Clinical characteristics of pyogenic liver abscess with and without biliary surgery history: a retrospective single-center experience.

BACKGROUND & AIMS: Pyogenic liver abscess (PLA) is a common hepatobiliary infection that has been shown to have an increasing incidence, with biliary surgery being identified as a trigger. Our aim was to investigate the clinical characteristics and treatments of PLA patients with and without a history of biliary surgery (BS). METHODS: The study included a total of 353 patients with PLA who received treatment at our hospital between January 2014 and February 2023. These patients were categorized into two groups: the BS group (n = 91) and the non-BS group (n = 262). In the BS group, according to the anastomosis method, they were further divided into bilioenteric anastomoses group (BEA, n = 22) and non-bilioenteric anastomoses group (non-BEA, n = 69). Clinical characteristics were recorded and analyzed. RESULTS: The percentage of PLA patients with BS history was 25.78%. The BS group exhibited elevated levels of TBIL and activated APTT abnormalities (P = 0.009 and P = 0.041, respectively). Within the BS group, the BEA subgroup had a higher prevalence of diabetes mellitus (P < 0.001) and solitary abscesses (P = 0.008) compared to the non-BEA subgroup. Escherichia coli was more frequently detected in the BS group, as evidenced by positive pus cultures (P = 0.021). The BS group exhibited reduced treatment efficacy compared to those non-BS history (P = 0.020). Intriguingly, the BS group received a higher proportion of conservative treatment (45.05% vs. 21.76%), along with reduced utilization of surgical drainage (6.59% vs. 16.41%). CONCLUSIONS: Patients with BS history, especially those who have undergone BEA, have an increased susceptibility to PLA formation without affecting prognosis.

The epidemic of acute lymphoid leukemia in China: current trends and future prediction.

Background: China has experienced one of the fastest increases in the incidence of acute lymphoid leukemia (ALL). The aim of this study was to assess the long-term trends of the incidence and mortality of ALL in mainland China between 1990 and 2019 and to project these trends through 2028. Methods: Data on ALL were extracted from the Global Burden of Disease Study 2019; population data were extracted from World Population Prospects 2019. An age-period-cohort framework was used in the analysis. Results: The net drift for the incidence of ALL was 7.5% (95% confidence interval [CI]: 7.1%, 7.8%) per year in women and 7.1% (95% CI: 6.7%, 7.6%) in men, and local drift was found to be higher than 0 in every studied age group (p<0.05). The net drift for mortality was 1.2% (95% CI: 1.0%, 1.5%) in women and 2.0% (95% CI: 1.7%, 2.3%) in men. Local drift was lower than 0 in boys aged 0-4 years and girls aged 0-9 years and higher than 0 in men aged 10-84 years and women aged 15-84 years. The estimated period relative risks (RRs) for both incidence and mortality showed increasing trends in the recent period. The cohort RRs for incidence showed increasing trends in both sexes; however, the cohort RR for mortality was decreased in the recent birth cohort (women born after 1988-1992 and men born after 2003-2007). Compared with that in 2019, the incidence of ALL in 2028 is projected to increase by 64.1% in men and 75.0% in women, and the mortality is predicted to decrease by 11.1% in men and 14.3% in women. The proportion of older adult/adults individuals with incident ALL and ALL-related death was projected to increase. Conclusions: Over the last three decades, the incidence and mortality rates of ALL have generally increased. It is projected that the incidence rate of ALL in mainland China will continue to increase in the future, but the associated mortality rate will decline. The proportion of older adult/adults individuals with incident ALL and ALL-related death was projected to increase gradually among both sexes. More efforts are needed, especially for older adult/adults individuals.

Overexpression of HSF2 binding protein suppresses endoplasmic reticulum stress via regulating subcellular localization of CDC73 in hepatocytes.

