Most Australian Paediatric centres still employ standard IFX infu

Most Australian Paediatric centres still employ standard IFX infusions with little published data regarding rapid infusion protocols in paediatric practice. Aim: From a Tertiary Paediatric

IBD centre, we describe the practice and safety of rapid, 1 hour IFX infusion since implementing a rapid infusion policy in October 2011. Methods: Retrospective chart review of children diagnosed with Crohn’s Disease and fulfilling Australian criteria for Infliximab therapy attending the Royal Akt inhibitor Children’s Hospital, Brisbane from October 2011 to May 2013. The Rapid Infusion policy is to give the 3 Induction and 1st maintenance infusion in the standard fashion, increasing the rate to completion over 2.5 hours. All subsequent infusions, commencing with 5th infusion are given over 1 hour. Pre-medication (loratidine, hydrocortisone, paracetamol) is not routinely given, only after a documented infusion reaction. Results: 50 children have been treated using the rapid infusion policy and received 373 IFX infusions. No serious or anaphylactic reaction requiring adrenalin has been observed. 3 (6%) of children experienced a transfusion reaction (1 fever to 38oC; 1 mild temporary rash; 1 nausea) in 3/373 infusions (0.8%) but only during the first 3, induction, 2 hour infusions. No child experienced a transfusion reaction during subsequent rapid 1 hour infusions. check details Each child who experienced

a reaction has subsequently tolerated 1 hour rapid infusions, with premedication, without recurrence of transfusion reaction. There were no predictive factors for reaction. 50/50 children and their parents report satisfaction with the shorter duration infusion Aprepitant and shorter hospital stay. The Infusion centre has been able to increase

the number of children receiving Infliximab infusion at each session, improving timely access to scheduled therapy. Conclusions: This audit of practice confirms that the Rapid Infusion IFX protocol commencing at Infusion 5 and without routine pre-medication is safe, practical and well accepted by children and care-givers, improving patient acceptance and access to efficacious medication. Even faster infusions are described and safe in Adult practice and may provide further improvement in paediatric care and service delivery. (1) Donnellan FC et al. “Accelerated infliximab infusions are safe and well tolerated in patients with inflammatory bowel disease”. European Journal of Gastroenterology & Hepatology 2009:21(1):71–75 J KERR,1 A NAIR,2 R HINDS1,2 1Department of Paediatric Gastroenterology, Monash Children’s Hospital, Clayton, Victoria, Australia, 2Department of Paediatrics, Monash University, Clayton, Victoria, Australia Introduction: Infliximab (IFX) is commonly used in the management of children with Crohn’s disease (CD). IFX is used in Australia when there has been inadequate response to other treatments or in the presence of fistulising disease.

Ig-stimulated T-cells Administration of soluble VSIG4 Ig to wild

Ig-stimulated T-cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged this website the survival of mice with established CIH. Conclusion: Collectively, our results suggest that VSIG4+ KCs play a critical role in the induction and maintenance

of liver T- and NKT-cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune-mediated liver injury including autoimmune hepatitis. (HEPATOLOGY 2012;56:1838–1848) Despite the risk of immune activation by continuous exposure to potential antigens, the liver avoids overactivation of the innate and adaptive immune responses by inducing tolerance.1, 2 Many studies have investigated the molecular and cellular selleck compound basis of liver tolerance. Initial studies focused on identifying tolerance-inducing soluble factors from liver nonparenchymal cells, including hepatic stellate cells (HSCs) and liver-resident antigen-presenting cells (APCs), such as liver sinusoid endothelial cells (LSECs), hepatic dendritic cells (DCs),

and Kupffer cells (KCs).3 Among them, KCs are believed to induce liver tolerance by producing an immunosuppressive cytokine, interleukin (IL)-10, and immunosuppressive metabolites including nitric oxide, prostaglandin E2 (PGE2), and 15-deoxy-delta 12,14-PGJ2 (15d-PGJ2).3–6 Alternative mechanisms for liver tolerance have also been suggested. KCs prime CD4+ T-cells to be converted to regulatory T cells (Tregs) with a CD25low FoxP3neg phenotype NADPH-cytochrome-c2 reductase that can inhibit the proliferation of naïve CD4+ T-cells.7, 8 The functional significance of B7-H1 (PD-L1 or CD274), a coinhibitory ligand, in liver tolerance was demonstrated by showing that B7-H1-expressing KCs directly suppress T-cell proliferation and cytokine production by way of the B7-H1:PD-1 pathway.9 These results suggest that coinhibitory ligands in the liver microenvironment are important for regulating local immune responses. Despite the increasing

