Heparanase inhibition leads to improvement in patients with acute gastrointestinal injuries induced by sepsis.

BACKGROUND: Patients with sepsis are at high risk for acute gastrointestinal injury (AGI), but the diagnosis and treatment of AGI due to sepsis are unsatisfactory. Heparanase (HPA) plays an important role in septic AGI (S-AGI), but its specific mechanism is not completely understood, and few clinical reports are available. AIM: To explore the effect and mechanism of HPA inhibition in S-AGI patients. METHODS: In our prospective clinical trial, 48 patients with S-AGI were randomly assigned to a control group to receive conventional treatment, whereas 47 patients were randomly assigned to an intervention group to receive conventional treatment combined with low molecular weight heparin. AGI grade, sequential organ failure assessment score, acute physiology and chronic health evaluation II score, D-dimer, activated partial thromboplastin time (APTT), anti-Xa factor, interleukin-6, tumour necrosis factor-α, HPA, syndecan-1 (SDC-1), LC3B (autophagy marker), intestinal fatty acid binding protein, D-lactate, motilin, gastrin, CD4/CD8, length of intensive care unit (ICU) stay, length of hospital stay and 28-d survival on the 1st, 3rd and 7th d after treatment were compared. Correlations between HPA and AGI grading as well as LC3B were compared. Receiver operator characteristic (ROC) curves were generated to evaluate the diagnostic value of HPA, intestinal fatty acid binding protein and D-lactate in S-AGI. RESULTS: Serum HPA and SCD-1 levels were significantly reduced in the intervention group compared with the control group (P < 0.05). In addition, intestinal fatty acid-binding protein, D-lactate, AGI grade, motilin, and gastrin levels and sequential organ failure assessment score were significantly decreased (P < 0.05) in the intervention group. However, LC3B, APTT, anti-Xa factor, and CD4/CD8 were significantly increased (P < 0.05) in the intervention group. No significant differences in interleukin-6, tumour necrosis factor-α, d-dimer, acute physiology and chronic health evaluation II score, length of ICU stay, length of hospital stay, or 28-d survival were noted between the two groups (P > 0.05). Correlation analysis revealed a significant negative correlation between HPA and LC3B and a significant positive correlation between HPA and AGI grade. ROC curve analysis showed that HPA had higher specificity and sensitivity in diagnosis of S-AGI. CONCLUSION: HPA has great potential as a diagnostic marker for S-AGI. Inhibition of HPA activity reduces SDC-1 shedding and alleviates S-AGI symptoms. The inhibitory effect of HPA in gastrointestinal protection may be achieved by enhanced autophagy.

OL-SLAM: A Robust and Versatile System of Object Localization and SLAM.

This paper proposes a real-time, versatile Simultaneous Localization and Mapping (SLAM) and object localization system, which fuses measurements from LiDAR, camera, Inertial Measurement Unit (IMU), and Global Positioning System (GPS). Our system can locate itself in an unknown environment and build a scene map based on which we can also track and obtain the global location of objects of interest. Precisely, our SLAM subsystem consists of the following four parts: LiDAR-inertial odometry, Visual-inertial odometry, GPS-inertial odometry, and global pose graph optimization. The target-tracking and positioning subsystem is developed based on YOLOv4. Benefiting from the use of GPS sensor in the SLAM system, we can obtain the global positioning information of the target; therefore, it can be highly useful in military operations, rescue and disaster relief, and other scenarios.

Systematic appraisal of the guidelines for the diagnosis and treatment of Hirschsprung's disease.

BACKGROUND: Some guidelines for management of Hirschsprung's disease (HSCR, HD) have been developed, but their quality is vague. This study will systematically assess the quality of guidelines and analyze the key recommendations and the best evidence for guidelines. METHODS: Applicable guidelines were retrieved using a systematic search of databases. The Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool was used to assess the quality of the guidelines. Then, the recommendations and evidence for the included guidelines were extracted and compared. RESULTS: A total of nine guidelines were included in this study, and only one had an overall standardized score of more than 60%, indicating that it is worthy of recommendation. The problems identified included ambiguous and low-quality evidence; obvious distributional heterogeneity among the recommendations; a lack of in-depth discussion on the interpretation of staging, diagnostic methods, conservative treatment, and surgical staging of disease. CONCLUSION: The quality of guidelines varies widely, and there is a lack of high-quality professional opinions and supporting evidence for the main recommendations. At present, only comprehensive guidelines can be considered high-quality and there is still room for improvement.

Role of heparinase in the gastrointestinal dysfunction of sepsis (Review).