BACKGROUND: Endoplasmic reticulum (ER) stress plays an important role in the occurrence and development of various liver diseases. However, there are no effective prevention and treatment strategies. We aimed to determine the role of heat shock factor 2 binding protein (HSF2BP) in ER stress. METHODS: HSF2BP expression in mice and cultured hepatocytes was measured during ER stress induced by tunicamycin, and its importance in ER stress was evaluated in hepatocyte-specific HSF2BP transgenic (TG) and knockout (KO) mice. The effects and mechanisms of HSF2BP on ER stress were further probed in hepatic ischemia-reperfusion (I/R) injury. RESULTS: HSF2BP expression was significantly upregulated during tunicamycin-induced ER stress in mice and cultured hepatocytes. Liver injury and ER stress were reduced in HSF2BP overexpressing mice after treating with tunicamycin, but were aggravated in HSF2BP knockout mice compared to the controls. In hepatic I/R injury, HSF2BP expression was significantly upregulated, and HSF2BP overexpressing mice had reduced liver injury and inflammation. These improvements were associated with ER stress inhibition. However, these results were reversed in hepatocyte-specific HSF2BP knockout mice. HSF2BP overexpression increased cytoplasmic CDC73 levels and inhibited the JNK signaling pathway. CDC73 knockdown using siRNA eliminated the protection exerted by HSF2BP overexpression in hypoxia/reoxygenation (H/R)-induced ER stress in hepatocytes. CONCLUSION: HSF2BP is a previously uncharacterized regulatory factor in ER stress-likely acts by regulating CDC73 subcellular localization. The feasibility of HSF2BP-targeted treatment in ER stress-related liver disease deserves future research.

Effectiveness and tolerability of camrelizumab combined with molecular targeted therapy for patients with unresectable or advanced HCC.

There is a lack of effective programmed cell death protein 1 (PD-1)-targeted immunotherapy with good tolerability in patients with advanced hepatocellular carcinoma (HCC) and severely compromised liver function. We assessed patient outcomes after combined camrelizumab and molecular targeted therapy in a multicenter cohort study in China. The study included 99 patients with advanced HCC (58 Child-Pugh A and 41 Child-Pugh B), 84 of them received camrelizumab combined with molecular targeted therapy from January 10, 2019, to March 31, 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were assessed. The median follow-up was 12.1 months. For patients with Child-Pugh B, the OS probability at 12-months, ORR and DCR were 49.7%, 31.7% and 65.9%, respectively, and the median PFS was 5.1 months [95% confidence interval (CI) 3.0-7.1], which were comparable with Child-Pugh A patients, although median OS was shorter in Child-Pugh B patients (20.5 vs.13.4 months, P = 0.12). In multivariate analysis, macrovascular infiltration (MVI), but not sex, age, hepatitis B virus etiology, extrahepatic metastasis, Child-Pugh B, or AFP > 400 ng/ml, was associated with 12-months OS [hazard ratio (HR) 2.970, 95% CI 1.276-6.917, P = 0.012] and ORR (HR 2.906, 95% CI 1.18-7.16, P = 0.020). Grade 3/4 immune-related AEs occurred in 26.8% of Child-Pugh B patients, including one potentially treatment-related death. In both groups, the most common AEs were immune thrombocytopenia and hepatotoxicity. Camrelizumab combined with targeted therapy showed favorable effectiveness and tolerability with manageable toxicities in Chinese HCC patients, regardless of Child-Pugh A/B liver function. MVI was associated with suboptimal immunotherapy response and poor prognosis.

The epidemic of stroke mortality attributed to high body mass index in mainland China: Current trends and future prediction.

Background: High body mass index (BMI) is an important risk factor for stroke. The aim of this study was to assess the long-term trend of high BMI-attributed stroke mortality and make projections through 2030. Methods: Data were extracted from the Global Burden of Disease Study 2019 and World Population Prospects 2019. An age-period-cohort framework was used in the analysis. Results: From 1990 to 2019, the age-standardized mortality rate (ASMR) of high BMI-attributed stroke among females decreased by 15.2%, while among males, it increased by 31.1%. All of the age groups studied showed an increasing pattern over the last 30 years in males, and in female, the age groups encompassing participants who were 25-69 years old showed a decreasing pattern. In the same birth cohort, high BMI-attributable stroke mortality rates increased exponentially with age in both sexes. For females, the period rate ratios (RR) showed a downward trend after 2000-2004, and the cohort RR also showed a downward trend after the birth cohort 1930-1934. For males, the period RR showed an upward trend, but this increase was halted in the most recent period, and the cohort RRs showed a monotonic increasing pattern. It was projected that the ASMR of high BMI-attributed stroke would decrease among females and increase among males in the near future and that the proportion of elderly individuals with death due to high BMI-attributed stroke was projected to increase. Conclusions: Over the last three decades, the high BMI-attributed stroke mortality rate decreased among females and increased among males, and these trends are projected to continue in the future. In addition, the proportion of elderly individuals with high BMI-attributed stroke mortality was projected to increase gradually in both men and women. More health-promoting efforts are needed, especially for elderly individuals and males.

