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Recently, a new kind of f (z) theory is proposed to provide a different perspective for the development of reliable alternative models of gravity in which the f (R) Lagrangian terms are reformulated as polynomial parametrizations f (z). In the previous study, the parameters in the f (z) models have been constrained by using cosmological data. In this paper, these models will be tested by the observations in the solar system. After solving the Ricci scalar as a function of the redshift, one could obtain f (R) that could be used to calculate the standard Parametrized-Post-Newtonian (PPN) parameters. First, we fit the parametric models with the latest cosmological observational data. Then, the tests are performed by solar system observations. And last we combine the constraints of solar system and cosmology together and reconstruct the f (R) actions of the f (z) parametric models. [ABSTRACT FROM AUTHOR]

Objective: Lactulose is effective in the treatment and prevention of overt hepatic encephalopathy (OHE), but there are limited data on its use on microbiota in relations to minimal hepatic encephalopathy (MHE) recovery. The present study aimed to assess the efficacy of lactulose in recovery of MHE in aspects of cognitive function, quality of life, and impact on intestinal microbiota. Methods: This multicenter, open‐label randomized controlled trial was conducted in 11 teaching hospitals in China. Participants were randomly allocated on a 2:1 basis to receive lactulose (Gp‐L) or no therapy as control (Gp‐NL) for 60 days. The primary endpoint was the MHE reversal rate. Gut microbiota were compared between MHE patients and healthy volunteers, as well as lactulose‐responders and non‐responders. Results: A total of 98 cirrhotic patients were included in the study, with 31 patients in the Gp‐NL group and 67 patients in the Gp‐L group. At day 60, the MHE reversal rate in Gp‐L (64.18%) was significantly higher than that in Gp‐NL (22.58%) (P =.0002) with a relative risk of 0.46 (95% confidence interval 0.32‐0.67). Number needed to treat was 2.4. Further, there was significantly more improvement in physical functioning in Gp‐L (4.62 ± 6.16) than in Gp‐NL (1.50 ± 5.34) (P =.0212). Proteobacteria was significantly higher in MHE patients compared with healthy volunteers (12.27% vs 4.65%, P < .05). Significant differences were found between lactulose responders and non‐responders in Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. Conclusions: Treatment with lactulose significantly improves MHE recovery rate, and gut microbiota change in MHE patients can modulate the effectiveness of this therapy. Chinese Clinical Trial Register (ChiCTR) (ID: ChiCTR‐TRC‐12002342). [ABSTRACT FROM AUTHOR]

Aiming at the demand for high-speed, easy-controllability, and integration of pneumatic soft robots and elastomer actuators, this study presents a squeezing-tube-driven pump (STDP) for soft pneumatic robotics based on spiral spring winding. This concept contains a customized spiral spring and a pneumatic tube with high-elasticity. The spiral spring is driven by an electric motor and coerced into winding deformation. Furthermore, the pneumatic tube is extruded by the spring and then the air in the tube is fast compressed to drive soft pneumatic grippers. The mechanical model and simulation are utilized to explain the operating principle of STDP. The air pressure and rotation angle of the spring under various rotation speeds are in a close linear correlation verified by the experimental results, which provides feasibility for easy controlling and rapid actuation. Finally, fast-gripping tests with an integrated gripper–pump system and a pneumatic muscle actuation test are presented to show the advantages of the proposed pump, respectively. [ABSTRACT FROM AUTHOR]

Background Although the migration of hepatic stellate cells ( HSCs) is essential to the hepatic fibrotic response, the intracellular and extracellular signals that regulate their migration are poorly understood. Aims To investigate the role of Rho guanosine triphosphatase (Rho GTPase) signalling, specifically via RhoA, in transforming growth factor β1 ( TGFβ1)-induced HSC migration. Methods Both primary rat HSCs and the HSC-T6 rat hepatic stellate cell line were used in this study. Cell migration was evaluated using the Transwell Boyden Chamber assay, whereas cytoskeletal changes were observed using laser confocal microscopy. Western blotting was used to detect the expression of Rho GTPases (RhoA, Rac1 and Cdc42) in HSCs, and their activation was determined using glutathione S-transferase ( GST) pull-down assays. Finally, the specific effects of RhoA on TGFβ1-induced cell migration were analysed in HSC-T6 cells stably transfected with constitutively active ( CA, Q63L) or dominant-negative ( DN, T19N) RhoA mutants. Results Transforming growth factor β1 induced cytoskeletal remodelling and migration of rat HSCs following RhoA activation. The level of RhoA activation determined the motility of the HSCs. Conclusions These findings broaden our understanding of the intracellular and extracellular signals that regulate HSC migration. Furthermore, RhoA may be a candidate therapeutic target for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Background & Aims: One major cause of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of pyrrolizidine alkaloid (PA)-containing products. Over 8000 PA-induced HSOS cases have been reported worldwide and at least 51 among them were suspected to be attributed to exposure to the Chinese medicine ‘Tusanqi’. PA-induced hepatotoxicity involves cytochrome P450-mediated metabolic activation of PAs to electrophilic pyrrolic metabolites which react with macromolecules, such as proteins. However, no studies have found such protein adduction in HSOS patients. We report one HSOS case confirmed by liver biopsy, where the patient claimed taking ‘Tusanqi’ as self-medication. Methods: The herb was analyzed by HPLC–MS, and its induced hepatotoxicity in rats was assessed by monitoring the alteration of serum ALT level and liver morphology. Blood pyrrole–protein adducts were determined by UPLC–MS. Results: The herb the patient consumed was identified as Gynura segetum, an erroneous substitute of non-PA-containing Sedum aizoon, called ‘Tusanqi’. Hepatotoxic PAs senecionine and seneciphylline were detected in G. segetum. In the PA-exposed patient, serum pyrrole–protein adducts were detected by a newly developed analytical approach. The animal study showed a good correlation of liver injury with the ingestion of G. segetum. Conclusions: For the first time, serum pyrrole–protein adducts were unequivocally detected in a PA-induced HSOS patient, and such adducts show a potential to be developed as a biomarker for the assessment of PA-induced HSOS. Similar to the well-known case of aristolochic acid-poisoning, the observed HSOS was confirmed to arise from the consumption of PA-containing G. segetum, an erroneous substitute of non-PA-containing S. aizoon. [ABSTRACT FROM AUTHOR]

