Parabolic relationship between sex-specific serum high sensitive C reactive protein and non-alcoholic fatty liver disease in Chinese adults: a large population-based study.

OBJECTIVES: To evaluate the association between sex-specific serum high sensitive C reactive protein (hsCRP) levels and NAFLD in a large population-based study. RESULTS: From Q1 to Q4, the incidence ratios were 21.1 (95% CI 17.5 24.7), 18.6 (95% CI 16.5 20.8), 24.8 (95% CI 22.4 27.2) and 31.1 (95% CI 28.5 33.6) in males and 6.2 (95% CI 4.4 8.0), 6.0 (95% CI 5.1 7.1), 11.4 (95% CI 9.2 13.7) and 19.5 (95% CI 16.1 22.9) in females. Compared with a 1.7-fold increase (Q4 vs Q2) in males, actuarial incidence increased 3.3-fold (Q4 vs Q2) in females. After adjusting for known confounding variables in this study, in the longitudinal population, compared with the reference group, those in Q1, Q3, and Q4 had HRs of 1.63 (95% CI 1.29-2.05), 1.11 (95% CI 0.93-1.31), 1.14 (95% CI 0.97-1.35) in male and 1.77 (95% CI 1.25-2.49), 1.22 (95% CI 0.93-1.59), 1.36 (95% CI 1.03-1.80) in female for NAFLD, respectively. METHODS: 8618 subjects from Wenzhou Medical Center of Wenzhou People's Hospital were included. Sex specific hsCRP quartiles (Q1 to Q4) were defined: 0-0.1, 0.2-0.4, 0.5-0.8 and 0.9-25.9 for male; 0-0.1, 0.2-0.6, 0.7-1.2 and1.3-28.4 for female. Applying Q2 as reference, Hazard ratios (HRs) and 95% confidence intervals (CIs) for NAFLD were calculated across each quartile of hsCRP. CONCLUSIONS: We report that a sex-specific hsCRP level is independently associated with NAFLD. The association between hsCRP and NAFLD was significantly stronger in females than in males.

Platelet-to-Lymphocyte Ratio: A Novel Prognostic Factor for Prediction of 90-day Outcomes in Critically Ill Patients With Diabetic Ketoacidosis.

Diabetic ketoacidosis (DKA) is a life-threatening acute complication of diabetes mellitus and the novel systemic inflammation marker platelet-to-lymphocyte ratio (PLR) may be associated with clinical outcome in patients with DKA. This study aimed to investigate the utility of PLR in predicting 90-day clinical outcomes in patients with DKA. Patient data exacted from the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) database was analyzed. A cutoff value for PLR of 267.67 was determined using Youden index (P < 0.05) and used to categorize subjects into a high PLR group and a low PLR group. The hazard ratios (HRs) and 95% confidence intervals (CIs) for DKA were calculated across PLR. Clinical outcomes in our study were defined as intensive care unit (ICU) 90-day readmission and all-cause mortality. A total of 278 ICU admissions were enrolled and stratified by cutoff value of PLR. The incidence of readmission and mortality was 17.8% in the high PLR group, significantly higher than 7.4% in the low PLR group. In the multivariable model, after adjusting for known confounding variables including clinical parameters, comorbidities, laboratory parameters, the HRs for DKA were 2.573 (95% CI 1.239-5.345; P = 0.011), 2.648 (95% CI 1.269-5.527; P = 0.009), and 2.650 (95% CI 1.114-6.306; P = 0.028), respectively. The Kaplan-Meier survival curve showed that a high PLR level was associated with a higher risk for 90-day outcomes in patients with DKA. The authors report that higher PLR presents a higher risk for 90-day incidence of readmission and mortality in patients with DKA. It appears to be a novel independent predictor of 90-day outcomes in critically ill DKA patients in ICU units.

Kidney bioengineering in regenerative medicine: An emerging therapy for kidney disease.

The prevalence of end-stage renal disease is emerging as a serious worldwide public health problem because of the shortage of donor organs and the need to take lifelong immunosuppressive medication in patients who receive a transplanted kidney. Recently, tissue bioengineering of decellularization and recellularization scaffolds has emerged as a novel strategy for organ regeneration, and we review the critical technologies supporting these methods. We present a summary of factors associated with experimental protocols that may shed light on the future development of kidney bioengineering and we discuss the cell sources and bioreactor techniques applied to the recellularization process. Finally, we review some artificial renal engineering technologies and their future prospects, such as kidney on a chip and the application of three-dimensional and four-dimensional printing in kidney tissue engineering.