Heparinase (HPA) is a ß-D glucuronidase that belongs to the endoglycosidase enzyme family, and plays an important role in numerous pathological and physiological processes, including inflammation, angiogenesis and tumor metastasis. When the expression of HPA is abnormally high, the side chain of heparin sulfate proteoglycans degrades, destroying the cell barrier and leading to the occurrence and development of inflammation, with systemic inflammation occurring in severe cases. Sepsis is a major cause of mortality in critically ill patients. In sepsis, the gastrointestinal tract is the first and most frequently involved target organ, which often leads to gastrointestinal dysfunction. HPA overexpression has been determined to accelerate sepsis progression and gastrointestinal dysfunction; thus, it was hypothesized that HPA may play an important role and may serve as an index for the diagnosis of gastrointestinal dysfunction in sepsis. HPA inhibitors may therefore become applicable as targeted drugs for the treatment of gastrointestinal dysfunction in patients with sepsis. The present review mainly discussed the role of HPA in gastrointestinal dysfunction of sepsis.

Kir4.1 may represent a novel therapeutic target for diabetic retinopathy (Review).

As the major cause of irreversible loss of vision in adults, diabetic retinopathy (DR) is one of the most serious complications of diabetes. The imbalance of the retinal microenvironment and destruction of the blood-retinal barrier have a significant role in the progression of DR. Inward rectifying potassium channel 4.1 (Kir4.1) is located on Müller cells and is closely related to potassium homeostasis, water balance and glutamate clearance in the whole retina. The present review discusses the functions of Kir4.1 in regulating the retinal microenvironment and related biological mechanisms in DR. In the future, Kir4.1 may represent a novel alternative therapeutic target for DR through affecting the retinal microenvironment.

Stimulation of AMPK Prevents Diabetes-Induced Photoreceptor Cell Degeneration.

Diabetic retinopathy (DR) is a kind of severe retinal neurodegeneration. The advanced glycation end products (AGEs) affect autophagy, and mitochondrial function is involved in DR. Adenosine-activated protein kinase (AMPK) is an important metabolic sensor that can regulate energy homeostasis in cells. However, the effect of AMPK in DR is still not fully understood. In this study, we investigated the effect of AMPK on diabetes-induced photoreceptor cell degeneration. In vivo, a diabetic mouse model was established by streptozotocin (STZ) injection. Haematoxylin-eosin (HE) staining was used to observe retinal morphology and measure the thicknesses of different layers in the retina. Electroretinogram (ERG) was used to evaluate retinal function. In vitro, 661w cells were treated with AGEs with/without an AMPK agonist (metformin) or AMPK inhibitor (compound C). Flow cytometry and CCK-8 assays were used to analyse apoptosis. Mitochondrial membrane potential was analysed by JC-1. Western blotting and qRT-PCR were used to examine the expression of related proteins and genes, respectively. The wave amplitude and the thickness of the outer nuclear layer were decreased in diabetic mice. The expression of rhodopsin and opsin was also decreased in diabetic mice. In vitro, the percentage of apoptotic cells was increased, the expression of the apoptosis-related protein Bax was increased, and Bcl-2 was decreased after AGE treatment in 661w cells. The expression of the autophagy-related protein LC3 was decreased, and p62 was increased. The mitochondrial-related gene expression and membrane potential were decreased, and mitochondrial morphology was abnormal, as observed by TEM. However, AMPK stimulation ameliorated this effect. These results indicate that AMPK stimulation can delay diabetes-induced photoreceptor degeneration by regulating autophagy and mitochondrial function.

Systematic evaluation of the diagnostic approach of inflammatory bowel disease guidelines.

OBJECTIVE: To collect and evaluate the diagnostic approach of inflammatory bowel disease (IBD) guidelines and provide useful feedback for guideline developers and evidence-based clinical information to help physicians make decisions. METHODS: Diagnostic guidelines for IBD were retrieved by performing systemic and manual searches. Qualified clinical practice guidelines (CPGs) were included and then evaluated by four well-trained evaluators using the AGREE II instrument. To reduce the bias generated in this process, we used the Measurement Scale of Rate of Agreement (MSRA) tool to interpret the results. Guidelines with good recommendation distributions among the diagnostic field were further reclassified and evaluated. RESULTS: Fifteen diagnostic CPGs for IBD were identified and evaluated, and 70.3% (11/15) of the CPGs were above the recommended level. We observed heterogeneity among the diagnostic CPGs for IBD and discrepancies among different domains in one specific guideline. Potential improvements were identified in the fields of stakeholder involvement, rigour of development and applicability. By further analysing the heterogeneity of the recommendations and evidence in 5 UC-CPGs, we found the following issues: no discussion of diagnosing severe complications of UC, disputed significance of serologic and genetic diagnoses of UC, insufficient attention towards medical histories/physical examinations/differential diagnoses and discrepancy in classification criteria. CONCLUSION: The included diagnostic CPGs for IBD were generally of good quality, but heterogeneity was identified. Addressing these issues will provide useful feedback for the guideline updating process, and it will also benefit current clinical practice and eventually patient outcome.