Abstract: Activated hepatic stellate cells (HSCs) play a crucial role in the development of liver fibrosis. Noninvasive monitoring of the activation of HSCs has been challenging due to the lack of specific receptors or motifs on the cells. The present study provides the evidence that integrin αvβ3 expressed on HSCs is a biomarker reflecting the activation of HSCs. Solid-phase synthesis of cRGDyK (Arg-Gly-Asp-DTyr-Lys) peptide and FAM-conjugated peptide were employed for binding to integrin αvβ3. The increased expression of integrin αv and β3 at mRNA and protein levels was detected during HSC activation. The affinity of cRGDyK to integrin αvβ3 was examined by both radioligand binding assay and FAM-conjugated peptide binding measurements. Quantitative RT-PCR and Western blotting showed a less dramatic, but significant increase in αv and β3 integrin mRNA and protein expression following activation of rat HSCs. Radioiodinated cRGDyK binds to both purified and membrane-bound integrin αvβ3 with high affinity in a dissociable manner. FAM-conjugated cRGDyK was coupled to activated HSCs in a time- and dose-dependent, receptor-mediated manner. Activated HSCs express sufficient number of integrin αvβ3 receptor. cRGDyK peptide binds to both purified and membrane-bound integrin αvβ3 with high affinity in a reversible fashion. Thus, the cRGDyK peptide represented a new agent potentially useful for the diagnosis of liver fibrosis. [Copyright &y& Elsevier]

OBJECTIVE: To assess the effectiveness of Chinese-made ulinastatin in the treatment of patients with acute edematous pancreatitis (AEP) and acute hemorrhagic and necrotic pancreatitis (AHNP). METHODS: A multicenter randomized controlled clinical trial was performed. Stratified by AHNP or AEP, patients were randomly allocated into either the treatment group (with ulinastatin) or the control group (treatment with cabexate or octreotide). Clinical symptoms and signs were scored as none, mild, moderate or severe. Laboratory tests included serum amylase, liver and renal function tests, routine blood tests, serum glucose, calcium, blood pH and PaO2 . Clinical results were assessed as cured, significantly effective, effective and non-effective. All adverse effects were recorded. RESULTS: From April to July 2000, a total of 94 patients with acute pancreatitis were enrolled into the study (50 males; 44 females). In this patient group, there were 68 cases of mild pancreatitis and 26 cases of severe pancreatitis. The study showed that the global effective rates of ulinastatin and cabexate in treating AEP were 100%, whereas the cured rate for ulinastatin was 83.3%, which was a little higher than that for cabexate (71.4%), but this difference was not statistically significant. Clinical symptoms, such as abdominal pain and distension, almost disappeared within 3-5 days in both groups for both treatment protocols. The global effective rate of ulinastatin in treating AHNP was similar to that of octreotide (78.6 vs 81.9%; P = 0.840). The main complication in AHNP was pancreatic pseudocyst. Only one case showed increased levels of alanine aminotransferase. No adverse effects, including allergy, skin rash and decreases in the white blood cell count, were noted. No abnormalities in liver and renal function, electrolytes or routine blood tests were noted. CONCLUSIONS: Ulinastatin was shown to be effective in treating AEP and AHNP with few adverse effects. [ABSTRACT FROM AUTHOR]

Hepatic sinusoidal obstruction syndrome ( HSOS), characterized by hepatomegaly, ascites and hyperbilirubinemia, is caused by toxic injury to hepatic sinusoidal endothelial cells. One major etiology of HSOS in China is the intake of products containing pyrrolizidine alkaloids ( PA) such as Tusanqi. The manifestations of patients with HSOS are usually non-specific, presenting with abnormal liver function and portal hypertension. Diagnosis of the disease depends mostly on liver histopathology when clinical and imaging data are not sufficient. A history of Tusanqi intake is mostly important for the diagnosis. Due to a lack of effective, evidence-based treatments for HSOS, avoiding the mistaken use of PA-containing products including Tusanqi is important for the prevention of HSOS. [ABSTRACT FROM AUTHOR]

Antiviral therapy is important in patients with hepatitis B virus ( HBV)-related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child-Pugh or model for end-stage liver disease ( MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir ( ETV) or tenofovir disoproxil fumarate ( TDF) is the first-line therapy for nucleos(t)ide analogue ( NA)-naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug-resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma ( HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug-resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV-related cirrhosis and a long-term follow-up in China, where a large number of such patients are found, are recommended. [ABSTRACT FROM AUTHOR]

