Efficacy and safety of dexmedetomidine in sepsis patients requiring mechanical ventilation: a systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Currently, dexmedetomidine is widely used in the treatment of sepsis patients requiring mechanical ventilation; however, its role remains controversial. The aim of this study was to assess the efficacy and safety of dexmedetomidine in sepsis patients requiring mechanical ventilation. METHODS: The PubMed, Embase and Cochrane Library electronic databases were searched to identify relevant studies; Review Manager version 5.4 was used to perform the meta-analysis. Primary outcomes included the all-cause mortality rate at the longest follow-up available and the duration of mechanical ventilation. Secondary outcomes included length of intensive care unit (ICU) stay, length of hospital stay, and adverse events (bradycardia). RESULTS: Five randomized controlled trials (RCTs), including 926 patients, were assessed. Overall, dexmedetomidine did not reduce all-cause mortality in mechanically ventilated patients with sepsis (relative risk [RR]: 0.9, 95% confidence interval [CI]: 0.77 to 1.05, p = 0.18, I2 = 37%). However, dexmedetomidine was associated with decreases in the length of hospital stay (mean difference [MD]: -2.99, 95% CI: -4.72 to -1.26, p = 0.0007, I2 = 0%), ICU length of stay (MD: -1.15, 95% CI: -2.06 to -0.24, p = 0.01, I2 = 32%) and duration of mechanical ventilation (MD: -0.72, 95% CI: -1.38 to -0.07, p = 0.03, I2 = 20%). However, dexmedetomidine increased the risk for bradycardia (22% versus 12.6%, respectively; RR: 1.73, 95% CI: 1.24 to 2.41, p = 0.001, I2  = 0%). WHAT IS NEW AND CONCLUSION: Results suggested that dexmedetomidine did not reduce all-cause mortality in mechanically ventilated patients with sepsis. However, it was associated with decreases in length of hospital stay, ICU length of stay and duration of mechanical ventilation, although it increased the risk for bradycardia.

Impacts of a Specific Cyclooxygenase-2 Inhibitor on Pressure Overload-Induced Myocardial Hypertrophy in Rats.

OBJECTIVE: The aim of this study was to observe the impacts of the specific cyclooxygenase-2 inhibitor celecoxib on cardiac structures, functions, and inflammatory factors during the process of pressure overload-induced myocardial hypertrophy. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into 3 groups: the sham operation group, the surgery group, and the celecoxib group. The model was established according to the abdominal aortic coarctation method. RESULTS: At 16 weeks, rats in the celecoxib group were fed a celecoxib-mixed diet (10 mg/kg) for 8 consecutive weeks. At week 24 after model establishment, the cardiac structures and functions were observed; changes in the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, prostaglandin E2 (PGE2), C-reactive protein (CRP), and uric acid (UA) were detected; and the contents of Smad1/2/3 proteins (Smad1, Smad2, and Smad3)  were determined. Left ventricular mass index, the heart weight/body weight ratio, and TNF-α, TGF-ß, PGE2, CRP, and UA levels of the celecoxib group were all significantly decreased relative to those of the surgery group (P < .05); moreover, the cardiac functions were significantly improved compared to those of the surgery group (P < .05). CONCLUSIONS: These results show that inflammatory factors are involved in the myocardial hypertrophy process and that celecoxib may reverse myocardial hypertrophy through a variety of pathways.

Polymorphisms in the precursor microRNAs and aflatoxin B1-related hepatocellular carcinoma.

The altered expression of some microRNAs (miRNAs) is observed in hepatocellular carcinoma (HCC); however, the genetic polymorphisms in the precursor miRNAs (pre-miRNAs) in aflatoxin B1 (AFB1)-related HCC have not yet been investigated. A hospital-based case-control study, including 1,706 HCC cases and 2,270 controls without any liver diseases or tumors, was conducted in a high AFB1 exposure area of China to assess the relationship between 48 polymorphisms in the pre-miRNAs and AFB1-related HCC risk and prognosis. Among 48 polymorphisms, only rs28599926 (in the miRNA 1268a) affected HCC risk. Compared with the homozygote of rs28599926C alleles (rs28599926-CC), the genotypes of rs28599926 T alleles (namely rs28599926-CT or -TT) increased HCC risk (odds ratio [OR]: 1.63 and 5.52, 95% confidence interval [CI]: 1.40-1.90 and 4.27-7.14, respectively). Significant interactive effects between risk genotypes and AFB1 exposure status were also observed in the joint effects analysis. This polymorphism was associated not only with larger tumor size, higher portal vein tumor risk, and tumor dedifferentiation, but also with higher AFB1 adducts levels and increasing the mutation risk of TP53 gene. Furthermore, rs28599926 modified the tumor recurrence-free survival (hazard ratio [HR]: 2.86, 95% CI: 2.36-3.43) and overall survival (HR: 2.12, 95% CI: 1.86-2.41) of cases. Additionally, one target of miR-1268a was show to be the ADAMTS4 mRNA and rs28599926 polymorphism might modify ADAMTS4 expression. These findings indicate that polymorphisms in the pre-miRNAs may be risk and prognostic biomarkers of AFB1-related HCC, and rs28599926 in miR-1268a is such a potential candidate. © 2015 Wiley Periodicals, Inc.

