Notch1 regulates hepatic thrombopoietin production.

ABSTRACT: Notch signaling regulates cell-fate decisions in several developmental processes and cell functions. However, the role of Notch in hepatic thrombopoietin (TPO) production remains unclear. We noted thrombocytopenia in mice with hepatic Notch1 deficiency and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO messenger RNA levels, concomitant with lower numbers of platelets and impaired megakaryocyte differentiation and maturation, which were rescued by addition of exogenous TPO. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes, consistent with the RNA-sequencing analysis. JAK2/STAT3 phosphorylation and TPO production was also impaired in cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Consistently, hepatocyte-specific Notch1 deletion inhibited JAK2/STAT3 phosphorylation and hepatic TPO production induced by administration of desialylated platelets in vivo. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation in hepatocytes. Hepatocyte Ashwell-Morell receptor (AMR), a heterodimer of asialoglycoprotein receptor 1 [ASGR1] and ASGR2, physically associates with Notch1, and inhibition of AMR impaired Notch1 signaling activation and hepatic TPO production. Furthermore, blockage of Delta-like 4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation, and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.

Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing.

Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.

Protein tyrosine phosphatase PTPN22 negatively modulates platelet function and thrombus formation.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a protein tyrosine phosphatase that negatively regulates T-cell signaling. However, whether it is expressed and functions in platelets remains unknown. Here we investigated the expression and role of PTPN22 in platelet function. We reported PTPN22 expression in both human and mouse platelets. Using PTPN22-/- mice, we showed that PTPN22 deficiency significantly shortened tail-bleeding time and accelerated arterial thrombus formation without affecting venous thrombosis and the coagulation factors VIII and IX. Consistently, PTPN22-deficient platelets exhibited enhanced platelet aggregation, granule secretion, calcium mobilization, lamellipodia formation, spreading, and clot retraction. Quantitative phosphoproteomic analysis revealed the significant difference of phosphodiesterase 5A (PDE5A) phosphorylation in PTPN22-deficient platelets compared with wild-type platelets after collagen-related peptide stimulation, which was confirmed by increased PDE5A phosphorylation (Ser92) in collagen-related peptide-treated PTPN22-deficient platelets, concomitant with reduced level and vasodilator-stimulated phosphoprotein phosphorylation (Ser157/239). In addition, PTPN22 interacted with phosphorylated PDE5A (Ser92) and dephosphorylated it in activated platelets. Moreover, purified PTPN22 but not the mutant form (C227S) possesses intrinsic serine phosphatase activity. Furthermore, inhibition of PTPN22 enhanced human platelet aggregation, spreading, clot retraction, and increased PDE5A phosphorylation (Ser92). In conclusion, our study shows a novel role of PTPN22 in platelet function and arterial thrombosis, identifying new potential targets for future prevention of thrombotic or cardiovascular diseases.

Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis.

B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.

The Impact of Parental Myopia and High Myopia on the Hyperopia Reserve of Preschool Children.

INTRODUCTION: The aim of this study was to explore the association between parental myopia and high myopia with children's refraction and ocular biometry in large-scale Chinese preschool children from the Beijing Hyperopia Reserve Study. SUBJECTS/METHODS: This cross-sectional kindergarten-based study enrolled children aged 3-6 years. Cycloplegic refraction, axial length (AL), and corneal radius (CR) were measured for all children. Parents were asked to complete a questionnaire about refractive status (no myopia, mild myopia <-3 D, moderate myopia ≥-3 D and ≤-6, and high myopia >-6 D). RESULTS: The study enrolled 2,053 children (1,069 boys and 984 girls), with a mean age of 4.26 ± 0.96 years and mean spherical equivalent refraction (SER) of 1.11 ± 0.97 diopter. Of the children, 90.7% had at least one myopic parent, and 511 children (24.9%) had at least one highly myopic parent. SER decreased significantly with increasing severity of parental myopia (p < 0.001). Preschool children's myopia was independently associated with parental myopia (OR, 10.4 and 11.5 for one and two highly myopic parent[s]). Age (OR = 1.1), gender (OR = 1.7; girls as references), near work time (OR = 1.2), and both maternal (OR, 1.4 and 2.0 for moderate and high myopia) and paternal myopia (OR, 1.6 and 1.9 for moderate and high myopia) were independent risk factors for lacking hyperopia reserve. CONCLUSION: Severe parental myopia was associated with a lower SER, longer AL, and higher AL/CR ratio in preschool children. Parental myopia and near work may predispose children to faster elimination of hyperopia reserves before exposure to higher educational stress.