A network meta-analysis of the efficacy and side effects of UDCA-based therapies for primary sclerosing cholangitis.

OBJECTIVES: Therapies for treatment of patients with primary sclerosing cholangitis (PSC) include administration of ursodeoxycholic acid (UDCA) alone, or combination with metronidazole (MTZ) or mycophenolate mofetil (MMF), respectively. However, the optimum regimen still remains inconclusive. We aimed to compare interventions in terms of patient mortality or liver transplantation (MOLT), progression of liver histological stage (POLHS), serum bilirubin, alkaline phosphatase (ALP) levels and adverse events (AE). METHODS: We searched PubMed, Embase and the Cochrane Library for randomized controlled trials until 31, Jan 2015. We estimated hazard ratios (HRs), odds ratios (ORs) and mean difference (MD) between treatments on clinical outcomes. Sensitivity analyses based on the dose of UDCA, quality of trials or treatment duration were also performed. RESULTS: Ten RCTs were included. Compared with UDCA plus MTZ, UDCA (HR 0.28, 95%CI 0.01-3.41), UDCA plus MMF (HR 0.08, 95%CI 0.00-4.18), or OBS (HR 0.28, 95%CI 0.01-3.98) all provided an increased risk of MOLT. UDCA provided a significant reduction in bilirubin and ALP levels compared with OBS (MD -13.92, P < 0.001; MD -484.34, P < 0.001; respectively). With respect to POLHS, although differing not significantly, UDCA plus MTZ had a tendency to improve LHS more than UDCA (OR 1.33), UDCA plus MMF (OR 3.24) or OBS (OR 1.08). Additionally, UDCA plus MTZ (MD -544.66, P < 0.001) showed a significant reduction in ALP levels compared with OBS, but appeared to be associated with more AEs compared with UDCA (OR 5.09), UDCA plus MMF (OR 4.80) or OBS (OR 7.21). CONCLUSIONS: MTZ plus UDCA was the most effective therapy in survival rates and liver histological progression.

New advances in liver decellularization and recellularization: innovative and critical technologies.

Techniques for producing decellularized scaffolds for use in liver tissue engineering are emerging as promising methods for tissue reconstruction. In this article, the authors present an overview of liver decellularization methods developed and applied in recent years. These include the widespread use of various perfusion methods for the generation of a 3D scaffold, which may function as a template for either cell recellularization or direct biological application. The authors evaluate methods for scaffold production and explore some factors that may affect the decellularization process. In addition to tissue engineering, this overview includes a description of other potential applications for a decellularized liver scaffold. The authors also introduce the concept of fabrication of fragile biomaterial architecture and finally review the cell types applied to liver scaffold engineering.

Optimal drug regimens for primary biliary cirrhosis: a systematic review and network meta-analysis.

OBJECTIVE: Most comprehensive treatments for PBC include UDCA, combination of methotrexate (MTX), corticosteroids (COT), colchicine (COC) or bezafibrate (BEF), cyclosporin A (CYP), D-penicillamine (DPM), methotrexate (MTX), or azathioprine (AZP). Since the optimum treatment regimen remains inconclusive, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse event (AE). METHODS: We searched PubMed, Embase, Scopus and the Cochrane Library for randomized controlled trials until August 2014. We estimated HRs for MOLT and ORs for AE. The sensitivity analysis based on dose of UDCA was also performed. RESULTS: The search identified 49 studies involving 12 different treatment regimens and 4182 patients. Although no statistical significance can be found in MOLT, COT plus UDCA was ranked highest for efficacy outcome amongst all the treatment regimes. While for AEs, compared with OBS or UDCA, monotherapy with COC (OR 5.6, P < 0.001; OR 5.89, P < 0.001), CYP (OR 3.24, P < 0.001; OR 3.42, P < 0.001), DPM (OR 8.00, P < 0.001; OR 8.45, P < 0.001) and MTX (OR 5.31, P < 0.001; OR 5.61, P < 0.001) were associated with statistically significant increased risk of AEs. No significant differences were found for other combination regimes. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Consistently, in the sensitivity analysis, results closely resembled our primary analysis. CONCLUSIONS: COT plus UDCA was the most efficacious among treatment regimens both for MOLT and AEs.