Bioinformatics analysis of the potential biomarkers for acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is caused by uncontrolled inflammation, and the activation of alveolar macrophages (AM) is involved in pathophysiologic procedures. The present study aimed to identify key AM genes and pathways and try to provide potential targets for prognosis and early intervention in ARDS. METHODS: The mRNA expression profile of GSE89953 was obtained from the Gene Expression Omnibus database. The LIMMA package in R software was used to identify differentially expressed genes (DEGs), and the clusterProfiler package was used for functional enrichment and pathway analyses. A protein-protein interaction network of DEGs was constructed to identify hub genes via the STRING database and Cytoscape software. Hub gene expression was validated using differentially expressed proteins (DEPs) obtained from the ProteomeXchange datasets to screen potential biomarkers. RESULTS: A total of 166 DEGs (101 up-regulated and 65 down-regulated) were identified. The up-regulated DEGs were mainly enriched in regulation of the ERK1 and ERK2 cascade, response to interferon-gamma, cell chemotaxis, and migration in biological processes. In the KEGG pathway analysis, up-regulated DEGs were mainly involved in rheumatoid arthritis, cytokine-cytokine receptor interactions, phagosome, and the chemokine signaling pathway. The 12 hub genes identified included GZMA, MPO, PRF1, CXCL8, ELANE, GZMB, SELL, APOE, SPP1, JUN, CD247, and CCL2. CONCLUSION: SPP1 was consistently differentially expressed in both DEGs and DEPs. SPP1 could be a potential biomarker for ARDS.

Regulatory T Cells as a Novel Candidate for Cell-Based Therapy in Kidney Disease.

Kidney disease is a significant health concern worldwide. Ineffective treatment can lead to disastrous consequences, such as organ failure and death. Research has turned to cell-based therapy, but has yet to produce an effective and reliable treatment for kidney disease. To address this problem, we examined four datasets of gene expression profiles from diseased and healthy kidney tissue in humans, mice, and rats. Differentially expressed genes (DEGs) were screened and subjected to enrichment analyses. Up-regulated genes in diseased kidney tissue were significantly enriched in pathways associated with regulatory T cells (Tregs). Analysis with the xCell tool showed that Tregs were generally increased in diseased kidney tissue in all species. To validate these results in vivo, kidneys were removed from mice with Adriamycin-induced nephropathy, and histology confirmed increase of Tregs. Furthermore, Tregs were adoptively transferred from healthy mice into mice with kidney injury, restoring normal structure to the damaged kidneys. Treg cells that were co-cultured with M2c macrophages exhibited up-regulation of chemokine receptors CCR2, CCR5, CCR7, CD62L, and CX3CR1. This may be the mechanism by which M2c cells enhance the migration of Tregs to the site of inflammation. We propose that Tregs may be an effective, novel candidate for cell-based therapy in pre-clinical kidney injury models.

Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/eIF2α/ATF4/CHOP Signaling Pathway.

Apoptosis induced by endoplasmic reticulum (ER) stress plays a crucial role in mediating brain damage after ischemic stroke. Recently, Hes1 (hairy and enhancer of split 1) has been implicated in the regulation of ER stress, but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear. In this study, using a mouse model of ischemic stroke via transient middle cerebral artery occlusion (tMCAO), we found that Hes1 was induced following brain injury, and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome, suggesting that Hes1 knockdown exacerbates ischemic stroke. In addition, mechanistically, Hes1 knockdown promoted apoptosis and activated the PERK/eIF2α/ATF4/CHOP signaling pathway after tMCAO. These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis. Furthermore, inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO, implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2α/ATF4/CHOP signaling pathway. Taken together, these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis, thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.