Pharmacokinetics of YK-1169 in healthy subjects and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation.

OBJECTIVE: This study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime-avibactam (YK-1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation. METHODS: YK-1169 single-ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2-h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2-h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK-1169 (2.5 g) to assess drug-drug interactions. The minimum inhibitory concentrations (MICs) of YK-1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens. RESULTS: Cefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime Cmax,ss and AUC0-∞,ss were 9.20 and 16.0 µg/mL, 407.2 and 659.45 µg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. The avibactam Cmax,ss and AUC0-∞,ss were 0.545 and 0.837 µg/mL, 53.31 and 79.55 µg·h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was ≤8 mg/L. The regimens of 2.5 (q8h, 2-h infusion), 3.75 (q8h, 2-, 3- and 4-h infusions) and 7.5 g (24-h continuous infusion) reached a 90% cumulative fraction of response. CONCLUSION: YK-1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt) 2 h should be considered in future clinical trials.

Portal Vein Recanalization for Noncirrhotic Portal Vein Cavernous Transformation: Transjugular Intrahepatic Portosystemic Shunt Creation versus Portal Vein Stent Placement.

PURPOSE: To compare the clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation versus portal vein stent placement (PVS) in patients with noncirrhotic cavernous transformation of the portal vein (CTPV). MATERIALS AND METHODS: In this retrospective study, clinical data from patients with noncirrhotic CTPV who underwent TIPS creation or PVS were compared. A total of 54 patients (mean age, 43.8 years ± 15.8; 31 men and 23 women) were included from January 2013 to January 2021; 29 patients underwent TIPS creation, and 25 patients underwent PVS. Stent occlusion, variceal rebleeding, survival, and postprocedural complications were compared between the 2 groups. RESULTS: The mean follow-up time was 40.2 months ± 26.2 in the TIPS group and 35.3 months ± 21.1 in the PVS group. The stent occlusion rate in the PVS group (16%, 4 of 25) was significantly lower than that in the TIPS group (41.4%, 12 of 29) during the follow-up (P = .042). The cumulative variceal rebleeding rates in the TIPS group were significantly higher than those in the PVS group (28% vs 4%; P = .027). The procedural success rate was 69% in the TIPS group and 86% in the PVS group (P = .156). There was a higher number of severe adverse events after TIPS than after PVS (0% vs 24%; P = .012). CONCLUSIONS: Portal vein recanalization with PVS may be a preferable alternative to TIPS creation in the treatment of noncirrhotic CTPV because of higher stent patency rates, lower risk of variceal rebleeding, and fewer adverse events.

Using multi-sourced big data to correlate sleep deprivation and road traffic noise: A US county-level ecological study.

BACKGROUND: Road traffic noise is a serious public health problem globally as it has adverse psychological and physiologic effects (i.e., sleep). Since previous studies mainly focused on individual levels, we aim to examine associations between road traffic noise and sleep deprivation on a large scale; namely, the US at county level. METHODS: Information from a large-scale sleep survey and national traffic noise map, both obtained from government's open data, were utilized and processed with Geographic Information System (GIS) techniques. To examine the associations between traffic noise and sleep deprivation, we used a hierarchical Bayesian spatial modelling framework to simultaneously adjust for multiple socioeconomic factors while accounting for spatial correlation. FINDINGS: With 62.90% of people not getting enough sleep, a 10 dBA increase in average sound-pressure level (SPL) or Ls10 (SPL of the relatively noisy area) in a county, was associated with a 49% (OR: 1.49; 95% CrIs:1.19-1.86) or 8% (1.08; 1.00-1.16) increase in the odds of a person in a particular county not getting enough sleep. No significant association was observed for Ls90 (SPL of the relatively quiet area). A 10% increase in noise exposure area or population ratio was associated with a 3% (1.03; 1.01-1.06) or 4% (1.04; 1.02-1.06) increase in the odds of a person within a county not getting enough sleep. INTERPRETATION: Traffic noise can contribute to variations in sleep deprivation among counties. This study suggests that policymakers could set up different noise-management strategies for relatively quiet and noisy areas and incorporate geospatial noise indicators, such as exposure population or area ratio. Furthermore, urban planners should consider urban sprawl patterns differently in terms of noise-induced sleep problems.

