bluuebunny/crossref_metadata_2025 huggingface dataset:
The c‐kit‐encoded tyrosine kinase regulates the proliferation of early pre‐B cells
Authors: Rolink Anton , Streb Martin , Nishikawa Shin‐Ichi , Melchers Fritz
Published: March 2007

A monoclonal antibody (mAb; ACK2) recognizing the extracellular domains of the c‐kit‐encoded tyrosine kinase has been employed to demonstrate that c‐kit is involved in B lymphocyte development. The c‐kit‐encoded tyrosine kinase is expressed on the surface of normal DHJH‐rearranged murine pre‐B cell clones which proliferate continuously at that stage in vitro on stromal cells and in the presence of recombinant interleukin 7. These pre‐B cell clones, capable of differentiation to surface immunoglobulin‐positive B cells in vitro and in vivo, are inhibited by the mAb in their proliferation while remaining capable of differentiation to surface immunoglobulin‐positive B cells. Stimulation of mature B cells by mitogens is unimpaired by the mAb. This indicates that c‐kit regulates early antigen‐independent, but not late antigen‐dependent, B cell development.
Infinite Molecular {[Pt3n(CO)6n]2–}∞ Conductor Wires by Self‐Assembly of [Pt3n(CO)6n]2– (n = 5–8) Cluster Dianions Formally Resembling CO‐Sheathed Three‐Platinum Cables
Authors: Femoni Cristina , Kaswalder Francesco , Iapalucci Maria Carmela , Longoni Giuliano , Zacchini Stefano
Published: March 2007

Miscellaneous tetrasubstituted ammonium salts of [Pt3n(CO)6n]2– (n = 5–8) clusters, obtained by the stoichiometric oxidation of the corresponding [Pt9(CO)18]2– salts with tropylium tetrafluoroborate, self‐assemble into infinite semicontinuous or continuous {[Pt3n(CO)3n(μ‐CO)3n]2–}∞ conductor wires upon crystallization. Pellets of these salts exhibit conductor behavior that roughly depends on the interdianion gap along the wires. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Multivariate analysis of 2‐DE protein patterns – Practical approaches
Authors: Jacobsen Susanne , Grove Harald , Nedenskov Jensen Kristina , Sørensen Helle A. , Jessen Flemming , Hollung Kristin , Uhlen Anne Kjersti , Jørgensen Bo M. , Færgestad Ellen Mosleth , Søndergaard Ib
Published: March 2007

Practical approaches to the use of multivariate data analysis of 2‐DE protein patterns are demonstrated by three independent strategies for the image analysis and the multivariate analysis on the same set of 2‐DE data. Four wheat varieties were selected on the basis of their baking quality. Two of the varieties were of strong baking quality and hard wheat kernel and two were of weak baking quality and soft kernel. Gliadins at different stages of grain development were analyzed by the application of multivariate data analysis on images of 2‐DEs. Patterns related to the wheat varieties, harvest times and quality were detected on images of 2‐DE protein patterns for all the three strategies. The use of the multivariate methods was evaluated in the alignment and matching procedures of 2‐DE gels. All the three strategies were able to discriminate the samples according to quality, harvest time and variety, although different subsets of protein spots were selected. The explorative approach of using multivariate data analysis and variable selection in the analyses of 2‐DEs seems to be promising as a fast, reliable and convenient way of screening and transforming many gel images into spot quantities.
Sur model with spatial effects: an application to mental health expenditure
Authors: Moscone Francesco , Tosetti Elisa , Knapp Martin
Published: March 2007

This study analyses, through the adoption of a seemingly unrelated regression approach, the temporal evolution of policy interactions among local authorities in England when allocating mental health resources. This new approach in health economics may shed light on the degree of interdependence between adjacent municipalities at a specific point in time (e.g. before, during, or after a change in policy), exploiting the information carried by the panel, rather than that of a single cross‐section. Copyright © 2007 John Wiley & Sons, Ltd.
Genotypic analysis of hepatitis C virus in American patients
Authors: Mahaney Kevin , Tedeschi Valeria , Maertens Geert , Di Bisceglie Adrian M. , Vergalla John , Hoofnagle Jay H. , Sallie Richard
Published: March 2007

We examined hepatitis C virus genotypes in 98 American patients with chronic hepatitis C virus infection by means of two methods; restriction fragment length polymorphism analysis and line probe assay, which is based on type-specific sequence variations in the 5′ untranslated region. Type 1 was present in 73 patients (74%), type 2 in 15 (15%), type 3 in 6 (6%) and type 4 in 1 (1%). Line probe assay further subdivided type 1 into 1a (n = 35) and type 1b (n = 37) and type 2 into type 2a (n = 6) and 2b (n = 9). Two patients (2%) had both restriction fragment length polymorphism and line probe assay evidence of dual infection (with types 1 and type 2) while another case had both type 1a and 1b by line probe assay. One patient was untypable by either technique. There was no correlation between infecting genotype and presumed cause, serum indexes of necroinflammatory activity, or age or sex of the patients studied or known duration of infection. Patients with type 2 hepatitis C virus had more severe liver disease histologically (p = 0.0027) compared with other genotypes but, paradoxically, had significantly lower levels of circulating hepatitis C virus RNA (12.1 ± 12.8 × 105 genome equivalents/ml) than other types (36.4 ± 44.8 × 105 genome equivalents/ml, p < 0.001). Response to interferon was less likely to be sustained in patients infected with type 1 than in those infected with other types (7% vs. 40%, p < 0.05). Thus hepatitis C virus genotype may have some influence on the clinical pattern of hepatitis, particularly with regard to the disease severity and response to interferon. The restriction fragment length polymorphism and line probe assays produced concordant results in 97 of 98 cases; however, whereas restriction fragment length polymorphism provides a relatively easy and reliable method for genotyping hepatitis C virus, the line probe assay is more rapid, uses standardized reagents, does not require radioisotopes and has the advantage of distinguishing the subtypes of genotype 1 and 2.
Detection of α-fetoprotein mRNA, an indicator of hematogenous spreading hepatocellular carcinoma, in the circulation: A possible predictor of metastatic hepatocellular carcinoma
Authors: Matsumura Masayuki , Niwa Yasuro , Kato Naoya , Komatsu Yutaka , Shiina Shuichiro , Kawabe Takao , Kawase Takeo , Toyoshima Hiroshi , Ihori Masashi , Shiratori Yasushi , Omata Masao
Published: March 2007

