bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition by recombinant human interleukin-6 of the glucagon-dependent induction of phosphoenolpyruvate carboxykinase and of the insulin-dependent induction of glucokinase gene expression in cultured rat hepatocytes: Regulation of gene transcription and messenger RNA degradation
Authors: Christ Bruno , Nath Annegret , Heinrich Peter C. , Jungermann Kurt
Published: March 2007

The influence of recombinant human interleukin-6, the major mediator of the inflammatory response in liver, on the glucagon- and insulin-dependent induction of the phosphoenolpyruvate carboxykinase and glucokinase gene, respectively, was monitored on the level of gene transcription, mRNA abundance and enzyme activity in cultured rat hepatocytes. As control markers of the interleukin-6-induced acute-phase response the mRNA levels of the acute phase proteins α2-macroglobulin and β-fibrinogen were determined. In cultured rat hepatocytes, recombinant human interleukin-6, added simultaneously with glucagon and insulin, lowered the maximal increase in glucagon-induced phosphoenolpyruvate carboxykinase mRNA levels after 2 hr and the maximal increase in glucokinase mRAN levels after 3 hr to about 30%, respectively. It inhibited the glucagon-induced increase in phosphoenolpyruvate carboxykinase gene transcription and phosphoenolpyruvate carboxykinase enzyme activity, as well as the insulin-induced increases in glucokinase gene transcription and glucokinase enzyme activity. Recombinant human interleukin-6 increased the mRNA levels of the acute-phase proteins α2-macroglobulin and β-fibrinogen gradually over 4 to 6 hr. Recombinant human interleukin-6, added 2 hr after glucagon or 3 hr after insulin at the maximum of the hormone-induced enzyme mRNA levels, almost doubled the decay rate of phosphoenolpyruvate carboxykinase mKNA and glucokinase mRNA. The results show that interleukin-6 induced the expression of inflammatory proteins and simultaneously inhibited the hormone-induced expression of enzymes of intermediary metabolism. This inhibition occurred by way of both a decrease in the synthesis of specific mRNA and an acceleration of the degradation of mRNA, whereas the induction of the inflammatory proteins is known to occur at the transcriptional level. (Hepatology 1994;20:1577-1583).
Neonatal capsaicin treatment does not prevent splanchnic vasodilatation in portal-hypertensive rats
Authors: Fernández Mercedes , Casadevall Maria , Schuligoi Rufina , Pizcueta Pilar , Panés Julián , Barrachina Dolores M. , Donnerer Josef , Piqué Josep M. , Esplugues Juan V. , Bosch Jaume , Rodés Juan , Holzer Peter
Published: March 2007

It has been suggested that the peripheral sensory neurons are involved in the splanchnic hemodynamic changes of portal hypertension. Therefore the influence of permanent ablation of sensory neurons by neonatal capsaicin pretreatment (50 mg/kg, subcutaneously) on the development of the hyperdynamic splanchnic circulation in portal-hypertensive rats was studied. In adulthood, portal hypertension was induced with partial portal vein ligation. In study 1, systemic and splanchnic hemodynamics were measured by means of a radiolabeled-microsphere technique in portal-hypertensive rats, under ketamine anesthesia, pretreated with capsaicin or vehicle. Mean arterial pressure, heart rate, cardiac index, systemic and splanchnic vascular resistance, portal pressure, portal venous inflow, portal-collateral resistance and portalsystemic shunting were not significantly different between capsaicin-pretreated and vehicle-pretreated rats. In study 2, gastric mucosal blood flow, measured by means of hydrogen gas clearance, and the hemoglobin and oxygen content of the gastric mucosa, as assessed with reflectance spectrophotometry, were not significantly different in the two groups of anesthetized portal-hypertensive rats pretreated with capsaicin or vehicle. In study 3, we confirmed the effectiveness of neonatal capsaicin pretreatment by measuring calcitonin gene—related peptide content of the gastric corpus wall. Capsaicin pretreatment caused a depletion of calcitonin gene—related peptide by at least 98% compared with that in vehicle-pretreated rats. These results do not support a role of capsaicin-sensitive sensory neurons that innervate the gastrointestinal tract in the development of the splanchnic vasodilatation characteristically observed in chronic portal hypertension. (Hepatology 1994;20:1609-1614).
A marriage of mice produces answers to old questions about man
Authors: Cooper Allan
Published: March 2007

The atherogenic macromolecule lipoprotein(a) [Lp(a)] has resisted in vivo analyses partly because it is found in a limited number of experimental animals. Although transgenic mice expressing human apolipoprotein (a) [apo(a)] have previously been described, they failed to assemble Lp(a) particles because of the inability of human apo(a) to associate with mouse apolipoprotein B (apoB). We isolated a 90-kilobase P1 phagemid containing the human apoB gene and with this DNA generated 13 lines of transgenic mice of which 11 expressed human apoB. The human apoB transcript was expressed and edited in the liver of the transgenic mice. Plasma concentrations of human apoB, as well as low density lipoprotein (LDL), were related to transgene copy number; the transgenic line with the most copies of human apoB had a >4-fold increase in LDL cholesterol compared with nontransgenics and a lipoprotein profile similar to that of humans. When human apoB and apo(a) transgenic mice were bred together, plasma apo(a) in mice expressing both human proteins was tightly associated with lipoproteins in the LDL density region. These studies demonstrate the successful expression of human apoB and the efficient assembly of Lp(a) in mice.
A phylogenetic analysis identifies heterogeneity among hepatocellular carcinomas
Authors: McGlynn Katherine A. , Edmonson Michael N. , Michielli Rita A. , London Thomas W. , Lin Wen Yao , Chen Gong-Chao , Shen Fu-Min , Buetow Kenneth H.
Published: March 2007