HSF2BP protects against acute liver injury by regulating HSF2/HSP70/MAPK signaling in mice.

Heat shock proteins (HSPs) depletion and protein misfolding are important causes of hepatocyte death and liver regeneration disorder in liver injury. HSF2BP, as its name implies, is a binding protein of HSF2, but the specific role of HSF2BP in heat shock response (HSR) remains unknown. The aim of this study is to identify the role of HSF2BP in HSR and acute liver injury. In this study, we found that HSF2BP expression increased significantly within 24 h after APAP administration, and the trend was highly consistent with that of HSP70. hsf2bp-KO and hsf2bp-TG mouse models demonstrated HSF2BP reduced hepatocyte death, ameliorated inflammation, and improved liver function in APAP- or D-GalN/LPS- induced liver injury. Meanwhile, a significant increase of the survival rate was observed in hsf2bp-TG mice after APAP administration. Further studies showed that HSF2BP upregulated the expression of HSF2 and HSP70 and inhibited the activation of Jnk1/2 and P38 MAPK. Additionally, HSP70 siRNA pretreatment abolished the effect of HSF2BP on the MAPK pathway in APAP-treated hepatocytes. The results reveal that HSF2BP is a protective factor in acute liver injury, and the HSF2BP/HSP70/MAPK regulatory axis is crucial for the pathogenesis of liver injury. HSF2BP is a potential therapeutic target for liver injury.

Risk Factors for 28-Day Mortality in a Surgical ICU: A Retrospective Analysis of 347 Cases.

PURPOSE: Advances in surgical techniques and intensive care over the past decades have significantly reduced the mortality rates of critically ill surgical patients. However, evaluations of risk factors associated with mortality in surgical intensive care units (ICUs) are limited. The aim of this study was to analyze the independent risk factors for 28-day mortality of surgical ICU patients. PATIENTS AND METHODS: The clinical data of adult patients who were admitted to the surgical ICU in the First Affiliated Hospital of Xi'an Jiaotong University from June 2013 to June 2017 were collected. Univariate and multivariable logistic regression analyses were performed to examine risk factors associated with 28-day mortality. RESULTS: A total of 347 patients were included in this analysis. The overall 28-day mortality rate was 32.6%. The major causes of surgical ICU admission were gastrointestinal diseases (46.7%), infection (20.5%), trauma (8.9%), respiratory diseases (8.9%) and cardiovascular diseases (6.6%). The univariate analysis showed age, total bilirubin, prothrombin time, international normalized ratio, arterial lactate level, APACHE II and SOFA score at ICU admission were significantly associated with 28-day mortality. In the multivariate analysis, however, age [Odds Ratio (OR): 2.899, 95% CI: 1.427-5.890, P=0.003], hypertension [OR: 3.630, 95% CI: 1.545-8.531, P=0.003], platelet count [OR: 1.004, 95% CI: 1.001-1.007, P=0.015], arterial lactate level [OR: 1.186, 95% CI: 1.088-1.293, P<0.001] and SOFA score [OR: 1.289, 95% CI: 1.131-1.469, P<0.001] were identified as the independent risk factors for 28-day mortality of patients in the surgical ICU. CONCLUSION: In patients admitted to the surgical ICU, age 65 and older, a high arterial lactate level and SOFA score at ICU admission were associated with increased 28-day mortality.

T-tube vs no T-tube for biliary tract reconstruction in adult orthotopic liver transplantation: An updated systematic review and meta-analysis.