We attempted to detect circulating hepatocellular carcinoma by demonstrating hepatocyte-associated mRNA in the nuclear cell component of peripheral blood using nested reverse transcription—polymerase chain reaction because of the extremely small number of tumor cells in the circulation. Albumin mRNA was demonstrated not only in the liver tissue (hepatocytes) and HepG2 cells but also in nuclear cells of the blood from normal healthy volunteers (neutrophils and lymphocytes) by reverse transcription—polymerase chain reaction. In contrast, α-fetoprotein mRNA was demonstrated in the liver tissue, as well as in HepG2 cells, but not in peripheral blood of normal healthy volunteers, indicating the possibility of using α-fetoprotein mRNA for detection of benign and malignant hepatocytes among the population of neutrophils and lymphocytes. α-Fetoprotein mRNA in peripheral blood was detected in 17 of 33 cases of hepatocellular carcinoma (52%), 2 of 13 cases of cirrhosis (15%) and 2 of 17 cases of chronic hepatitis (12%). α-Fetoprotein mRNA was not demonstrated in 26 cases of normal healthy volunteers (0%). Among the patients with hepatocellular carcinoma, total volume of tumor tissue, maximum size of tumor and serum α-fetoprotein level were markedly increased in the patients with α-fetoprotein mRNA in blood. In addition, α-fetoprotein mRNA was detected in the blood of all 6 patients showing metastasis at extrahepatic organs (100%), in contrast to 11 of 27 cases without metastasis (41%). From these results, we conclude that the presence of α-fetoprotein mRNA in peripheral blood may be an indicator of circulating malignant or benign hepatocytes, which might predict hematogenous spreading metastasis of tumor cells in patients with hepatocellular carcinoma. (Hepatology 1994;20:1418-1425).
FK 506 renal toxicity and lack of detectable cytochrome P-450 3A in the liver graft of a patient undergoing liver transplantation
Authors: Lemoine Antoinette , Azoulay Daniel , Dennison Ashley , Kiffel Liliane , Pichard Lydiane , Furlan Valérie , Bienvenu Thierry , Fredj Gilles , Debuire Brigitte , Maurel Patrick , Bismuth Henri , Beaune Philippe
Published: March 2007

Many commonly used drugs are substrates for hepatic cytochrome P-450 3A in human beings, and its role in the metabolism of potentially toxic immunosuppressants has been highlighted (cyclosporine, FK 506). One hundred fifty human liver grafts were biopsied before and after liver transplantation, and levels of cytochromes P-450 3A, 1A2, 2D6 and 2C were estimated by means of the Western-blot technique and correlated with histological appearance, glycogen content and clinical course. In 15 of the grafts, cyclosporine oxidase was also measured, and in 12 of 15 recipients, urinary 6β-hydroxycortisol excretion was assayed. A wide range of cytochrome P-450 3A values were observed (25 to 366 arbitrary units/mg; mean, 105 ± 63 arbitrary units/mg). In one graft (no. 730) no cytochrome P-450 3A was detectable on immunoblotting, despite increasing homogenate concentrations. In this sample, cytochromes P-450 1A2, 2D6, and 2C were present in normal ranges. Levels of cyclosporine oxidase and 6β-hydroxycortisol in the urine specimens of the recipient were found to be low. The recipient of graft 730 experienced reversible complications of FK 506 therapy despite adherence to the administration protocol and drug plasma level in the normal range. The subsequent appearance of the cytochrome P-450 3A was associated with the consequent tolerance of oral FK 506. The absence of detectable amounts of P-450 3A in one biopsy from a donated human liver graft dramatically emphasizes the extreme range of this enzyme levels and has important clinical implications. (Hepatology 1994;20:1472-1477).
Effect of distal splenorenal shunt on survival of patients with primary biliary cirrhosis
Authors: Boyer Thomas D. , Kokenes Dennis D. , Hertzler Gary , Kutner Michael H. , Henderson Michael J.
Published: March 2007

Distal splenorenal shunt is known to effectively control bleeding from esophageal and gastric varices; however, the effect of this selective shunt on liver function is less well understood. We examined retrospectively the effect of distal splenorenal shunt on the survival of 19 patients with primary biliary cirrhosis subjected to surgery for bleeding varices over a 20-yr period and had been followed for at least 1 yr. Actual Kaplan-Meier survival curve was compared with predicted survival curve based on the Mayo Clinic model using clinical data collected at the time of surgery. The patients median length of follow-up was 65.9 mo. Ten of the 19 patients died or underwent orthotopic liver transplantation during the period of observation. The actual Kaplan-Meier and predicted Mayo Clinic model survival curves were similar and did not differ significantly. Survival was best in patients with good liver function (i.e., low Mayo risk scores). Distal splenorenal shunt, therefore, did not appear to have an adverse effect on the survival of patients with primary biliary cirrhosis. We conclude that variceal bleeding in primary biliary cirrhosis patients with good liver function should not be considered an indication for liver transplantation. Instead, if treatment with sclerotherapy or β-blockers fails then distal splenorenal shunt will prevent recurrent bleeding in 90% of patients and leave them with an excellent prognosis. (Hepatology 1994;20:1482-1486).
Serial recording of sensory evoked potentials: A noninvasive prognostic indicator in fulminant liver failure
Authors: Madl Christian , Grimm Georg , Ferenci Peter , Kramer Ludwig , Yeganehfar Wafa , Oder Walter , Steininger Rudolf , Zauner Christian , Ratheiser Klaus , Stockenhuber Felix , Lenz Kurt
Published: March 2007