Primary hepatocellular carcinoma (HCC) is a significant cause of cancer morbidity and mortality on the global scale. Although epidemiologic studies have identified major risk factors for HCC, the sequence of oncogenic events at the molecular level remains poorly understood. While genetic allele loss appears to be a common event, the significance of the loss is not clear. In order to determine whether allele loss appears to be a random event among HCCs or whether patterns of loss cluster in groups of tumors, a phylogenetic approach was used to examine 32 tumors for genome-wide loss of heterozygosity employing 391 markers. Clusters identified by the phylogenetic analysis were then contrasted to compare candidate locus variation among individuals and to determine whether certain clusters exhibited higher loss rates than other clusters. The analysis found that 3 major and 1 minor cluster of loss could be identified and, further, these clusters were distinguished by variable rates of loss (cluster 1,29%; cluster 3, 16%). The analyses also indicated that the allele loss rates in HCC were not insignificant and that the patterns of allele loss were complex. In addition, the results indicated that an individual’s constitutional genotype at the EPHX1 locus may be a critical factor in determining the path of tumor evolution. In conclusion, it appears that in HCC, allele loss is not random, but clusters into definable groups that are characterized by distinctive rates of loss. (Hepatology2002;36:1341-1348).
“A la carte” treatment of portal hypertension: Adapting medical therapy to hemodynamic response for the prevention of bleeding
Authors: Bureau Christophe , Péron Jean-Marie , Alric Laurent , Morales Joséphine , Sanchez Jérôme , Barange Karl , Payen Jean-Louis , Vinel Jean-Pierre
Published: March 2007

We report the results of adapting medical therapy to the monitoring of hemodynamic response in the prevention of a first variceal bleeding or rebleeding in patients with cirrhosis. Hepatic venous pressure gradient (HVPG) was measured before and after propranolol was initiated. The patients were considered responders if HVPG decreased below 12 mm Hg or at least 20% as compared with baseline value. If patients were not responders, isosorbide-5 mononitrate (I-5MN) was added, and a third hemodynamic study was performed. Thereafter, the patients were followed for a mean of 28 months. Thirty-four consecutive patients were treated to prevent a first bleeding episode in 20 patients and a rebleeding in 14 patients. HVPG value was initially 19.8 ± 4.6 mm Hg and decreased to 17.6 ± 5.7 mm Hg (P < (.05) after propranolol alone. Thirteen patients (38%) were responders to propranolol. I-5MN improved hemodynamic response in 7 cases. Among these 20 (59%) hemodynamic responders, only 2 (10%) experienced variceal bleeding, as compared with 9 of 14 (64%) nonresponders (P < 0.05). Using multivariate analysis, only hemodynamic response was found to have an independent predictive value for the risk of variceal bleeding. In conclusion, hemodynamic response to drug therapy identifies patients who are efficiently protected from variceal bleeding as well as nonresponders in whom an alternative treatment should be considered. (Hepatology2002;36:1361-1366).
Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome
Authors: Colombo Carla , Battezzati Pier Maria , Crosignani Andrea , Morabito Alberto , Costantini Diana , Padoan Rita , Giunta Annamaria
Published: March 2007

Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. We have assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, we enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis. Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes. In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation. (Hepatology2002;36:1374-1382).
Evolution of autoimmune hepatitis to primary sclerosing cholangitis: A sequential syndrome
Authors: Abdo Ayman A. , Bain Vincent G. , Kichian Krikor , Lee Samuel S.
Published: March 2007

Recently, the autoimmune hepatitis (AIH)/primary sclerosing cholangitis (PSC) overlap syndrome has been reported increasingly. In this syndrome, patients present with features of both AIH and PSC. It has been suggested that the 2 diseases may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC, but clear confirmation of evolution has not been documented in adults. We describe 6 adult cases in which PSC was diagnosed many years after well-established AIH. Six patients are described in whom AIH definitely was diagnosed at presentation. No evidence of biliary disease was noted on the initial liver biopsy or endoscopic retrograde cholangiography (ERCP). All patients responded well to immunosuppressive therapy. After an average duration of follow-up of 4.6 years they became resistant to immunosuppression, and developed clear features of PSC, which was confirmed by ERCP in all patients. The average age of the patients at first presentation was 31.3 years, 2 were women and 4 were men, and 3 had ulcerative colitis. We found no specific features at presentation that could predict this evolutionary outcome. In conclusion, patients with well-established AIH can, after variable duration of follow-up, develop PSC. In patients with AIH who become resistant to immunosuppression of develop significant cholestasis, PSC should be ruled out by ERCP. (Hepatology2002;36:1393-1399).
Oral lichen planus pathogenesis: A role for the HCV-specific cellular immune response
Authors: Pilli Massimo , Penna Amalia , Zerbini Alessandro , Vescovi Paolo , Manfredi Maddalena , Negro Francesco , Carrozzo Marco , Mori Cristina , Giuberti Tiziana , Ferrari Carlo , Missale Gabriele
Published: March 2007