Recent advances in re-engineered liver: de-cellularization and re-cellularization techniques.

Allogeneic transplantation is the definitive treatment for patients with end-stage liver disease but is limited by donor shortage and very high cost. Through de-cellularization and re-cellularization methods, re-engineered liver may provide a promising alternative for treating patients with end-stage liver disease. To achieve this, the prevention of the native extracellular matrix ultrastructure plays a central role in de-cellularization protocol; the re-seeding cell types, as well as re-seeding strategies, need more explorations in re-cellularization protocol. Some success of this approach has been published in a rat model; however, the re-engineered liver remains functional in vivo for only several hours, which suggests that the recent protocol may be far from the ideal target. This Review highlights the challenges still to be overcome and presents an overview and summary of methods of de-cellularization and re-cellularization strategies, together with a view on future directions that may lead to the regeneration of a functional liver.

Decellularization technology in CNS tissue repair.

Decellularization methodologies have been successfully used in a variety of tissue engineering and regenerative technologies and methods of decellularization have been developed for target tissues and organs of interest. The technology to promote regeneration and functional recovery in the CNS, including brain and spinal cord, has, however, made slow progress mainly because the intrinsic regenerative potential of the CNS is regarded as low. To date, currently available therapies have been unable to provide significant functional recovery and successful therapies, which could provide functional restoration to the injured brain and spinal cord are controversial. In this review, the authors provide a critical analysis, comparing the advantages and limitations of the major decellularization methods and considering the effects of these methods upon the biologic scaffold material. The authors also review studies that supplement decellularized grafts with exogenous factors, such as stem cells and growth factors, to both promote and enhance regeneration through decellularized allografts.

Network meta-analysis of randomized controlled trials: efficacy and safety of UDCA-based therapies in primary biliary cirrhosis.

Major ursodeoxycholic acid (UDCA)-based therapies for primary biliary cirrhosis (PBC) include UDCA only, or combined with either methotrexate (MTX), corticosteroids (COT), colchicine (COC), or bezafibrate (BEF). As the optimum treatment regimen is unclear and warrants exploration, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse events (AE).PubMed, the Cochrane Library, and Scopus were searched for randomized controlled trials up to August 31, 2014. We estimated the hazard ratios (HRs) for MOLT and odds ratios (ORs) for AE. A sensitivity analysis based on the dose of UDCA was also executed.Thirty-one eligible articles were included. Compared with COT plus UDCA, UDCA (HR 0.38, 95% confidence interval [CI] 0.09-1.39), BEF plus UDCA (HR 0.29, 95% CI 0.02-4.83), COC plus UDCA (HR 0.39, 95% CI 0.07-2.25), MTX plus UDCA (HR 0.28, 95% CI 0.05-1.63), or OBS (HR 0.49, 95% CI 0.11-2.01) all provided an increased risk of MOLT. With respect to drug AE profile, although not differing appreciably, BEF plus UDCA was associated with more AEs compared with UDCA (OR 3.16, 95% CI 0.59-20.67), COT plus UDCA (OR 2.27, 95% CI 0.15-33.36), COC plus UDCA (OR 1.00, 95% CI 0.09-12.16), MTX plus UDCA (OR 2.03, 95% CI 0.23-17.82), or OBS (OR 3.00, 95% CI 0.53-20.75). The results of sensitivity analyses were highly consistent with previous analyses.COT plus UDCA was the optimal UDCA-based regimen for both MOLT and AEs. BEF plus UDCA was most likely to cause AEs, whereas monotherapy with UDCA and coadministriation of COT plus UDCA appeared to be associated with the fewest AEs for PBC treatment.

Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target.

