bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological variations of stem cell factor and stromal‐derived factor‐1 in murine models of liver injury and regeneration
Authors: Swenson E. Scott , Kuwahara Reiichiro , Krause Diane S. , Theise Neil D.
Published: August 2010

Background/Aims: Stem cell factor (SCF) and stromal‐derived factor‐1 (SDF‐1) regulate the regenerative response to liver injury, possibly through activation of liver progenitor ‘oval’ cells and recruitment of circulating, marrow‐derived progenitors.

Methods: We performed a detailed analysis of SCF, SDF‐1 and oval cell proliferation induced by tyrosinaemia, 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) or liver irradiation in mice by ELISA and immunofluorescence.

Results: Liver injury in the tyrosinaemia mouse is characterized by a dramatic decline in plasma SCF and absence of oval cell proliferation. In contrast, DDC induces bile duct (BD) and oval cell proliferation, and a modest decline in plasma SCF. Focal liver irradiation increases plasma SCF, but not oval cell density. In normal mouse liver, SCF is localized primarily to Kupffer cells, cholangiocytes and arterial smooth muscle, with little or no expression in hepatocytes. However, SCF appears in hepatocyte nuclei after injury, where its function is unknown. In all three models, SDF‐1 is expressed exclusively in BD epithelium, indicating that tissue SDF‐1 levels are proportional to the total mass of oval cells and cholangiocytes. However, increased plasma levels of SDF‐1 in fumaryl acetoacetate hydroxylase‐null mice were not accompanied by oval cell proliferation.

Conclusion: Changes in SCF and SDF‐1 varied with the nature of liver injury and were not directly related to oval cell proliferation.
Asymptomatic individuals at genetic risk of haemochromatosis take appropriate steps to prevent disease related to iron overload
Authors: Allen Katrina J. , Nisselle Amy E. , Collins Veronica R. , Williamson Robert , Delatycki Martin B.
Published: August 2010

Background/Aims: If community screening for hereditary haemochromatosis is to be considered, compliance with preventative measures and absence of significant psychological morbidity must be demonstrated.

Methods: Workplace screening for the HFE C282Y mutation and then clinical care for C282Y homozygotes was instituted. Data were collected on understanding of test results, perceived health status and anxiety for C282Y homozygotes compared with controls. Uptake of clinical care, compliance and response to treatment and changes in diet were monitored for up to 4 years for C282Y homozygotes.

Results: After 11 307 individuals were screened, 40/47 (85%) newly identified C282Y homozygotes completed questionnaires 12 months after diagnosis compared with 79/126 (63%) of controls. Significantly more C282Y homozygotes correctly remembered their test result compared with controls (95 vs 51%, P<0.0001). No significant difference in perceived health status was observed within or between the two groups at 12 months compared with baseline. Anxiety levels decreased significantly for C282Y homozygotes at 12 months compared with before testing (P<0.05). Forty‐five of the 47 (95.8%) C282Y homozygotes accessed clinical care for at least 12 months. All 22 participants requiring therapeutic venesection complied with treatment for at least 12 months (range 12–47 months).

Conclusion: Individuals at a high genetic risk of developing haemochromatosis use clinical services appropriately, maintain their health and are not ‘worried well’. Population genetic screening for haemochromatosis can be conducted in the work place in a way that is acceptable and beneficial to participants.
Liver adenomatosis: re‐evaluation of aetiology and management
Authors: Veteläinen Reeta , Erdogan Deha , De Graaf Wilmar , Ten Kate Fiebo , Jansen Peter L. M. , Gouma Dirk J. , Van Gulik Thomas M.
Published: August 2010

Background: Liver adenomatosis (LA) is a rare benign parenchymal liver disease with unknown aetiology. In recent reports, LA has been associated with hepatic steatosis, with potential implications for the management of this disease. The aim of this study was to determine prognosis and optimal management of patients with LA.

Methods: Clinical presentation, diagnostic studies and management of patients with LA were analysed in our centre. Furthermore, a Medline search of all published case reports and series of LA patients was performed.

Results: Ninety‐four patients with LA have been reported in the literature. Fifty‐two per cent of females had a history of oral contraceptive use. Eighteen per cent of patients had steatosis in nontumoral tissue. In our own series, five of six patients had histologically confirmed steatosis. Forty‐three per cent of patients presented with acute pain, of whom 46% had a haemorrhagical complication, in contrast to 2% of nonsymptomatic patients. Tumours <5 cm tended to increase in size during follow‐up and only in four patients tumour regression was observed.

Conclusion: Liver adenomatosis is a progressive, benign parenchymal disease mainly occurring in females. There is a potential link with hepatic steatosis with implications for the management of patients with LA. Noninvasive diagnosis is difficult because of the variety of tumoral and nontumoral components. Management should primarily be conservative.
Accelerated orthotopic hepatocellular carcinomas growth is linked to increased expression of pro‐angiogenic and prometastatic factors in murine liver fibrosis
Authors: Kornek Miroslaw , Raskopf Esther , Tolba Rene , Becker Ursula , Klöckner Maren , Sauerbruch Tilman , Schmitz Volker
Published: August 2010

Background: Most experimental therapy studies are performed in mice that bear subcutaneous or orthotopic hepatoma but are otherwise healthy. We questioned whether a pre‐existing fibrosis affects tumour development of implanted syngenic hepatoma cells. To further investigate a selected panel of factors involved in tumour growth, tumour organ samples were characterized for gene expression of vascular endothelial growth factor (VEGF)‐A/‐C, VEGF receptors Flt1, Flk‐1, Flt‐4 and for VEGF‐A protein levels.