BACKGROUND: Whether to use a T-tube for biliary anastomosis during orthotopic liver transplantation (OLT) remains a debatable question. Some surgeons chose to use a T-tube because they believed that it reduces the incidence of biliary strictures. Advances in surgical techniques during the last decades have significantly decreased the overall incidence of postoperative biliary complications. Whether using a T-tube during OLT is still associated with the reduced incidence of biliary strictures needs to be re-evaluated. AIM: To provide an updated systematic review and meta-analysis on using a T-tube during adult OLT. METHODS: In the electronic databases MEDLINE, PubMed, Scopus, ClinicalTrials.gov, the Cochrane Library, the Cochrane Hepato-Biliary Group Controlled Trails Register, and the Cochrane Central Register of Controlled Trials, we identified 17 studies (eight randomized controlled trials and nine comparative studies) from January 1995 to October 2020. The data of the studies before and after 2010 were separately extracted. We chose the overall biliary complications, bile leaks or fistulas, biliary strictures (anastomotic or non-anastomotic), and cholangitis as outcomes. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to describe the results of the outcomes. Furthermore, the test for overall effect (Z) was used to test the difference between OR and 1, where P ≤ 0.05 indicated a significant difference between OR value and 1. RESULTS: A total of 1053 subjects before 2010 and 1346 subjects after 2010 were included in this meta-analysis. The pooled results showed that using a T-tube reduced the incidence of postoperative biliary strictures in studies before 2010 (P = 0.012, OR = 0.62, 95%CI: 0.42-0.90), while the same benefit was not seen in studies after 2010 (P = 0.60, OR = 0.76, 95%CI: 0.27-2.12). No significant difference in the incidence of overall biliary complications (P = 0.37, OR = 1.41, 95%CI: 0.66-2.98), bile leaks (P = 0.89, OR = 1.04, 95%CI: 0.63-1.70), and cholangitis (P = 0.27, OR = 2.00, 95%CI: 0.59-6.84) was observed between using and not using a T-tube before 2010. However, using a T-tube appeared to increase the incidence of overall biliary complications (P = 0.049, OR = 1.49, 95%CI: 1.00-2.22), bile leaks (P = 0.048, OR = 1.91, 95%CI: 1.01-3.64), and cholangitis (P = 0.02, OR = 7.21, 95%CI: 1.37-38.00) after 2010. A random-effects model was used in biliary strictures (after 2010), overall biliary complications (before 2010), and cholangitis (before 2010) due to their heterogeneity (I 2 = 62.3%, 85.4%, and 53.6%, respectively). In the sensitivity analysis (only RCTs included), bile leak (P = 0.66) lost the significance after 2010 and a random-effects model was used in overall biliary complications (before 2010), cholangitis (before 2010), bile leaks (after 2010), and biliary strictures (after 2010) because of their heterogeneity (I 2 = 92.2%, 65.6%, 50.9%, and 80.3%, respectively). CONCLUSION: In conclusion, the evidence gathered in our updated meta-analysis showed that the studies published in the last decade did not provide enough evidence to support the routine use of T-tube in adults during OLT.

Milk fat globule EGF factor 8 restores mitochondrial function via integrin-medicated activation of the FAK-STAT3 signaling pathway in acute pancreatitis.

Acute pancreatitis (AP) remains a significant clinical challenge. Mitochondrial dysfunction contributes significantly to the pathogenesis of AP. Milk fat globule EGF factor 8 (MFG-E8) is an opsonizing protein, which has many biological functions via binding to αvß3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining a normal mitochondrial function. However, MFG-E8's role in AP has not been evaluated. METHODS: Blood samples were acquired from 69 healthy controls and 134 AP patients. Serum MFG-E8 levels were measured by ELISA. The relationship between serum concentrations of MFG-E8 and disease severity were analyzed. The role of MFG-E8 was evaluated in experimental models of AP. RESULTS: Serum concentrations of MFG-E8 were lower in AP patients than healthy controls. And serum MFG-E8 concentrations were negatively correlated with disease severity in AP patients. In mice, MFG-E8 administration decreased L-arginine-induced pancreatic injury and mortality. MFG-E8's protective effects in experimental AP were associated with improvement in mitochondrial function and reduction in oxidative stress. MFG-E8 knockout mice suffered more severe pancreatic injury and greater mitochondrial damage after l-arginine administration. Mechanistically, MFG-E8 activated the FAK-STAT3 pathway in AP mice. Cilengitide, a specific αvß3/5 integrin inhibitor, abolished MFG-E8's beneficial effects in AP. PF00562271, a specific FAK inhibitor, blocked MFG-E8-induced STAT3 phosphorylation. APTSTAT3-9R, a specific STAT3 antagonist, also eliminated MFG-E8's beneficial effects under such a condition. CONCLUSIONS: MFG-E8 acts as an endogenous protective mediator in the pathogenesis of AP. MFG-E8 administration protects against AP possibly by restoring mitochondrial function via activation of the integrin-FAK-STAT3 signaling pathway. Targeting the action of MFG-E8 may present a potential therapeutic option for AP.