number of coinhibitory ligands that play negative roles in T-cell responses, few studies have focused on the cellular and molecular mechanisms of liver tolerance mediated by these coinhibitory ligands. Recently, V-set and Ig domain-containing 4 (VSIG4, also referred to as CRIg or Z39Ig) was identified as a B7-related immunoglobulin superfamily member that is exclusively expressed on tissue-resident macrophages and particularly on liver KCs.10 VSIG4 is a complement receptor for C3b and iC3b, and its binding to the convertase subunit C3b interferes with C5 binding to C3b, thus blocking the alternative complement pathway and subsequent suppression of inflammatory responses.10 VSIG4 also acts as a coinhibitory ligand that negatively modulates adaptive immunity.

Conclusion: Our data suggest that YAP promotes cholangiocyte and

Conclusion: Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis-induced human liver disease. (HEPATOLOGY 2012;56:1097–1107) “
“Recently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the

risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC). We examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case–control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC. In the case–control study, multivariate analysis Dabrafenib revealed that high platelet counts see more (odds ratio [OR] = 4.84; 95% confidence interval [CI] = 1.29–29.54; P = 0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time = 23.3 months). On multivariate analysis, high tumor number, high des-γ-carboxyprothrombin

(DCP) and Child–Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR = 1.73; 95% CI = 0.99–3.14; P = 0.055). HCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child–Pugh class A, are at risk for EHM. THE PROGNOSIS OF hepatocellular carcinoma (HCC) oxyclozanide patients has been improved due to the prevalence of surveillance systems and advances in diagnostic and treatment modalities.[1-4] There are several options for the treatment of HCC at early-to-intermediate stages, such as surgery, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). However, in cases with extrahepatic metastasis (EHM), the only available evidence-based treatment is molecular-targeted

therapy (sorafenib) and the prognosis of these patients is still poor.[5, 6] Based on the report of the Liver Cancer Group of Japan, the 5-year survival of HCC patients with EHM (tumor–node–metastasis stage IVB) is 16.5%, which is much shorter than the average survival of HCC patients (54.2%).[7] Therefore, information about risk factors for EHM is important in order to decide the best strategies for treating HCC. Extrahepatic metastasis, which is known to be closely related to dedifferentiation, is rarely observed when the primary lesion in the liver is well-differentiated HCC. Kanda et al. reported on risk factors for EHM, which included vascular invasion of HCC and elevated tumor markers, and most of the factors were related to tumor characteristics.

6 The onset and severity of denture stomatitis is of multifactori

6 The onset and severity of denture stomatitis is of multifactorial origin, being influenced by factors such as salivary flow, denture cleanliness, age of prosthesis, denture base material, denture trauma, continuous denture wearing, smoking, and nutritional intake.7–10 Nevertheless, fungal biofilms play the most important role clinically.11,12 Denture-induced stomatitis is primarily caused by the opportunistic fungal pathogen Candida albicans; however, an increasing proportion of other Candidal species are

being implicated in pathogenesis, including C. glabrata.13 Although not life threatening per se, the collective presence of Candida species within the saliva, adhesion to the oral mucosa, and the colonization and development of biofilms on the denture surface are associated click here with mild-to-severe pathophysiological effects, according to Newton’s criteria.14–17 Once formed, cells within the biofilm undergo profound phenotypic changes. Most notably, they exhibit increased resistance

to antifungal agents.18,19 It has also been demonstrated that formation of biofilms in the cracks and imperfections of denture bases makes the biofilm resilient to physical forces, most notably removal by brushing.13,17,20 These studies highlight the inherent difficulties experienced by denture wearers in minimizing the fungal this website burden of their dentures, thereby preventing the onset of denture-induced stomatitis. Recent studies have established that sonication significantly