Exposure to air pollution is associated with an increased risk of metabolic dysfunction-associated fatty liver disease.

BACKGROUND & AIMS: Accumulating animal studies have demonstrated the harmful contribution of ambient air pollution (AP) to metabolic dysfunction-associated fatty liver disease (MAFLD), but corresponding epidemiological evidence is limited. We examined the associations between long-term AP exposure and MAFLD prevalence in a Chinese population. METHODS: We conducted a cross-sectional study of 90,086 participants recruited in China from 2018 to 2019. MAFLD was assessed based on radiologically diagnosed hepatic steatosis and the presence of overweight/obese status, diabetes mellitus, or metabolic dysregulation. Residence-specific levels of air pollutants, including particulate matter with aerodynamic diameters of ≤1 µm (PM1), ≤2.5 µm (PM2.5), and ≤10 µm (PM10), and nitrogen dioxide (NO2), were estimated by validated spatiotemporal models. We used logistic regression models to examine the AP-MAFLD associations and further evaluated potential effect modifications by demographics, lifestyle, central obesity, and diabetes status. RESULTS: Increased exposure levels to all 4 air pollutants were significantly associated with increased odds of MAFLD, with odds ratios (ORs) of 1.13 (95% CI 1.10-1.17), 1.29 (1.25-1.34), 1.11 (1.09-1.14), and 1.15 (1.12-1.17) for each 10 µg/m3 increase in PM1, PM2.5, PM10, and NO2, respectively. Further stratified analyses revealed that individuals who are male, alcohol drinkers, and current and previous smokers, those who consume a high-fat diet, and those with central obesity experience more significant adverse effects from AP exposure than other individuals. CONCLUSIONS: This study provides evidence that long-term exposure to ambient PM1, PM2.5, PM10, and NO2 may increase the odds of MAFLD in the real world. These effects may be exacerbated by unhealthy lifestyle habits and central obesity. LAY SUMMARY: We conducted an epidemiological study on the potential effect of ambient air pollution on the risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in approximately 90 thousand adults in China. We found that long-term exposure to ambient air pollution may increase the odds of MAFLD, especially in individuals who are male, smokers, and alcohol drinkers, those who consume a high-fat diet, and those with central obesity.

Sitafloxacin pharmacokinetics/pharmacodynamics against multidrug-resistant bacteria in a dynamic urinary tract infection in vitro model.

OBJECTIVES: Sitafloxacin is one of the newer generation fluoroquinolones with highly active against multidrug-resistant (MDR) bacteria. Our objectives were to identify the sitafloxacin pharmacokinetic/pharmacodynamic (PK/PD) index and breakpoints against MDR isolate in the urinary tract infection model. METHODS: Forty-eight MDR isolates underwent sitafloxacin and levofloxacin microdilution susceptibility testing. A 24 h in vitro model was established that simulated the healthy subjects urodynamics of sitafloxacin fumarate injection. Ten MDR isolates (four carbapenem-resistant Escherichia coli, three carbapenem-resistant P. aeruginosa and three vancomycin-resistant E. faecium) were selected. The drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid Emax model was fitted to the killing effect data. Monte Carlo simulations were performed to assess target attainment for the sitafloxacin fumarate doses of 100 and 200 mg q24h. RESULTS: Analysis indicated that the MICs of sitafloxacin were all significantly lower than that of levofloxacin (P < 0.01). The UAUC0-24h/MIC targets required to achieve stasis, 1-log10 killing and 2-log10 killing were 63.60, 79.49 and 99.45 (carbapenem-resistant E. coli), 60.85, 90.31 and 128.95 (carbapenem-resistant P. aeruginosa), 65.91, 77.81 and 103.11 (vancomycin-resistant E. faecium). Monte Carlo simulation showed the infusion of sitafloxacin fumarate 100 mg q24h was able to achieve 90% probability of target attainment against bacteria with MIC of 8 mg/L for the common complicated urinary tract infections. CONCLUSIONS: Sitafloxacin fumarate injection is an alternative therapeutic agent for the treatment of UTIs caused by MDR isolates.