Involvement of GPX4 in irisin's protection against ischemia reperfusion-induced acute kidney injury.

Ischemia reperfusion (I/R)-induced acute kidney injury (AKI) is a common and serious condition. Irisin, an exercise-induced hormone, improves mitochondrial function and reduces reactive oxygen species (ROS) production. Glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis and its inactivation aggravates renal I/R injury by inducing ROS production. However, the effect of irisin on GPX4 and I/R-induced AKI is still unknown. To study this, male adult mice were subjected to renal I/R by occluding bilateral renal hilum for 30 min, which was followed by 24 hr reperfusion. Our results showed serum irisin levels were decreased in renal I/R mice. Irisin (250 µg/kg) treatment alleviated renal injury, downregulated inflammatory response, improved mitochondrial function, and reduced ER stress and oxidative stress after renal I/R, which were associated with upregulation of GPX4. Treated with RSL3 (a GPX4 inhibitor) abolished irisin's protective effect. Thus, irisin attenuates I/R-induced AKI through upregulating GPX4.

Clinical Features and Prognosis of Gas-Forming and Non-Gas-Forming Pyogenic Liver Abscess: A Comparative Study.

Background: Gas-forming pyogenic liver abscess (GFPLA) accounts for up to 30% of all pyogenic liver abscess (PLA) cases. However, little is known of the differences in clinical features and prognosis between GFPLA and non-GFPLA. Aim: This retrospective study compared the clinical features and prognosis of GFPLA and non-GFPLA. Patients and Methods: Data for 392 patients with PLA treated from January 1, 2007 to December 31, 2016 were reviewed. Gas-forming pyogenic liver abscess was defined as gas in the abscess. Liver abscesses were considered non-GFPLA (n = 326) or GFPLA (n = 66). The clinical features and outcomes of patients with GFPLA were compared with that of patients without GFPLA. Results: The groups were similar in gender ratio, age, smoking, drinking, and comorbidities. Klebsiella pneumoniae was the most common pathogenic bacteria, but the negative rate of bacterial culture of the non-GFPLA group was higher than that of the GFPLA. In etiologies, the GFPLA group had more biliary source infection and less cryptogenic infection. In addition, the GFPLA group had a higher rate of previous hepatobiliary surgery, especially biliary enteric anastomosis. Compared with the non-GFPLA group, the percentage of the GFPLA group with antibiotic agents combined with percutaneous drainage was higher, whereas the percentages given antibiotic agents alone and antibiotic agents combined with surgical drainage were lower. Patients with GFPLA had higher rates of sepsis and pleural effusion, and longer hospital stays than did non-GFPLA patients. No patient died during hospitalization. Conclusions: The GFPLA group had more biliary source infection and less cryptogenic infection in etiologies. Gas-forming pyogenic liver abscess is associated with past hepatobiliary surgery, especially biliary enteric anastomosis and has high rates of sepsis and long hospitalization. Thus, the patients with PLA with a history of hepatobiliary surgery should be monitored more closely in the early stage of the PLA. It needs to be recognized as a distinct clinical entity.

Luteolin Suppresses Sepsis-Induced Cold-Inducible RNA-Binding Protein Production and Lung Injury in Neonatal Mice.