Sensory evoked potentials are markedly changed in patients with fulminant liver failure. It is unknown, however, whether serial recordings of sensory evoked potentials provide useful prognostic informations for patient management in fulminant liver failure. Ninety recordings of bilateral median nerve—stimulated short-and long-latency sensory evoked potentials were performed in 25 patients with fulminant liver failure (9 patients spontaneously recovered and survived, 8 patients were referred to emergency liver transplantation and 8 patients died). In all nine survivors the cortical long-latency sensory evoked potential N70 peak was constantly detectable between 74 and 162 ms. In all eight patients who subsequently underwent liver transplantation and in seven of eight patients who died, loss of the N70 peak developed during the course of fulminant liver failure. In 4 of 15 patients who were selected for liver transplantation according to the King's College criteria, the N70 peak was constantly detectable. All four transplantation candidates spontaneously recovered and survived without transplantation. In contrast, eight patients never did fulfill the criteria for liver transplantation. Five of them with constantly detectable N70 peak recovered spontaneously. However, in the remaining three patients loss of the N70 peak developed, and they ultimately died. The probability of correct outcome prediction by sensory evoked potentials is superior to that based on clinical criteria alone (0.96 vs. 0.72). Therefore serial recording of sensory evoked potentials may help identify (a) a subgroup among liver transplantation candidates who may spontaneously recover without transplantation and (b) a subgroup of patients with severe brain dysfunction who should undergo early liver transplantation even though they do not fulfill King's College criteria. (Hepatology 1994;20:1487-1494).
Induction of hepatic ito cell nitric oxide production after acute endotoxemia
Authors: Helyar Lesley , Bundschuh Daniela S. , Laskin Jeffrey D. , Laskin Debra L.
Published: March 2007

Nitric oxide is a highly reactive mediator released in the liver by hepatocytes, Kupffer cells and endothelial cells during endotoxin-induced inflammation. In this study we determined whether Ito cells also produce nitric oxide after exposure to endotoxin. For induction of endotoxemia, rats were injected intravenously with Escherichia coli lipopolysaccharide (2.5 mg/kg). Ito cells were isolated from the animals 48 hr later by means of in situ perfusion of the liver with protease and collagenase followed by purification on an arabinogalactan gradient. Ito cells from untreated and endotoxemic rats were found to produce low levels of nitric oxide in response to interferon-γ. In both cell types, this response depended on L-arginine and was blocked by NG-monomethyl-L-arginine, a specific nitric oxide synthase inhibitor. Cells from rats treated with endotoxin produced significantly more nitric oxide than did cells from untreated animals; this was due, at least in part, to increased expression of protein for an inducible form of nitric oxide synthase. These cells also responded to stimulation with lipopolysaccharide in vitro, as well as the combination of interferon-γ and lipopolysaccharide, which was synergistic in stimulating nitric oxide production. Tumor necrosis factor-α and macrophage colony—stimulating factor were also found to stimulate nitric oxide production by Ito cells from endotoxemic rats. In addition, in these cells, tumor necrosis factor-α synergized with interferon-γ in inducing nitric oxide production. The combination of interferon-γ and lipopolysaccharide was also found to inhibit Ito cell DNA synthesis, as measured on the basis of [3H]-thymidine uptake. This inhibitory effect was readily blocked by NG-monomethyl-L-arginine. In contrast, macrophage colony—stimulating factor, as well as granulocyte/macrophage colony—stimulating factor, stimulated Ito cell DNA synthesis, which was not significantly affected by NG-monomethyl-L-arginine. These observations suggest that the effects of inflammatory mediators on Ito cell DNA synthesis depend in part on their ability to stimulate nitric oxide production. Our finding that Ito cells produce nitric oxide indicates that these cells have the capacity to participate in hepatic inflammatory responses during acute endotoxemia. (Hepatology 1994;20:1509-1515).
Alteration in vascular reactivity in isolated aortic rings from portal vein—constricted rats
Authors: Karatapanis Stelios , McCormick Aiden P. , Kakad Shilpa , Chin Jason K. T. , Islam Mohammed , Jeremy Jamie , Harry David , McIntyre Neil , Burroughs Andrew K. , Jacobs Michael
Published: March 2007

It has been suggested that increased production of nitric oxide by an inducible nitric oxide synthase isoenzyme is important in the pathogenesis of the vascular abnormalities seen in human beings and animals with portal hypertension. We investigated this hypothesis by studying the in vitro vascular reactivity of isolated aortic rings from portal vein—constricted and sham-operated rats. Aortic rings from portal vein—constricted rats exhibited significantly impaired contractility to phenylephrine and potassium chloride compared with control rats. Preincubation with the nitric oxide synthase inhibitor nitro-l-arginine methyl ester significantly increased contractility to phenylephrine and potassium chloride in both portal-hypertensive and control tissues, with greater effect in the portal-hypertensive rings. Despite nitro-l-arginine methyl ester, maximal contractions were still significantly smaller in the portal-hypertensive tissues. Vascular relaxation evoked by acetylcholine, but not by the endothelium-independent vasodilator glyceryltrinitrate, was significantly impaired in the portalhypertensive group. Our results demonstrate significant impairment in vascular function in aortic rings in this model of portal hypertension. The addition of a nitric oxide synthase inhibitor partly corrected these changes, suggesting that although nitric oxide is likely an important mediator, other factors may also be involved in the pathogenesis of these alterations in vascular function. (Hepatology 1994;20:1516-1521).
Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures
Authors: Fournier Thierry , Mejdoubi Najet , Monnet Dagui , Durand Geneviève , Porquet Dominique
Published: March 2007