A Multicenter Study of Prevalence and Risk Factors for Allergic Rhinitis in Primary School Children in 5 Cities of Hubei Province, China.

BACKGROUND: Few data are available concerning the prevalence and risk factors for allergic rhinitis (AR) in school children in Hubei Province which is located in the central part of China. This study investigated the epidemiological features of AR among school children in Hubei Province. METHODS: A cross-sectional questionnaire survey on AR in school children was carried out in 5 cities in Hubei Province by cluster sampling from June to September 2018. Questionnaires were filled out by children and their parents jointly. The diagnostic criteria of AR were according to the SFAR. Questions from the questionnaire were used to examine the pattern of AR. Logistic regression analysis was used to assess the risk factors for childhood allergies. RESULTS: The total prevalence rate of AR was 16.16%, with 24.31% (Wuhan), 4.34% (Xiangyang), 4.31% (Tianmen), 10.92% (Jingmen), and 11.42% (Huangshi), respectively. The prevalence of AR was positively correlated with gross domestic product per capita (p < 0.05). Multivariate analysis revealed that male, city of Wuhan, family history of allergy, food allergy, drug allergy, air purifier, exposure to dust, living in towns or urban area before 2 years old, maternal age for 26-35 years old, and frequent application of antibiotics increased the risk of AR, while daily outdoor time for 1-2 h, daily sleeping time >8 h, siblings, and breastfeeding for >6 months reduced the risk significantly. CONCLUSION: We found the apparent geographic variation of children allergies in Hubei Province. Both genetic and environment factors had impacts on the prevalence of AR in school children. Public policies should specifically target at the local risk factors for different areas.

The effectiveness of travel restriction measures in alleviating the COVID-19 epidemic: evidence from Shenzhen, China.

With the expansion of the global novel coronavirus disease (COVID-19) pandemic, unprecedented interventions have been widely implemented in many countries, including China. In view of this scenario, this research aims to explore the effectiveness of population mobility restriction in alleviating epidemic transmission during different stages of the outbreak. Taking Shenzhen, a city with a large immigrant population in China, as a case study, the real-time reproduction number of COVID-19 is estimated by statistical methods to represent the dynamic spatiotemporal transmission pattern of COVID-19. Furthermore, migration data between Shenzhen and other provinces are collected to investigate the impact of nationwide population flow on near-real-time dynamic reproductive numbers. The results show that traffic flow control between populated cities has an inhibitory effect on urban transmission, but this effect is not significant in the late stage of the epidemic spread in China. This finding implies that the government should limit international and domestic population movement starting from the very early stage of the outbreak. This work confirms the effectiveness of travel restriction measures in the face of COVID-19 in China and provides new insight for densely populated cities in imposing intervention measures at various stages of the transmission cycle.

Relationships between building attributes and COVID-19 infection in London.

In the UK, all domestic COVID-19 restrictions have been removed since they were introduced in March 2020. After illustrating the spatial-temporal variations in COVID-19 infection rates across London, this study then particularly aimed to examine the relationships of COVID-19 infection rates with building attributes, including building density, type, age, and use, since previous studies have shown that the built environment plays an important role in public health. Multisource data from national health services and the London Geomni map were processed with GIS techniques and statistically analysed. From March 2020 to April 2022, the infection rate of COVID-19 in London was 3,159.28 cases per 10,000 people. The spatial distribution across London was uneven, with a range from 1,837.88 to 4,391.79 per 10,000 people. During this period, it was revealed that building attributes played a significant role in COVID-19 infection. It was noted that higher building density areas had lower COVID-19 infection rates in London. Moreover, a higher percentage of historic or flat buildings tended to lead to a decrease in infection rates. In terms of building use, the rate of COVID-19 infection tended to be lower in public buildings and higher in residential buildings. Variations in the infection rate were more sensitive to building type; in particular, the percentage of residents living in flats contributed the most to variations in COVID-19 infection rates, with a value of 2.3%. This study is expected to provide support for policy and practice towards pandemic-resilient architectural design.

