metabolomic markers with the potential to diagnose AAD and distinguish between two subtypes of AAD. METHODS: Thirty-five patients with AAD, including 20 with Stanford type A and 15 with Stanford type B were enrolled in this study, together with 20 healthy controls. All patients with AAD were admitted within 72 h of onset. Serum metabolomics profiles were determined by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and the data were analysed by principal component analysis and partial least squares discriminant analysis. RESULTS: A total of 17 metabolites differing between the control and AAD groups were finally screened and identified as lysophosphatidylcholines (LPC) and sphingolipids including sphinganine, phytosphingosine, sphingomyelin, and ceramide. Compared with those in the healthy control group, LPC levels were significantly lower in both the Stanford type A and type B AAD groups. Interestingly, sphingolipids, including sphinganine, phytosphingosine, and ceramide, were remarkably reduced in the Stanford type A AAD group, but not in the Stanford type B AAD group. Subgroup analysis showed that the changes in LPC and sphingolipid levels were unrelated to hypertension or gender. CONCLUSIONS: The present results indicate that LPCs and sphingolipids are significantly altered in patients with AAD, and several sphingolipids, such as sphinganine, phytosphingosine, and ceramide, were dramatically decreased in patients with Stanford type A AAD. A combination of these two families of metabolites could serve as a potential biomarker for the diagnosis of AAD and distinguishing between Stanford type A and Stanford type B.

Clinical characteristics and prognosis of serous body cavity effusions in patients with sepsis: a retrospective observational study.

BACKGROUND: Cavity effusion is common in patients with infectious diseases. However, the incidence rate and characteristics of serous cavity effusions (SCE) in septic patients are not clear to date. The objective of this study was to investigate the incidence and characteristics of SCE in septic patients and to explore the correlations between the bloody effusions and the illness severity/prognosis in septic patients. METHODS: From January 2010 to January 2015, a total of 214 patients with severe sepsis and septic shock were enrolled in this retrospective observational study. Thoracentesis or abdominal paracentesis was performed in 45 septic patients because of massive pleural effusions or ascites. The serum concentrations of VEGF, VEGFR, Ang, sICAM-1, sVCAM-1, E-selectin, Serpine1 and VE-cadherin in 45 septic patients underwent paracentesis were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of the 214 septic patients, 155 (72.4%) had SCE according to imaging or ultrasound manifestations. 45 subjects with SCE underwent therapeutic thoracentesis or abdominal paracentesis. Effusion laboratory analysis showed that exudates were predominant when compared with transudates (95.6% vs. 4.4%), and 16 (35.6%) patients suffered bloody effusions. Compared with patients with non-bloody effusions, those with bloody effusions showed higher critical illness scores (13 vs. 17 for APACHE II; 7 vs. 9 for SOFA), and higher mortality (6.9% vs. 62.5%). Moreover, patients with bloody effusions had delayed TT and APTT, increased D-dimer concentration, and higher serum levels of CRP and PCT (P < 0.05). In addition, the serum levels of Ang2, sVCAM-1 and E-selectin were significantly higher in patients with bloody effusions than in those with non-bloody effusions (P < 0.05). However, the serum level of VEGFR2 was lower in patients with bloody fluids (P = 0.025). CONCLUSIONS: The incidence of serous cavity effusion is high in patients with sepsis. The septic patients with bloody effusions suffer a more inflammatory burden and a worse prognosis compared to septic patients with non-bloody effusions.

hsa-miR-320d and hsa-miR-582, miRNA Biomarkers of Aortic Dissection, Regulate Apoptosis of Vascular Smooth Muscle Cells.