Hepatitis C virus infection can be associated with different extrahepatic manifestations, including lichen planus; however, no clear role for HCV in their pathogenesis has been established. T cells were isolated from lichen biopsy specimens of 7 HCV positive patients with oral lichen planus. HCV-specific CD4+ T-cell lines were obtained in 4 patients from lichen lesions but only in 2 of them from the peripheral blood. Different clonal populations were found in oral tissue and peripheral blood of individual patients, as shown by TCR-Vβ analysis of antigen-specific T cells. Frequency of HCV-specific CD8+ cells tested with 4 different HCV tetramers was significantly higher in the lichen tissue than in the circulation; moreover, lichen-derived HCV-specific CD8+ T cells showed the phenotype of recently activated T cells because most of them were CD69+ and produced interferon gamma (IFN-γ) but expanded poorly in vitro upon antigen stimulation. The specificity of HCV-reactive T-cell recruitment into the lichen tissue was further confirmed by the absence of HBV-specific T cells within lichen lesions in 3 additional patients with lichen planus associated with HBV infection. Our study shows HCV-specific T-cell responses at the site of the lesions of an HCV-associated dermatologic disease, sustained by HCV-specific T cells with phenotypic and functional characteristics of terminally differentiated effector cells. In conclusion, this finding and the detection of HCV RNA strands in the lichen tissue strongly suggest a role for HCV-specific T-cell responses in the pathogenesis of oral lichen planus associated with HCV infection. (Hepatology2002;36:1446-1452).
Endogenous interferon γ protects against cholestatic liver injury in mice
Authors: Sewnath Miguel E. , Van Der Poll Tom , Van Noorden Cornelis J. F. , Ten Kate Fiebo J. W. , Gouma Dirk J.
Published: March 2007

Cholestatic patients suffer from high perioperative morbidity and mortality, but the pathophysiology is still unknown. Interferon γ (IFN-γ) may play a role during cholestasis. Therefore, bile duct ligation (BDL) was induced in IFN-γ α-chain receptor—deficient (IFN-γR1—/—) and wild-type (IFN-γR1+/+) mice. BDL elicited increased IFN-γ messenger RNA and protein levels in the liver. One week after BDL, IFN-γR1+/+ mice showed less severe jaundice and liver injury than IFN-γR1—/— mice, as reflected by lower bilirubin and liver enzyme levels. In accordance, livers of IFN-γR1+/+ mice displayed smaller areas of necrosis by two-thirds than IFN-γR1—/— mice on histopathologic examination (P< 0.05), whereas mitotic activity and proliferating cell nuclear antigen (PCNA) labeling index was more than twice as high in IFN-γR1+/+ mice (P< 0.05). Livers of IFN-γR1+/+ mice displayed higher rates of apoptosis as indicated by DNA fragmentation rate, the number of apoptotic bodies, and poly ADP-ribose polymerase (PARP) immunostaining. BDL was not associated with lethality in IFN-γR1+/+ mice; IFN-γR1—/— mice, however, died from 10 days onward and survival after 2 weeks was 62% (10 of 16). In conclusion, these data suggest that IFN-γ protects against liver injury during extrahepatic cholestasis by stimulation of apoptosis and subsequent proliferation of hepatocytes, leading to elegant removal of damaged hepatocytes, thus preventing necrosis and concomitant inflammatory responses. (Hepatology2002;36:1466-1477).
The effect of ethanol on asialoglycoprotein receptor—mediated phagocytosis of apoptotic cells by rat hepatocytes
Authors: McVicker Benita L. , Tuma Dean J. , Kubik Jacy A. , Hindemith Agnes M. , Baldwin Cheryl R. , Casey Carol A.
Published: March 2007

Apoptotic cell death is a well-defined process that is controlled by intrinsic cellular mechanisms followed by the generation of apoptotic bodies and their subsequent rapid elimination through the action of phagocytic cells. Within the liver, the asialoglycoprotein receptor (ASGP-R) has been shown to be involved in the phagocytosis of apoptotic hepatocytes, as well as altered cellular endocytic events after ethanol administration. The goal of the present study was to further clarify the capacity of ASGP-R to phagocytose apoptotic cells in relationship to the damaging events that occur with alcohol consumption. For these experiments, we used an in vitro suspension assay coupled with flow cytometry to measure apoptotic cell engulfment by rat hepatocytes after chronic ethanol administration. The results of this assay indicated that the phagocytosis of apoptotic cells was decreased significantly (30% to 42%, P < 0.05) in the presence of antibody specific for ASGP-R as well as the introduction of competing sugars in the media. In addition, uptake of apoptotic cells was impaired by 40% to 60% (P < 0.05) in cells obtained from ethanol-fed animals as compared with controls. In conclusion, the ASGP-R is involved in the recognition and uptake of apoptotic cells and this process is altered significantly by ethanol treatment. These findings may play a role in a better understanding of the clinical manifestations of alcohol-induced liver injury as altered uptake of apoptotic cells via ASGP-R may result in the release of proinflammatory mediators, the introduction of autoimmune responses, and inflammatory injury to the tissue. (Hepatology2002;36:1478-1487).
Establishment of a highly efficient gene transfer system for mouse fetal hepatic progenitor cells
Authors: Yasuchika Kentaro , Hirose Tetsuro , Fujii Hideaki , Oe Shoshiro , Hasegawa Koichi , Fujikawa Takahisa , Azuma Hisaya , Yamaoka Yoshio
Published: March 2007