reduces the fungal burden upon removable dentures, and that microwave technology may Niclosamide offer a potential method of denture disinfection;21,22 however, these technologies have limited applicability due to either excessive costs or the capacity to damage the denture base material.23 Denture wearers therefore have to rely on the use of over-the-counter oral hygiene products, which has increased based on the large consumer base in this specialized healthcare market.6 This study aims to examine the efficacy of four over-the-counter denture cleansers to establish their respective capacities to remove and/or kill C. albicans biofilms. C. albicans-type strain ATCC 90028 and 16 clinical strains of C. albicans isolated from a recent denture stomatitis study were used in these investigations.13 All the isolates were stored on Sabouraud dextrose (SAB) agar plates (Oxoid, Cambridge, UK) at 4°C. C. albicans were propagated on SAB agar plates at 37°C overnight. A colony of each isolate was inoculated into 10 ml of yeast peptone dextrose (YPD, Oxoid) and placed in a shaker at 30°C overnight. The cells were washed by centrifugation in sterile phosphate-buffered saline (PBS; pH 7.4, Oxoid). The yeast cells were then counted using a Neubauer hemocytometer and adjusted to the required concentration in RPMI 1640 medium (Sigma, Dorset, UK).

78; 95%CI 0 96 to 2 53, p 0 38) However the overall effect leans

78; 95%CI 0.96 to 2.53, p 0.38). However the overall effect leans toward the study treatment (prucalopride). The test for heterogeneity was not significant. The numbers of adverse events were more common with prucalopride than with placebo (RR 1.22; 95% CI 1.14 to 1.32, p < 0.00001). Conclusion: Prucalopride has no significant effect compared to placebo for the treatment of chronic idiopathic constipation. The drug appeared safe, but adverse events were significantly common, particularly headache, nausea and diarrhea, and patients should be warned of these potential side effects of treatment. Key Word(s): 1. Prucalopride;

2. Chronic constipation; 3. Efficacy; 4. Side effects; Presenting Author: HUI SU Additional Authors: JUNGUO JIANG, LIANGKUI LIU, MINGMING MENG, HONG LIU, JING

Metabolism inhibitor WU Corresponding Author: JING WU Affiliations: Objective: take high resolution gastrointestinal examination and 24 hour esophageal PH -Z monitoring, for systemic sclerosis patients with symptoms of gastrointestinal involvement, to improve the understanding of the gastrointestinal involvement manifestations in systemic sclerosis patient. Methods: for 1 case of gastrointestinal involvement of systemic sclerosis patient, INK 128 ic50 take high resolution esophageal pressure monitoring, 24 hours esophageal PH -Z monitoring, high resolution anorectal pressure monitoring (3D), to analyze the result, explain the clinical symptoms. Results: esophageal pressure monitoring showed esophageal body no creep, LES pressure relief; 24 hours

PH-Z monitoring showed severe gastroesophageal reflux, visible obvious weak acid reflux, correlation analysis considering the symptoms associated with acid reflux; Anorectal pressure monitoring showed the anal sphincter pressure band short, anal sphincter resting pressure and maximum systolic pressure is normal, the anorectal inhibitory reflex, simulated defecate are normal, defecate initial feeling and maximum tolerance amount are significantly 4-Aminobutyrate aminotransferase reduced. Conclusion: high resolution gastrointestinal monitoring can make us intuitive see the manifestations of esophageal sphincter and esophageal peristalsis, rectum anus defecate function affected in systemic sclerosis patients with gastrointestinal involvement. Key Word(s): 1. systemic sclerosis; 2. Gastrointestinal; 3. dynamics; 4. High resolution; Presenting Author: HOYEEW HIRAI Additional Authors: SIEWC NG, JESSICAYL CHING, JAMESYW LAU, RAYMOND TANG, ARICJ HUI, PHYLIS LAM, ALMAN CHUI, ALICE FAN, JUSTIN WU, FRANCISKL CHAN, JOSEPHJY SUNG Corresponding Author: HOYEEW HIRAI Affiliations: The Chinese University of Hong Kong Objective: Few studies have evaluated risk factors and the magnitude of risk for advanced colorectal neoplasms and serrated lesions in Chinese subjects.

23 Therefore, we next compared the transcriptional levels of miR-

23 Therefore, we next compared the transcriptional levels of miR-492 with that of KRT19 and its pseudogene. Upon PLAG1 knockdown, a strong decrease in miR-492 levels was not associated with changes in transcriptional activity of KRT19 (Fig. 1). However, miR-492 induction by PLAG1 overexpression resulted in a moderate induction of KRT19 in HepT1, but not in HUH6 cell clones. Interestingly, PLAG1 modulation was accompanied