INTRODUCTION: Fibroblast growth factor 19 (FGF19) is a member of the hormone-like FGF family and has activity as an ileum-derived postprandial hormone. It shares high binding affinity with ß-Klotho and together with the FGF receptor (FGFR) 4, is predominantly targeted to the liver. The main function of FGF19 in metabolism is the negative control of bile acid synthesis, promotion of glycogen synthesis, lipid metabolism and protein synthesis. AREAS COVERED: Drawing on in vitro and in vivo studies, this review discusses FGF19 and some underlying mechanisms of action of FGF19 as an endocrine hormone in several liver diseases. The molecular pathway of the FGF19-FGFR4 axis in non-alcoholic liver disease and hepatocellular carcinoma are discussed. Furthermore, definition of function and pharmacological effects of FGF19 for liver disease are also presented. EXPERT OPINION: A series of studies have highlighted a crucial role of FGF19 in liver disease. However, the conclusions of these studies are partly paradoxical and controversial. An understanding of the underlying biological mechanisms which may explain inconsistent findings is especially important for consideration of potential biomarker strategies and an exploration of the putative therapeutic efficacy of FGF19 for human liver disease.

Factors associated with efficacy of pegylated interferon-α plus ribavirin for chronic hepatitis C after renal transplantation.

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease after renal transplantation (RT), which reduces both graft and patient survival. After RT, the most widely used approach is interferon (IFN)-based therapy of hepatitis C which may be unsatisfactory with both poor efficacy and an increasing risk of allograft rejection. Thus, it is not recommended unless patients develop fibrosing cholestatic hepatitis. Several recent studies, however, suggest that treatment was possible with preservation of both renal and liver functions. From the limited studies on HCV infection after RT, several factors have been identified as important tools for the management of therapy in these patients. Infection with HCV genotypes 2 and 3, low baseline viral load and absence of advanced fibrosis/cirrhosis in the liver are associated with a sustained virologic response (SVR). After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of SVR independent of HCV genotype. Furthermore, some factors must be taken into consideration in order to avoid allograft rejection, such as the time between transplantation and therapy for HCV, the dose and duration of regimen and renal function. Careful evaluation of predictions of stable renal function and SVR for those patients helps to reduce inefficient treatment regimes and to increase the cure rate in addition to reducing the possible risk. In this review, the latest information was collected and we focus on the discussion of the factors influencing the attainment of SVR after RT.

[TcpC induces apoptosis of macrophages through promoting ROS production].

OBJECTIVE: To investigate the effects of Toll/interleukin 1 receptor domain-containing protein(TcpC)on macrophages and its mechanisms. METHODS: Murine macrophage J774A cells were co-cultured with TcpC producing wild type E. coli strain CFT073 (TcpC(wt)) or tcpc gene-deleted CFT073 mutant (TcpC(mut)) in Transwell system, respectively. Apoptosis of J774A cells co-cultured with TcpC(wt) or TcpC(mut) was analyzed by Annexin/PI double staining. The levels of reactive oxygen species (ROS) in J774A cells were determined by DCFH-DA staining after treatment with TcpC(wt) or TcpC(mut) at 6 h, 12 h,24 h or 36 h. After the ROS was scavenged by N-acetylcysteine (NAC), the changes of J774A cell apoptosis were also examined. The expression of caspase-3 in J774A cells co-cultured with TcpC(wt) or TcpC(mut) in the presence or absence of 0.1 mmol NAC was detected by Western blot. RESULTS: J774A cells co-cultured with TcpC(wt) for 24 h or 36 h showed significantly increased apoptosis (27.39% ± 4.05% and 28.45% ± 4.55%,respectively) when compared to control group (7.96% ± 1.63% and 10.55% ± 1.44%,P<0.01) or TcpC(mut) group (11.45% ± 2.77% and 19.26%± 2.89%,P<0.01). Levels of ROS in J774A cells treated with TcpC(wt) for 24 h (108.8 ± 9.73) or 36 h (100.3 ± 10.11) were significantly higher than those in control group (56.8 ± 4.11 and 52.8 ± 4.42,P<0.01) or TcpC(mut) (69.7 ± 5.66 and 62.6 ± 4.56, P < 0.01). The pro-apoptotic effects of TcpC(wt) on J774A cells were reversed by 0.1 or 1 mMol NAC treatment. Expression of caspase-3 in J774A cells co-cultured with TcpC(wt) (0.43 ± 0.04) decreased significantly when compared to control group (0.75 ± 0.08,P<0.05) or TcpC(mut) group (0.80 ± 0.12,P<0.05). However,total caspase-3 expression was restored in J774A cells co-cultured with TcpC(wt) in the presence of 0.1 mmol NAC (0.80 ± 0.09). CONCLUSION: TcpC can promote ROS production in macrophages,hereby inducing macrophage apoptosis.