Because of a donor shortage problem in liver transplantation, cell transplantation has been anticipated as a useful bridge or substitute therapy, and has necessitated the development of cell sources other than donated organs. Therefore, the use of fetal hepatic progenitor cells (HPCs) is now being focused on. In this study, we intended to establish an efficient ex vivo nonviral gene-transfer system using a newly developed isolation and culture system for mouse fetal HPCs. Fetal HPCs, characterized using immunocytochemistry and reverse-transcription polymerase chain reaction (RT-PCR) for lineage markers, were collected from E13.5 Balb/c mice using change in size because of cell aggregation by their homophilic cell-to-cell binding occurring during suspension culture. Optimal conditions for culture and ex vivo gene transfection for fetal HPCs were determined by 3H-thymidine incorporation and the expression efficacy of transfected red fluorescent protein (DsRed) gene in different culture media. The optimum timing for gene transfection was also evaluated. To evaluate the in vivo expression of the transferred gene, DsRed-transferred fetal HPCs were transplanted into 70% partially hepatectomized allogenic mice. The highest efficacy of DsRed gene transfection into fetal HPCs in vitro (45% ± 12.3%) was achieved with culture media, which also enabled the highest 3H-thymidine incorporation, containing the deleted form of hepatocyte growth factor (dHGF) and insulin, and when transfection was performed immediately after isolation. In vivo DsRed expression in fetal HPCs was maintained concomitantly with albumin expression even after HPC transplantation. In conclusion, we established a highly efficient in vitro gene transfer system for mouse fetal HPCs using a newly developed isolation and culture system. (Hepatology2002;36:1488-1497).
TRAIL-mediated apoptosis requires NF- k B inhibition and the mitochondrial permeability transition in human hepatoma cells
Authors: Kim Young-Soo , Schwabe Robert F. , Qian Ting , Lemasters John J. , Brenner David A.
Published: March 2007

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a wide range of malignant cells. However, several cancers, including human hepatoma, are resistant to TRAIL. In this study, we analyzed TRAIL-induced pro- and antiapoptotic signaling pathways in human hepatoma cells. Nuclear factor k B (NF-kB) was found to be a critical TRAIL-induced antiapoptotic factor in the PLC/PRF/5, HepG2, and Hep3B cell lines. TRAIL-induced NF-kB activation was preceded by IkBα kinase (IKK) activation and IkBα degradation and depended on TRAF2, NF-kB-inducing kinase (NIK), IKK1, and IKK2. Accordingly, inhibition of NF-kB by adenoviral dominant negative (dn) TRAF2, NIKdn, IKK1 dn, IKK2dn, or IkBsr sensitized PLC/PRF/5 cells to rhTRAIL, resulting in 40% to 50% cell death after 48 hours as compared with < 10% with rhTRAIL alone. Agonistic anti-TRAIL receptor 1 and anti-TRAIL receptor 2 antibodies or combinations of both were equally efficient in inducing apoptosis as rh TRAIL, indicating that decoy receptors did not contribute to resistance toward TRAIL under the conditions of our study. TRAIL-mediated apoptosis depended on FADD, caspase 8 and 3 as demonstrated by the ability of FADDdn, CrmA, and pharmacologic caspase inhibitors to prevent apoptosis. Confocal microscopy showed the onset of the mitochondrial permeability transition (MPT) 5 hours after rh TRAIL plus actinomycin D, which was followed by cytochrome c release. The MPT was critical for TRAIL-induced apoptosis as demonstrated by the ability of pharmacologic MPT inhibitors to completely protect PLC/PRF/5 cells. In conclusion, NF-kB prevents TRAIL-induced apoptosis in human hepatoma through a TRAIL-activated TRAF2-NIK-IKK pathway. Inhibition of NF-kB unmasks a TRAIL-induced apoptotic signaling cascade that involves FADD, caspase 8, the MPT, and caspase 3. (Hepatology2002;36:1498-1508).
Hepatoma-derived growth factor is highly expressed in developing liver and promotes fetal hepatocyte proliferation
Authors: Enomoto Hirayuki , Yoshida Kenya , Kishima Yoshihiko , Kinoshita Taisei , Yamamoto Mitsunari , Everett Allen D. , Miyajima Atsushi , Nakamura Hideji
Published: March 2007

