Non-coding RNAs modulate pyroptosis in myocardial ischemia-reperfusion injury: A comprehensive review.

Reperfusion therapy is the most effective treatment for acute myocardial infarction. However, reperfusion itself can also cause cardiomyocytes damage. Pyroptosis has been shown to be an important mode of myocardial cell death during ischemia-reperfusion. Non-coding RNAs (ncRNAs) play critical roles in regulating pyroptosis. The regulation of pyroptosis by microRNAs, long ncRNAs, and circular RNAs may represent a new mechanism of myocardial ischemia-reperfusion injury. This review summarizes the currently known regulatory roles of ncRNAs in myocardial ischemia-reperfusion injury and interactions between ncRNAs. Potential therapeutic strategies using ncRNA modulation are also discussed.

Network meta-analysis of comparative efficacy and safety of intubation devices in children.

To evaluate the comparative efficacy and safety of different intubation devices on intubation outcomes in pediatric intubation. We identified relevant studies from previous meta-analyses and literature retrieval in PubMed, EMBASE, and Cochrane Library. The primary outcome was the first-pass success (FPS), and the secondary outcome included the time to intubation (TTI) and the risk of local complications (LC). Network meta-analysis was performed using STATA 14.0. Twenty-three randomized comparative trials (RCTs) including 12 devices were included. Compared with Macintosh, Airtraq (odds ratio [OR] = 13.05, 95% confidence interval [CI] = 4.68 to 36.38), Miller (OR = 4.77, 95%CI = 1.32 to 17.22), Glidescope (OR = 2.76, 95%CrI = 1.60 to 4.75) and McGrath (OR = 4.61, 95%CI = 1.18 to 17.99) obtained higher PFS. Meanwhile, Airtraq was superior to Glidescope (OR = 0.21, 95%CI = 0.07 to 0.65) for PFS. For TTI, Canada was superior to other intubation devices, as well as CMAC was superior to TruViewEVO2, Glidescope, and StorzDCI. Airtraq lowered the risk of LC compared with Macintosh and Pentax but there was no statistical difference between Airtraq and KingVision. Airtraq may be the optimal option for FPS, Canada for TTI, and KingVision for LC in pediatric intubation.

Use of Ilizarov Device to Gain Early Range of Motion in the Treatment of Pediatric Talus Body Fractures: A Series of Four Cases and Literature Review.

BACKGROUND: Talus fractures are rare in children but can lead to severe outcomes if untreated. The Ilizarov external fixator has been used in the treatment of a variety of lower extremity pathologies. The purpose of this study was to investigate the clinical outcomes of talus body fractures treated with the Ilizarov external fixator. CASE PRESENTATION: Four male pediatric patients (age range, 5-11 years) with talus body fractures who were treated by open reduction and internal fixation combined with Ilizarov external fixator between November 2015 and April 2016 were reviewed. Mean follow-up period was 4 years (range, 4-5). Clinical outcome was evaluated using the clinical rating scale of the American Orthopaedic Foot and Ankle Society (AOFAS). All four patients achieved good to excellent results at the last follow-up. None of the patients developed avascular necrosis. One patient developed automatic fusion of tibiotalar joint. CONCLUSION: Use of the Ilizarov external fixator to gain early range of motion is a valuable option for treatment of talus body fractures in children.

Airway Fusobacterium is Associated with Poor Response to Immunotherapy in Lung Cancer.