Results: The presented data show that tumour sizes were 3.7‐fold increased and fibrotic livers had numerous satellites. Increased tumour sizes were associated with elevated intratumoral VEGF‐A protein amounts and intratumoral increased VEGF receptor gene expression levels in tumour tissue from fibrotic livers as compared with non‐fibrotic livers. Additionally, intratumoral gene expression levels of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9 were elevated in fibrotic mice.

Conclusion: Our results indicate that liver fibrosis stimulates tumour development of implanted syngenic hepatoma cells. Accelerated tumour growth was going along with elevated intratumoral VEGF‐A and VEGF‐A receptor status, which most probably mediated pro‐angiogenic and prometastatic effects in this model. Furthermore, advanced tumour spread was associated with increased MMP‐2/‐9 expression. These data suggest that the intratumoral VEGF‐A proteins levels and VEGF receptor status contribute to accelerated hepatocellular carcinoma development in fibrotic mice and that elevated MMP‐2, MMP‐9 and VEGF‐C levels could promote tumour metastasis in this model.
Trafficking of recirculating lymphocytes in the rat liver: rapid transmigration into the portal area and then to the hepatic lymph
Authors: Xu Xue‐Dong , Ueta Hisashi , Zhou Shu , Shi Changde , Koga Daisuke , Ushiki Tatsuo , Matsuno Kenjiro
Published: August 2010

Background: We have investigated how recirculating lymphocytes patrol the liver in a normal steady state.

Methods: Thoracic duct lymphocytes of congeneic rats were intravenously transferred to host rats and donor cell trafficking in the liver and hepatic lymph was examined. Host hepatic lymph nodes (HLNs) were selectively removed, which allowed liver‐derived donor cells to collect in the thoracic duct without transit in the intervening HLNs.

Results: The number of donor cells in the thoracic duct lymph significantly increased over the baseline 3, 5 and 11 h after transfer in the HLN‐removed, non‐pretreated, and HLN‐ligated (in which a lymph efflux was blocked) groups, respectively. Histologically, donor cells appeared in the portal area from 0.5 h after transfer and frequently attached to the basal lamina of portal vein both externally and internally. Three hours after transfer, a few donor cells appeared in the subcapsular sinus of HLNs.

Conclusion: The minimal transit time of rat recirculating lymphocytes is 3–4 h in the liver and 5–8 h in the hepatic LNs, in a normal steady state. Recirculating lymphocytes might transmigrate through the portal vein as well as the sinusoid in the periportal zone. This rapid transit might enable an efficient surveillance of the liver portal area by the recirculating lymphocytes.
A decision analysis study of the value of a liver biopsy in nonalcoholic steatohepatitis
Authors: Gaidos Jill K. J. , Hillner Bruce E. , Sanyal Arun J.
Published: August 2010

Objectives: Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent clinical syndrome reflecting a mixture of pathological liver histology with the potential to progress to cryptogenic cirrhosis. Liver biopsy (LB) is the only way to determine the severity of disease. However, LB is invasive, has complications and financial costs. The aim of this study is to determine the benefits of early LB for diagnosis and early treatment.

Methods: A decision tree model tracked the potential outcomes of NAFLD between an LB‐directed approach vs. no initial LB. Each specific biopsy category determined subsequent care actions. The baseline probabilities were determined by literature review and expert opinion.

Results: An initial LB strategy was projected to have a lower mortality compared with the no initial LB group and fewer transplant eligible patients after 5 years. If the prevalence of NAFLD is increased, the mortality increases in both the study groups. With improved efficacy of medical and/or surgical intervention, the mortality rate was decreased.

Conclusion: This decision tree model provides a context for balancing the risk and benefit of LB in NAFLD. With early biopsy, and early intervention, the relative return of preventing advanced liver disease per LB was high.
Hepatic granulomas: histological and molecular pathological approach to differential diagnosis–a study of 442 cases
Authors: Drebber Uta , Kasper Hans‐Udo , Ratering Judith , Wedemeyer Inga , Schirmacher Peter , Dienes Hans‐Peter , Odenthal Margarete
Published: August 2010

Background/Aims: The incidence of hepatic granulomas is reported in 2–15% of liver biopsies. This study was carried out to evaluate the incidence and aetiology of hepatic granulomas in a German Institute of Pathology with specialization in liver diseases.

Methods: A retrospective case review was performed on 12 161 liver biopsies of the Institute of Pathology (University of Cologne) between 1996 and 2004. Aetiology was determined according to histomorphological changes, clinicopathological data and liver tissue polymerase chain reaction (PCR) for detection of diverse putative pathogens in the liver tissue.

Results: Four hundred and forty‐two liver biopsies revealed granulomatous lesions (3.63%). Two hundred and fifteen cases (1.77% of all biopsies and 48.64% of granulomatous lesions) were diagnosed as primary biliary cirrhosis. In 37 cases (0.3% of all biopsies and 8.37% of granulomatous lesions), the diagnosis of sarcoidosis was established. A positive PCR result for an infectious pathogen was obtained in 15 samples (3.39%) [Bartonella henselae (n=2), Listeria (n=3), Mycobacterium tuberculosis (n=3), Yersinia pseudotuberculosis (n=1), cytomegalovirus (n=2), Epstein–Barr virus (n=4)]. In six cases, a putative diagnosis was established according to the report of clinical conditions. In 11 cases (2.48%), drugs were the putative causative agent. In 158 cases (36%) a definite diagnosis could not be established.