Inhibition of cyclooxygenase-2 enhanced intestinal epithelial homeostasis via suppressing ß-catenin signalling pathway in experimental liver fibrosis.

The intestinal barrier dysfunction is crucial for the development of liver fibrosis but can be disturbed by intestinal chronic inflammation characterized with cyclooxygenase-2 (COX-2) expression. This study focused on the unknown mechanism by which COX-2 regulates intestinal epithelial homeostasis in liver fibrosis. The animal models of liver fibrosis induced with TAA were established in rats and in intestinal epithelial-specific COX-2 knockout mice. The impacts of COX-2 on intestinal epithelial homeostasis via suppressing ß-catenin signalling pathway were verified pharmacologically and genetically in vivo. A similar assumption was tested in Ls174T cells with goblet cell phenotype in vitro. Firstly, disruption of intestinal epithelial homeostasis in cirrhotic rats was ameliorated by celecoxib, a selective COX-2 inhibitor. Then, ß-catenin signalling pathway in cirrhotic rats was associated with the activation of COX-2. Furthermore, intestinal epithelial-specific COX-2 knockout could suppress ß-catenin signalling pathway and restore the disruption of ileal epithelial homeostasis in cirrhotic mice. Moreover, the effect of COX-2/PGE2 was dependent on the ß-catenin signalling pathway in Ls174T cells. Therefore, inhibition of COX-2 may enhance intestinal epithelial homeostasis via suppression of the ß-catenin signalling pathway in liver fibrosis.

Celecoxib reduces hepatic vascular resistance in portal hypertension by amelioration of endothelial oxidative stress.

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

Retrospective Comparison of Clinical Outcomes Following Splenic Vein Stenting and Splenic Arterial Embolization in Sinistral Portal Hypertension-Related Gastrointestinal Bleeding.

BACKGROUND. Sinistral portal hypertension (SPH) is caused by an obstruction of the splenic vein and is a potential cause of upper gastrointestinal bleeding. Although splenic arterial embolization (SAE) and splenic vein stenting are accepted treatment options for SPH, their outcomes have not been compared directly. OBJECTIVE. This retrospective study compared the outcomes of splenic vein stenting and SAE for SPH-related gastrointestinal bleeding. METHODS. Data of patients with SPH treated by interventional radiology between January 1, 2013, and June 1, 2019, who had at least 6 months of clinical follow-up were retrospectively identified from the electronic database at our hospital. Patients were divided into the SAE group (SAE alone), splenic vein stenting-SAE group (SAE immediately after splenic vein stenting failure using the same procedure as the SAE group), and splenic vein stenting group (successful treatment with SVS). Patients' baseline characteristics and follow-up data were retrieved, and their clinical outcomes were compared. RESULTS. Thirty-seven patients with SPH were included. We assigned 11, 12, and 14 patients to the SAE, splenic vein stenting-SAE, and splenic vein stenting groups, respectively. Rebleeding (e.g., hematemesis, melena, or both) was significantly less common (p = .01) in the splenic vein stenting group (7.1% [1/14]) than in the SAE and splenic vein stenting-SAE groups combined (47.8% [11/23]). Splenectomy to resolve rebleeding was not significantly different (p = .63) in the splenic vein stenting group (7.1% [1/14]) compared with the SAE and splenic vein stenting-SAE groups combined (17.4% [4/23]). No interventional procedure-related deaths were observed during follow-up in any group. CONCLUSION. When feasible, splenic vein stenting is a safe and effective treatment of SPH-related gastrointestinal bleeding that appears to better prevent rebleeding than SAE. CLINICAL IMPACT. Splenic vein stenting should be recommended over SAE for the treatment of SPH-related upper gastrointestinal bleeding when possible.