ABSTRACT: Neonatal sepsis is a life-threatening inflammatory condition. Extracellular cold-inducible RNA-binding protein (CIRP), a proinflammatory mediator, plays a critical role in the pathogenesis of sepsis-induced lung injury in neonates. Luteolin, a polyphenolic flavonoid, has potent anti-inflammatory properties. However, the effects of luteolin on CIRP production and neonatal sepsis-induced lung injury remained unknown. We therefore hypothesize that treatment with luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. To study this, sepsis was induced in C57BL/6J mouse pups (5-7 days) by intraperitoneal cecal slurry injection (CSI). One hour after CSI, luteolin (10 mg/kg body weight) or vehicle (normal saline) was administered through intraperitoneal injection. CIRP mRNA and protein were determined and lung injury was assessed at 10 h after CSI. Our results showed that administration of luteolin decreased CIRP mRNA and protein, improved lung architecture, reduced lung edema, and apoptosis after CSI. To examine the direct effect of luteolin on CIRP production, peritoneal macrophages were isolated from neonatal mice and stimulated with 100 ng/mL LPS with or without the presence of luteolin. The result indicates that luteolin directly inhibited LPS-induced CIRP production in neonatal macrophages. In addition, luteolin also downregulated hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor 3 (NLRP3) expression in septic neonates and in LPS-stimulated neonatal macrophages. In conclusion, administration of luteolin suppresses CIRP production and attenuates lung injury in neonatal sepsis. The beneficial effect of luteolin may be related to downregulation of HIF-1α and NLRP3 expression in neonatal macrophages. Luteolin may be developed as an adjunctive therapy for neonatal sepsis.

Neutrophil-to-lymphocyte ratio predicts acute kidney injury occurrence after gastrointestinal and hepatobiliary surgery.

BACKGROUND: Postoperative acute kidney injury (AKI) is a complex pathological process involved intrarenal and systemic inflammation caused by renal hypoperfusion, nephrotoxic drugs and urinary obstruction. Neutrophil-to-lymphocyte ratio (NLR) is a marker of inflammation reflecting the progress of many diseases. However, whether NLR at admission can predict the occurrence of AKI after surgery in the intensive care unit (ICU) remains unknown. AIM: To clarify the relationship between NLR and the occurrence of AKI in patients with gastrointestinal and hepatobiliary surgery in the ICU. METHODS: A retrospective analysis of 282 patients receiving surgical ICU care after gastrointestinal and hepatobiliary surgery in our hospital from December 2014 to December 2018 was performed. RESULTS: Postoperative AKI occurred in 84 patients (29.79%) in this cohort. NLR by the multivariate analysis was an independent risk factor for occurrence of postoperative AKI in patients with gastrointestinal and hepatobiliary surgery in the ICU. In this cohort, receiver operating characteristic curves of AKI occurrence showed that the optimal cut-off value of NLR was 8.380. NLR was found to be significantly correlated with the white blood cell count, neutrophil count, lymphocyte count, arterial lactate and dialysis (P < 0.05). Additionally, NLR value at admission was higher in AKI patients compared with the non-AKI patients and increased with the severity of AKI. Patients with NLR ≥ 8.380 exhibited significantly higher incidences of postoperative AKI and severe AKI than patients with NLR < 8.380 (AKI: 38.12% vs 14.85%, P < 0.001; severe AKI: 14.36% vs 1.98%, P = 0.001). CONCLUSION: NLR at admission is a predictor of AKI occurrence in patients with gastrointestinal and hepatobiliary surgery in ICU. NLR should be included in the routine assessment of AKI occurrence.

Exercise hormone irisin mitigates endothelial barrier dysfunction and microvascular leakage-related diseases.

Increased microvascular leakage is a cardinal feature of many critical diseases. Regular exercise is associated with improved endothelial function and reduced risk of cardiovascular disease. Irisin, secreted during exercise, contributes to many health benefits of exercise. However, the effects of irisin on endothelial function and microvascular leakage remain unknown. In this study, we found that irisin remarkably strengthened endothelial junctions and barrier function via binding to integrin αVß5 receptor in LPS-treated endothelial cells. The beneficial effect of irisin was associated with suppression of the Src-MLCK-ß-catenin pathway, activation of the AMPK-Cdc42/Rac1 pathway, and improvement of mitochondrial function. In preclinical models of microvascular leakage, exogenous irisin improved pulmonary function, decreased lung edema and injury, suppressed inflammation, and increased survival. In ARDS patients, serum irisin levels were decreased and inversely correlated with disease severity and mortality. In conclusion, irisin enhances endothelial barrier function and mitigates microvascular leakage-related diseases.

Overexpression of Platelet-Derived Growth Factor Receptor Α D842V Mutants Prevents Liver Regeneration and Chemically Induced Hepatocarcinogenesis via Inhibition of MET and EGFR.

Platelet-derived growth receptor α (PDGFRα) is a key factor in many pathophysiological processes. The expression level of PDGFRα is significantly elevated in the early stage of liver development and maintained at a lower level in adult normal livers. In this study, we constructed a liver-specific PDGFRαD842 mutant transgenic (TG) mice model to explore the effect of continuous activation of PDGFRα on liver regeneration and hepatocarcinogenesis. 14-day-old TG and wild-type (WT) mice were intraperitoneally injected with diethylnitrosamine (DEN) at a dose of 25 µg/g body weight. Two-month-old male TG and WT mice were subjected to partial hepatectomy (PH). The liver tissues were collected for further analysis at different time points. Overexpression of PDGFRα D842V and its target genes, Akt, c-myc and cyclin D1 in hepatocytes with no overt phenotype versus WT mice were compared. Unexpectedly, a dramatic decrease in hepatocyte proliferation was noted after PH in TG versus WT mice, possibly due to the downregulation of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR). No TG mice developed HCC spontaneously after 14 months follow-up. However, TG mice were more resistant to DEN-induced hapatocarcinogenesis at 6, 10, and 12 months of age, showing delayed hepatocyte proliferation and apoptosis, lower tumor incidence, smaller size and fewer number, compared with age-matched WTs, partially through downregulation of MET and EGFR. In conclusion, continuous activation of PDGFRα signaling by expression of PDGFRα D842V does not promote, but inhibit hepatic regeneration and hepatocarcinogenesis, possibly through compensatory downregulation of MET and EGFR.

Effect of diabetes mellitus on short-term prognosis of 227 pyogenic liver abscess patients after hospitalization.

BACKGROUND: Pyogenic liver abscess (PLA) is an inflammatory disease with increasing incidence. When it occurs with diabetes mellitus (DM), the risk of recurrence and mortality may increase. However, the effect of DM on the short-term prognosis of PLA patients after hospitalization remained unknown. METHODS: Two hundred twenty-seven PLA patients who received treatment at the First Affiliated Hospital of Xi'an Jiaotong University from January 2011 to January 2018 were retrospectively enrolled. They were divided into two groups as the DM group (n = 61) and the Non-DM group (n = 166). In the DM group, HbA1C level < 7% was considered to be good-control of glycaemia (n = 23). The clinical characteristics and overall short-term survival were analyzed. RESULTS: The proportion of PLA patients with DM was 26.87%. In the DM group, there was a higher incidence of hypertension and Candida spp. infection. Conservative administration and percutaneous drainage were mainly used in patients with good- (60.87%) and poor-control (60.53%) of glycaemia, respectively. During follow-up, 24 (10.57%) died due to uncontrolled systemic infections and other serious complications. Compared with PLA patients without DM, patients in the DM group had significantly increased 6-month mortality rate after discharge (Log-Rank test, P = 0.021). Poor-control of glycaemia did not reduce the six-month survival, while the recurrence rate of PLA within 3 months showed an almost 3-fold increase (13.16% vs. 4.35%). Further multivariate analyses found that DM was the only independent risk factor for the PLA six-month survival (odds ratio [OR]: 3.019, 95% confidence interval [CI]: 1.138-8.010, P = 0.026). However, the blood glucose level had no significant effect on the short-term survival of PLA patients with DM (Log-Rank test, P = 0.218). CONCLUSIONS: In PLA patients, DM aggravated short-term mortality and blood glucose levels should be well controlled.

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVß5 receptor.

Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco-2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK-UCP 2 pathway via binding to the integrin αVß5 receptor. Inhibition of integrin αVß5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVß5-AMPK-UCP 2 pathway.

The Impact of Serum Glucose on the Predictive Value of Serum Lactate for Hospital Mortality in Critically Ill Surgical Patients.