Conclusions: Hepatic granulomas have a broad range of underlying aetiologies. With a combined histological, clinical, serological, and molecular approach, we were able to clarify the cause in 64% of the cases. Owing to the diverse prognosis and therapeutic implications, a detailed interdisciplinary workup of all liver biopsies with granulomatous lesions is mandatory.
Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha‐2a
Authors: Marcellin Patrick , Lau George K. K. , Zeuzem Stefan , Heathcote E. Jenny , Pockros Paul J. , Reddy K. Rajender , Piratvisuth Teerha , Farci Patrizia , Chow Wan‐Cheng , Jia Ji‐Dong , Paik Woon , Wintfeld Neil , Pluck Nigel
Published: August 2010

Background/Aims: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha‐2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). Method: The HBV studies included both hepatitis B e antigen (HBeAg)‐positive (n=271) and HBeAg‐negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 μg peginterferon alpha‐2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health‐related quality of life (HRQL) was assessed using the Short‐Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24‐week treatment‐free follow‐up period was also included. Results: Differences (HBV vs HCV) were observed in the incidence of AEs (88–89 vs 96–100%), serious AEs (4–5 vs 7–16%) and treatment withdrawals (6–8 vs 17–33%). The frequency of depression‐related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. Conclusions: The safety and tolerability of peginterferon alpha‐2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon‐related AEs and a significantly lower incidence of depression.
Role of nitric oxide synthesized by nitric oxide synthase 2 in liver regeneration
Authors: Kumamoto Takafumi , Togo Shinji , Ishibe Atsushi , Morioka Daisuke , Watanabe Kazuteru , Takahashi Takuji , Shimizu Tetsuya , Matsuo Ken‐ichi , Kubota Toru , Tanaka Kuniya , Nagashima Yoji , Kawai Jun , Hayashizaki Yoshihide , Shimada Hiroshi
Published: August 2010

Background/Aims: Nitric oxide synthase 2 (NOS2) is expressed during liver regeneration after a partial hepatectomy (PHx); NOS2 subsequently synthesizes nitric oxide (NO). However, the role of NOS2‐synthesized NO in post‐PHx liver regeneration remains unclear. We investigated the role of NOS2‐synthesized NO in liver regeneration.

Methods: NOS2 knockout (NOS2‐KO) mice and control mice were subjected to PHx. Liver mass recovery and serum alanine aminotransferase (ALT) levels were then evaluated. The expressions of Ki‐67 and single‐strand DNA were also evaluated in remnant liver specimens. Differences in the gene expression profiles of the two groups of remnant liver specimens were analysed using a microarray and were validated using a reverse transcription‐polymerase chain reaction (RT‐PCR).

Results: In NOS2‐KO mice, liver regeneration was delayed and apoptosis and serum ALT levels were higher than the levels in the control mice. A microarray study and RT‐PCR revealed that heat shock protein 70 family (HSP70 family), haeme oxygenase 1 (Hmox1), neuropilin 1 (Nrp1) and epidermal growth factor receptor (EGFR) were downregulated in NOS2‐KO mice.

Conclusions: NOS2‐synthesized NO may improve hepatocyte viability through the induction of the HSP70 family and Hmox1 and may sensitize the remnant liver to growth factors through the induction of Nrp1 and EGFR post‐PHx.
Sialoadenectomy enhances hepatic injury induced by lipopolysaccharide/galactosamine in mice
Authors: Sánchez Olga , Almagro Albert , Viladrich Meritxell , Ramírez Ignasi , Soley Maria
Published: August 2010

Background: Submandibular salivary glands (SMGs) synthesize, accumulate and secrete a large amount of epidermal growth factor (EGF) in mice. It is known that surgical removal of SMG (sialoadenectomy) alters cell turnover in the liver and exacerbates liver injury induced by lipopolysaccharide/galactosamine (LPS/GalN).

Results: Here we show that such increased hepatotoxicity is not the consequence of the lack of EGF production from SMG. On the contrary, it appears to be the consequence of an inadequate cytokine production by the liver of sialoadenectomized mice. Thus, we found that the increase of plasma tumour necrosis factor‐α and interleukin‐6 was slower in sialoadenectomized than in sham‐operated mice. This is because of a decreased rate of production of both cytokines by the liver. We found that the increase of plasma corticosterone (CS) concentration is lower in sialoadenectomized than that in sham‐operated mice. Adrenalectomy exacerbated liver injury induced by LPS/GalN. In these animals, sialoadenectomy did not further increase the effect of LPS/GalN.

Conclusions: Our results suggest that the effect of sialoadenectomy on LPS/GalN‐induced liver toxicity may be the consequence of an altered cytokine production by the liver and a reduced CS release from adrenal glands.
Potential and limitations of lamivudine monotherapy in chronic hepatitis B: evidence from genotyping
Authors: Kennedy Patrick TF. , Phillips Natalie , Chandrasekhar Jaya , Jacobs Ruth , Jacobs Michael , Dusheiko Geoffrey
Published: August 2010

Background: Current oral therapy for hepatitis B virus (HBV) is limited by the presence of resistance leading to resumption of higher levels of HBV replication. Therefore, there is a need for a better definition of the potential role and limitations of lamivudine or similar therapies, used alone.

Aims: To examine the viability of lamivudine and similar monotherapies as a treatment strategy in chronic HBV in the face of the worldwide burden of disease.