by a strong anticorrelation between miR-492 expression and the pseudogene of KRT19. In order to identify BAY 73-4506 nmr the regulatory network and putative direct targets of miR-492 we generated clones that stably express the precursor of miR-492 (pMif-miR-492) and a control vector (pMif-control) in the HUH6 and HepT1 cell lines. pMif-miR-492 clones of both cell lines exhibited enhanced miR-492 expression levels compared to control clones (Fig. 3A) up to 15-fold in HepT1 and up to 4.4-fold in HUH6. Whole genome expression analysis identified 194 genes with significant (adjusted P-value ≤ 0.05) differential expression (Supporting Table 2). Because overexpression of miR-492 must be expected to repress the mRNA targets that are regulated by direct binding interaction of the miR sequence, we prioritized genes being strongly down-regulated and predicted by at least one target prediction program as potential IWR-1 mouse direct targets for quantitative confirmation (Fig. 3B). Significant

down-regulation was confirmed for HSD3B1 (3 beta-hydroxysteroid dehydrogenase), the transcription factor TCF21, the liver-related enzymes ST6GAL1 (ST6 beta-galactosamide alpha-2,6-sialyltranferase 1), BAAT (bile acid coenzyme A: amino acid N-acyltransferase), and GDA (guanine deaminase), the tumor suppressor gene CDKN2A (cyclin-dependent kinase inhibitor 2A), the liver protein ALB (albumin), as well as the proapoptotic gene BID (BH3 interacting domain death agonist) at least in one HB cell line (Fig.

3B). However, Endonuclease NINJ2 (ninjurin 2) expression could not be confirmed to be down-regulated in both miR-492 overexpressing cell lines. Furthermore, we confirmed a strong suppressing effect of miR-492 on the liver tumor-related genes AFP and CASP4 (caspase-4). These genes, however, are not direct targets of miR-492. Annotation and enrichment analyses of functional categories revealed that miR-492 up-regulated genes were most significantly enriched in gene clusters involved in developmental processes, anatomical structure development, and cell communication, whereas suppressed genes were most significantly overrepresented in the functional clusters of metal binding, extracellular space occurrence, and developmental processes (Supporting Table 3). Taken together, these data point to an important influence of miR-492 on a range of genes that are involved in liver metabolism and extracellular structures.

Owing to the greater availability of livestock, particularly catt

Owing to the greater availability of livestock, particularly cattle, in the peripheral areas as compared with resident livestock, a clear-cut difference in lion diet was evident within and outside protected area. Within the protected area also, including the NP which is located within the Gir PA (Fig. 1), livestock formed a significant Fulvestrant clinical trial part of lion’s diet. Livestock constituted 47% of lion diet within the Gir PA while in the peripheral areas, livestock constituted 76% of the 42 kills. Compensation claim records

of the Forest department also indicated that average livestock loss to predation per month within protected area to be 45 and outside protected area to be 89 (Pathak et al., 2002). Livestock remains were found in 21% of 29 kills collected from NP, 43% of 117 kills of SW and 69% of 32 kills outside protected area (Chellam, 1993). Livestock owners residing within 5 km of Gir PA do not have clear-cut grazing rights and therefore benefit less from proximity to the forest. Yet, more livestock predation occurs outside the protected area because of greater availability of livestock, low density of wild prey (mostly nilgai), and increased lion movement (Soni,

2000; Pathak et al., 2002; Meena, 2010). Thus, focal areas of interventions have to be outside the protected area. Abundance, size and temporal and spatial distribution of prey influence hunting strategy, activity and daily movement of lions (Schaller, 1972; Eloff, 1973; Stander, 1991; Patterson et al., 2004). Gir has high biomass of resident wild prey available throughout the year in addition to availability of relatively more vulnerable domestic livestock prey base. Felids require large prey and African lions Panthera leo leo preferentially prey upon species of an average weight of 350 kg, range 190–550 kg (Hayward & Kerley, 2005). Our study also indicates greater consumption of large-sized prey in adult age class (Fig. 2). Although, incidental observations of kills tend to be biased

towards large bodied prey because of easier detectibility, our kill data represented by SPTLC1 62% large bodied wild prey are yet comparable to findings from scat analysis. Monitoring lions with the help of radio-telemetry confirmed that 80% of kills (n=10) were of adult prey. Overall, in terms of relative number of individuals consumed, domestic prey occurred in low proportions (20%) yet in terms of biomass contribution, they accounted for 36% (Table 1). In the wild, lions have to hunt to meet their daily requirement of 5–7 kg (Schaller, 1972). In captivity, Asiatic lions (average body mass 100 kg) consume 6% of their total body mass as buffalo meat in a day (Mukherjee & Goyal, 2004) while in the wild, they consume 7–10% of their body weight (Mukherjee & Goyal, 2004).