Abnormal expression of microRNAs (miRNAs) has been associated with aortic dissection (AD). Next-generation sequencing was performed to identify the differentially expressed miRNAs in aortic tissue samples between AD and nondiseased individuals. Selected miRNAs, which showed significant variation between the 2 groups, were then transfected into human aortic vascular smooth muscle cells, and assessed for effects on cell migration and induced apoptosis. The changes in gene expression pattern in human aortic vascular smooth muscle cells transfected with the miRNAs were also investigated. Among the 314 miRNAs detected in the aortic tissues from both AD and normal subjects, 46 showed significantly different expression patterns. Only 7 of these differentially expressed miRNAs were found to be enriched in AD, whereas the majority had diminished. hsa-miR-320d and hsa-miR-582 were 2 representative miRNAs that exhibited a decrease of greater than 10-fold. Transfection of hsa-miR-320d and hsa-miR-582 did not affect the migration capability of the vascular smooth muscle cells, but remarkably enhanced the staurosporine and tumor necrosis factor-α-induced apoptosis by 15% and 29%, respectively. Furthermore, the transfection of both miRNAs affected the expression of a vast multitude of genes, most of which were related to apoptotic pathways. The fluorescence reporter assays demonstrated that hsa-miR-320d and hsa-miR-582 bind the 3' UTR region of TRIAP1 and NET1 genes, respectively. These results suggest that hsa-miR-320d and hsa-miR-582 may serve as putative biomarkers for AD research.

Acute Aortic Dissection Biomarkers Identified Using Isobaric Tags for Relative and Absolute Quantitation.

The purpose of this study was to evaluate the utility of potential serum biomarkers for acute aortic dissection (AAD) that were identified by isobaric Tags for Relative and Absolute Quantitation (iTRAQ) approaches. Serum samples from 20 AAD patients and 20 healthy volunteers were analyzed using iTRAQ technology. Protein validation was performed using samples from 120 patients with chest pain. A total of 355 proteins were identified with the iTRAQ approach; 164 proteins reached the strict quantitative standard, and 125 proteins were increased or decreased more than 1.2-fold (64 and 61 proteins were up- and downregulated, resp.). Lumican, C-reactive protein (CRP), thrombospondin-1 (TSP-1), and D-dimer were selected as candidate biomarkers for the validation tests. Receiver operating characteristic (ROC) curves show that Lumican and D-dimer have diagnostic value (area under the curves [AUCs] 0.895 and 0.891, P < 0.05). For Lumican, the diagnostic sensitivity and specificity were 73.33% and 98.33%, while the corresponding values for D-dimer were 93.33% and 68.33%. For Lumican and D-dimer AAD combined diagnosis, the sensitivity and specificity were 88.33% and 95%, respectively. In conclusion, Lumican has good specificity and D-dimer has good sensitivity for the diagnosis of AAD, while the combined detection of D-dimer and Lumican has better diagnostic value.

Lumican as a novel potential clinical indicator for acute aortic dissection: A comparative study, based on multi-slice computed tomography angiography.

The aim of the present study was to investigate the association between serum lumican levels and acute aortic dissection (AAD) severity. A total of 82 patients with chest or back pain and 30 healthy volunteers were recruited. Among the patients, there were 70 cases of AAD and 12 cases of intramural hematoma (IMH). AAD severity was determined using multi-slice computed tomography angiography (MSCTA). Serum was collected from the patients upon admission, and lumican levels were detected using an enzyme-linked immunosorbent assay. In addition, correlation analyses were conducted between lumican levels and AAD severity by designing a 'SCORE X, RANGE Y' system to measure the number of affected vital arteries and vertical range of false lumen, based on the MSCTA. Lumican levels differed significantly among the AAD patients (2.32±4.29 ng/ml), IMH patients (0.72±0.32 ng/ml) and healthy volunteers (0.85±0.53 ng/ml; P=0.003). In the AAD patients presenting within 12-72 h of symptom onset, the Spearman's rho correlation coefficient between lumican and SCORE or RANGE was 0.373 (P=0.046) and 0.468 (P=0.010), respectively. The present results suggest that lumican may be a potential marker for aiding the diagnosis and screening for AAD, and may be used to predict the severity of AAD.

Diagnostic and prognostic utility of tissue factor for severe sepsis and sepsis-induced acute lung injury.