Hepatoma-derived growth factor (HDGF) is a heparin-binding protein, which has been purified from the conditioned media of HuH-7 hepatoma cells. Recent studies have suggested the involvement of HDGF in development of the kidney and cardiovascular systems. In the present study, we investigated the possibility that HDGF was also involved in liver development. Northern blot and immunostaining revealed unique expression patterns of HDGF in liver development. HDGF expression was strongly detected in the fetal liver of the midgestation stage and was markedly decreased near birth. Its expression was mainly detected in stromal cells, including immature hepatocytes. Expression in hepatocytes decreased with differentiation. Administration of recombinant HDGF enhanced the growth of primary cultured fetal hepatocytes significantly, although the effect was small. The effect of exogenous HDGF on the proliferation of neonatal hepatocytes was also small and significant only at one point, despite the lower expression of endogenous HDGF, suggesting that the differences exist between fetal and neonatal hepatocytes. However, adenoviral introduction of HDGF antisense cDNA into the fetal hepatocytes significantly suppressed their proliferation, and the inhibitory effect of HDGF antisense virus was reversed by exogenous HDGF. In conclusion, HDGF helps regulate the hepatocyte proliferation in liver development. (Hepatology2002;36:1519-1527).
Bridge over troubled water: Protection against hepatitis C virus persistence?
Authors: Thimme Robert , Spangenberg Hans-Christian , Blum Hubert E.
Published: March 2007

Background:

Neither previous hepatitis C (HCV) infection nor vaccination with HCV-derived antigens protects against reinfection. However, HCV infection and vaccination in chimpanzees has been shown to reduce the magnitude and duration of viraemia with re-challenge. We aimed to establish whether similar immunity could be achieved in man.

Methods:

From a study of injecting drug users, we identified 164 people who had no evidence of previous HCV infection and 98 individuals who had been previously, but were not currently, infected with HCV. We compared the incidence and persistence of HCV viraemia in these two groups over four consecutive 6-month periods.

Findings:

Of participants without previous HCV infection, the incidence of HCV infection was 21% (35/164). By contrast, people previously infected were half as likely to develop new viraemia (12% (12/98)), even after accounting for risk behaviour (hazard ratio, 0.45; 95% CI 0.23-0.88). Furthermore, in HIV-negative people, those previously infected were 12 times less likely than people infected for the first time to develop persistent infection (odds ratio 0.05, 95% CI 0.01-0.3), and median peak HCV RNA concentration was two logs lower. HCV persisted in six of six HIV-1 positive people, even in one man who had previously cleared HCV infection when he was HIV-1 negative.

Interpretation:

There is an alarming frequency of HCV infection and persistence among injecting drug users. Our data suggest that immunity against viral persistence can be acquired, and that vaccines should be tested to reduce the burden of HCV-related liver disease.
Hepatitis C virus and lymphomagenesis: Another piece of evidence
Authors: Hermine O , Lefrere F , Bronowicki Jp , Mariette X , Jondeau K , Eclache-Saudreau V , Delmas B , Valensi F , Cacoub P , Brechot C , Varet B , Troussard X , Negro Francesco
Published: March 2007

Some epidemiologic studies suggest a link between hepatitis C virus (HCV) infection and some B-cell non-Hodgkin’s lymphomas. We undertook this study after a patient with splenic lymphoma with villous lymphocytes had a hematologic response after antiviral treatment of HCV infection. Nine patients who had splenic lymphoma with villous lymphocytes and HCV infection were treated with interferon alfa-2b (3 million IU three times per week) alone or in combination with ribavirin (1000 to 1200 mg per day). The outcomes were compared with those of six similarly treated patients with splenic lymphoma with villous lymphocytes who tested negative for HCV infection. Of the nine patients with HCV infection who received interferon alfa, seven had a complete remission after the loss of detectable HCV RNA. The other two patients had a partial and a complete remission after the addition of ribavirin and the loss of detectable HCV RNA. One patient had a relapse when the HCV RNA load again became detectable in blood. In contrast, none of the six HCV-negative patients had a response to interferon therapy. In patients with splenic lymphoma with villous lymphocytes who are infected with HCV, treatment with interferon can lead to regression of the lymphoma.
Inhibition of Hbv Replication by Sirna in A Stable Hbv–Producing Cell Line
Authors: Konishi Masayoshi , Wu Catherine H. , Wu George Y.
Published: March 2007

Potent inhibition of endogenous gene expression by RNA interference has been achieved by using sequence–specific posttranscriptional gene silencing through the action of small interfering RNA molecules (siRNA). In these reports, the natural function of genes could be deduced through the ensuing loss of function. Based on the extraordinary effectiveness in silencing endogenous genes, we wondered whether siRNA could be applied against viral replication in a hepatitis B virus (HBV) model using HBV–specific siRNA. To test this idea, HepG2 2.2.15, a human hepatoblastoma cell line that constitutively produces infectious HBV particles, was transfected with HBV–specific siRNAs and controls. HBV surface antigen (HBsAg) secretion into culture media was inhibited by 78%, 67%, and 42% with siRNA against the polyadenylation (PA), precore (PreC), and surface (S) regions, respectively, compared with controls as detected by enzyme–linked immunosorbent assay. After exposure to HBVPA siRNA, Northern blot analysis showed that HBV pregenomic RNA levels were decreased by 72%, and levels of HBV RNA containing the polyadenylation signal sequence were suppressed by 86%, as detected by RNase protection assay. Levels of HBV coreassociated DNA, a replication intermediate, also decreased by 71%. Immunocytochemistry revealed that 30% to 40% of the cells transfected with HBVPA siRNA were completely negative for detectable HBsAg levels. Controls consisting of treatment with HBV–specific siRNA alone, lipofection reagent alone, or random double–stranded RNA (dsRNA) lipofection complex failed to decrease HBV surface antigen, HBV messenger RNA (mRNA), or core–associated HBV–DNA levels. In conclusion, siRNA inhibits hepatitis B viral replication in a cell culture system. Future studies are needed to explore the specific delivery of siRNA to liver cellsin vivoand the applicability of this approach. (Hepatology 2003;38:842-850).
Chronic Hepatitis C Virus Infection Established and Maintained in Chimpanzees Independent of Dendritic Cell Impairment
Authors: Rollier Christine , Drexhage Joost A.R. , Verstrepen Babs E. , Verschoor Ernst J. , Bontrop Ronald E. , Koopman Gerrit , Heeney Jonathan L.
Published: March 2007