Therefore, we conducted a prospective cohort study in a clinical

Therefore, we conducted a prospective cohort study in a clinical setting to assess bleeding risk attributable to gastric biopsy in patients taking antiplatelet agents and the validity of performing endoscopic biopsy with small cup biopsy forceps. Methods: The study was performed during

the 1-year for 5374 scheduled esophagogastroduodenoscopy performed. 1128 patients, Idasanutlin manufacturer including 65 patients taking antiplatelet agents underwent gastric biopsy with small cup biopsy forceps, and 2025 biopsy specimens were obtained from each part of the stomach. Clinical bleeding was investigated during and after endoscopy. Two pathologists assessed the presence of muscularis mucosae in biopsy specimens in addition to the suitability of specimens for histological diagnosis. Results: Ratio of appropriate

specimens obtained with small cup biopsy forceps was 99.3% (2010/2025) and muscularis mucosae was detected ERK inhibitor in 27.8% (538/1394) of specimens. After endoscopy, 1 patient of 1049 patients who took no antithrombotic agents experienced major bleeding (0.095%); however, 65 patients receiving antiplatelet treatment experienced no bleeding. Conclusion: Endoscopic forceps with a small cup is useful and the absolute risk attributable to gastric biopsy in patients taking antiplatelet agents seems to be low. Key Word(s): 1. endoscopic biopsy; 2. antiplatelet agent; 3. bleeding; 4. biopsy forceps; 5. antithrombotic agent Presenting Author: KUNIO IWATSUKA Additional Authors: TAKUJI GOTODA, SHIN KONO, SHO SUZUKI, NAOKO YAGI, CHIKA KUSANO, MASAKATSU FUKUZAWA, TAKASHI KAWAI, FUMINORI MORIYASU Corresponding Author: KUNIO IWATSUKA Affiliations:

Tokyo Medical University, Tokyo Medical University, Tokyo Medical University, Tokyo Medical University, Tokyo Medical University, Tokyo Medical University, Tokyo Medical University Hospital, Tokyo Medical University Objective: Despite improvements in pharmacological Tenofovir price and endoscopic hemostasis, gastrointestinal bleeding (GIB) remains fatal clinical event in the elderly patients. With increasing numbers of the elderly population, endoscopists might face such kind of serious cases. The aims of this study are to research treatment outcomes and clinical features of GIB in elderly patients. Methods: Medical records of 185 patients (mean age 68.2 years, range 10–99 years, male/female 123/62) with GIB who underwent esophagogastroduodenoscopy or colonoscopy from April 2012 to March 2014 were reviewed. Clinical outcomes and clinicopathological features including pre-existing co-morbidities, prescribed drugs (antiplatelet agent, anticoagulant, NSAIDs, corticosteroid) were compared between younger <70 years old) and elderly groups (≤70 years old). Results: Following features were specifically found in elderly patients (N = 100) compared to non-elderly patients (N = 85): presence of co-morbid diseases (90.0% vs. 62.4%: p < 0.001), low hemoglobin level (9.0 vs. 10.6 g/dl: p < 0.

Methods: A retrospective histological evaluation of 75 patients w

Methods: A retrospective histological evaluation of 75 patients with AIH was performed to define emperipolesis and related histological features. Confocal staining of cellular markers of immune cellls (CD4, CD8, CD19, CD56, CD163, and CD11b), hepatocytes (CK8/18) and Caspase 3 was performed to illustrate the cellular types of

emperipolesis. Caspase 3 was added into confocal staining to show the consequence of cell-in-cell structure. Results: Emperipolesis was observed in 57.3% (43/75) of the patients with autoimmune hepatitis in H&E staining, which was significantly higher than in the patients with primary biliary cirrhosis (18.9%), chronic hepatitis B (19.6%) and drug-induced liver injury (25.6%). Among AIH patients, the patients with emperipolesis had significantly higher serum ALT/AST levels than those without it. In histology, the existence of emperipolesis was associated Proteases inhibitor with more severe inflammatory and necrotic features and more advanced fibrosis stages. The immune cells inside hepatocytes were identified as CD8 T cells in the process of emperipolesis in patients with autoimmune hepatitis.