The serum level of rat α1-acid glycoprotein is significantly increased by treatment with phenobarbital, and in vivo studies have shown that phenobarbital seems to act mainly at the transcriptional level. To show the direct mediating effect of phenobarbital on α1-acid glycoprotein gene expression, we investigated the ability of primary cultured rat hepatocytes to respond to in vitro phenobarbital administration. Phenobarbital increased both α1-acid glycoprotein secretion and corresponding mRNA levels in primary rat hepatocytes cultured on matrigel. Used in combination with interleukin-1, interleukin-6 and dexamethasone, phenobarbital had an additive or synergistic effect on α1-acid glycoprotein synthesis. These results show that (a) phenobarbital acts directly on hepatocytes by in creasing α1-acid glycoprotein gene expression and (b) this effect is mediated by a specific mechanism independent of pathways involved in α1-acid glycoprotein induction by interleukin-1, interleukin-6 and glucocorticoids. (Hepatology 1994;20:1584-1588).
Effect of simvastatin, an inhibitor of hydroxy-methylglutaryl coenzyme a reductase, on the growth of human ito cells
Authors: Mallat Ariane , Preaux Anne-Marie , Blazejewski Sylvie , Dhumeaux Daniel , Rosenbaum Jean , Mavier Philippe
Published: March 2007

During hepatic fibrogenesis, Ito cells proliferate, acquire a myofibroblastlike phenotype and synthesize increased amounts of extracellular matrix components. In this study, we have assessed the effects of simvastatin, an inhibitor of hydroxy-methylglutaryl-coenzyme A reductase, on the growth of human myofibroblastlike Ito cells. Cells were grown from explants of normal human liver and characterized by a positive staining for desmin and smooth muscle α-actin. Simvastatin (0.1 to 10 μmol/L) induced a marked dose-dependent decrease of [3H]thymidine incorporation in human Ito cells, whether stimulated by human serum or by purified growth factors. Simvastatin-induced inhibition of DNA synthesis was confirmed by nuclear autoradiography and was not explained by a cytotoxic effect. The growth inhibitory effect of simvastatin was specifically due to inhibition of hydroxy-methylglutaryl-coenzyme A reductase because it was overcome by addition of mevalonic acid, the product of the enzymatic reaction. The reduction in [3H]thymidine incorporation was not affected by supplementation of culture medium with purified cholesterol-low-density lipoprotein or isopentenyl adenine. It was partially reversed by addition of farnesol. These results show that simvastatin decreases the growth of human Ito cells, independently of its effect on cholesterol synthesis. This decrease may be due in part either to reduced farnesylation of proteins involved in growth factor signaling pathway or to inhibition of N-linked protein glycosylation. Whether this effect exists in vivo and could thus lead to a parallel decrease of fibrosis deposition within the liver requires further study. (Hepatology 1994;20:1589-1594).
Effects of high-normal and low-normal serum potassium levels on hepatic encephalopathy: Facts, half-facts or artifacts?
Authors: Conn Harold O.
Published: March 2007

An inverse relation is known to link blood potassium with renal synthesis and the release of ammonia. Given the liability of hyperammonemia for precipitating hepatic encephalopathy (HE), 28 patients affected by stage I HE were equally divided into two groups and maintained up to their death at the highest (5.4-5.5 mEq/l) or the lowest (3.5-3.6 mEq/l) normokalemia levels. When compared with the lowest normokalemia group, the highest one showed an early, albeit transient, improvement in the mental state (as assessed by both EEG and psychiatric investigations) and to a lesser extent in hepatic functions (as assessed by the variations in serum bilirubin, GPT, GGT and plasma prothrombin time). In the highest normokalemia group the survival was also prolonged. The cause of this improvement may be related to the induced decrease in blood pH, the consequent depression of renal ammoniagenesis and the rise in the arterial and urine NH+
4/HN3 ratios. These factors reduce the entry of ammonia into the cells and enhance the urinary excretion of this metabolite, respectively.
Dodging cellular customs: Smuggling macromolecules into hepatocytes
Authors: Basu Soumit K. , Chowdhury Jayanta Roy
Published: March 2007

The potential of reconstituted Sendai viral envelopes containing only the fusion protein (F-virosomes) was evaluated for a targeted cytosolic delivery of lysozyme to human hepatoblastoma cells (HepG2) in culture. 125I-Lysozyme loaded into F-virosomes was used to monitor its fusion-mediated transfer to the HepG2 cells. Using fusion assay based on the transfer of water soluble probe, we have demonstrated the existence of aqueous connection between F-virosomes and target cells. Target specificity of the F-virosomes was ensured by the strong interaction between terminal β-galactose moiety of F protein and the asialoglycoprotein receptor on the membrane of HepG2 cells. Incubation of the loaded F-virosomes with cells resulted in fusion-mediated injection, as inferred from the ability of cells to internalize lysozyme in the presence of azide (an inhibitor of the endocytotic process). Binding as well as fusion of the F-virosomes to HepG2 cells was solely mediated by the F protein. Introduction of 125I-lysozyme into the HepG2 cells was confirmed by selective accumulation of acid and anti-body-precipitable radioactivity in the cytosolic compartment. The structural integrity of the internalized lysozyme was also assessed. The potential usefulness of F-virosomes with defined specificities as biological carrier for both in vitro and in vivo cytosolic delivery of macromolecules and drugs has been established.
Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis
Authors: Bañares Rafael , Moitinho Eduardo , Matilla Ana , García-Pagán Juan Carlos , Lampreave José Luis , Piera Carlos , Abraldes Juan G. , De Diego Alejandro , Albillos Agustín , Bosch Jaime
Published: March 2007