Chronic hepatitis C virus (HCV) infection in humans is associated with an impairment of dendritic cells (DC). It has been hypothesized that impairment of DC function may be a central mechanism facilitating the establishment of a chronic carrier state. However, the majority of patients studied with DC impairment to date have been identified and, thus, inadvertently selected because of clinical manifestations leading to their diagnosis, which may have been many years following actual infection. We set out to determine whether impaired DC function occurred in the earlier asymptomatic phase of infection and turned to a well–defined cohort of HCV–infected chimpanzees in which the specific date of infection and the nature of the inoculum were well characterized. Results revealed that, in contrast to the observations in human subjects with advanced clinical hepatitis, there was neither impairment of the allostimulatory capacity of monocyte–derived DC from HCV chronic carriers nor impairment of the maturation process. Decreased allostimulatory capacity was only detected in 2 animals and, interestingly, in those that possessed the highest viral loads. Nevertheless, HCV sequences were undetectable in any of the DC derived from HCV–infected chimpanzees. In conclusion, these findings suggest that the mechanisms of establishing persistent HCV infection are separate and independent from those responsible for impaired DC function. Indeed, the maturation and allostimulatory impairment, as described in patient studies, are not necessary prerequisites but rather possible consequences of persistent and active HCV infection associated with disease progression. (Hepatology 2003;38:851-858).
Decreased Hepatic Nitric Oxide Production Contributes to the Development of Rat Sinusoidal Obstruction Syndrome
Authors: Deleve Laurie D. , Wang Xiangdong , Kanel Gary C. , Ito Yoshiya , Bethea Nancy W. , McCuskey Margaret K. , Tokes Zoltan A. , Tsai Jeffrey , McCuskey Robert S.
Published: March 2007

This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. NG–nitro–L–arginine methyl ester (L–NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V–PYRRO/NO, a liver–selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vivo microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in vitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V–PYRRO–NO prevented the monocrotaline–induced increase in MMP–9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up–regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion. (Hepatology 2003;38:900-908).
Influence of Newly Synthesized Cholesterol on Bile Acid Synthesis During Chronic Inhibition of Bile Acid Absorption
Authors: Bertolotti Marco , Zambianchi Lisa , Carulli Lucia , Simonini Maria Sole , Puppo Marina Del , Kienle Marzia Galli , Loria Paola , Pinetti Adriano , Carulli Nicola
Published: March 2007

The effects of newly synthesized cholesterol availability on bile acid synthesis are largely unknown, particularly in humans. The present study was aimed to study the changes induced on bile acid synthesis by simvastatin, a competitive inhibitor of hydroxymethyl glutaryl–CoA (HMG–CoA) reductase, the rate–limiting enzyme of cholesterol synthesis, during pharmacologic interruption of the enterohepatic circulation. Six patients with primary hypercholesterolemia were studied in basal conditions, after treatment with the bile acid binding resin cholestyramine alone (8–16 g/d for 6-8 weeks) and subsequently in combination with simvastatin (40 mg/d for 6-8 weeks). Cholesterol 7α–hydroxylation rate, a measure of total bile acid synthesis, was assayed in vivo by tritium release analysis. Serum lathosterol levels were assayed by gas chromatography—mass spectrometry as a measure of cholesterol synthesis. Serum total and low–density lipoprotein–cholesterol were reduced significantly after cholestyramine (by 26% and 30%, respectively) and during combined treatment (by 47% and 55%). 7α–Hydroxylation rates increased nearly 4–fold with cholestyramine alone; addition of simvastatin induced a significant decrease of hydroxylation rates (cholestyramine alone, 1,591 ± 183 mg/d; plus simvastatin, 1,098 ± 232 mg/d; mean ± SEM; P < .05). Hydroxylation rates significantly correlated with serum lathosterol/cholesterol ratio (r = 0.79, P < .05). In conclusion, in conditions of chronic stimulation bile acid synthesis may be affected by changes in newly synthesized cholesterol availability. The finding might relate to the degree of substrate saturation of microsomal cholesterol 7α–hydroxylase; alternatively, newly synthesized cholesterol might induce a stimulatory effect on cholesterol 7α–hydroxylase transcription. (Hepatology 2003;38:939–946).
Chromosomal 20q gain in the DNA diploid component of aneuploid colorectal carcinomas
Authors: De Angelis Paula M. , Stokke Trond , Beigi Marzieh , Flatberg Gøril , Enger Marianne , Haug Kristiane , Aass Hans Christian D. , Schjølberg Aasa , Andresen Per Arne , Ariansen Sarah , Bø Anne Signe , Mjåland Odd , Clausen Ole Petter
Published: March 2007