Emperipolesis of CD8 T cells induced Caspase 3 expression of infiltrated hepatocytes. Conclusion: Emperipolesis is a relatively specific histological feature of autoimmune hepatitis. Apoptosis of hepatocytes infiltrated by CD8 T cells may reflect another mechanism of immune-mediated liver injury in autoimmune hepatitis. Key Word(s): 1. Autoimmune hepatitis; 2. histology; 3. cell-in-cell; 4. entosis; Presenting Author: PEI WANG Additional Authors: XIAOLI PAN, JIN YE Corresponding Author: PEI WANG Affiliations: Objective: To determine the prevalence PD0325901 order Metalloexopeptidase and the clinical, serological, and histological characters of IgG4-associated

AIH. Methods: According to the liver biopsy, the clinical features and laboratory findings of 14 patients with AIH, 12 patients with AIH-PBC overlap syndrome, 9 patients with primary biliary cirrhosis (PBC) and 9 chronic hepatitis patients with hepatitis B virus (HBV) infection were retrospectively analyzed in our hospital among 2007 and 2012. Liver biopsy tissues from these patients were stained by hematoxylin-eosin to evaluate the histological features, and by immunohistochemistry to mark the IgG4 positive plasma cells. Results: Three of the 14 liver specimens from patients with AIH and one of the 12 liver specimens from patients with AIH-PBC overlap syndrome showed positive staining for IgG4, whereas none of the samples from patients with PBC and patients with HBV hepatitis was positive. The IgG4-associated AIH patients had significantly higher total serum IgG levels and AIH scores as compared with the IgG4 Conclusion: IgG4-associated AIH was found in over 21.4% of Chinese patients with type 1 AIH in our cohort. AIH may be classified into either an IgG4-associated type or an IgG4 non-associated type, which is useful for guiding the clinical practice. Key Word(s): 1. Autoimmune hepatitis; 2.

6C) The liver is a major organ for HGF synthesis, but the decrea

6C). The liver is a major organ for HGF synthesis, but the decrease in the mature form of HGF in the hepsin−/− mice was not caused by decreased synthesis of pro-HGF, because western blotting analysis of liver lysates revealed that there was no significant difference in the level of pro-HGF in WT and hepsin−/− mice (Fig. 6D). Hepsin−/− mouse livers may therefore be defective in converting pro-HGF produced in the liver into mature HGF that is released into the serum after processing; such a decreased level of mature HGF would be expected to cause diminished

HGF signal transduction in the livers of hepsin−/− mice. Correspondingly, see more we observed that the level of c-Met phosphorylation (HGF activation site, residues Y1234 and Y1235, in the tyrosine kinase domain) was significantly decreased in hepsin−/− livers, as compared to WT livers, whereas the total c-Met level appeared unchanged (Fig. 6E). Furthermore, when both WT

and hepsin−/− mice were treated with an antibody against hepsin, only WT mice exhibited a decrease in HGF and phosphorylated c-Met (Supporting Fig. 17). All of these results indicate that the c-Met-signaling pathway was down-regulated in the hepsin−/− mouse liver because of the defect in pro-HGF Selleckchem R428 activation in the liver. It has been shown that HGF down-regulates the level of connexin expression in vitro.23 In addition, we observed increased connexin expression and decreased HGF/c-Met signaling in hepsin−/− mouse livers. Therefore, we hypothesized that

the decreased HGF level in hepsin−/− mice caused an increase in both the expression of connexins and hepatocyte size in the liver. To test this, we first analyzed the level of connexin expression in WT and hepsin−/− mouse livers treated with HGF or an antagonist of the HGF receptor, NK4. HGF treatment decreased the expression of connexins in hepsin−/− mice (Fig. 7A), whereas NK4 increased the expression of connexins in WT mice (Fig. 7B). Consistently, hepsin−/− mice had significantly enlarged liver sinusoids after HGF treatment (Fig. 8A), and WT mice had significantly narrowed liver sinusoids after NK4 treatment Erastin (Fig. 8B). A dose-dependent increase in the level of phosphorylated c-Met was also detected after HGF treatment (Supporting Fig. 18). Overall, these results suggest that hepsin regulates the liver architecture through the HGF/c-Met/connexin-signaling axis. The identification of novel phenotypes in our hepsin−/− mice establishes a strong connection in vivo between hepsin and the maintenance of liver architecture. We propose that hepsin deficiency reduces HGF maturation and downstream c-Met phosphorylation that is required for expressing proper levels of connexins, which are, in turn, critical for the maintenance of normal hepatocyte size and, ultimately, normal sinusoidal diameter (Supporting Fig. 19).