Abstract: No drugs have been approved clinically for the therapy of hepatic fibrosis. Though interferon-γ (IFN-γ) is a highly effective anti-fibrotic agent in vitro and in some animal models in vivo, its anti-fibrotic potential in clinical trials has been disappointing, due to unwanted off-target effects and a short half-life period which results in poor efficacy. The aims of this study are to develop a new targeted drug delivery system to selectively deliver IFN-γ to hepatic stellate cells (HSCs) and to investigate whether it will improve the anti-fibrotic effect of IFN-γ and reduce its side effects in fibrotic livers. Sterically stable liposomes (SSLs) were modified by cyclic peptides (pPB) with a specific affinity for platelet-derived growth factor receptor-β (PDGFR-β), and then IFN-γ was encapsulated in the targeted liposomes (pPB-SSL-IFN-γ). In vitro, pPB-SSL was found to be taken up and internalized by cultured activated HSCs. The binding of FITC-labeled pPB-SSL to activated HSCs was in a time-dependent and concentration-dependent manner, which could be inhibited by excess unlabelled pPB-SSL, PDGF-BB, suramin or monensin. The inhibitory effect of pPB-SSL-IFN-γ on the proliferation of activated HSCs was respectively 7.24-fold and 2.95-fold higher than that of free IFN-γ and IFN-γ encapsulated in untargeted SSLs. In healthy rats, the tissue distribution, living-body tracing image analyses and pharmacokinetics study showed that pPB-SSL-IFN-γ accumulated mainly in the livers and had a longer half-life than free IFN-γ (3.98±0.52h vs. 0.21±0.03h). Furthermore, in rats with hepatic fibrosis induced by thioacetamide injection, FITC-labeled pPB-SSL was found to predominantly localize in activated HSCs by immunofluorescent double staining for FITC and albumin or α-smooth muscle actin (α-SMA). The enhanced anti-fibrotic effect of pPB-SSL-IFN-γ treatnment was indicated by significant decreases in the histologic Ishak stage, collagen I-staining positive areas, and α-SMA expression levels in fibrotic livers. In addition, pPB-SSL-IFN-γ treatment improved the leukopenia caused by low- and high-dosage free IFN-γ treatments. In conclusion, IFN-γ encapsulated in pPB-SSL had an extended circulation half-life and was selectively delivered to activated HSCs, which enhanced the anti-fibrotic effect of IFN-γ and reduced its side-effects in rats with hepatic fibrosis. Thus, pPB-SSL-IFN-γ may be an effective agent for the therapy of hepatic fibrosis. [Copyright &y& Elsevier]

OBJECTIVE: Hepatic sinusoidal obstruction syndrome (HSOS) induced by a Chinese medicinal herb Tusanqi is increasingly being reported in recent years. The aim of the study was to investigate the possibility of using blood pyrrole-protein adducts test as a confirmatory diagnostic method. METHODS: Patients with HSOS according to international diagnostic criteria associated with Tusanqi from January 2006 to August 2010 in Zhongshan Hospital Fudan University were included and clinical features were collected. Pyrrole-protein adducts in blood sample were determined with ultra performance liquid chromatography-mass spectrometry (UPLC-MS) while pyrrolizidine alkaloids (PAs) in available herbal preparations were analyzed by high performance liquid chromatography-ultraviolet (HPLC-UV). RESULTS: Five patients (age 41-72 years, median age 54 years, all women) were included. Ascites (5/5), jaundice (5/5) and hepatomegaly (4/5) were common manifestations. The imaging features were diffused, patchy hepatic enhancement, periportal edema and ascites. Pathology ascertained that blood flow was obstructive at the site of sinusoid. PAs ( Seneionine and seneciphylline) were identified in all the three available herbal preparations ingested by the HSOS patients. Pyrrole-protein adducts were unequivocally found in all the five blood samples. Two patients recovered, two developed chronic illness and one died due to liver failure and hepatic encephalopathy. CONCLUSIONS: The detection of blood pyrrole-protein adducts using a UPLC-MS approach is a specific, reliable, unambiguous and confirmatory test for HSOS induced by PA, and should be used together with the conventional HSOS clinical diagnostic criteria for the definitive diagnosis of PA-induced HSOS. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocyte growth factor (HGF) was encapsulated into sterically stabilized liposomes (SSL) in order to protect it from in vivo degradation. Cyclic Arg-Gly-Asp (RGD) peptides were combined with maleimide-[poly (ethylene glycol)]-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (MAL-PEG-DOPE) incorporated into SSL. The average percentage of HGF encapsulated into liposomes was 32.38%, the size of liposomes was 91.56 nm and the polydispersity index was 0.164. In vivo, histological observation of the rat livers revealed that injection of RGD–SSL–HGF induced more significant remission of liver cirrhosis than injection of SSL–HGF, HGF alone, HGF plus RGD–SSL and saline. When the histological score, the collagen surface density, the hydroxyproline content and the expression of procollagen α1 (I) and α1 (III) mRNA in the liver were evaluated, all values were smallest in the RGD–SSL–HGF group. In contrast, an increase in apoptotic α-SMA-positive cells was noted in the RGD–SSL–HGF group. Together, this data suggests that targeted liposomes encapsulating HGF is a promising therapeutic modality in terms of promoting the remission of liver cirrhosis by promoting collagen fiber digestion, inhibiting collagen production, and promoting apoptosis of α-SMA-positive cells in rats with cirrhosis. [Copyright &y& Elsevier]