The order of appearance of different genetic aberrations during the shift from diploidy/near‐diploidy to aneuploidy in colorectal cancers is not yet clear. We studied genetic alterations in flow cytometrically‐sorted DNA diploid and corresponding aneuploid epithelial cell populations from each of 20 colorectal tumors using comparative genomic hybridization, FISH, and PCR. Analysis of the 19 cases in which aberrations were found in the flow‐sorted diploid population indicated that large‐scale aneuploidization in colorectal cancer was preceded by amplification of oncogene(s) localized to chromosome 20q13.2 and by KRAS mutations, but not by TP53 deletions or losses of large chromosomal regions such as 4q, 8p and 18q. © 2007 Wiley‐Liss, Inc.
Insulin down‐regulates TRAIL expression in vascular smooth muscle cells both in vivo and in vitro
Authors: Corallini Federica , Celeghini Claudio , Rizzardi Clara , Pandolfi Assunta , Di Silvestre Sara , Vaccarezza Mauro , Zauli Giorgio
Published: March 2007

To dissect the effect of hyperinsulinemia versus hyperglycemia on TNF‐related apoptosis inducing ligand (TRAIL) expression in the macrovascular district, we measured TRAIL mRNA and protein in four groups of animals: streptozotocin (SZT)‐induced diabetic rats, vehicle‐treated control animals, diabetic rats treated with insulin and non‐diabetic rats treated with insulin. While the aortas of diabetic rats did not show significant differences in TRAIL expression with respect to vehicle‐treated control animals, the aortas of both diabetic and non‐diabetic rats treated in vivo for 16 days with insulin showed a significant decrease in TRAIL expression with respect to either diabetic and control rats. Moreover, in vitro treatment of both rat and human vascular smooth muscle cells (VSMC) with insulin induced the down‐regulation of TRAIL protein. While the addition of recombinant TRAIL to rat VSMC promoted the dose‐dependent release of bioactive nitric oxide (NO), this effect was significantly counteracted by pre‐exposure of VSMC to insulin. These findings suggest that TRAIL might act as an endogenous regulator of the vascular tone and that chronic elevation of insulin might contribute to the vascular abnormalities characterizing type‐2 diabetes mellitus by down‐regulating TRAIL expression and activity. J. Cell. Physiol. 212: 89–95, 2007. © 2007 Wiley‐Liss, Inc.
Sonographic diagnosis of a round ligament cyst in the inguinal area
Authors: Oh Soon Nam , Jung Seung Eun , Lee Jae Mun , Chung Jae Hee , Park Gyeong Sin
Published: March 2007

We report a case of a 37‐year‐old female with a mesothelial cyst of the round ligament presenting as a palpable mass. The mass appeared sonographically as a fusiform structure with several cystic anechoic areas and was misdiagnosed preoperatively as herniation of the right ovary. © 2007 Wiley Periodicals, Inc. J Clin Ultrasound, 2007
Prenatal sonographic diagnosis of an extensive fetal axillary hemangiolymphangioma
Authors: Ozkur Ayhan , Kervancioglu Selim , Kervancioglu Resat , Dikensoy Ebru , Inaloz Huseyin Serhat , Sirikci Akif
Published: March 2007

Hemangiolymphangioma (HL) is an extremely rare malformation of both the lymphatic and blood vessels. We present a case of fetal axillary HL that was diagnosed sonographically at 36 weeks' gestation. Sonographic examination revealed a large, multilocular, cystic mass consistent with lymphangioma. At birth, a giant hemangioma was noticed involving the right hemitruncus. Based on clinical and sonographic findings, a diagnosis of HL was made. Surgical treatment was considered but was refused by the parents. The neonate died at 14 days of age, possibly due to an intralesional hemorrhage. © 2007 Wiley Periodicals, Inc. J Clin Ultrasound, 2007
Synthesis of carbon‐14 labeled dibutyltin dichloride
Authors: Lewin Anita , Jeffcoat Robert , Berrang Bertold
Published: March 2007

This report describes the preparation of carbon‐14 labeled dibutyltin dichloride from carbon‐14 labeled barium carbonate in 30% overall radiochemical yield. The key steps were (a) the preparation of carbon‐14 labeled butyl bromide from carbon‐14 labeled barium carbonate via carbon‐14 labeled butyl mesylate, and (b) the direct preparation of tetrabutyltin by the lithium‐mediated reaction of dibutyltin dichloride with carbon‐14 labeled butyl bromide. Copyright © 2007 John Wiley & Sons, Ltd.
Ultrastructure of the protonephridia of larval Rugiloricus cf. cauliculus, male Armorloricus elegans, and female Nanaloricus mysticus (Loricifera)
Authors: Neuhaus Birger , Kristensen Reinhardt Møbjerg
Published: March 2007