BACKGROUND: Tissue factor (TF) and tissue factor pathway inhibitor (TFPI) play a central role in the endothelial permeability regulation and dysfunction, which is associated with the development of sepsis and acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The aim of this study is to assess the diagnostic and prognostic values of TF and TFPI in patients with sepsis and sepsis-induced ARDS. METHODS: A total of 62 patients with sepsis, 167 patients with severe sepsis and 32 healthy volunteers were enrolled in this prospective observational study. TF and TFPI levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with sepsis-induced ARDS showed significantly higher median levels of TF compared with patients without ARDS (1425.5 (1019.9 to 2595.2) pg/ml vs 916.2 (724.1 to 1618.2) pg/ml, P < 0.001), and compared with sepsis patients (943.5 (786.4 to 992.4) pg/ml, P < 0.001) on the day of admission. However, there was no significant difference between sepsis patients and healthy subjects, or between septic shock and non-septic shock patients (P > 0.05). The AUC of TF for the diagnosis of sepsis-induced ARDS was 0.749 (95% confidence interval (CI) 0.675-0.822). Plasma TF levels in the non-survivors of severe sepsis were significantly higher than those of survivors (1618.6 (1017.1 to 2900.8) pg/ml vs. 979.9 (757.2 to 1645.5) pg/ml, P < 0.001), and multivariate logistic regression showed the plasma value of TF was the independent predictor for 30-day mortality in patients with severe sepsis (P = 0.0022, odds ratio (OR) = 1.41, 95% CI 1.24-1.69). The AUC of TF for predicting 30-day mortality in severe sepsis patients was 0.718 (95% CI 0.641-0.794). However, there was no significant difference in the plasma TFPI values among the healthy control, sepsis and severe sepsis groups (P > 0.05). CONCLUSIONS: Our data showed that tissue factor is a valuable diagnostic biomarker for the diagnosis of sepsis-induced ARDS. Moreover, tissue factor is a strong prognostic marker for short-term mortality in severe sepsis and sepsis-induced ARDS patients.

Genetic variation in the tissue factor gene is associated with clinical outcome in severe sepsis patients.

INTRODUCTION: Activation of inflammation and coagulation was closely related and mutually interdependent in sepsis. Tissue factor (TF) and its endogenous inhibitor, tissue factor pathway inhibitor (TFPI) was the main regulators of the initiation of coagulation process. Altered plasma levels of TF and TFPI have been related to worse outcome in sepsis. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the TF and TFPI genes were associated with risk and outcome for patients with severe sepsis. METHODS: Seventeen SNPs in TF and TFPI were genotyped in samples of sepsis (n =577) and severe sepsis patients (n =476), and tested for association in this case-control collection. We then investigated correlation between the associated SNPs and the mRNA expression, and protein level of the corresponding gene. The mRNA levels of TF were determined using real-time quantitative reverse transcription-polymerase chain reaction and the soluble plasma levels of TF were measured using enzyme linked immunosorbent assay (ELISA) method. RESULTS: Association analysis revealed that three TF SNPs in perfect linkage disequilibrium, rs1361600, rs3917615 and rs958587, were significantly associated with outcome of severe sepsis. G allele frequency of rs1361600 in survivor patients was significantly higher than that in nonsurvivor severe sepsis patients (P =4.91 × 10(-5), odds ratio (OR) =0.48, 95% confidence interval (CI) 0.33 to 0.69). The association remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. Lipopolysaccharide-induced TF-mRNA expression levels in peripheral blood mononuclear cells from subjects carrying rs1361600 AG and GG genotypes, were significantly lower than those subjects carrying AA genotype (P =0.0012). Moreover, severe sepsis patients of GG and GA genotypes showed lower serum levels of TF than patients with AA genotype (P adj =0.02). The plasma levels of TF were also associated with outcome of severe sepsis patients (P adj =0.01). However, genotype and allele analyses did not show any significant difference between sepsis and severe sepsis patients. CONCLUSIONS: Our findings indicate that common genetic variation in TF was significantly associated with outcome of severe sepsis in Chinese Han population.

Complementary and alternative medicine is expected to make greater contribution in controlling the prevalence of influenza.

Influenza pandemics are a serious threat to public health in today's world. In the past 10 years, the outbreak of three forms of severe influenza--H5N1, H1N1, and H7N9--has caused tremendous loss of life and property. In order to better cope with pandemics, antivirals such as oseltamivir are being stockpiled in great quantities, placing a substantial burden on government budgets and potentially resulting in massive waste because of the uncertainty as to when an influenza pandemic will strike and whether emerging virus strains will be resistant to the stockpiled drugs. Complementary and alternative medicine (CAM) is generally available, affordable, and commonly used in China and many other countries and CAM has a long track record of fighting influenza. The Chinese Government appropriated funds to intensively investigate herbal medicines in accordance with the principles of evidence-based medicine in order to identify effective, inexpensive, and easily stockpiled medicines. Thus far, several drugs including Shufeng Jiedu capsules, Lianhua Qingwen capsules, Maxing Shigan decoction, Yinqiao powder, and Jinhua Qinggan granules have demonstrated effectiveness in fighting influenza. In the future, CAM is expected to make greater contribution in controlling the prevalence of influenza pandemics.