[Effect of activation of nuclear factor-KappaB on modulation of secretion of intercellular adhesion molecule-1 by A549 cell].

OBJECTIVE: To investigate the effects of interleukin-1beta (IL-1beta) on intercellular adhesion molecule-1 (ICAM-1) expression on A549 cell and underlying signal transduction pathways. METHODS: A549 cells were pre-incubated with SC-514 [nuclear factor-KappaB (NF-KappaB) inhibitor (IKappaB) kinase-2 (IKK-2) inhibitor] and/or pre-treated with 1 microg/L IL-1beta. The phosphorylated IKappaBalpha (pIKappaBalpha) and degradation of IKappaBalpha were determined by Western blotting with specific antibody at 5, 10, 30 and 60 minutes. Laser scanning confocal microscope (LSCM) was used to examine the nuclear translocation of p65 at 30 minutes after stimulation. The DNA binding activity of p65 in nuclear extracts was detected at 1 hour following IL-1beta treatment. Chromatin immunoprecipitation (ChIP) assays combined with polymerase chain reaction (PCR) were used to evaluate interaction between p65 and ICAM-1 promoter site DNA at 1 hour after stimulation. The expression of ICAM-1 mRNA was assessed by reverse transcription (RT)-PCR at 4 hours, and the ICAM-1 expression on A549 cell surface was measured by enzyme linked immunosorbent assay (ELISA) at 24 hours after IL-1beta was added. RESULTS: IL-1beta induced rapid pIKappaBalpha augmentation and its subsequent degradation. LSCM graphs showed that IL-1beta stimulated the translocation of p65 from the cytosol to the nucleus. IL-1beta significantly increased the DNA binding ability of p65 (P<0.01) in cell nuclear extracts. ChIP-PCR suggested that both acetylated histone 4 and p65 were recruited to ICAM-1 promoter. IL-1beta significantly augmented ICAM-1 mRNA level at 4 hours and expression of ICAM-1 on A549 cell surface at 24 hours (both P<0.01). The IKK-2 inhibitor, SC-514, inhibited IL-1beta induced IKappaBalpha protein activity, blocked p65 nuclear translocation, caused a significant reduction in IL-1beta induced DNA binding activity for p65 and ICAM-1 mRNA expression, and suppressed ICAM-1 expression on A549 cell surface (all P<0.01). CONCLUSION: These results suggest that the activation of NF-KappaB mediates IL-1beta induced ICAM-1 expression in A549 cells.

Association between miR-499 rs3746444 polymorphism and coronary heart disease susceptibility: An evidence-based meta-analysis of 5063 cases and 4603 controls.

MicroRNA-499 (miR-499) rs3746444 polymorphism has been associated with the risk of coronary heart disease (CHD). However, results from several studies are inconsistent. This meta-analysis aimed to further investigate the possible association between miR-499 rs3746444 polymorphism and CHD risk. A total of 9 case-control studies included 5063 CHD cases and 4603 healthy subjects. The A allele at rs374644 was associated with significantly decreased CHD risk in the total population according to the allelic model (OR = 0.80, 95% CI = 0.68-0.93, P = 0.005), homozygous model (OR = 0.52, 95% CI = 0.39-0.71, P < 0.001) and heterozygous model (OR = 0.57, 95% CI = 0.43-0.77, P < 0.001). A similar trend was found specifically in Asian and Chinese populations. In contrast, the wild-type GG genotype at rs374644 was associated with significantly increased CHD risk in the total population, according to the dominant model (OR = 1.83, 95% CI = 1.39-2.42, P < 0.001), and a similar trend was found in Asian and Chinese populations. These results indicate that in the total population, as well as in Asian and Chinese populations, the wild-type GG genotype at rs374644 may be related to increased susceptibility to CHD, while the A allele may be protective against CHD.

Diagnostic and prognostic potential of serum microRNA-4651 for patients with hepatocellular carcinoma related to aflatoxin B1.