Short-term carvedilol administration is more powerful than propranolol in decreasing hepatic venous pressure gradient (HVPG) in cirrhotic patients, but induces arterial hypotension that may prevent its long-term use in portal hypertensive patients. This study compared the HVPG reduction and safety of long-term carvedilol and propranolol. Fifty-one cirrhotic patients were randomly assigned to receive carvedilol (n = 26) and propranolol (n = 25). Hemodynamic measurements and renal function were assessed at baseline and after 11.1 ± 4.1 weeks. Carvedilol caused a greater decrease in HVPG than popranolol (− 19 ± 2% vs. − 12 ± 2%;P< 0.001). The proportion of patients achieving an HVPG reduction ≥20% or ≤ 20 mm Hg was greater after carvedilol (54% vs. 23%;P< 0.05). Carvedilol, but not propranolol caused a significant decrease in mean arterial pressure (MAP) (- 11 ± 1% vs. - 5 ± 3%;P= 0.05) and a significant increase in plasma volume (PV) and body weight (11 ± 5% and 2 ± 1%, respectively;P< 0.05). Glomerular filtration rate (GFR) was unchanged with either drug, but the dose of diuretics was increased more frequently after carvedilol (27% vs. 8%P= 0.07). Adverse events requiring discontinuation of treatment occurred in 2 patients receiving carvedilol and in 3 receiving propranolol. In conclusion, carvedilol has a greater portal hypotensive effect than propranolol in patients with cirrhosis. However, its clinical applicability may be limited by its systemic hypotensive effects. Further trials are needed to confirm the therapeutic potential of carvedilol. (Hepatology2002;36:1367-1373).
Extrahepatic manifestations of hepatitis C among United States male veterans
Authors: El-Serag Hashem B. , Hampel Howard , Yeh Christine , Rabeneck Linda
Published: March 2007

Hepatitis C virus (HCV) has been associated with several extrahepatic conditions. To date, most studies assessing these associations involved small numbers of patients and lacked a control group. Using the computerized databases of the Department of Veterans Affairs, we carried out a hospital-based case-control study that examined all cases of HCV-infected patients hospitalized during 1992 to 1999 (n = 34,204) and randomly chosen control subjects without HCV (n = 136,816) matched with cases on the year of admission. The inpatient and outpatient files were searched for several disorders involving the skin (porphyria cutanea tarda [PCT], vitiligo, and lichen planus); renal (membranous glomerulonephritis [GN] and membranoproliferative glomerulonephritis); hematologic (cryoglobulin, Hodgkin’s and non-Hodgkin’s lymphoma [NHL]); endocrine (diabetes, thyroiditis); and rheumatologic (Sjögren’s syndrome). The association between HCV and these disorders was examined in multivariate analyses that controlled for age, gender, ethnicity, and period of military service. Patients in the case group were younger in age (45 vs. 57 years), were more frequently nonwhite (39.6% vs. 26.3%), and were more frequently male (98.1% vs. 97.0%). A significantly greater proportion of HCV-infected patients had PCT, vitiligo, lichen planus, and cryoglobulinemia. There was a greater prevalence of membranoproliferative GN among patients with HCV but not membranous GN. There was no significant difference in the prevalence of thyroiditis, Sjögren’s syndrome, or Hodgkin’s or NHL. However, NHL became significant after age adjustment. Diabetes was more prevalent in controls than cases, but no statistically significant association was found after adjustment for age. In conclusion, we found a significant association between HCV infection and PCT, lichen planus, vitiligo, cryoglobulinemia, membranoproliferative GN, and NHL. Patients presenting with these disorders should be tested for HCV infection. (Hepatology2002;36:1439-1445).
Immunization With An Adjuvant Hepatitis B Vaccine After Liver Transplantation for Hepatitis B–Related Disease
Authors: Bienzle Ulrich , Günther Matthias , Neuhaus Ruth , Vandepapeliere Pierre , Vollmar Jens , Lun Andreas , Neuhaus Peter
Published: March 2007

Patients who undergo transplantation for hepatitis B virus (HBV)–related diseases are treated indefinitely with hepatitis B hyperimmunoglobulin (HBIG) to prevent endogenous HBV reinfection of the graft. Active immunization with standard hepatitis B vaccines in these patients has recently been reported with conflicting results. Two groups of 10 liver transplant recipients on continuous HBIG substitution who were hepatitis B surface antigen (HBsAg) positive and HBV DNA negative before transplantation were immunized in a phase I study with different concentrations of hepatitis B s antigen formulated with the new adjuvants 3–deacylated monophosphoryl lipid A (MPL) and Quillaja saponaria (QS21) (group I/vaccine A: 20 μg HBsAg, 50 μg MPL, 50 μg QS21; group II/vaccine B: 100 μg HBsAg, 100 μg MPL, 100 μg QS21). Participants remained on HBIG prophylaxis and were vaccinated at weeks 0, 2, 4, 16, and 18. They received 3 additional doses of vaccine B at bimonthly intervals if they did not reach an antibody titer against hepatitis B surface antigen (anti–HBs) greater than 500 IU/L. Sixteen (8 in each group) of 20 patients (80%) responded (group I: median, 7,293 IU/L; range, 721-45,811 IU/L anti–HBs; group II: median, 44,549 IU/L; range, 900-83, 121 IU/L anti–HBs) and discontinued HBIG. They were followed up for a median of 13.5 months (range, 6-22 months). The vaccine was well tolerated. In conclusion, most patients immunized with the new vaccine can stop HBIG immunoprophylaxis for a substantial, yet to be determined period of time. (Hepatology 2003;38:811-819).
Long–Term Interleukin 10 Therapy in Chronic Hepatitis C Patients Has A Proviral and Anti–Inflammatory Effect
Authors: Nelson David R. , Tu Zhengkun , Soldevila-Pico Consuelo , Abdelmalek Manal , Zhu Haizhen , Xu Yi Ling , Cabrera Roniel , Liu Chen , Davis Gary L.
Published: March 2007