Methods: We have reviewed the role of lamivudine monotherapy in the treatment of chronic HBV in a single tertiary referral liver centre over a 9‐year period. We analysed the outcome in 90 patients where lamivudine has apparently conferred long‐term viral suppression and investigated the development of genotypic resistance in the absence of ostensible phenotypic resistance. Patients were subdivided into hepatitis B e antigen (HBeAg)‐positive and anti‐HBe‐positive groups.

Results: Virtually all HBeAg‐positive patients who failed to seroconvert have progressed to combination antiviral therapy. Only 19%(7/36) of HBeAg‐negative patients have continued suppression without detectable genotypic change after 4 years of therapy.

Conclusions: These data demonstrate that despite a relatively low level of viraemia in HBeAg‐negative patients, we could detect resistance mutations by direct sequencing in all patients with amplifiable HBV DNA. Our results suggest that for patients with ongoing replication at ‘amplifiable’ levels of HBV DNA, but <105 copies/ml, genotypic selection is readily detectable. Lamivudine monotherapy has not sufficed for the overwhelming majority of patients.
Intracrine signalling of activin A in hepatocytes upregulates connective tissue growth factor (CTGF/CCN2) expression
Authors: Gressner Olav A. , Lahme Birgit , Siluschek Monika , Rehbein Katharina , Weiskirchen Ralf , Gressner Axel M.
Published: August 2010

Background/Aims: Up to now, the effect of activin A on the expression of the important transforming growth factor (TGF)‐β downstream modulator connective tissue growth factor (CTGF) is not known, but might be of relevance for the functional effects of this cytokine on several liver cell types.

Methods: In this study, activin A‐dependent CTGF expression in hepatocytes (PC) primed by exogenous activin A and in PC maintained under complete activin‐free culture conditions was analysed by Western blots, metabolic labelling, gene silencing, reverse transcriptase‐polymerase chain reaction (RT‐PCR) and CTGF reporter gene assays. This study was supplemented by immunocytochemical staining of activin A and CTGF in PC of injured liver.

Results: Using alkaline phosphatase α‐alkaline phosphatase staining, it is demonstrated that activin A becomes increasingly detectable during the course of CCl4‐liver damage. Addition of activin A to cultured PC induced CTGF protein expression via phosphorylation of Smad2 and Smad3. This induction can be inhibited by the antagonist follistatin and α‐activin A antibody respectively. When PC were cultured under serum(i.e. activin A)‐free culture conditions, a time‐dependent increase of activin expression during the course of the culture was proven by RT‐PCR. Silencing of inhibin βA gene expression under serum‐free conditions by small interfering RNAs greatly suppressed CTGF synthesis and the phosphorylations of Smad2 and Smad3. However, both the extracellularly acting follistatin and the α‐activin A antibody could not inhibit spontaneous CTGF expression, which, however, was achieved by the cell‐permeable TGF‐β Alk4/Alk5 receptor‐kinase‐inhibitor SB431542.

Conclusions: In conclusion, the results point to activin A as an inducer of CTGF synthesis in PC. Intracellular activin A contributes to spontaneous CTGF expression in PC independent of exogenous activin A, which is proposed to occur via Alk4/Alk5‐receptors. The findings might be important for many actions of activin A on the liver.
Is serum alanine transaminase level a reliable marker of histological disease in chronic hepatitis C infection?
Authors: Sanai Faisal M. , Benmousa Ali , Al‐Hussaini Hussa , Ashraf Suhail , Alhafi Osama , Abdo Ayman A. , Alameri Hatem F. , Akbar Hisham O. , Bzeizi Khalid I.
Published: August 2010

Background: Approximately 20–30% of patients chronically infected with hepatitis C virus (HCV) have persistently normal alanine transaminase (PNALT) levels. These patients are described to have a mild degree of histological liver damage. We aimed to assess the histological liver changes in HCV patients with PNALT.

Patients and methods: Sixty‐five patients with HCV and PNALT (group A) underwent a liver biopsy. PNALT was defined as three or more determinations identified to be within the normal range over 6 months or longer. The demographical features and histological changes were compared with 66 consecutive patients with chronic HCV infection and elevated ALT (group B). All patients had a detectable HCV RNA. Histological disease was scored according to the METAVIR system.

Results: Females were more likely to have normal ALT levels (65%). The mean ALT level in Group A and B was 30 and 105 IU/L respectively. No patient in either group had normal histology. The mean necro‐inflammatory scores in groups A and B (2.0±0.68 vs 2.09±0.67) and the mean fibrosis scores (2.11±0.87 vs 2.24±1.04) were not significantly different. Bridging fibrosis in groups A and B was seen in 24.6 and 37.9% patients, respectively, while cirrhosis was seen in 6.2 and 7.6% patients respectively. Hepatic steatosis in groups A and B (0.94±0.86 vs 1.0±1.02 respectively) was also not significantly different and did not show any association with the fibrosis scores across the two groups. In group A, the necro‐inflammatory and fibrosis scores of patients with and without steatosis were not statistically significant. Age was the only predictor of normal ALT levels. However, increasing age did not show a significant increase in histological activity in either group beyond a certain age.

Conclusion: This study demonstrates that ALT is a poor surrogate marker for inflammation and fibrosis in HCV patients. Given the presence of significant necro‐inflammation in PNALT patients, the risk/benefit ratio justifies treatment without the need for a liver biopsy.
Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia
Authors: Harada Kenichi , Sato Yasunori , Isse Kumiko , Ikeda Hiroko , Nakanuma Yasuni
Published: August 2010

Background/Aims: Biliary epithelial cells (BECs) possess negative regulatory mechanisms of Toll‐like receptor (TLR)‐based tolerance to bacteria (e.g. endotoxin tolerance). Viral infections of the Reoviridae genus with a dsRNA genome are suspected to be part of the aetiology of biliary atresia (BA), but the negative biliary mechanisms remain unexplored.

Methods: Cultured human intrahepatic BECs (HIBECs) pretreated with polyinosinic–polycytidylic acid [poly(I:C)] (a synthetic analogue of viral dsRNA) for 24 h were exposed to poly(I:C) in fresh medium. The activation of nuclear factor‐κB (NF‐κB) and the expression of myxovirus resistance protein A (MxA) and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) mRNAs were evaluated. Moreover, after the pretreatment, the transition of these molecules was examined in poly(I:C)‐free conditions.

Results: Treatment with poly(I:C) significantly upregulated NF‐κB activity in fresh HIBECs, and pretreatment failed to show tolerance to poly(I:C). The production of MxA and TRAIL was also preserved. Moreover, upregulation in the pretreated HIBECs was well preserved in poly(I:C)‐free medium for at least 72 h.

Conclusions: BECs fail to show tolerance to poly(I:C), and once innate immunity is activated it is sustained in poly(I:C)‐free conditions, suggesting that the initiation of the immune response to dsRNA in HIBECs and its presence after the clearance of virus are closely associated with the progression of BA.
Effect of adrenomedullin on hepatic damage in hepatic ischaemia/reperfusion injury in rats
Authors: Kerem Mustafa , Bedirli Abdulkadir , Pasaoglu Hatice , Ofluoğlu Ebru , Yilmazer Demet , Salman Bulent , Yilmaz Tonguc Utku
Published: August 2010

Aims: Adrenomedullin (AM) is a multifunctional peptide with a putative beneficial role after an ischaemic insult. The aim of this study was to evaluate the effect of AM on partial hepatic ischaemia reperfusion (I/R) injury.

Methods: Rats were subjected to 1 h of 70% hepatic ischaemia, followed by reperfusion or sham. At the end of ischaemia, vehicle (phosphate‐buffered saline solution), N‐nitro‐l‐arginine methyl ester (l‐NAME) and AM with or without l‐NAME were infused via the portal vein. Analysis was performed at pre‐ischaemia, ischaemia onset and 1, 2 and 4 h after reperfusion. Hepatic tissue blood flow (HTBF) was evaluated by laser Doppler.

Results: Plasma AM levels in the I/R groups were significantly lower than the levels in the sham group. AM treatment significantly reduced levels of aspartate transaminase and tissue arginase (P<0.05). Significant decreases of tumour necrosis factor‐α, interleukin‐1β and endothelin‐1 levels were also found in the serum. Endothelin‐1, malondialdehyde and necrosis were observed more frequently in liver tissue in the AM group than the control (P<0.05). Tissue nitric oxide, energy charge and HTBF were significantly increased in AM treatment experiments (P<0.05).

Conclusion: The improved HTBF, energy charge and nitric oxide and the reduction of hepatic necrosis, oxidative stress, liver enzymes, endotelin‐1 and pro‐inflammatory cytokines demonstrate that treatment with AM attenuates liver I/R injury.
All‐trans‐retinoic acid ameliorates carbon tetrachloride‐induced liver fibrosis in mice through modulating cytokine production
Authors: Hisamori Shigeo , Tabata Chiharu , Kadokawa Yoshio , Okoshi Kae , Tabata Rie , Mori Akira , Nagayama Satoshi , Watanabe Go , Kubo Hajime , Sakai Yoshiharu
Published: August 2010

Background/Aims: Liver fibrosis with any aetiology, induced by the transdifferentiation and proliferation of hepatic stellate cells (HSCs) to produce collagen, is characterized by progressive worsening in liver function, leading to a high incidence of death. We have recently reported that all‐trans‐retinoic acid (ATRA) suppresses the transdifferentiation and proliferation of lung fibroblasts and prevents radiation‐ or bleomycin‐induced lung fibrosis.

Methods: We examined the impact of ATRA on carbon tetrachloride (CCl4)‐induced liver fibrosis. We performed histological examinations and quantitative measurements of transforming growth factor (TGF)‐β1 and interleukin (IL)‐6 in CCl4‐treated mouse liver tissues with or without the administration of ATRA, and investigated the effect of ATRA on the production of the cytokines in quiescent and activated HSCs.

Results: CCl4‐induced liver fibrosis was attenuated in histology by intraperitoneal administration of ATRA, and the overall survival rate at 12 weeks was 26.5% without ATRA (n=25), whereas it was 75.0% (n=24) in the treatment group (P=0.0187). In vitro studies disclosed that the administration of ATRA reduced (i) the production of TGF‐β1, IL‐6 and collagen from HSCs, (ii) TGF‐β‐dependent transdifferentiation of the cells and IL‐6‐dependent cell proliferation and (iii) the activities of nuclear factor‐κB p65 and p38mitogen‐activated protein kinase, which stimulate the production of TGF‐β1 and IL‐6, which could be the mechanism underlying the preventive effect of ATRA on liver fibrosis.

Conclusions: Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.
Protection by bicyclol derivatives against acetaminophen‐induced acute liver failure in mice and its active mechanism
Authors: Hou Yan , Li Libo , Wei Huailing , Wu Liping , Tong Yuanfeng , Wu Song , Liu Gengtao
Published: August 2010

Background/Aims: To find a novel drug against acute liver failure, a methionine derivative of bicyclol (WLP‐S‐10) was studied in acetaminophen‐injected mice.