BACKGROUND: The serum microRNAs have been reported as potential biomarkers for hepatitis virus-related hepatocellular carcinoma (HCC); however, their role in aflatoxin B1 (AFB1)-related HCC to has not yet been evaluated. MATERIALS AND METHODS: We conducted a case-control study, including 366 HCC cases and 662 controls without any evidence of tumors, to identify and assess diagnostic and prognostic potential of serum microRNAs for AFB1-related HCC. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to elucidate diagnostic performance, and to compare the microRNAs with α-fetoprotein (AFP) at a cutoff of 20 ng/mL (AFP20) and 400 ng/mL (AFP400). RESULTS: We found 8 differentially expressed microRNAs via the microRNA array analysis; however, only microRNA-4651 was further identified to detect AFB1-positive HCC but not AFB1-negative HCC. For AFB1-positive HCC, microRNA-4651 showed higher accuracy and sensitivity than AFP400 (AUC, 0.85 vs. 0.72; Sensitivity, 78.1% vs. 43.0%). Compared to AFP20, microRNA-4651 exhibited higher potential in identifying small-size (0.68 vs. 0.84 for AUC and 36.7% vs. 75.5% for sensitivity, respectively) and early-stage HCC (0.69 vs. 0.84 for AUC and 38.7% vs. 75.7% for sensitivity, respectively). Additionally, miR-4651 was also associated with HCC prognosis (hazard risk value, 2.67 for overall survival and 3.62 for tumor recurrence analysis). CONCLUSIONS: These data suggest that serum microRNA-4651 may be a useful marker for HCC diagnosis and prognosis, especially AFB1-positive cases.

An rs4705342 T>C polymorphism in the promoter of miR-143/145 is associated with a decreased risk of ischemic stroke.

The expression of miR-143/miR-145 was up-regulated in ischemic stroke (IS), which may be used as biomarkers and/or therapeutic targets for IS. We aimed to investigate the association of rs4705342 and rs4705343 polymorphisms in the promoter of miR-143/145 with risk of IS. The study population comprised 445 patients with IS and 518 controls. The rs4705342 genotype was analyzed by using a TaqMan Assay and the rs4705343 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Relative expression of miR-143/miR-145 was measured by quantitative real-time PCR. We found that the rs4705342 was associated with a decreased risk of IS (TC vs. TT: adjusted OR = 0.74, 95% CI, 0.57-0.97; CC vs. TT: adjusted OR = 0.53, 95% CI, 0.34-0.83). Haplotype analysis showed that the TC haplotype was associated with an increased risk of IS risk (OR = 1.33, 95% CI, 1.01-1.75), whereas the CT haplotype was associated with a decreased risk of IS risk (OR = 0.68, 95% CI, 0.50-0.92). Importantly, patients carrying the rs4705342TC/CC genotypes had a lower level of miR-145 (P = 0.03). We found for the first time that the rs4705342 CC was a protective factor for IS, probably by reducing the level of miR-145.

Associations of IL-27 polymorphisms and serum IL-27p28 levels with osteosarcoma risk.

Interleukin (IL)-27 is a novel cytokine secreted by stimulation of antigen-presenting cells. No previous studies currently reported the role of IL-27 in the carcinogenesis of osteosarcoma. We aimed to investigate the association of IL-27 polymorphisms and serum IL-27p28 with osteosarcoma risk in a Chinese population.One hundred and sixty osteosarcoma patients and 250 health controls were selected. IL-27 gene -964 A/G, 2905 T/G, and 4730 T/C polymorphisms were determined by using polymerase chain reaction-restriction fragment length polymorphism. Enzyme-linked immunosorbent assay were used to detect serum IL-27p28 levels.The serum IL-27p28 levels were significantly lower in osteosarcoma patients compared with those in controls (P < 0.01). Serum IL-27p28 levels in stages III-IV were lower than those in stages I-II of osteosarcoma (P < 0.05); similar results were also found in patients with metastasis, that is, patients with metastasis have higher IL-27p28 levels than those without metastasis (P < 0.05). There were no associations between genotype and allele frequencies of IL-27 -964 A/G, 2905 T/G, 4730 T/C, and the risk of osteosarcoma (P > 0.05). Stratification analysis also failed to show the associations between -964 A/G, 2905 T/G, and 4730 T/C polymorphisms and the clinical stage and metastasis of osteosarcoma (P > 0.05). Three possible haplotypes (ATT, GTT, and GGC) were identified, but no associations were found between them and the osteosarcoma risk (P > 0.05).This study indicates that the lower serum IL-27p28 levels may be associated with development and progression of osteosarcoma, but IL-27 gene -964 A/G, 2905 T/G, and 4730 T/C polymorphisms and their haplotypes are not associated with osteosarcoma risk.