An imbalance in Th1 and Th2 cytokine production is implicated in disease progression of HCV. Our aim was to determine the effect of IL–10 administration in patients with HCV–related liver disease. Thirty patients with advanced fibrosis who had failed antiviral therapy were enrolled in a 12–month treatment regimen with SQ IL–10 given daily or thrice weekly. Liver biopsies were performed before and after therapy. Serum and PBMC were collected for HCV RNA, ALT, and functional T–cell analysis. IL–10 led to significant improvement in serum ALT (mean ALT: day 0 = 142 ± 17 vs. month 12 = 75 ± 10; P < .05). Hepatic inflammation score decreased by at least 2 in 13 of 28 patients (mean decrease from 4.6 ± 0.3 to 3.7 ± 0.3, P < .05) and 11 of 28 showed a reduction in fibrosis score (mean change from 5.0 ± 0.2 to 4.5 ± 0.3, P < .05). Serum HCV RNA levels increased by 0.5 log during therapy (mean HCV RNA day 0: 12.3 ± 3.0 Meq/mL; 12 months: 38 Meq/mL; P < .05) and returned to baseline at the end of follow–up (11.0 ± 2.4 Meq/ml). Five patients developed viral loads of greater than 120 Meq/mL and two of these developed an acute flare in serum ALT. IL–10 caused a decrease in the number of HCV–specific CD4+ and CD8+ IFN–γ secreting T cells and alterations in PBMC cytokine production towards a Th2 dominant profile. These changes parallel the improvement in ALT and rise in HCV RNA. In conclusion, long–term rIL–10 therapy appears to decrease disease activity, but also leads to increased HCV viral burden via alterations in immunologic viral surveillance. (Hepatology 2003;38:859-868).
P38 Mapk Mediates Fibrogenic Signal Through Smad3 Phosphorylation in Rat Myofibroblasts
Authors: Furukawa Fukiko , Matsuzaki Koichi , Mori Shigeo , Tahashi Yoshiya , Yoshida Katsunori , Sugano Yasushi , Yamagata Hideo , Matsushita Masanori , Seki Toshihito , Inagaki Yutaka , Nishizawa Mikio , Fujisawa Junichi , Inoue Kyoichi
Published: March 2007

Hepatic stellate cells (HSCs) spontaneously transdifferentiate into myofibroblast (MFB)–phenotype on plastic dishes. This response recapitulates the features of activation in vivo. Transforming growth factor β (TGF–β) plays a prominent role in stimulating liver fibrogenesis by MFBs. In quiescent HSCs, TGF–β signaling involves TGF–β type I receptor (TβRI)–mediated phosphorylation of serine residues within the conserved SSXS motif at the C–terminus of Smad2 and Smad3. The middle linker regions of Smad2 and Smad3 also are phosphorylated by mitogenactivated protein kinase (MAPK). This study elucidates the change of Smad3–mediated signals during the transdifferentiation process. By using antibodies highly specific to the phosphorylated C–terminal region and the phosphorylated linker region of Smad3, we found that TGF–β–dependent Smad3 phosphorylation at the C–terminal region decreased, but that the phosphorylation at the linker region increased in the process of transdifferentiation. TGF–β activated the p38 MAPK pathway, further leading to Smad3 phosphorylation at the linker region in the cultured MFBs, irrespective of Smad2. The phosphorylation promoted hetero–complex formation and nuclear translocation of Smad3 and Smad4. Once combined with TβRI–phosphorylated Smad2, the Smad3 and Smad4 complex bound to plasminogen activator inhibitor–type I promoter could enhance the transcription. In addition, Smad3 phosphorylation mediated by the activated TβRI was impaired severely in MFBs during chronic liver injury, whereas Smad3 phosphorylation at the linker region was remarkably induced by p38 MAPK pathway. In conclusion, p38 MAPK—dependent Smad3 phosphorylation promoted extracellular matrix production in MFBs both in vitro and in vivo. (Hepatology 2003;38:879-889).
Interferon Alfa Down–Regulates Collagen Gene Transcription and Suppresses Experimental Hepatic Fibrosis in Mice
Authors: Inagaki Yutaka , Nemoto Tomoyuki , Kushida Miwa , Sheng Yin , Higashi Kiyoshi , Ikeda Kazuo , Kawada Norifumi , Shirasaki Fumiaki , Takehara Kazuhiko , Sugiyama Kota , Fujii Mitsukiyo , Yamauchi Hiroshi , Nakao Atsuhito , de Crombrugghe Benoit , Watanabe Tetsu , Okazaki Isao
Published: March 2007