BACKGROUND: Lactate has been widely used as a risk indicator of outcomes in critically ill patients due to its ready measurement and good predictive ability. However, the interconnections between lactate metabolism and glucose metabolism have not been sufficiently explored, yet. In this study, we aimed to investigate whether glucose levels could influence the predictive ability of lactate and design a more comprehensive strategy to assess the in-hospital mortality of critically ill patients. METHODS: We analyzed the clinical data of 293 critically ill patients. The primary outcome was in-hospital mortality. The logistic regression analysis and the area under the receiver operating characteristic curve (AUROC) were applied to evaluate the predictive ability of lactate in association with glucose. RESULTS: The lactate level showed significant association with in-hospital mortality, and its predictive ability was also comparable to other prognostic scores such as the SOFA score and APACHE II score. We further divided 293 patients into three groups based on glucose levels: low-glucose group (<7 mmol/L), medium-glucose group (7-9 mmol/L), and high-glucose group (>9 mmol/L). The lactate level was associated with in-hospital mortality in the low- and high- glucose groups, but not in the medium-glucose group, whereas the SOFA score and APACHE II score were associated with in-hospital mortality in all three glucose groups. The AUROC of lactate in the medium-glucose group was also the lowest among the three glucose groups, indicating a decrease in its predictive ability. CONCLUSIONS: Our findings demonstrated that the predictive ability of lactate to assess in-hospital mortality could be influenced by glucose levels. In the medium glucose level (i.e., 7-9 mmol/L), lactate was inadequate to predict in-hospital mortality and the SOFA score; the APACHE II score should be utilized as a complementation in order to obtain a more accurate prediction.

Effect of low-dose aspirin administration on long-term survival of cirrhotic patients after splenectomy: A retrospective single-center study.

BACKGROUND: Cirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC). Portal vein thrombosis is not uncommon after splenectomy in cirrhotic patients, and many such patients take oral anticoagulants including aspirin. However, the long-term impact of postoperative aspirin on cirrhotic patients after splenectomy remains unknown. AIM: The main purpose of this study was to investigate the effect of postoperative long-term low-dose aspirin administration on the development of HCC and long-term survival of cirrhotic patients after splenectomy. METHODS: The clinical data of 264 adult patients with viral hepatitis-related cirrhosis who underwent splenectomy at the First Affiliated Hospital of Xi'an Jiaotong University from January 2000 to December 2014 were analyzed retrospectively. Among these patients, 59 who started taking 100 mg/d aspirin within seven days were enrolled in the aspirin group. The incidence of HCC and overall survival were analyzed. RESULTS: During follow-up, 41 (15.53%) patients developed HCC and 37 (14.02%) died due to end-stage liver diseases or other serious complications. Postoperative long-term low-dose aspirin therapy reduced the incidence of HCC from 19.02% to 3.40% after splenectomy (log-rank test, P = 0.028). Univariate and multivariate analyses showed that not undertaking postoperative long-term low-dose aspirin therapy [odds ratio (OR) = 6.211, 95% confidence interval (CI): 1.142-27.324, P = 0.016] was the only independent risk factor for the development of HCC. Similarly, patients in the aspirin group survived longer than those in the control group (log-rank test, P = 0.041). Univariate and multivariate analyses showed that the only factor that independently associated with improved overall survival was postoperative long-term low-dose aspirin therapy [OR = 0.218, 95%CI: 0.049-0.960, P = 0.044]. CONCLUSION: In patients with viral hepatitis-related cirrhosis, long-term post-splenectomy administration of low-dose aspirin reduces the incidence of HCC and improves the long-term overall survival.

Low Serum Irisin Concentration Is Associated with Poor Outcomes in Patients with Acute Pancreatitis, and Irisin Administration Protects Against Experimental Acute Pancreatitis.

Aims: Severe acute pancreatitis (AP) is a serious condition without specific treatment. Mitochondrial dysfunction plays a crucial role in the pathogenesis of AP. Irisin, a novel exercise-induced hormone, contributes to many health benefits of physical activity. We and others have shown that irisin protects against ischemia reperfusion-induced organ injury by alleviating mitochondrial damage. However, the role of irisin in AP has not been evaluated. The purpose of this study was to investigate the role of serum irisin levels in patients with AP and the effect of irisin administration in experimental AP. Results: Serum irisin levels were decreased in AP patients, and low serum irisin levels were associated with worse outcomes in these patients. Treatment with exogenous irisin increased survival and mitigated pancreatic injury in experimental AP. The protective effects of irisin in AP were associated with improvement in mitochondrial function and reduction in ER stress. Moreover, irisin upregulated UCP2 expression in the pancreas, and administration of genipin, a specific UCP2 antagonist, abolished irisin's beneficial effects in L-arginine-induced AP. Innovation and Conclusion: Low serum irisin was associated with poor outcomes in AP patients, and irisin administration protected against experimental AP by restoring mitochondrial function via activation of UCP2. Restoration of mitochondrial function by irisin may offer therapeutic potential for patients with AP. Antioxid. Redox Signal. 31, 771-785.