Abstract: Nitric oxide synthases (NOS) and cyclooxygenase-2 (COX-2) are important enzymes involved in ulcer healing but interactions between them have not been clearly defined. The aim of this study was to investigate the effects of selective or non-selective inhibition of NOS on the expression and activity of COX-2 during healing of acetic acid-induced gastric ulcers in rats. N-[3-(aminomethyl)benzyl] acetamidine (1400W), a potent selective inhibitor of inducible nitric oxide synthase (iNOS), at a dose of 0.1 mg/kg/day, was found to reduce the ulcer sizes at day 3 and 7 post-ulcer induction. On the other hand, 15 mg/kg/day of N G-nitro-l-arginine methyl ester (l-NAME), a non-selective NOS inhibitor that suppresses both iNOS and endothelial nitric oxide synthase (eNOS), enlarged the ulcer sizes over the same time periods. The expression of COX-2 and COX activity, together with NF-κB activation in the ulcer tissues were down-regulated by l-NAME but not 1400W. It is concluded that iNOS may contribute to ulcer formation while COX-2 and eNOS promote ulcer healing. eNOS enhances COX-2 expression possibly through the activation of NF-κB. [Copyright &y& Elsevier]

AbstractAims: Many treatment trials for Helicobacter pylori have been reported but few have evaluated treatment in terms of both cost and effectiveness. It is important to find a therapy with a high eradication rate and low cost, especially in China. The aim of the study is to assess the efficiency of therapy for duodenal ulcers, including ulcer healing, H. pylori eradication and ulcer recurrence. Methods: Ninety-six consecutive patients with duodenal ulcers and H. pylori infection were randomly allocated into two groups: AMT group (amoxycillin + metronidazole + tagamet); OA group (omeprazole + amoxycillin). Side-effects were recorded during the treatment period. Endoscopic examinations were repeated at the 7th or 8th week to assess ulcer healing. Patients were followed up for 6 months and repeat endoscopy was performed. Ulcer healing rate, H. pylori eradication rate and ulcer recurrence rate were compared. All costs were recorded and a cost-effectiveness analysis was conducted. Results: In the AMT and OA groups, the ulcer healing rate was 83.7 and 93.5%, respectively (P = 0.27). The eradication rate of H. pylori was 65.1 and 69.6%, respectively and was significantly higher in patients with an ulcer diameter ≤ 1 cm compared with those with an ulcer diameter > 1 cm, irrespective of treatment group. There was no difference in recurrence rate, duration of pain or the time lost because of the disease. Moderate or severe side-effects were found in 8.9% in AMT group and 6.5% in OA group. The cost of treatment for ulcer healing, H. pylori eradication and reduction in ulcer recurrence were all lower in the AMT group than in the OA group. Sensitivity analysis supported the result that AMT was more cost effective than OA. Conclusions: The AMT therapy was more effective and less costly than the OA therapy, especially in patients with H. pylori-related duodenal ulcers < 1 cm diameter. © 1999 Blackwell Science Asia Pty Ltd. [ABSTRACT FROM AUTHOR]

Laboratory experiments on fluid flow through fracture are important in solving the fluid-in-rush problems that happen during the tunnel excavation. In order to study the mechanism of fluid flow through a rough-walled microfracture, fluid flow experiments were carried out and the fiber Bragg grating (FBG) strain sensors were applied to monitor the deformation of the microfracture surface during the seepage process. Considering the difficulty of collection of undisturbed rock samples from the deep locations, a methodology to simulate fluid flow through a fractured rock mass using analog materials containing a single fracture was developed. This method is easy to simulate the fluid flow through a fracture of certain aperture. Experimental data showed that Forchheimer equation could provide an excellent description of the nonlinear relationship between hydraulic gradient and flow velocity, and the variations of Forchheimer coefficients with joint roughness coefficient (JRC) were studied. It was found that the deformation of the microfracture surface subjected to seepage could be accurately captured by the quasi-distributed FBG strain sensors. The test results also demonstrated that the surface strain is significantly affected by hydraulic pressure. [ABSTRACT FROM AUTHOR]