Prognostic value of FOXQ1 in patients with malignant solid tumors: a meta-analysis.

BACKGROUND: Forkhead box Q1 (FOXQ1, also known as HFH1), a member of the forkhead transcription factor family, has been demonstrated to be overexpressed in multiple tumors and is thought to be an indicator of poor clinical outcomes. METHODS: A meta-analysis using qualified relevant literature was performed to evaluate the prognostic significance of FOXQ1 in various malignant solid tumors. A search of electronic databases was conducted in MEDLINE, Embase, and the Cochrane Library to identify relevant studies published from 1966 to July 30, 2016, and the studies were identified by further evaluation. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for analyses were assessed to investigate the association between FOXQ1 expression and overall survival (OS) of patients with malignant solid tumors. RESULTS: A total of 1,520 patients from six studies (seven cohorts) with multiple malignant solid tumors were included. For OS, high FOXQ1 expression could significantly predict worse outcome with the pooled HR of 1.38 (95% CI: 1.17-1.59; P<0.001). The subgroup analysis suggested that the elevated levels of FOXQ1 appear to be associated with worse OS in hepatocellular carcinoma (HR =1.34; 95% CI: 1.11-1.57; P<0.001) and other cancers (HR =1.62; 95% CI: 1.09-2.14; P<0.001). CONCLUSION: This meta-analysis indicated that the high expression of FOXQ1 is associated with an adverse OS in malignant solid tumors, suggesting that FOXQ1 may be a predictor of poor prognosis for the development of malignant solid tumors.

Recombinant human lactoferrin enhances the efficacy of triple therapy in mice infected with Helicobacter pylori.

Helicobacter pylori (H. pylori) is a life-threatening pathogen which causes chronic gastritis, gastric ulcers and even stomach cancer. Treatment normally involves bacterial eradication; however, this type of treatment only has a rate of effectiveness of <80%. Thus, it is a matter of some urgency to develop new therapeutic strategies. Lactoferrin, a member of the transferrin family of iron-binding proteins, has been proven to be effective in removing a vast range of pathogens, including H. pylori. In the present study, we examined the effectiveness of recombinant human lactoferrin (rhLf) isolated from transgenic goats as a treatment for H. pylori in vitro and in vivo. For the in vivo experiments, BALB/c mice received an intragastric administration of 0.1 ml of a suspension of H. pylori. The mice were then divided into 4 groups: group A, treated with saline; group B, treated with 1.5 g of rhLF; group C, treated with the standard triple therapy regimen; and group D, treated with the standard triple therapy regimen plus.5 g of rhLF. Following sacrifice, the stomach tissues of the mice were histologically examined for the presence of bacteria. For the in vitro experiments, the bacteria were cultured in BHI broth and RT-qPCR and western blot analysis were carried out to determine the mRNA and protein levels of virulence factors (CagA and VacA) in the cultures. Our results revealed that rhLf not only inhibited the growth of H. pylori, but also suppressed the expression of two major virulence factors. Moreover, rhLf markedly increased bacterial eradication and effectively reduced the inflammatory response when combined with the standard triple therapy regimen. These results provide evidence supporting the use of rhLF as an adjuvant to traditional therapeutic strategies in the treatment of H. pylori.

Duodenal ferroportin is up-regulated in patients with chronic hepatitis C.

Hepatitis C virus (HCV) infection is a leading cause of liver-related mortality. Chronic hepatitis C (CHC) is frequently associated with disturbances in iron homeostasis, with serum iron and hepatic iron stores being elevated. Accumulating evidence indicates that chronic HCV infection suppresses expression of hepatic hepcidin, a key mediator of iron homeostasis, leading to iron overload conditions. Since hepcidin mediates degradation of ferroportin, a basolateral transporter involved in the release of iron from cells, diminished hepcidin expression probably leads to up-regulation of ferroportin-1 (Fpn1) in patients with CHC. In this study, we determined the protein levels of duodenal Fpn1, and found that its expression was significantly up-regulated in patients with CHC. The expression of duodenal Fpn1 is negatively correlated with mRNA levels of hepcidin, and positively correlated with serum iron parameters. Although iron is a critical factor for growth of a variety of pathogenic bacteria, our results suggest that iron overload in blood does not increase the infection rate of bacteria in patients with CHC.

Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress.

Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up-regulating protein levels of p53 as well as mRNA and protein levels of p21(Cip1) in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53-positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-α inhibited the expression of p21(Cip1) and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3-mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21(Cip1) are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia.