Serum Lactate Is an Indicator for Short-Term and Long-Term Mortality in Patients with Acute Pancreatitis.

BACKGROUND: Serum lactate, as a single and an easily available biomarker, has been applied in various diseases. AIMS: In this study, we aimed to explore the predictive value of serum lactate for short-term and long-term prognosis in acute pancreatitis (AP) admitted in intensive care unit (ICU) based on a large-scale database. METHODS: AP patients admitted in ICU in the MIMIC-IV database were included. We constructed three different models to investigate the relationships between serum lactate and clinical outcomes, including 30-day, 180-day and 1-year mortality in AP. Smooth fitting curves were performed for intuitively demonstrating the relationship between serum lactate and different outcomes in AP by the generalized additive model. RESULTS: A total of 895 AP patients admitted in ICU were included. The mortalities of 30 days, 180 days, and 1 year were 12.63% (n = 113), 16.87% (n = 151), and 17.54% (n = 157). In model B, with 1-mmol/L increment in serum lactate, the values of OR in 30-day, 180-day and 1-year mortality were 1.20 (95%CI 1.04-1.37, P = 0.0094), 1.21 (95%CI 1.06-1.37, P = 0.0039), and 1.21 (95%CI 1.07-1.38, P = 0.0035). The AUCs of serum lactate for predicting 30-day, 180-day, and 1-year mortality in AP were 0.688 (95%CI 0.633-0.743), 0.655 (95%CI 0.605-0.705), and 0.653 (95%CI 0.603-0.701), respectively. The cut-off value of serum lactate predicting 30-day, 180-day and 1-year mortality in AP was 2.4 mmol/L. CONCLUSION: Serum lactate could be an indicator for short-term and long-term mortality in patients with AP admitted in ICU.

Inhibition of Soluble Epoxide Hydrolase in Macrophages Ameliorates the Formation of Foam Cells　- Role of Heme Oxygenase-1.

BACKGROUND: Accumulation of foam cells in the neointima represents an early stage of atherosclerosis. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl) urea (TPPU), a novel soluble epoxide hydrolase inhibitor (sEHi), effectively elevates epoxyeicosatrienoic acid (EET) levels. The effects of EETs on macrophages foam cells formation are poorly understood.Methods and Results:Incubation of foam cells with TPPU markedly ameliorate cholesterol deposition in oxidized low-density lipoprotein (oxLDL)-loaded macrophages by increasing the levels of EETs. Notably, TPPU treatment significantly inhibits oxLDL internalization and promotes cholesterol efflux. The elevation of EETs results in a decrease of class A scavenger receptor (SR-A) expression via downregulation of activator protein 1 (AP-1) expression. Additionally, TPPU selectively increases protein but not the mRNA level of ATP-binding cassette transporter A1 (ABCA1) through the reduction of calpain activity that stabilizes the protein. Moreover, TPPU treatment reduces the cholesterol content of macrophages and inhibits atherosclerotic plaque formation in apolipoprotein E-deficient mice. These changes induced by TPPU are dependent on heme oxygenase-1 (HO-1) activation. CONCLUSIONS: The present study findings elucidate a precise mechanism of regulating cholesterol uptake and efflux in macrophages, which involves the prevention of atherogenesis by increasing the levels of EETs with TPPU.

A potent soluble epoxide hydrolase inhibitor, t-AUCB, modulates cholesterol balance and oxidized low density lipoprotein metabolism in adipocytes in vitro.

The cholesterol metabolism in adipose tissue is dependent on the balance between cholesterol uptake and efflux. Adipocytes dysfunction and its cholesterol imbalance are associated with obesity. Adipocytes are the site for clearance of oxidized low density lipoprotein (oxLDL) in blood. Soluble epoxide hydrolase (sEH) is highly expressed in adipocytes. sEH converts epoxyeicosatrienoic acids (EETs) into less bioactive dihydroxyeicosatrienoic acids, which regulate cholesterol metabolism in adipocytes and block the development of atherosclerosis. In vitro, 3T3-L1 differentiated adipocytes were incubated with the sEH inhibitor t-AUCB (0, 1, 10, 50 or 100 µmol/l) for 24 h with or without the PPARγ inhibitor GW9662. To determine the effect of t-AUCB on oxLDL endocytosis, degradation and cholesterol efflux from adipocytes, we demonstrated that t-AUCB enhances the CD36-mediated recognition and degradation of oxLDL and improves cholesterol efflux via the upregulation of ABCA1 expression. Furthermore, t-AUCB blocked TNF-α secretion and increased adiponectin levels found in adipocytes culture medium. We provide evidence that these effects are PPARγ-dependent. These results suggest that an increase in EETs because of sEH inhibition could maintain cellular cholesterol homeostasis by the regulation of oxLDL clearance and cholesterol efflux via the EETs-PPARγ pathway.

Association between admission hemoglobin level and prognosis in sepsis patients based on a critical care database.

This study aimed to explore the association between admission hemoglobin level and clinical outcomes in sepsis based on Medical Information Mart for Intensive Care IV(MIMIC-IV) database. It was a retrospective study. Sepsis patients in the database were included. Data extraction from MIMIC-IV was performed by PostgreSQL 9.6 software. Three different models including crude model (adjusted for none), model I (adjusted for gender and age) and model II (adjusted for all potential cofounders) were constructed. A generalized liner model and a smooth fitting curve for indicating the relationship between hemoglobin level and 30-day mortality were performed. 6249 septic patients with a 30.18% of 30-day mortality were included. With 1 g/dl increment in hemoglobin level, the values of odds ratio (OR) in crude model, model I and model II were 0.96 (95% confidential interval (CI) 0.94-0.99, P = 0.0023), 0.96 (95%CI 0.93-0.98, P = 0.0010) and 0.87 (95%CI 0.79-0.95, P = 0.0020), respectively. The smooth fitting curve indicated a non-linear relationship and the turning point was 7.2 g/dl. Compared the hemoglobin group < 7.2 g/dl, the risk of 30-day mortality significantly decreased by 32% in the hemoglobin group ≥ 7.2 g/dl (OR = 0.68, 95%CI 0.51-0.93, P = 0.0142). The non-linear relationship between admission hemoglobin level and 30-day mortality in sepsis was found. Hemoglobin supplementation might be beneficial for septic patients with hemoglobin level < 7.2 g/dl.

The next generation of novel low-density lipoprotein cholesterol-lowering agents: proprotein convertase subtilisin/kexin 9 inhibitors.

Proprotein convertase subtilisin/kexin 9 (PCSK9) has been shown to degrade hepatic low-density lipoprotein receptors (LDLR). Gain-of-function mutations promote the development of familial hypercholesterolemia, whereas loss-of-function mutations are associated with lower levels of circulating low-density lipoprotein cholesterol (LDL-C) and significant protection against coronary heart disease. The major classes of commonly prescribed lipid-lowering medications, such as statins, increase serum PCSK9 levels, thus PCSK9 inhibition would increase the efficacy of statins on LDL-C lowering. Therefore, PCSK9 is an attractive therapeutic target for the new generation of cholesterol-lowering drugs. Here, we present a brief overview of the development of PCSK9 inhibitors and highlight the effect of currently prescribed LDL-C-lowering drugs on PCSK9, and the strategies that are being explored for its therapeutic inhibition. Current research and clinical trial results indicate that a PCSK9 inhibitor may be an exciting new therapeutic drug for the treatment of dyslipidemia and relevant cardiovascular diseases.

[Soft tissue repairing and functional reconstruction in limb salvage operation on extremity bone malignant tumors].

OBJECTIVE: To investigate the effect and the significance of soft tissue repairing and functional reconstruction in limb salvage operation on extremity malignant bone tumors by individualized prosthesis replacement after malignant tumor resection with the help of Neo-adjuvant chemo-therapy. METHODS: A total of 78 patients with malignant bone tumor were recruited, including 42 males and 36 females. Aged 19~61, with an average of (29.12+/-9.47).Tumor in 14 patients was in the proximal humerus, 11 in the proximal femur, 27 in the distal femur, 3 in femoral middle part, and 23 in the proximal tibial. There were 29 cases of osteogenic sarcoma, 18 chondroma sarcomatosum, 7 malignant enchondroma with pathological fracture, 20 malignant giant cell tumor,and 4 malignant inflammatory myofibroblastoma of the bone. Soft tissue repairing and functional reconstruction were carried out together with individualized prosthesis replacement. The type of the prostheses was as follows: 14 patients had long stem humerus head prosthesis, 50 made hinged knee prostheses with femoral or tibial component, 3 whole femur replacements, 7 long stem femoral head prostheses, 4 long stem hip prostheses. RESULTS: All patients were followed up for an average of (26.80+/-8.06) months (4~37 months) and postoperative functions were estimated according to Enneking system. Among the 78 patients, results in 48 (61.5%) were excellent, 17 (21.8%) were good, 10 (12.8%) were fair, and 3(4.9%) were poor. The satisfactory rate was 83.3%. CONCLUSION: Soft tissue repairing and functional reconstruction in limb salvage operation on extremity bone malignant tumors by individualized prosthesis replacement not only spare the limbs, but also keep their function.It can remove the psychologic obstacles caused by extremity absence, and is effective for bone malignant tumor.

Inhibition of soluble epoxide hydrolase in mice promotes reverse cholesterol transport and regression of atherosclerosis.

Adipose tissue is the body largest free cholesterol reservoir and abundantly expresses ATP binding cassette transporter A1 (ABCA1), which maintains plasma high-density lipoprotein (HDL) levels. HDLs have a protective role in atherosclerosis by mediating reverse cholesterol transport (RCT). Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has various beneficial effects on cardiovascular disease. The sEH is highly expressed in adipocytes, and it converts epoxyeicosatrienoic acids (EETs) into less bioactive dihydroxyeicosatrienoic acids. We previously showed that increasing EETs levels with a sEH inhibitor (sEHI) (t-AUCB) resulted in elevated ABCA1 expression and promoted ABCA1-mediated cholesterol efflux from 3T3-L1 adipocytes. The present study investigates the impacts of t-AUCB in mice deficient for the low density lipoprotein (LDL) receptor (Ldlr(-/-) mice) with established atherosclerotic plaques. The sEH inhibitor delivered in vivo for 4 weeks decreased the activity of sEH in adipose tissue, enhanced ABCA1 expression and cholesterol efflux from adipose depots, and consequently increased HDL levels. Furthermore, t-AUCB enhanced RCT to the plasma, liver, bile and feces. It also showed the reduction of plasma LDL-C levels. Consistently, t-AUCB-treated mice showed reductions in the size of atherosclerotic plaques. These studies establish that raising adipose ABCA1 expression, cholesterol efflux, and plasma HDL levels with t-AUCB treatment promotes RCT, decreasing LDL-C and atherosclerosis regression, suggesting that sEH inhibition may be a promising strategy to treat atherosclerotic vascular disease.

Proprotein convertase subtilisin/kexin type 9 potentially influences cholesterol uptake in macrophages and reverse cholesterol transport.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptor (LDLRs) molecules expressed on the cell surface. Gene inactivation of PCSK9 reduces the areas of atherosclerotic lesions in mice, and the effect is mainly dependent on LDLRs. Furthermore, a positive relationship between PCSK9 and cholesterol accumulation in the wall of the aorta has been established. However, the mechanism remains unknown. As PCSK9 is mainly expressed in atherosclerotic plaque and in the liver, we hypothesize that PCSK9 might increase oxidized LDL uptake and impair macrophage-mediated reverse cholesterol transport, contributing to the development of atherosclerosis.