Abstract The Yizuomao area, located in the south segment of Lesser Xing'an Range–Zhangguangcai Range, is an important part of ore-concentrated area in the east of Ha'erbin. The Yizuomao Complex comprises medium- to coarse-grained, medium- to fine-grained and fine-grained biotite-bearing alkali feldspar granite, and the results show 206Pb/238U ages of 195.3 ± 1.8 Ma, 200.6 ± 3.2 Ma and 205.2 ± 4.1 Ma, respectively. The geological characteristics for these deposits indicate that a genetic link between the emplacement of granite porphyries and skarn-type mineralization. The ages of regional mineralization and crystallization of the granite porphyrie suggest that skarn mineralization in the Yizuomao area occurred during the late Early–early Middle Jurassic. The Yizuomao Complex and associated granite porphyries have similar characteristics, as both comprise high–K calc–alkaline rocks containing high concentrations of SiO 2 and K 2 O + Na 2 O, and low concentrations of Ti, Fe, Mn and Ca. The magmatic rocks are depleted in Ba, Nb, Sr, and Ti, and enriched in Rb, Th, U, K and Pb, and have high Rb/Sr ratios, characteristic of highly fractionated I-type granites. Moreover, all display positive ε Hf (t) values from +5.6 to +14.3, and young zircon Hf single-stage and two-stage model ages, suggesting a significant contribution of juvenile material. Based on the geochronology, geochemistry and Hf isotopic data, we suggest that the Yizuomao Complex and associated granite porphyries were derived from partial melting of juvenile crust. The Yizuomao Complex was emplaced in the transformation period from the post-collision extension of the NCC and the Jiamusi-Khanka Massif to the subduction of Paleo-Pacific Plate. The granite porphyries that are intimately associated with the mineralization were the result of magmatic activity along an active continental margin related to subduction of the Paleo-Pacific Plate. Graphical abstract Unlabelled Image Highlights • There is a genetic link between the emplacement of granite porphyry and skarn-type mineralization. • The skarn mineralization in the Yizuomao area occurred in the Early to Middle Jurassic. • The Yizuomao Complex and associated granite porphyry were derived from partial melting of juvenile crust. [ABSTRACT FROM AUTHOR]

Summary: Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates. [ABSTRACT FROM AUTHOR]

The correlation between improvement in longitudinal liver stiffness and fibrosis regression has not been properly evaluated during long-term antiviral therapy in chronic hepatitis B (CHB) patients. In this study, liver stiffness was serially performed by FibroScan® every 26 weeks in a prospective cohort of CHB patients receiving entecavir. Results were compared with liver biopsies at baseline and week 78. A total of 120 treatment-naïve CHB patients were analyzed, in which 54 (45%) patients had fibrosis regression at 78 weeks of antiviral therapy. Liver stiffness measurement presented as a rapid-to-slow decline pattern and decreased more significantly in patients with fibrosis regression than those without improvement in fibrosis at week 78 (− 46.4 vs. − 28.6%, P < 0.001). Multivariate analysis revealed that percentage decline of 52-week and 78-week liver stiffness from baseline was independent predictive factors for fibrosis regression (OR = 46.6, P < 0.001; OR = 17.8, P = 0.002, respectively). Moreover, percentage decline of 78-week liver stiffness was moderately predictive of fibrosis regression (AUROC = 0.694, P < 0.001), while the optimal cutoff values were different between non-cirrhosis and cirrhosis patients (38 vs. 45%). Fibrosis regression could be predicted with a high positive predictive value (96%) in non-cirrhosis patients and could be excluded with a high negative predictive value (94%) in cirrhosis patients. In conclusion, serial liver stiffness measurement could be applied for longitudinal monitoring of fibrosis status in CHB patients. Continuous decline of liver stiffness after effective antiviral treatment could partially reflect fibrosis regression at an optimal cutoff value. [ABSTRACT FROM AUTHOR]

Th17 cells are involved in liver fibrosis by activating hepatic stellate cells (HSCs). We aimed to investigate whether HSCs are able to regulate the function of Th17 cells and to determine the relevant mechanism. Sixty-five patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. To determine the effect of HSCs on T cells, naïve CD4 + T cells and Th17 cells were sorted from CHB patients and cultured with or without activated-HSCs, and cytokine expression and gene transcription were analyzed. In addition, the regulatory mechanism of HSCs was investigated. ELISA and qRT-PCR showed that Th17 cells from CHB patients were more pathogenic, on the basis of the expression of IL-17A, IL-23R, RORC, CCL20 and CCR6, and meanwhile, they could activate the primary HSCs. Co-culture experiments indicated that activated HSCs dramatically promoted proliferation of CD4 + T cells in a time- and dose-dependent manner. In addition, they could induce naïve CD4 + T cells to become Th17 cells which had a more pathogenic phenotype. Moreover, activated HSCs-mediated induction of Th17 cells might depend on the release of IL-1β and IL-6 as well as on the COX-PGE2 pathway. Th17 cells cooperated with HSCs in a proinflammatory feedback loop might provide a better understanding of the pathogenic role of Th17 cells in the chronicity of HBV infection. [ABSTRACT FROM AUTHOR]

Background: We studied whether 48 weeks of pegylated interferon alfa-2b (peginterferon) add-on therapy increases serological response in hepatitis B virus (HBV) envelope antigen (HBeAg)-positive patients receiving nucleos(t)ide analogue (NA) therapy, compared with continued NA monotherapy.Methods: This randomized trial included HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of <2000 IU/mL. Patients were randomly assigned in a 1:1 ratio to 48 weeks of peginterferon add-on therapy (n = 39) or continued NA monotherapy (n = 38). Response (defined as HBeAg seroconversion with an HBV DNA load of <200 IU/mL) was assessed at week 48, with responders discontinuing NA therapy at week 72.Results: The primary end point (response at week 96) was achieved in 18% of patients who were assigned peginterferon add-on therapy versus 8% of patients assigned NA monotherapy (P = .31). Among 58 interferon-naive patients, add-on therapy led to a greater frequency of HBeAg seroconversion (30% vs 7%; P = .034) and response (26% vs 7%; P = .068) at week 96, compared with monotherapy. Among 8 responders at week 48 who discontinued NA therapy at week 72, 6 patients (75%) maintained a response until week 96 (4 of 6 [67%] in the add-on therapy group vs 2 of 2 [100%] in the monotherapy group; P = 1.00). Adverse events were mainly related to peginterferon.Conclusion: The primary end point was negative, but peginterferon add-on therapy appeared to result in a greater frequency of HBeAg seroconversion, compared with NA monotherapy, in interferon-naive patients receiving NA therapy.Clinical Trials Registration: NCT01532843. [ABSTRACT FROM AUTHOR]