PURPOSE: There is a major limitation in the immunotherapy for solid cancer is that it only benefited a minority of cancer patients. This study aims to investigate whether the differential composition of the lung microbiome could affect the sustained clinical responses in lung cancers treated with immunotherapy. METHODS: Twenty-seven non-responders and 19 responders treated with anti-PD-1 therapy were included in the discovery set. Bacterial load in bronchoalveolar lavage from lung cancer patients was examined by quantitative PCR of 16S rRNA copies. Bacterial 16S rDNA was sequenced using the Illumina HiSeq on the 16S rDNA V3-V4 variable region. Operational taxonomic unit (OTU) analysis was performed using VSEARCH v2. The α-diversity and ß-diversity were calculated using QIIME software. RESULTS: The mean copy number of bacterial 16S DNA levels significantly decreased after anti-PD-1 treatment (after: 1.8 ± 0.6×104 copies per milliliter vs prior to treatment: 3.3 ± 1.1x104, p = 0.0036). In addition, longitudinal analysis revealed that microbial diversity was reduced taxonomically after treatment compared to those prior to the treatment (Shannon values: before: 3.291 ± 0.067 vs after: 2.668 ± 0.168, p < 0.01). Further, we observed a reduction of Fusobacterium nucleatum, including phylum Fusobacteria (p < 0.01), class Fusobacteria (p < 0.01), order Fusobacteria (p < 0.01), family Fusobacteria (p < 0.01), genus Fusobacteria (p = 0.025) in the responders post anti-PD-1 treatment. However, there was no significant difference of Fusobacterium in non-responders. An independent cohort was used to validate the levels of Fusobacterium, demonstrating that patients with higher abundance of Fusobacterium prior to treatment were significantly more likely to have poor response to anti-PD-1 therapy (p < 0.001). CONCLUSION: Airway enriched Fusobacterium prior to anti-PD-1 therapy is associated with poor response in lung cancer, which indicated that potential resistance to immunotherapy can be attributed to lung microbiome.

Effects of different anesthesia methods on maternal and neonatal outcomes in pregnant patients with pulmonary arterial hypertension: a meta-analysis.

PURPOSE: To investigate the effects of different anesthesia methods on maternal and neonatal outcomes in pregnant patients with pulmonary arterial hypertension (PAH). METHODS: We searched PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang and QVIP for investigating the effects of general anesthesia (GA) and local anesthesia (LA) in pregnant patients with PAH. Results were expressed as weighted mean difference (WMD) or risk ratio (RR) with 95% confidence intervals (CIs). Publication bias was assessed by the Begg's test. RESULTS: Totally, 18 articles containing 628 LA and 481 GA patients were involved in our study. The postoperative blood oxygen saturation (WMD = - 4.040, 95%CI: - 5.505 to - 2.576) and maternal mortality rate (RR = 0.507, 95%CI: 0.300-0.858) were lower in LA group than those in GA group. The postoperative systolic blood pressure (WMD = 15.647, 95%CI: 13.294-18.000) and postoperative diastolic blood pressure (WMD = 6.758, 95%CI: 5.715-7.802) were high in LA group compared with those in GA group. The mechanical ventilation time (WMD = - 4.112, 95%CI: - 4.655 to - 3.569), ICU admission time (WMD = - 4.176, 95%CI: - 4.523 to - 3.828), length of stay (WMD = -7.289, 95%CI: -7.799-6.779) were shorter in LA group than those in GA group. All P values were < 0.05. CONCLUSIONS: LA is superior to GA in regards to the postoperative blood oxygen saturation, the postoperative systolic blood pressure, postoperative diastolic blood pressure, the mechanical ventilation time, ICU admission time, length of stay and the maternal mortality rate. REGISTRATION NUMBER: osf.io/juybq ( https://osf.io/search/ ).

Perinatal Management and Long-Term Follow-up of a Primipara With Severe Pulmonary Arterial Hypertension Associated With Systemic Lupus Erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) accounts for the largest portion of connective tissue disease-associated pulmonary arterial hypertension (PAH) in Asian countries, especially in China, and SLE-PAH poses multiple challenges during pregnancy and delivery. Patients with SLE-PAH tend to have lower survival rates and worse quality of life than other subgroups of PAH. CASE PRESENTATION: Presented in this report is a 28-year-old primipara who suffered from SLE for 13 years and SLE-PAH for nine years. She had cardiac care throughout these years. She was admitted at 26 weeks of gestation for progressive dyspnea on exertion and her condition improved after a three-week PAH-targeted therapy consisting of prostacyclin and PDE-5 inhibitor. At 29 weeks of gestation, she was infected with influenza H1N1 and her clinical status deteriorated with increased dyspnea. After two weeks of influenza therapy and maximization of PAH therapy, a cesarean delivery was performed under epidural anesthesia at 31 weeks of gestation. She was discharged ten days after delivery. Although the targeted therapy for both PAH and SLE was readjusted after delivery and regular follow-up showed a gradual recovery and a stable condition, she still died suddenly at home 12 months after delivery. The child is healthy. CONCLUSIONS: Sequential combination therapy of PAH and SLE and the structured perinatal management might lead to optimal short-term outcomes in the mother and fetus. Long-term outcomes in women with PAH who become pregnant are poor, with high rates of morbidity and mortality. Delivery strategies remain an important challenge for modern Pregnancy Heart Teams.

Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice.

BACKGROUND: Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system. TLR4 contributes to many aging-related chronic diseases. However, whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated. METHODS: The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4-/- mice. An intraperitoneal glucose tolerance test (IPGTT) and insulin sensitivity test (IST) were conducted to evaluate global insulin sensitivity. Echocardiography was used to measure cardiac structure and performance. An isolated artery ring assay was used to measure the vasodilator function of the thoracic aorta. The inflammatory response was reflected by the serum concentration of cytokines. RESULTS: TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. CONCLUSION: In summary, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.

Association Between Insomnia and Migraine Risk: A Case-Control and Bidirectional Mendelian Randomization Study.

BACKGROUND: The causal relationship between insomnia and migraine is contradictory and no study has been carried out among the Chinese population to date. METHODS: In this case, we conducted a case-control study and a bidirectional mendelian randomization (MR) analysis to determine whether insomnia is causally related to the development of migraine. The instrumental variables for insomnia were derived from the largest genome-wide association study of 1,331,010 participants, while the genetic instruments for migraine were available from the largest meta-analysis of migraine with 59,674 cases and 316,078 controls. RESULTS: In case-control study, subjects with insomnia have significantly higher risk of migraine (OR=4.29, 95% CI: 3.21-5.74, P<0.001), compared with those without insomnia. The bidirectional two-sample MR analysis revealed that insomnia was significantly associated with higher risk of migraine (OR=1.24, 95% CI: 1.11-1.38, P=1.01×10-4), and the results were validated in the UK Biobank data. The results showed no indication for directional pleiotropy effects as assessed by the MR-Egger intercept (P>0.05). CONCLUSION: Conclusively, our study highlighted that increased migraine risk was confined to subjects with a genetic pre-disposition to insomnia, and these findings had potential implications for improving the sleep quality to reduce the burden of migraine.

Bacterial composition, function and the enrichment of plant growth promoting rhizobacteria (PGPR) in differential rhizosphere compartments of Al-tolerant soybean in acidic soil.

Low pH with aluminum (Al) toxicity are the main limiting factors affecting crop production in acidic soil. Selection of legume crops with acid tolerance and nitrogen-fixation ability should be one of the effective measures to improve soil quality and promote agricultural production. The role of the rhizosphere microorganisms in this process has raised concerns among the research community. In this study, BX10 (Al-tolerant soybean) and BD2 (Al-sensitive soybean) were selected as plant materials. Acidic soil was used as growth medium. The soil layers from the outside to the inside of the root are bulk soil (BS), rhizosphere soil at two sides (SRH), rhizosphere soil after brushing (BRH) and rhizosphere soil after washing (WRH), respectively. High-throughput sequencing of 16S rDNA amplicons of the V4 region using the Illumina MiSeq platform was performed to compare the differences of structure, function and molecular genetic diversity of rhizosphere bacterial community of different genotypes of soybean. The results showed that there was no significant difference in alpha diversity and beta diversity in rhizosphere bacterial community among the treatments. PCA and PCoA analysis showed that BRH and WRH had similar species composition, while BS and SRH also had similar species composition, which indicated that plant mainly affected the rhizosphere bacterial community on sampling compartments BRH and WRH. The composition and abundance of rhizosphere bacterial community among the treatments were then compared at different taxonomic levels. The ternary diagram of phylum level showed that Cyanobacteria were enriched in WRH. Statistical analysis showed that the roots of Al-tolerant soybean BX10 had an enrichment effect on plant growth promoting rhizobacteria (PGPR), which included Cyanobacteria, Bacteroides, Proteobacteria and some genera and species related to the function of nitrogen fixation and aluminum tolerance. The rhizosphere bacterial community from different sampling compartments of the same genotype soybean also were selectively enriched in different PGPR. In addition, the functional prediction analysis showed that there was no significant difference in the classification and abundance of COG (clusters of orthologous groups of proteins) function among different treatments. Several COGs might be directly related to nitrogen fixation, including COG0347, COG1348, COG1433, COG2710, COG3870, COG4656, COG5420, COG5456 and COG5554. Al-sensitive soybean BD2 was more likely to be enriched in these COGs than BX10 in BRH and WRH, and the possible reason remains to be further investigated in the future.