The equilibrium between the production and degradation of collagen is rigorously controlled by a number of growth factors and cytokines. Interferon alfa (IFN–α) is now widely used for the treatment of chronic hepatitis C, which can improve serum levels of fibrotic markers and the degree of hepatic fibrosis, not only in patients who responded to therapy but also in those in whom it is ineffective. These findings may suggest that IFN–α possesses direct antifibrotic effects in addition to its antiviral activity. However, in contrast to IFN–γ, which has been shown to suppress collagen gene transcription, little is known about the mechanisms responsible for the antifibrotic effects of IFN–α. Here, we report that IFN–α, when administered into transgenic mice harboring the α2(I) collagen gene (COL1A2) promoter sequence, significantly repressed promoter activation and prevented the progression of hepatic fibrosis induced by carbon tetrachloride injection. Transient transfection assays indicated that IFN–α decreased the steady–state levels of COL1A2 messenger RNA (mRNA) and inhibited basal and TGF–β/Smad3–stimulated COL1A2 transcription in activated hepatic stellate cells (HSC). These inhibitory effects of IFN–α on COL1A2 transcription were exerted through the interaction between phosphorylated Stat1 and p300. Blocking of the IFN–α signal by overexpressing the intracellular domain–deleted IFN receptor increased basal COL1A2 transcription and abolished the inhibitory effects of IFN–α. In conclusion, our results indicate that IFN–α antagonizes the TGF–β/Smad3–stimulated COL1A2 transcription in vitro and suppresses COL1A2 promoter activation in vivo, providing a molecular basis for antifibrotic effects of IFN–α. (Hepatology 2003;38:890-899).
Human Hepatic Stellate Cells Show Features of Antigen–Presenting Cells and Stimulate Lymphocyte Proliferation
Authors: Viñas Odette , Bataller Ramón , Sancho-Bru Pau , Ginès Pere , Berenguer Cristina , Enrich Carlos , Nicolás Josep M. , Ercilla Guadalupe , Gallart Teresa , Vives Jordi , Arroyo Vicente , Rodés Juan
Published: March 2007

Following cell activation, hepatic stellate cells (HSCs) acquire proinflammatory and profibrogenic properties. We investigated whether activated HSCs also display immune properties. Here we show that cultured human HSCs express membrane proteins involved in antigen presentation, including members of the HLA family (HLA–I and HLA–II), lipid–presenting molecules (CD1b and CD1c), and factors involved in T–cell activation (CD40 and CD80). Exposure of HSCs to proinflammatory cytokines markedly up–regulates these molecules. Importantly, cells freshly isolated from human cirrhotic livers (in vivo activated HSCs) highly express HLA–II and CD40, suggesting that HSCs can act as antigen–presenting cells (APCs) in human fibrogenesis. We also explored whether human HSCs can efficiently process exogenous antigens. Activated HSCs internalize low– and high–molecular–weight dextran and transferrin, indicating that they can perform fluid–phase and receptor–mediated endocytosis. Moreover, HSCs can perform phagocytosis of macromolecules because they internalize latex particles as well as bacteria. Interestingly, both culture–activated and in vivo activated HSCs express high levels of CD68, a protein involved in antigen trafficking. Finally, we studied whether HSCs modulate T–lymphocyte proliferation. In basal conditions, coculture of irradiated HSCs barely induces allogeneic T–lymphocyte proliferation. However, cytokine–stimulated HSCs stimulate the allogeneic T–lymphocyte response in an HLA–II—dependent manner. In conclusion, human activated HSCs express molecules for antigen presentation, internalize macromolecules, and modulate T–lymphocyte proliferation. These results suggest that HSCs may play a role in the immune function of the liver. (Hepatology 2003;38:919-929).
Feedback Regulation of Bile Acid Synthesis in Primary Human Hepatocytes: Evidence That Cdca Is the Strongest Inhibitor
Authors: Ellis Ewa , Axelson Magnus , Abrahamsson Anna , Eggertsen Gösta , Thörne Anders , Nowak Grzegorz , Ericzon Bo-Göran , Björkhem Ingemar , Einarsson Curt
Published: March 2007

Primary human hepatocytes were used to elucidate the effect of individual bile acids on bile acid formation in human liver. Hepatocytes were treated with free as well as glycine–conjugated bile acids. Bile acid formation and messenger RNA (mRNA) levels of key enzymes and the nuclear receptor short heterodimer partner (SHP) were measured after 24 hours. Glycochenodeoxycholic acid (GCDCA; 100 μmol/L) significantly decreased formation of cholic acid (CA) to 44% ± 4% of controls and glycodeoxycholic acid (GDCA) decreased formation of CA to 67% ± 11% of controls. Glycoursodeoxycholic acid (GUDCA; 100 μmol/L) had no effect. GDCA or glycocholic acid (GCA) had no significant effect on chenodeoxycholic acid (CDCA) synthesis. Free bile acids had a similar effect as glycine–conjugated bile acids. Addition of GCDCA, GDCA, and GCA (100 μmol/L) markedly decreased cholesterol 7α–hydroxylase (CYP7A1) mRNA levels to 2% ± 1%, 2% ± 1%, and 29% ± 11% of controls, respectively, whereas GUDCA had no effect. Addition of GDCA and GCDCA (100 μmol/L) significantly decreased sterol 12α–hydroxylase (CYP8B1) mRNA levels to 48% ± 5% and 61% ± 4% of controls, respectively, whereas GCA and GUDCA had no effect. Addition of GCDCA and GDCA (100 μmol/L) significantly decreased sterol 27–hydroxylase (CYP27A1) mRNA levels to 59% ± 3% and 60% ± 7% of controls, respectively, whereas GUDCA and GCA had no significant effect. Addition of both GCDCA and GDCA markedly increased the mRNA levels of SHP to 298% ± 43% and 273% ± 30% of controls, respectively. In conclusion, glycine–conjugated and free bile acids suppress bile acid synthesis and mRNA levels of CYP7A1 in the order CDCA > DCA > CA > UDCA. mRNA levels of CYP8B1 and CYP27A1 are suppressed to a much lower degree than CYP7A1. (Hepatology 2003;38:930–938).
Effects of Cell Proliferation on the Uptake of Transferrin–Bound Iron by Human Hepatoma Cells
Authors: Lee Adrian W.M. , Oates Phillip S. , Trinder Deborah
Published: March 2007