Background & Aims Distinguishing between acute on chronic liver failure (ACLF) and decompensated liver cirrhosis is difficult due to a lack of pathological evidence. Methods A prospective single-center study investigated 174 patients undergoing liver transplantation due to acute decompensation of hepatitis B virus (HBV)-associated liver cirrhosis. Two groups were distinguished by the presence or absence of submassive hepatic necrosis (SMHN, defined as necrosis of 15–90% of the entire liver on explant). Core clinical features of ACLF were compared between these groups. Disease severity scoring systems were applied to describe liver function and organ failure. Serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes were used to study systemic and local inflammatory responses. Results SMHN was identified in 69 of 174 patients proven to have cirrhosis by histological means. Characteristic features of SMHN were extensive necrosis along terminal hepatic veins and spanning multiple adjacent cirrhotic nodules accompanied by various degrees of liver progenitor cell-derived regeneration, cholestasis, and ductular bilirubinostasis. Patients with SMHN presented with more severely impaired hepatic function, a higher prevalence of multiple organ failure (as indicated by higher CLIF-SOFA and SOFA scores) and a shorter interval between acute decompensation and liver transplantation than those without SMHN ( p <0.01 for all parameters). Further analyzes based on serum cytokine profile assays, gene expression microarrays and immunohistochemical analyzes revealed higher levels of anti-inflammatory cytokines in patients with SMHN. Conclusions SMHN is a critical histological feature of HBV-associated ACLF. Identification of a characteristic pathological feature strongly supports that ACLF is a separate entity in end-stage liver disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Schistosoma japonicum causes marked liver fibrosis, while lethal syndromes present in advanced schistosomiasis patients. Its management depends on the degree of fibrosis present. Patients and methods: Fifty-two patients were recruited to assess the diagnostic value of bio-markers in patients with advanced schistosomiasis japonica. Fibrosis was assessed in liver biopsies using METAVIR system. The correlation between conventional parameters and significant fibrosis (F2-F4) was assessed using univariate analysis and logistic regression. The method of area under receiver operating characteristic curves (AUROCs) was used as a measurement of diagnostic efficacy. Results: White blood cell counts, platelet counts and albumin (all P <0.05) were significantly lower, while prothrombin time, international normalized ratio (INR), hyaluronic acid (HA), IV collagen and ultrasound fibrosis scores (all P <0.01) were significantly elevated in F2-F4 patients compared with F0-F1 patients. HA and INR were identified as independent predictors by multivariate analysis (P =0.023 and P =0.013, respectively). Of the routine laboratory tests for the diagnosis of significant fibrosis, HA gave the best AUROC of 0.875 (95% confidence interval (CI): 0.701–0.997). We constructed a new simple index (INR×HA/100) to discriminate between F2-F4 patients and F0-F1 patients. It showed the highest AUROC of 0.921 (95% CI: 0.828-1.000), and had better diagnostic values than APRI and FIB-4. Conclusion: HA and INR were reliable markers for differentiating significant liver fibrosis in patients with advanced schistosomiasis japonica. And the new simple index can easily predict significant liver fibrosis with a high degree of accuracy. [Copyright &y& Elsevier]

Background: The migration of hepatic stellate cells (HSCs) is essential to the hepatic fibrotic response, and recently High-mobility group box 1 (HMGB1) has been shown up-regulated during liver fibrosis. Nevertheless, whether HMGB1 can modulate the proliferation and migration of HSCs is poorly understood, as well as the involved intracellular signaling. In this study, we examined the effect of HMGB1 on proliferation, migration, pro-fibrotic function of HSCs and investigated whether toll-like family of receptor 4 (TLR4) dependent signal pathway is involved in the intracellular signaling regulation. Methodology/Principal Findings: Modified transwell chamber system to mimic the space of Disse was used to evaluate the migration of human primary HSCs, and the protein expressions of related signal factors were evaluated by western blot. Cell proliferation was analyzed by MTT assay, the pro-fibrotic functions of HSCs by qRT-PCR and ELISA respectively. Recombinant human HMGB1 could significantly promote migration of HSCs under both haptotactic and chemotactic stimulation, especially the latter. Human TLR4 neutralizing antibody could markedly inhibit HMGB1-induced migration of HSCs. HMGB1 could enhance the phosphorylation of JNK and PI3K/Akt, and TLR4 neutralizing antibody inhibited HMGB1-enhanced phosphorylation of JNK and PI3K/Akt and activation of NF-κB. JNK inhibitor (SP600125) and PI3K inhibitor (LY 294002) significantly inhibited HMGB1-induced proliferation and migration of HSCs, and also reduced HMGB1-enhanced related collagen expressions and pro-fibrotic cytokines production. Conclusions/Significance: HMGB1 could significantly enhance migration of HSCs in vitro, and TLR4-dependent JNK and PI3K/Akt signal pathways are involved in the HMGB1-induced proliferation, migration and pro-fibrotic effects of HSCs, which indicates HMGB1 might be an effective target to treat liver fibrosis. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRs) are known to have an important role in modulating vascular biology. MiR21 was found to be involved in the pathogenesis of proliferative vascular disease. The role of miR21 in endothelial cells (ECs) has well studied in vitro, but the study in vivo remains to be elucidated. In this study, miR21 endothelial-specific knockout mice were generated by Cre/LoxP system. Compared with wild-type mice, the miR21 deletion in ECs resulted in structural and functional remodeling of aorta significantly, such as diastolic pressure dropping, maximal tension depression, endothelium-dependent relaxation impairment, an increase of opening angles and wall-thickness/inner diameter ratio, and compliance decrease, in the miR21 endothelial-specific knockout mice. Furthermore, the miR21 deletion in ECs induced down-regulation of collagen I, collagen III and elastin mRNA and proteins, as well as up-regulation of Smad7 and down-regulation of Smad2/5 in the aorta of miR21 endothelial-specific knockout mice. CTGF and downstream MMP/TIMP changes were also identified to mediate vascular remodeling. The results showed that miR21 is identified as a critical molecule to modulate vascular remodeling, which will help to understand the role of miR21 in vascular biology and the pathogenesis of vascular diseases. [ABSTRACT FROM AUTHOR]