The evaluation of potent antitumor activities of shikonin coumarin-carboxylic acid, PMMB232 through HIF-1α-mediated apoptosis.

In current study, a series of shikonin derivatives were synthesized and its anticancer activity was evaluated. As a result, PMMB232 showed the best antiproliferation activity with an IC50 value of 3.25±0.35µM. Further, treatment of HeLa cells with a variety of concentrations of target drug resulted in dose-dependent event marked by apoptosis. What's more, the mitochondrial potential (Δym) analysis was consistent with the apoptosis result. In addition, PARP was involved in the progress of apoptosis revealed by western blotting. To identify the detailed role and mechanism of PMMB232 in the progression of human cervical cancer, we detected the expression of HIF-1α and E-cadherin in HeLa cells. Results showed that expression of HIF-1α was downregulated, while E-cadherin protein was upregulated. Meanwhile, glycolysis related protein PDK1 was decreased in HeLa cells. Conversely, the expression of PDH-E1α was upregulated. Docking simulation results further indicate that PMMB232 could be well bound to HIF-1α. Taken together, our data indicate that compound PMMB232 could be developed as a potential anticancer agent.

Novel mechanisms for organic acid-mediated aluminium tolerance in roots and leaves of two contrasting soybean genotypes.

Aluminium (Al) toxicity is one of the most important limiting factors for crop yield in acidic soils. However, the mechanisms that confer Al tolerance still remain largely unknown. To understand the molecular mechanism that confers different tolerance to Al, we performed global transcriptome analysis to the roots and leaves of two contrasting soybean genotypes, BX10 (Al-tolerant) and BD2 (Al-sensitive) under 0 and 50 µM Al3+ treatments, respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that the expression levels of the genes involved in lipid/carbohydrate metabolism and jasmonic acid (JA)-mediated signalling pathway were highly induced in the roots and leaves of both soybean genotypes. The gene encoding enzymes, including pyruvate kinase, phosphoenolpyruvate carboxylase, ATP-citrate lyase and glutamate-oxaloacetate transaminase 2, associated with organic acid metabolism were differentially expressed in the BX10 roots. In addition, the genes involved in citrate transport were differentially expressed. Among these genes, FRD3b was down-regulated only in BD2, whereas the other two multidrug and toxic compound extrusion genes were up-regulated in both soybean genotypes. These findings confirmed that BX10 roots secreted more citrate than BD2 to withstand Al stress. The gene encoding enzymes or regulators, such as lipoxygenase, 12-oxophytodienoate reductase, acyl-CoA oxidase and jasmonate ZIM-domain proteins, involved in JA biosynthesis and signalling were preferentially induced in BD2 leaves. This finding suggests that the JA defence response was activated, possibly weakening the growth of aerial parts because of excessive resource consumption and ATP biosynthesis deficiency. Our results suggest that the Al sensitivity in some soybean varieties could be attributed to the low level of citrate metabolism and exudation in the roots and the high level of JA-mediated defence response in the leaves.

A comparison of anesthetic regimens using etomidate and propofol in patients undergoing first-trimester abortions: double-blind, randomized clinical trial of safety and efficacy.