Dimethyl fumarate inhibits antibody-induced platelet destruction in immune thrombocytopenia mouse.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized as a low platelet count resulting from immune-mediated platelet destruction. Dimethyl fumarate (DMF) is widely applied for the treatment of several autoimmune diseases with immunosuppressive effect. However, whether it ameliorates ITP is unclear. This study aims to evaluate whether DMF has a preventive effect on ITP in mice. METHODS: DMF (30, 60 or 90 mg/kg body weight) was intraperitoneally injected into mice followed by injection of rat anti-mouse integrin GPIIb/CD41antibody to induce ITP. Peripheral blood was isolated to measure platelet count and spleen mononuclear cells were extracted to measure Th1 and Treg cells along with detecting the levels of IFN-γ, and TGFß-1 in plasma and CD68 expression in spleen by immuohistochemical staining. Additionally, macrophage cell line RAW264.7 was cultured and treated with DMF followed by analysis of cell apoptosis and cycle, and the expression of FcγRI, FcγRIIb and FcγRIV mRNA. RESULTS: DMF significantly inhibited antiplatelet antibody-induced platelet destruction, decreased Th1 cells and the expression of T-bet and IFN-γ, upregulated Treg cells and the expression of Foxp3 and TGF-ß1 as well as reduced CD68 expression in the spleen of ITP mouse. DMF-treated RAW264.7 cells showed S-phase arrest, increased apoptosis and downregulated expression of FcγRI and FcγRIV. Meanwhile, in vitro treatment of DMF also decreased the expression of cyclin D1 and E2, reduced Bcl-2 level and increased Bax expression and caspase-3 activation. CONCLUSIONS: In conclusion, DMF prevents antibody-mediated platelet destruction in ITP mice possibly through promoting apoptosis, indicating that it might be used as a new approach for the treatment of ITP.

Characteristics of noise complaints and the associations with urban morphology: A comparison across densities.

This study aimed to characterise spatial-temporal distribution of noise complaints across urban areas with different densities and to analyse the associations between urban morphology and noise complaints. Taking New York City as the study area, crowdsourced noise complaint and urban morphology datasets from the government's open data source were statistically analysed. The results suggest that between boroughs the characteristics of noise complaints are different, in terms of their spatial-temporal distribution, their relation to transport network, land use, and building morphology. Noise complaints were clustered around the highest density area (Manhattan). The rate of noise complaints showed a year-on-year increase, peaking in autumn and spring. The rate of noise complaints is higher in areas with higher densities and roads that are 20-40 m wide, closer to road crossings, and in enclosed blocks. The relationships between noise complaints and urban morphology are weaker in high-density boroughs than in other boroughs.

Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats.

BACKGROUND: In liver cirrhosis, intestinal mucus barrier is rarely studied. AIMS: This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. METHODS: Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. RESULTS: The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. CONCLUSIONS: In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.

Detection of multiple lesions of gastrointestinal tract for endoscopy using artificial intelligence model: a pilot study.

BACKGROUND: This study was aimed to develop a computer-aided diagnosis (CAD) system with deep-learning technique and to validate its efficiency on detecting the four categories of lesions such as polyps, advanced cancer, erosion/ulcer and varices at endoscopy. METHODS: A deep convolutional neural network (CNN) that consists of more than 50 layers were trained with a big dataset containing 327,121 white light images (WLI) of endoscopy from 117,005 cases collected from 2012 to 2017. Two CAD models were developed using images with or without annotation of the training dataset. The efficiency of the CAD system detecting the four categories of lesions was validated by another dataset containing consecutive cases from 2018 to 2019. RESULTS: A total of 1734 cases with 33,959 images were included in the validation datasets which containing lesions of polyps 1265, advanced cancer 500, erosion/ulcer 486, and varices 248. The CAD system developed in this study may detect polyps, advanced cancer, erosion/ulcer and varices as abnormality with the sensitivity of 88.3% and specificity of 90.3%, respectively, in 0.05 s. The training datasets with annotation may enhance either sensitivity or specificity about 20%, p = 0.000. The sensitivities and specificities for polyps, advanced cancer, erosion/ulcer and varices reached about 90%, respectively. The detect efficiency for the four categories of lesions reached to 89.7%. CONCLUSION: The CAD model for detection of multiple lesions in gastrointestinal lumen would be potentially developed into a double check along with real-time assessment and interpretation of the findings encountered by the endoscopists and may be a benefit to reduce the events of missing lesions.