Methods: At first, 10 derivatives of bicyclol were tested in male KunMing strain mice injected with CCl4, acetaminophen or d‐galactosamine plus lipopolysaccharide (LPS), serum alanine aminotransferase (ALT) and mortality rate were determined. Among the 10 derivatives, a methionine derivative of bicyclol (WLP‐S‐10) was shown to be the most effective. A single dose of WLP‐S‐10 200 mg/kg was intraperitoneally injected 1 h before administration of a lethal dose of acetaminophen; the mortality rate, liver lesions, serum ALT, aspartate aminotransferase (AST) and liver glutathione (GSH) were determined. Mitochondrial GSH and adenosine triphosphate (ATP) levels, cytochrome C and apoptosis‐inducing factor (AIF) leakage, mitochondrial swelling and membrane potential were determined.

Results: As a result, WLP‐S‐10 200 mg/kg significantly reduced liver injury induced by CCl4 and decreased the mortality rate of mice because of acute liver failure caused by lethal dosage of acetaminophen or d‐galactosamine plus LPS. WLP‐S‐10 200 mg/kg markedly reduced liver necrosis, serum ALT and AST elevation and GSH depletion after injection of acetaminophen. WLP‐S‐10 inhibited mitochondrial swelling, breakdown of membrane potential and depletion of mitochondrial ATP, and also reduced release of cytochrome C and AIF from mitochondria induced by acetaminophen.

Conclusions: The results indicate that WLP‐S‐10 is a novel potential compound against acetaminophen‐induced acute liver failure in mice, and its active mechanism is mainly related to protection against necrosis and apoptosis of hepatocytes through inhibition of mitochondrial energy (ATP) depletion and AIF and cytochrome C release.
Changing aetiology of liver dysfunction in the new generation of a hepatitis B and C‐endemic area: cross‐sectional studies on adolescents born in the first 10 years after universal hepatitis B vaccination
Authors: Kao Jung‐Ta , Wang Jing‐Houng , Hung Chao‐Hung , Hu Tsung‐Hui , Lee Chuan‐Mo , Hung Shu‐Fen , Lu Sheng‐Nan
Published: August 2010

Background/Aim: Geographical variation in viral hepatitis infection complicates various levels of liver diseases. This study elucidates the changing aetiology of alanine transaminase elevation (ALT levels >40 IU/L) in a previously hepatitis‐endemic township.

Design/Methods: Five cross‐sectional screenings were performed on teenagers born from 1984 to 1993. We examined hepatitis B surface antigen (HBsAg), anti‐hepatitis C virus (anti‐HCV), ALT and body mass index, and additionally checked hepatitis B envelope antigen (HBeAg) for positive HBsAg and HCV RNA for positive anti‐HCV. Teenagers with ALT elevation underwent an ultrasonography examination.

Results: This study enrolled 1788 (93.7%) of 1909 students, discovering individual prevalence of HBsAg (6.3%), anti‐hepatitis B core (anti‐HBc) (15.5%), anti‐HCV (2.2%), overweight (22.4%), obesity (12.8%) and ALT >40 IU/L (3.7%). HBsAg and anti‐HBc prevalence declined with trends, while obesity increased with trends (P<0.001). Among 66 ALT‐elevated teenagers, prevalence percentages of risk factors were HBsAg (22.7%), anti‐HCV (1.5%), obesity (45.5%), HBsAg with obesity (7.6%) and anti‐HCV with obesity (3.0%). Additionally, obesity showed predominance (85.7%) among aetiologies of teenagers with fatty livers (60.9%). The independently associated factors of ALT elevation included being male (odds ratio, 2.18; 95% confidence interval, 1.21–3.93), HBsAg (4.25; 1.06–17.13), HBeAg (7.24; 1.64–31.9), HCV RNA (29.03; 5.8–145.29) and obesity (16.5; 8.79–30.98).

Conclusion: In place of viral hepatitis, obesity is becoming the major aetiology of abnormal liver function among the young generation in a previously hepatitis‐endemic area.
Expression of multidrug resistance‐associated protein 1 in hepatocellular carcinoma is associated with a more aggressive tumour phenotype and may reflect a progenitor cell origin
Authors: Vander Borght Sara , Komuta Mina , Libbrecht Louis , Katoonizadeh Aezam , Aerts Raymond , Dymarkowski Steven , Verslype Chris , Nevens Frederik , Roskams Tania
Published: August 2010

Background: Hepatocellular carcinoma (HCC) responds poorly to chemotherapy owing to multidrug resistance (MDR). Recent studies showed that part of HCC could be of progenitor cell origin. Because some MDR‐conferring transporters [multidrug resistance‐associated protein 1 (MRP1), MDR1, MRP3 and breast cancer resistance protein (BCRP)] are expressed in hepatic progenitor cells (HPCs), expression in HCC might reflect a progenitor cell origin and provide the tumour cells with a MDR phenotype.

Methods: The transcriptional profile of transporter genes was assessed in 139 HCCs earlier subjected to global gene expression analysis. In addition, we performed real‐time reverse transcriptase‐polymerase chain reaction and immunohistochemistry for MRP1, MRP3, MDR1, BCRP and biliary/HPC markers keratin 7 and/or keratin 19 (K7/K19) on an independent set of 23 HCCs and surrounding liver.