Genetic variation in the TNF gene is associated with susceptibility to severe sepsis, but not with mortality.

BACKGROUND: Tumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-α (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS: Ten SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (P(adj) = 0.00046, odds ratio (OR)(adj) = 1.92) and sepsis patients (P(adj) = 0.002, OR(adj) = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (P(adj) = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis. CONCLUSIONS/SIGNIFICANCE: Our findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.

Genetic variation in the TNF receptor-associated factor 6 gene is associated with susceptibility to sepsis-induced acute lung injury.

BACKGROUND: Recent studies showed that overwhelming inflammatory response mediated by the toll-like receptor (TLR)-related pathway was important in the development of acute lung injury (ALI). The aim of this study was to determine whether common genetic variation in four genes of the TLR signaling pathway were associated with sepsis-induced ALI susceptibility and risk of death in Chinese Han population. METHODS: Fourteen tag single nucleotide polymorphisms (tagSNPs) in MyD88, IRAK1, IRAK4 and TRAF6 were genotyped in samples of sepsis-induced ALI (n = 272) and sepsis alone patients (n = 276), and tested for association in this case-control collection. Then, we investigated correlation between the associated SNP and the mRNA expression level of the corresponding gene. And we also investigated correlation between the associated SNP and tumor necrosis factor alpha (TNF-α) as well as interleukin-6 (IL-6) concentrations in peripheral blood mononuclear cells (PBMCs) exposed to lipopolysaccharides (LPS) ex vivo. The mRNA expression level was determined using real-time quantitative Polymerase Chain Reaction (PCR) assays, and concentrations of TNF-α and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The association analysis revealed that rs4755453, an intronic SNP of TRAF6, was significantly associated with susceptibility to sepsis-induced ALI. The C allele frequency of rs4755453 in the sepsis alone group was significantly higher than that in the sepsis-induced ALI group (P = 0.00026, odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.37-0.74). These associations remained significant after adjustment for covariates in multiple logistic regression analysis and for multiple comparisons. TRAF6 mRNA expression levels in PBMCs from homozygotes of the rs4755453G allele were significantly higher than that in heterozygotes and homozygotes of the rs4755453C allele at baseline (P = 0.012 and P = 0.003, respectively) as well as after LPS stimulation (P = 0.009 and P = 0.005). Moreover, the concentrations of TNF-α and IL-6 in cell culture supernatants were also significantly higher in the subjects with rs4755453GG genotype than in subjects with CG and CC genotype. None of the 14 tagSNPs showed associations with risk of death and severity among ALI cases. CONCLUSIONS: Our findings indicated that common genetic variants in TRAF6 were significantly associated with susceptibility to sepsis-induced ALI in Chinese Han population. This was the first genetic evidence supporting a role for TRAF6 in ALI.

Role of δ2 opioid receptor in cardioprotection against hypoxia-reoxygenation injury.

Several lines of in vivo evidence demonstrated that activation of δ-opioid receptors (ORs) with agonists mimics the cardioprotective effect of ischemic preconditioning. However, the subtypes of ORs involved and the molecular and cellular mechanisms are not entirely clear. To investigate the significance of the contribution by δ ORs to cardiomyocyte survival, we used an in vitro model of hypoxia/reoxygenation (H/R) in primary cultures of neonatal rat cardiomyocytes to study the role of different δ ORs in cardiomyocyte apoptosis and the relevant downstream signaling pathway. The results showed that apoptosis in neonatal cardiomyocytes induced by H/R was reversed by δ2 OR agonist, deltorphin E but not by δ1 OR agonist DPDPE; the deltorphin E-induced cytoprotection was totally abrogated by the MEK inhibitor PD98059 and overexpression of dominant interfering form of MEK1; in contrast, overexpression of constitutive active form of MEK1 exerted a similar protective effect as deltorphin E. These results suggest that δ2 OR, but not δ1 OR, plays a key role in preventing cardiomyocytes from apoptosis during H/R injury, which is mainly mediated by the MEK/ERK1/2 pathway.