[Blood and renal fractalkine expression in patients with lupus nephritis and its significance].

OBJECTIVE: To investigate the expression of fractalkine (FKN) in the blood and renal tissues of patients with lupus nephritis and explore its significance. METHODS: According to the pathological classification, 48 patients with lupus nephritis were divided into mild group (22 cases) and severe group (26 cases), with 26 healthy subjects as the control group. RT-PCR and enzyme-linked immunosorbent assay were employed to detect the expression of FKN mRNA and protein in the blood of the subjects, and FKN expression and localization in the renal tissue of the patients with lupus nephritis were detected using immunohistochemical staining. RESULTS: The patients in both the mild and severe groups showed significantly increased expression of blood FKN mRNA and protein compared with the normal controls, and the increase was more obvious in severe cases (P<0.01). In the renal tissues of the patients, FKN was located mainly in the cytoplasm of the glomerular podocytes and renal tubular epithelial, and the number of positive glomerular cells number was significantly greater in severe cases than in the mild cases (P<0.01); FKN expression in the cortical interstitium did not show a significant difference between the 3 groups. CONCLUSION: FKN expression in the blood and glomeruli of patients with lupus nephritis is related to the severity of renal pathologies.

[Detection of FasL mRNA, sFasL and their regulatory effect on T lymphocyte subsets in patients with severe acute pancreatitis].

OBJECTIVE: To investigate the levels of FasL mRNA in peripheral blood mononualear cells (PBMCs), serum soluble Fas ligand (sFasL) and their regulatory effect on T lymphocyte subsets in patients with severe acute pancreatitis (SAP). METHODS: Forty-eight patients with pancreatitis were randomly divided into two groups: 20 cases with SAP and 28 cases with mild acute pancreatitis (MAP). Twenty-eight healthy volunteers were selected as control group. The expression of FasL mRNA in PBMCs was detected by real-time quantitative PCR(qRT-PCR), and serum sFasL was measured by ELISA. T lymphocyte subsets in peripheral blood were detected by flow cytometry. RESULTS: Compared with control group and MAP group, FasL mRNA of PBMCs and serum sFasL increased significantly in SAP group (P<0.05), a little increase in MAP group, and there was no significant difference between MAP group and control group (P>0.05). The CD4(+) T cell ratio, CD4(+)/CD8(+) ratio decreased significantly in SAP group (P<0.05) vs control group and MAP group), and they were found negatively related to FasL mRNA, serum sFasL level. CONCLUSION: The SAP patients showed the significantly increased FasL mRNA of PBMCs and serum sFasL and decreased CD4(+) T-cell ratio, CD4(+)/CD8(+) ratio. FasL may mediate the apoptosis of T lymphocytes.

XRCC7 rs#7003908 Polymorphism and Helicobacter pylori Infection-Related Gastric Antrum Adenocarcinoma.

The X-ray repair cross-complementing group 7 (XRCC7) plays a key role in DNA repair that protects against genetic instability and carcinogenesis. To determine whether XRCC7 rs#7003908 polymorphism (XRCC7P) is associated with Helicobacter pylori (H. pylori) infection-related gastric antrum adenocarcinoma (GAA) risk, we conducted a hospital-based case-control study, including 642 patients with pathologically confirmed GAA and 927 individually matched controls without any evidence of tumours or precancerous lesions, among Guangxi population. Increased risks of GAA were observed for individuals with cagA positive (odds ratio (OR) 6.38; 95% confidence interval (CI) 5.03-8.09). We also found that these individuals with the genotypes of XRCC7 rs#7003908 G alleles (XRCC7-TG or -GG) featured increasing risk of GAA (ORs 2.80 and 5.13, resp.), compared with the homozygote of XRCC7 rs#7003908 T alleles (XRCC7-TT). GAA risk, moreover, did appear to differ more significantly among individuals featuring cagA-positive status, whose adjusted ORs (95% CIs) were 15.74 (10.89-22.77) for XRCC7-TG and 38.49 (22.82-64.93) for XRCC7-GG, respectively. Additionally, this polymorphism multiplicatively interacted with XRCC3 codon 241 polymorphism with respect to HCC risk (ORinteraction = 1.49). These results suggest that XRCC7P may be associated with the risk of Guangxiese GAA related to cagA.