BACKGROUND: This prospective study compared the safety, recovery time and side effects of six distinct general anesthesia regimens for first-trimester surgical abortion. STUDY DESIGN: Two hundred forty women scheduled for surgical abortion at 6 to 8 weeks of gestation were randomized into three groups (n=40) of propofol: group P (2 mg/kg propofol alone), group PF (2 mg/kg propofol+1 mcg/kg fentanyl), group PMF (2 mg/kg propofol+1 mcg/kg fentanyl+0.02 mg/kg midazolam) and three groups (n=40) of etomidate: group E (0.2 mg/kg etomidate alone), group EF (0.2 mg/kg etomidate+1 mcg/kg fentanyl) and group EMF (0.2 mg/kg etomidate+1 mcg/kg fentanyl+0.02 mg/kg midazolam). Vital signs including pulse oxygen saturation (SpO2), mean arterial pressure (MAP) and heart rate were recorded as the primary outcomes. The recovery time and side effects were recorded as secondary outcomes. RESULTS: During induction, SpO2 and MAP decreased significantly in all the three groups of propofol and were significantly lower than those in the groups of etomidate. Mean recovery times to both eye opening and to obeying commands were significantly shorter in group PF than those in groups P and PMF, while there were no significant differences among the three groups of etomidate. Compared with the etomidate groups, the incidence of injection-induced pain was significantly higher, while the scores of myoclonus and postoperative nausea and vomiting were lower, in the three propofol groups. Moreover, myoclonus scores as well as nausea and vomiting scores were lower in group EMF than in groups E and EF. CONCLUSIONS: The results of this study suggest that (a) etomidate is much safer than propofol for first-trimester surgical abortions and (b) using a lower dose of etomidate, supplemented with fentanyl and midazolam, is more beneficial than the use of etomidate with or without fentanyl in reducing adverse effects like myoclonus and postoperative nausea and vomiting.

Inhibitory effect of live-attenuated Listeria monocytogenes-based vaccines expressing MIA gene on malignant melanoma.

Listeria monocytogenes (LM), a Gram-positive facultative intracellular bacterium, can be used as an effective exogenous antigen expression vector in tumor-target therapy. But for successful clinical application, it is necessary to construct attenuated LM stain that is safe yet retains the potency of LM based on the full virulent pathogen. In this study, attenuated LM and recombinants of LM expressing melanoma inhibitory activity (MIA) were constructed successfully. The median lethal dose (LD(50)) and invasion efficiency of attenuated LM strains were detected. The recombinants were utilized for immunotherapy of animal model of B16F10 melanoma. The level of MIA mRNA expression in tumor tissue was detected by using real-time polymerase chain reaction (PCR) with specific sequence, meanwhile the anti-tumor immune response was assayed by flow cytometric analysis and enzyme-linked immunosorbent spot (ELISPOT) assay. The results showed the toxicity and invasiveness of attenuated LM were decreased as compared with LM, and attenuated LM expressing MIA, especially the double-genes attenuated LM recombinant, could significantly induce anti-tumor immune response and inhibit tumor growth. This study implicates attenuated LM may be a safer and more effective vector for immunotherapy of melanoma.

PI3K, Rac1 and pPAK1 are overexpressed in extramammary Paget's disease.

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K), Ras-related C3 botulinum toxin substrate 1 (Rac1) and P21-activated protein kinase 1 (PAK1) appear to play important roles in the pathogenesis of several tumors, but their expressions in extramammary Paget's disease (EMPD) have not been investigated yet. OBJECTIVES: To investigate the potential contribution of the PI3K, Rac1 and PAK1 to the development of EMPD. METHODS: Thirty-five paraffin-embedded EMPD specimens were subjected to immunohistochemical staining for PI3K (85α), Rac1 and pPAK1. RESULTS: All the 35 primary EMPD specimens, including 20 non-invasive EMPD, 13 invasive EMPD and 2 metastatic lymph nodes, showed cytoplasm overexpression of PI3K (85α), Rac1 and pPAK1. The expression (% positive cells) of PI3K(85α), Rac1 and pPAK1 (90.1 ± 8.6, 91.4 ± 9.5 and 89.6 ± 10.8% ) in EMPD were significantly higher than in apocrine glands of normal skin ( 20.1 ± 11.9, 29.8 ± 8.9, 41.1 ± 13.4%), and the expression in invasive EMPD with lymph node metastasis (98.2 ± 1.7, 98.8 ± 0.7 and 98.4 ± 0.9%) are significantly higher than in invasive EMPD without lymph node metastasis (94.1 ± 2.6, 96.5 ± 1.7 and 95.3 ± 1.1%) and non-invasive EMPD (85.2 ± 8.4, 87.1 ± 9.9 and 83.1 ± 10.6%). There were significant positive correlations of the expression levels between PI3K (85α) and Rac1, as well as between Rac1 and pPAK1 in EMPD. CONCLUSIONS: These results indicate that PI3K, Rac1 and PAK1 may play important roles in the pathogenesis of EMPD.