Results: Micro‐array analysis showed that MRP1 was the only transporter with increased mRNA levels in HCC compared with the surrounding tissue. MRP1 mRNA levels were significantly higher in HCCs with poor survival and the ‘hepatoblast subtype’ of HCC, thought to be derived from HPCs. In 11 of 23 HCCs of the independent set, we found a diffuse protein expression of MRP1 compared with negative hepatocytic expression observed in normal (surrounding) hepatocytes. MRP1 was expressed in K19+ non‐neoplastic HPCs and K19+ tumour cells. In addition, MRP3 and BCRP were expressed in K7/K19+ tumour cells. MRP1 expression was high in poorly differentiated HCCs, large tumours (>7 cm) and microvascular invasive tumours.

Conclusions: MRP1 correlated with K19 mRNA and protein expression in two independent series of HCC. In addition, MRP1 was, together with MRP3 and BCRP, colocalized with K7/K19 in the tumour. Therefore, MRP1 expression could be a reflection of the HPC origin of this subgroup of HCCs and may result in an aggressive tumour phenotype.
The turning black tide: energy prices and the Canadian dollar
Authors: Issa Ramzi , Lafrance Robert , Murray John
Published: August 2010

Abstract.  This paper revisits the relationship between energy prices and the Canadian dollar, using an equation first developed by Amano and van Norden (1995). They found evidence of a negative relationship between these two variables, such that higher real energy prices led to a depreciation of the Canadian dollar. Based on structural break tests, we find a break point in the sign of this relationship, which changes from negative to positive in the early 1990s. The timing of the break is consistent with major changes in Canada's energy policies and in energy‐related cross‐border trade and investment.
Heterogeneity of southern countries and southern intellectual property rights policy
Authors: Kim Jeong‐Eon , Lapan Harvey E.
Published: August 2010

Abstract.  We develop a model with one innovating northern firm and heterogeneous southern firms that compete in a final product market. We assume southern firms differ in their ability to adapt technology and study southern incentives to protect intellectual property rights. We find that, in a non‐cooperative equilibrium, governments resist IPR protection, but collectively southern countries benefit from some protection. We show that, in general, countries with more efficient firms prefer higher collective IPR protection than those with less efficient firms. Given the aggregate level of IPR protection, it is more efficient if the more efficient countries have weaker IPR protection.
Foreign direct investment and spillovers: gradualism may be better
Authors: Desmet Klaus , Meza Felipe , Rojas Juan A.
Published: August 2010

Abstract.  The standard argument says that in the presence of positive spillovers foreign direct investment should be promoted and subsidized. In contrast, this paper claims that the very existence of spillovers may require temporarily restricting FDI. Our argument is based on two features of spillovers: they are limited by the economy's absorptive capacity and they take time to materialize. By letting in capital more gradually, initial investment has the time to create spillovers – and upgrade the economy's absorptive capacity – before further investment occurs. The economy converges to a steady state with a superior technology and a greater capital stock.
Selling licences for a process innovation: the impact of the product market on the selling mechanism
Authors: Bagchi Aniruddha
Published: August 2010

Abstract.  This article considers the sale by a research lab of licences for a cost‐reducing innovation. The marginal cost of a firm that wins a licence is private information and the acquisition of a licence imposes a negative externality on the other firms. The lab's optimal revenue is determined from a class of mechanisms in which the lab selects the number of licences and the reserve price before the sale. The role of the downstream product market in the determination of the number of licences is analyzed. Furthermore, it is also shown that the optimal reserve price may be zero.
Innis Lecture: Canadian policies for broad‐based prosperity
Authors: Trefler Daniel
Published: August 2010

Abstract.  Canadian policy makers operate in the fog of myth, a myth that has been repeated so often it is mistaken for truth. According to this myth there is only one path to prosperity, and if we are to successfully travel this path, first charted by Americans, then we must abandon our most disadvantaged. We must sacrifice our core Canadian values of community and caring on the altar of competitiveness. Yet the facts of the last three decades scream out against this myth. Over that time Canada's per capita GDP fell by almost 20% relative to the United States. And this sacrifice of prosperity did not make us a more caring society. Instead, it depleted our fiscal resources by a staggering $68 billion per year and left us without the wherewithal to take care of our most disadvantaged. In this paper I debunk the myth that there is a trade‐off between a prosperous society and a caring society. In place of the myth I offer up a cohesive picture of what ails Canada and how we can cure it.
Decomposition of s‐concentration curves
Authors: Makdissi Paul , Mussard Stéphane
Published: August 2010

Abstract.  For any given order of inverse stochastic dominance, standard concentration curves are decomposed into three components, called contribution curves. Those components correspond to within‐group inequalities, between‐group inequalities, and transvariational inequalities. We prove, for all orders, that contribution curve dominance implies systematically welfare‐improving tax reforms and conversely. Accordingly, as welfare expansions may be costly in terms of particular inequalities, we propose targeted fiscal reforms.
Campaign spending limits, incumbent spending, and election outcomes
Authors: Milligan Kevin , Rekkas Marie
Published: August 2010

Abstract.  We study the impact of campaign spending limits for candidates in Canadian federal elections. We first demonstrate that spending limits are binding mostly for incumbent candidates. We then use this information to produce endogeneity‐corrected estimates for the impact of incumbent spending on electoral vote shares. Furthermore, we examine the impact of spending limits on broader measures of electoral outcomes, finding that larger limits lead to less close elections, fewer candidates, and lower voter turnout.
Fiscal policy, rent seeking, and growth under electoral uncertainty: theory and evidence from the OECD
Authors: Angelopoulos Konstantinos , Economides George
Published: August 2010

Abstract.  We construct a general equilibrium model of economic growth and optimally chosen fiscal policy, in which individuals compete with each other for a share of government spending and two political parties alternate in power according to exogenous electoral uncertainty. The main prediction is that uncertainty about remaining in power results in increased fiscal spending, which in turn distorts incentives by pushing individuals away from productive work to rent‐seeking activities; then, distorted incentives hurt growth. This scenario receives empirical support in a dataset of 25 OECD countries over the period 1982–96. In particular, uncertainty about remaining in power leads to larger government shares in GDP, which in turn exert an adverse effect on the ICRG index measuring incentives and this is bad for growth.
Climate policy and the optimal extraction of high‐ and low‐carbon fossil fuels
Authors: Smulders Sjak , Van Der Werf Edwin
Published: August 2010

Abstract.  We study how restricting CO2 emissions affects resource prices and depletion over time. We use a Hotelling‐style model with two non‐renewable fossil fuels that differ in their carbon content (e.g., coal and natural gas) and in addition are imperfect substitutes in final good production. We show that an economy facing a CO2 flow‐constraint may substitute towards the relatively dirty input. As the economy tries to maximize output per unit of emissions it is not only carbon content that matters: productivity matters as well. With an announced constraint the economy first substitutes towards the less productive input such that more of the productive input is available when constrained. Preliminary empirical results suggest that it is cost‐effective to substitute away from dirty coal to cleaner oil or gas, but to substitute from natural gas towards the dirtier input oil.
What labelling policy for consumer choice? The case of genetically modified food in Canada and Europe
Authors: Gruère Guillaume P. , Carter Colin A. , Farzin Y. Hossein
Published: August 2010

Abstract.  Faced with divergent opinions among consumers on the use of genetically modified (GM) foods, Canada has adopted a voluntary labelling approach for non‐GM foods, whereas the European Union has a mandatory labelling policy for GM foods. Interestingly, both labelling systems have resulted in very little, if any, additional consumer choice. Using an analytical model, we show that the coexistence of GM and non‐GM products at the retail level depends on the labelling policy, consumer perceptions, and the type of product. Although voluntary labelling tends to favour the use of GM products, it is more likely to provide consumer choice.
Viewpoint: Agglomeration research in the age of disaggregation
Authors: Strange William C.
Published: August 2010

Abstract This paper selectively reviews recent research on the economics of agglomeration. Theory offers a long list of forces that might explain the spatial concentration of economic activity. The increased availability of disaggregated data – by firm, by worker, and by geographical unit – presents opportunities to substantially advance the understanding of urban growth and industrial clustering. At present, however, there remains great uncertainty about the forces that produce agglomeration. This suggests that public policy towards cities ought to be characterized by caution.
The spatial sorting and matching of skills and firms
Authors: Mion Giordano , Naticchioni Paolo
Published: August 2010

Abstract In this paper we make use of a matched employer‐employee database for Italy to look at the spatial distribution of wages. Using this rich database we aim to open up the black box of agglomeration economies exploiting the micro dimension of interaction among economic agents, both individuals and firms. We provide evidence that firm size and, especially, skills are sorted across space and account for a large portion of the spatial wage variation. Our data also support the assortative matching hypothesis, which we show not to be driven by co‐location of good workers and firms. Finally, we point out that assortative matching is negatively related to local market size.
Are firms that receive R&D subsidies more innovative?
Authors: Bérubé Charles , Mohnen Pierre
Published: August 2010

Abstract This paper looks at the effectiveness of R&D grants for Canadian plants that already benefit from R&D tax credits. Using a non‐parametric matching estimator and data from the 2005 Survey of Innovation from Statistics Canada, we find that firms that benefited from both policy measures introduced more new products than their counterparts that only benefited from R&D tax incentives. They also made more world‐first product innovations and were more successful in commercializing their innovations. The paper gives also a detailed step‐by‐step explanation of how to apply the non‐parametric matching technique.
On the emergence of an MFN club: equal treatment in an unequal world
Authors: Saggi Kamal , Sengul Faruk
Published: August 2010

Abstract Motivated by GATT, we endogenize the formation of a club whose members have to abide by the MFN principle of non‐discrimination. The underlying model is that of oligopolistic intraindustry trade. While an MFN club does not alter average tariff levels across countries, it increases aggregate world welfare; makes non‐members worse off; and can immiserize its high cost members. These results imply that (i) core WTO rules such as MFN are valuable even if multilateral negotiations deliver limited trade liberalization and (ii) the distributional effects of MFN maybe one reason why developing countries have been granted Special and Differential treatment at the WTO.
Equity market and foreign capital
Authors: Furukawa Yoko
Published: August 2010

Abstract I present a model that demonstrates that the market mechanism is not always effective in stabilizing an open equity market. Foreign capital inflows create multiple equilibria in the equity market, which may simultaneously trigger a currency crisis as well as an equity market crash even if the equity market is well developed.
Does antidumping use contribute to trade liberalization in developing countries?
Authors: Moore Michael O. , Zanardi Maurizio
Published: August 2010

Abstract Some supporters of antidumping have argued that this procedure serves as a kind of ‘safety valve’ for protectionist pressure. In this paper, we investigate whether there is empirical evidence that the use of antidumping actions has contributed to ongoing tariff reductions over the period 1988 to 2004 in a sample of 23 developing countries, some of which have become aggressive users of antidumping in recent years. The evidence is not supportive of the safety valve argument for these countries. Instead, evidence suggests that past use of antidumping may have led to less rather than more trade liberalization.