The effects of cellular proliferation on the uptake of transferrin–bound iron (Tf–Fe) and expression of transferrin receptor–1 (TfR1) and transferrin receptor–2 (TfR2) were investigated using a human hepatoma (HuH7) cell line stably transfected with TfR1 antisense RNA expression vector to suppress TfR1 expression. At transferrin (Tf) concentrations of 50 nmol/L and 5 μmol/L, when Tf–Fe uptake occurs by the TfR1– and TfR1–independent (NTfR1)–mediated process, respectively, the rate of Fe uptake by proliferating cells was approximately 250% that of stationary cells. The maximum rate of Fe uptake by the TfR1– and NTfR1–mediated process by proliferating cells was increased to 200% and 300% that of stationary cells, respectively. The maximum binding of Tf by both TfR1– and NTfR1–mediated processes by proliferating cells was increased significantly to 160% that of stationary cells. TfR1 and TfR2–α protein levels expressed by proliferating cells was observed to be approximately 300% and 200% greater than the stationary cells, respectively. During the proliferating growth phase, expression of TfR1 messenger RNA (mRNA) increased to 300% whereas TfR2–α mRNA decreased to 50% that of stationary cells. In conclusion, an increase in Tf–Fe uptake by TfR1–mediated pathway by proliferating cells was associated with increased TfR1 mRNA and protein expression. An increase in Tf–Fe uptake by NTfR1–mediated pathway was correlated with an increase in TfR2–α protein expression but not TfR2–α mRNA. In concluion, TfR2–α protein is likely to have a role in the mediation of Tf–Fe uptake by the NTfR1 process by HuH7 hepatoma cell in proliferating and stationary stages of growth. (Hepatology 2003;38:967-977).
A simple set of numerical invariants for the analysis of images
Authors: Shahshahani Mehrdad , Targhi Alireza Tavakoli
Published: March 2007

A new invariant, which captures some of the perceptual and conceptual features in an image is introduced. The effectiveness of the invariant is demonstrated empirically through applications to images. It is shown that extraneous objects in a texture environment can be detected and parts of a single image with distinct structural features are distinguished and separated. The invariants are not sensitive to local perturbations. Changes in the lighting or the orientation do not reduce their effectiveness. The method is based on the variation of local statistical properties of a single image and makes no use of memory or training. © 2007 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 16, 240–248, 2006
Protective effect of diphenylmethyl selenocyanate against CCl4‐induced hepatic injury
Authors: Das Rajat Kumar , Hossain Sk. Ugir , Bhattacharya Sudin
Published: March 2007

Organoselenocyanates represent an important class of chemopreventive agent, which possess antioxidative, antimutagenic as well as cancer chemopreventive properties. The present study is an attempt to evaluate the protective effect of diphenylmethyl selenocyanate — a synthetic organoselenocyanate against carbon tetrachloride (CCl4)‐induced hepatic damage in Swiss albino mice in vivo.

Mice were pretreated with the Se‐compound orally in a duration dependent manner (7 and 15 days) to observe its protective action against an acute toxic dose (24 h) of CCl4 (single injection at a dose of 20 µl and 50 µl kg−1 b.w.) that induced hepatic necrosis and caused DNA damage (strand breaks) in the hepatocytes.

This study revealed that pretreatment with the Se‐compound reduced the extent of massive hepatic necrosis in a duration dependent manner, but it had no modulatory effect on hepatocellular apoptosis caused by acute toxic doses of CCl4. It was also found that the Se‐compound could significantly (P < 0.01) prevent the CCl4‐induced elevation of DNA damage in hepatocytes measured by comet assay in a duration dependent manner.

So these findings will further strengthen the view that organoselenocyanate is an effective chemopreventive agent against acute hepatic damage, caused by halogenated alkanes such as CCl4. Copyright © 2007 John Wiley & Sons, Ltd.
Strong correlation between summer temperature and pollen accumulation rates for Pinus sylvestris, Picea abies and Betula spp. in a high‐resolution record from northern Sweden
Authors: Barnekow L. , Loader N. J. , Hicks S. , Froyd C. A. , Goslar T.
Published: March 2007

Highly resolved pollen spectra analysed from a 47 cm peat monolith recovered from a mire in northern Sweden exhibit climatic sensitivity in the pollen accumulation rates (PAR) of boreal treeline species. Robust temporal control, afforded through multiple AMS radiocarbon dating of the post‐atomic‐bomb‐test period (AD 1961–2002), provides a unique opportunity to compare pollen accumulation rates with the instrumental meteorological record. Strong correlations are observed between summer temperature and PAR for Pinus sylvestris, Picea abies and Betula spp. (excluding B. nana). Despite well constrained, contiguous (‘annual’) sampling, the temporal resolution of the pollen signal preserved within each sample appears to be degraded to ca. 3–5 year resolution. This is likely to reflect processes occurring during peat accumulation and pollen deposition, as well as dating uncertainties and the effects of subsampling. These findings identify limitations to the maximum resolution that may realistically be recovered from the peat archive using high‐resolution sampling protocols and AMS 14C dating. We also identify the need for additional work to quantify the role of climate on peat accumulation and the resultant impact on assemblage‐based palaeoenvironmental reconstructions within mire sequences. The strongest climate association observed for Picea abies (r = 0.53; n = 36) was extended through the monolith beyond the 42 year period of ‘annual’ sampling and the response successfully correlated with the Bottenviken historical instrumental record to AD 1860. Although only presenting data from a single site, and requiring wider replication, we conclude that for sites close to the ecological limits of tree species, where levels of anthropogenic/non‐climatic forcing on pollen production are low, well‐dated records of PAR may potentially provide a proxy for reconstructing past summer temperature variability. Copyright © 2007 John Wiley & Sons, Ltd.
Existence of EF‐equivalent non‐isomorphic models
Authors: Havlin Chanoch , Shelah Saharon
Published: March 2007

We prove the existence of pairs of models of the same cardinality λ which are very equivalent according to EF games, but not isomorphic. We continue the paper [4], but we do not rely on it. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)