Abstract: The aims of this study were to elucidate the immunomodulatory effects of glycyrrhizin (GL) on CD4+T cell responses during liver fibrogenesis. To obtain in vivo evidence about the effects of GL on CD4+T cells in livers and spleens of concanavalin A (ConA)-induced mouse model, mice were administrated with ConA together with or without GL for 8weeks. Mice treated with GL dramatically prevented liver inflammation and fibrosis. Besides, GL inhibited the infiltration of T helper (Th) cell type 1, Th2, Th17 and regulatory T cells (Treg) in livers and spleens of mouse fibrosis models, and regulated the Th1/Th2 and Treg/Th17 balances respectively to a relative dominance of Th1 and Treg lineages in livers. Moreover, GL dramatically enhanced the antifibrotic cytokine interferon (IFN)‐γ and interleukin (IL)-10. GL at a concentration of 10 or 100μg/mL was respectively incubated with ConA-stimulated splenic CD4+T cells in vitro, and JNK inhibitor (SP600125), ERK inhibitor (U0126), p38 inhibitor (SB203580) or PI3K/AKT inhibitor (LY29400225) was added during the incubation. Notably, GL not only inhibited ConA-induced proliferation of splenic CD4+T cells but also enhanced the mRNAs of IFN-γ and IL-10 in these cells. Be similar to the effects of GL, SP600125, U0126 and LY29400225, however not SB203580, also inhibited ConA-induced CD4+T cell proliferation, indicating the involvement of JNK, ERK and PI3K/AKT in this process. Moreover, GL significantly inhibited ConA-induced phosphorylation of JNK, ERK and PI3K/AKT in vitro. Collectively, GL might alleviate liver injury and fibrosis progression via regulation of CD4+T cell response in JNK, ERK and PI3K/AKT-dependent pathways. [Copyright &y& Elsevier]

Abstract: The aim of the study was to investigate the effect of curcumin on the liver fibrosis induced by carbon tetrachloride (CCl4) in rats, and to elucidate its underlying molecular mechanisms. Rats were administered with CCl4 together with or without curcumin for 6weeks. Hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis; and activated hepatic stellate cells were assessed. Moreover, the mRNA and protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, high-mobility group box 1 (HMGB1), Toll like receptor (TLR) 2 and TLR4 were determined by quantitative real time PCR, Western blot or immunohistochemistry. Treatment with curcumin significantly attenuated CCl4-induce liver injury, hepatic inflammation and reduced the levels of proinflammatory mediators (TNF-α, IL-6 and MCP-1). Moreover, curcumin significantly inhibited extracellular matrix deposition, reduced the number of activated stellate cells, and decreased the levels of HMGB1, TLR4 and TLR2 expression in the rat model of fibrogenesis. These results suggest that curcumin could be an effective agent for preventing liver fibrosis and its mechanism may in part be a consequence of the reduction TLR2, TLR4 and HMGB1 expression. [Copyright &y& Elsevier]

Abstract: Background: Intravascular Brachytherapy as a tool to reduce restenosis is thought to alter vascular wall biology and vessel wall protein function. Platelet accumulation is also indeed important in the genesis of restenosis. We examine the in vitro effects of beta-radiation on the certain vessel wall extra cellular matrix proteins. We hypothesized that vessel wall (proteins) had become less prone to thrombosis. Methods: We examined platelet adhesion to 20-Gy beta radiation treated extra cellular matrix proteins under flow conditions. Platelet flow adhesion was evaluated or quantified by image analysis, aggregation size analysis using the Watershed program and real-time fluorescence images of thrombus formation. The effect of beta radiation on vWF was further showing by measuring the binding of domain-specific antibodies to radiation treated vWF. Results: 20-Gy beta radiation significantly decreased platelet adhesion to extra cellular matrix protein; vWF and collagen Type III and had no effect on the adhesion upon fibrinogen and fibronectin. The beta-radiation affected mostly the AI, A2 and A3 domains of the vWF molecule on the surface, whereas the D′–D3 and B–C1 domains on the surface remain unaffected and suggesting a significant decrease in vWF binding capacity to the GPIb, heparin and collagen ligands. Conclusion: Beta radiation treatment can alter the reactivity of the certain vessel wall extra cellular matrix proteins, in particular vWF and collagen. The vessel wall may become less prone to platelet adhesion, which results in decrease thrombus formation. It might help to reduce the onset of acute coronary occlusion after the intervention. [Copyright &y& Elsevier]