The protonephridial system of several Loricifera was studied by transmission electron microscopy. A larval specimen of Rugiloricus cf. cauliculus possesses two protonephridia, which are “capped” frontally by a compact mass of still undifferentiated gonadal cells. Each protonephridium consists of four monociliary terminal cells and four canal cells with a diplosome but no cilia. Because of incomplete series of sections and unsatisfactory fixation, the outleading cell(s) could not be detected. In a male specimen of Armorloricus elegans, each gonad contains two protonephridia that open into the gonadal lumen. Each protonephridium consists of two monociliary terminal cells, each forming a filter, two nonciliated canal cells, and two nephroporus cells. The protonephridial lumina of the latter cells fuse to one common lumen, which unites with the gonadal lumen. Preliminary observations on the protonephridia of a female Nanaloricus mysticus reveal a more complicated arrangement of interdigitating terminal and canal cells. One or two terminal cells form their own individual filter or four cells form a common compound filter. The cilium of the terminal cells of all species investigated are surrounded by a palisade of nine microvilli that support the filter barrier made of an extracellular matrix. An additional filter diaphragm could be traced between the pores in the cell wall of each terminal cell of A. elegans. The urogenital system of the Loricifera differs from that of the Priapulida in that the protonephridia of the former are completely integrated into the gonad, whereas the excretory organs of the latter open into the urogenital duct caudally of the gonads. J. Morphol., 2007. © 2007 Wiley‐Liss, Inc.
Morphological specializations in heterocongrinae (Anguilliformes: Congridae) related to burrowing and feeding
Authors: De Schepper N. , De Kegel B. , Adriaens D.
Published: March 2007

The remarkable lifestyle of heterocongrines has drawn the attention of many authors in the past, though no or little attention has been paid to the morphology of the tail and the head of these species. In order to examine the true nature of possible morphological specializations of the head and tail and their relation to their tail‐first burrowing habit and/or feeding mode, a detailed myological and osteological study of Heteroconger hassi and Heteroconger longissimus was performed. The osteological similarities of the cranial skeleton between H. hassi and H. longissimus are striking. Most of the cranial muscles show no variation in presence, insertion or origin between these two species except for the adductor mandibulae complex, the adductor hyomandibulae and the intermandibularis. The adductor mandibulae complex is small, compared to that of other anguilliform species, and is probably related to their suction‐dominated feeding mode and a diet, comprising mainly small, soft prey items. Heterocongrinae have undergone several morphological specializations in the tail for their tail‐first burrowing lifestyle. The skeleton and musculature of the tail of H. hassi and H. longissimus are similar. In both species the caudal skeleton is highly reduced and fortified, forming a firm, pointed burrowing tool. Intrinsic caudal musculature is reduced and some muscles (interradials, supracarinalis) are even absent. J. Morphol., 2007. © 2007 Wiley‐Liss, Inc.
Thermotropic Phase Behavior of a Liquid‐Crystalline Poly(ether ester) Derived from Hydroxydibenzoic Acid, 2‐Methyl‐1,3‐propanediol and R‐1,3‐Butanediol
Authors: Fernández‐Blázquez Juan P. , Bello Antonio , Pérez Ernesto
Published: March 2007

The thermotropic phase behavior of a liquid‐crystalline poly(ether ester) derived from 4′‐hydroxybiphenyl‐4‐carboxylic acid and two different spacer diols (2‐methyl‐1,3‐propanediol and R‐1,3‐butanediol) has been analyzed by differential scanning calorimetry, real time synchrotron X‐ray diffraction and solid‐state 13C NMR. It has been found that the polymer develops a smectic mesophase that presents order inside the layers. This mesophase has a slow rate of formation, in such a way that it is possible to obtain either an amorphous glass or a liquid‐crystalline glass. These two phases exhibit different and independent glass transition temperatures: 95 °C for the amorphous one and 85 °C for the mesophase. The diffractogram of this mesophase shows two clear diffractions in the wide‐angle region and a long spacing (of low intensity) in the small‐angle region. All those features are characteristic of a mesophase of intermediate order, presumably of the type SmI, in contrast to the low‐ordered SmCalt mesophase reported for the racemic polymer. Thus, the chirality of the spacer, which provides structural regularity, makes easier the packing of the chains, so that a more ordered mesophase is obtained. In addition, both the solid‐state 13C NMR line shapes and the value of $T_{1\rho }^H $ are practically the same for the quenched and the annealed samples, indicating that the “ordered” phase obtained by annealing is not a three‐dimensional crystal, thus confirming its assignment as mesophase, with a considerable degree of conformational disorder.

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A longitudinal look at rural consumer adoption of online shopping
Authors: Lennon Sharron J. , Kim Minjeong , Johnson Kim K. P. , Jolly Laura D. , Damhorst Mary Lynn , Jasper Cynthia R.
Published: March 2007

Innovation diffusion theory guided research on the process of online apparel shopping adoption (i.e., changes in online shopping adoption) among rural consumers. Rural consumers in 11 states completed surveys in 2000 ( n = 2,198) and in 2003 (n = 879). Variables measured in 2000 were used to predict online apparel purchasing in 2003; structural equation modeling was used for data analysis and yielded satisfactory fit. Results revealed strong support for innovation diffusion theory: Previous practice and characteristics of the decision‐making unit ( education, income, innovativeness) affected belief structures. Although beliefs about online shopping measured in 2000 did not affect online apparel shopping adoption in 2000, they did affect online apparel shopping adoption in 2003, demonstrating the dynamic nature of innovation diffusion. Characteristics of the decision‐making unit (education, income) indirectly affected online apparel shopping via their influence on previous practice, which was the strongest predictor of online apparel purchasing in 2000 and 2003. General beliefs about the Internet and beliefs about the compatibility of online shopping with respondents' lifestyles predicted online apparel shopping in 2003, whereas beliefs about the benefits and advantages of online shopping did not. © 2007 Wiley Periodicals, Inc.