Abstract: Background and aims: Few drugs have been confirmed to be effective for fulminant hepatic failure (FHF). The purpose of this study was to prepare sterically stable liposomes (SSL) encapsulating hepatic stimulator substance (HSS) and determine their therapeutic effect on FHF. Methods: HSS were encapsulated into SSL (HSS-SSL). FHF was induced in rats by thioacetamide (TAA) injection (400mg/kg, three times with a 24-h interval). The agents, including HSS-SSL, SSL, HSS, and sodium chloride (NS), were each injected intravenously 2h after the second and the third TAA injection. Results: Freshly prepared HSS-SSL had a mean size of 93.59nm and the average encapsulation efficiency was 37.20%. HSS encapsulated in SSL showed a longer half life and more potent target to injured livers than free HSS. Twenty-four hours after the third TAA-injection, the survival rate of HSS-SSL-treated rats (80%) was significantly higher than that of rats treated with NS (20%), SSL (25%), or HSS (50%). Histopathologic examination showed that there was the least necrosis and inflammation in the livers of HSS-SSL-treated rats. The incidence of stage 3 or 4 hepatic encephalopathy in HSS-SSL-treated rats was significantly lower than that in rats treated with other agents. The serum pro-inflammatory cytokine levels and hepatic lipid peroxidation levels were both markedly reduced, while hepatocyte proliferative rate was markedly increased after HSS-SSL treatment. Conclusion: Encapsulation by SSL markedly improved the therapeutic effect of HSS on FHF in rats. Encapsulation by SSL may be an effective approach to enhance the therapeutic potency of drugs for FHF. [Copyright &y& Elsevier]

A new complex [Fe(N-isonicotinamidosalicylaldimine)Cl2] has been synthesized by template reaction at room temperature and structurally characterized by X-ray single-crystal analysis. The complex crystallizes in triclinic crystal system, Pī space group, a = 7.273(6) Å, b = 10.015(8) Å, c = 10.479(8) Å, α = 71.067(10)°, β = 89.964(11)°, γ = 75.528(10)°, V = 696.4(9) Å3 and Z = 2. The coordination geometry around the Fe(III) ion is a distorted trigonal bipyramid with a O2N1Cl2 donor set. In the crystal structure, N–H···Cl, C–H···O and C–H···Cl hydrogen bonds and π···π stacking interactions involving aromatic and unclosed π-systems link the molecules to form supramolecular double layers. A new Fe(III) complex of N-isonicotinamidosalicylaldimine, an isonicotinyl hydrazone ligand, has been prepared and crystallographically characterized. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Selective cyclooxygenase-2 (COX-2) inhibitors have been shown to produce fewer gastrointestinal adverse reactions when compared with conventional nonselective nonsteroidal anti-inflammatory drugs and they suppress angiogenesis in tumors. The purpose of the present study was to investigate the effects of highly selective COX-2 inhibitor on angiogenesis and protein expression of angiogenic factor during gastric ulcer healing. Gastric ulcers were induced in male Sprague–Dawley rats by a luminal application of acetic acid solution. Rofecoxib, a selective COX-2 inhibitor, was administered at a dose of 10 mg/kg/day by gastric intubation for 14 successive days. The ulcer size was measured at different time intervals after ulcer induction. The microvessels that were immunohistologically positive for von Willebrand factor within the ulcer bed were counted. The protein levels of basic fibroblast growth factor (bFGF) and concentration of prostaglandin E2 (PGE2) in the ulcer tissues were analyzed with Western blotting and immunoassay methods, respectively. The results demonstrated that rofecoxib treatment significantly increased the ulcer size at days 6, 10, and 15. It decreased the number of microvessels, bFGF protein expression, and PGE2 level in the ulcer base at day 6. The findings that highly selective COX-2 inhibitor delayed ulcer healing in rats and impaired angiogenesis in the ulcer base raise cautions regarding the use of COX-2 inhibitors in patients with gastric ulcers. [Copyright &y& Elsevier]

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by defects in leukocyte NADPH oxidase. Various inherited defects in one of the membrane-bound components of NADPH oxidase, gp91-phox, cause X-linked (X91) CGD. Analysis of three patients with X91 CGD revealed that different mechanisms of molecular quality control lead to the common phenotype of absence of mature membrane-bound NADPH oxidase complex in leukocytes. In the first patient, aberrant intron splicing created a premature stop codon. However, the mutant mRNA was degraded prematurely, which prevented the production of truncated protein. In the second patient, a frameshift mutation with the potential to generate a gp91-phox polypeptide, with an aberrant and elongated C-terminus, led to barely detectable levels of gp91-phox, even though the reported functional domains of the protein appeared unaffected. In the third patient, a point mutation created a single amino acid change in the predicted FAD-binding site of gp91-phox. Although gp91-phox was detectable with Western blotting, no cytochrome b558 was expressed on the cell surface. These analyses showed that molecular quality control machinery plays an important role in the pathogenesis of CGD, not only in the X910 but also in the X91− form of this X-linked disease. [Copyright &y& Elsevier]