bluuebunny/crossref_metadata_2025 huggingface dataset:
Firm‐like behavior of journals? Scaling properties of their output and impact growth dynamics
Authors: Havemann Frank , Heinz Michael , Wagner‐Döbler Roland
Published: August 2004

In the study of growth dynamics of artificial and natural systems, the scaling properties of fluctuations can exhibit information on the underlying processes responsible for the observed macroscopic behavior according to H.E. Stanley and colleagues (Lee, Amaral, Canning, Meyer, & Stanley, 1998; Plerou, Amaral, Gopikrishnan, Meyer, & Stanley, 1999; Stanley et al., 1996). With such an approach, they examined the growth dynamics of firms, of national economies, and of university research fundings and paper output. We investigated the scaling properties of journal output and impact according to the Journal Citation Reports (JCR; ISI, Philadelphia, PA) and find distributions of paper output and of citations near to lognormality. Growth rate distributions are near to Laplace “tents,” however with a better fit to Subbotin distributions. The width of fluctuations decays with size according to a power law. The form of growth rate distributions seems not to depend on journal size, and conditional probability densities of the growth rates can thus be scaled onto one graph. To some extent even quantitatively, all our results are in agreement with the observations of Stanley and others. Further on, a Matthew effect of journal citations is confirmed. If journals “behave” like business firms, a better understanding of Bradford's Law as a result of competition among publishing houses, journals, and topics suggests itself.
MoF6 and WF6: Nonrigid Molecules?
Authors: Quiñones Gustavo Santiso , Hägele Gerhard , Seppelt Konrad
Published: August 2004

Calculations reveal that the octahedral–trigonal prismatic–octahedral rearrangement has particularly low‐energy barriers for MoF6, WF6, and (hypothetical) CrF6. Experimental evidence is obtained from the dynamic 19F NMR spectra of the derivatives CF3CH2OMoF5, CF3CH2OWF5, C6F5OMoF5, C6F5OWF5, and (CF3)3COWF5. The ground‐state structure of all these compounds is octahedral; at elevated temperatures the nonequivalent metal‐bound fluorine atoms undergo an intramolecular exchange. The exchange mechanism could be a 3+3 or a 2+4 twist; calculations favor the 3+3 twist.
Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate‐specific antigen level after radical prostatectomy and/or radiation therapy
Authors: Smith Matthew R. , Manola Judith , Kaufman Donald S. , George Daniel , Oh William K. , Mueller Elisabetta , Slovin Susan , Spiegelman Bruce , Small Eric , Kantoff Philip W.
Published: August 2004

BACKGROUND

The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator‐activated receptor γ agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable.

METHODS

Men with histologically confirmed prostate carcinoma, no recent hormone therapy, a rising serum PSA level after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases were assigned randomly to receive either oral rosiglitazone (4 mg twice daily) or placebo. The treatment was continued until the men developed disease progression or adverse effects. A positive outcome was defined as a posttreatment PSADT > 150% the baseline PSADT and no new metastases.

RESULTS

One hundred six men were enrolled. The median treatment duration was 315 days for men in the placebo group and 338 days for men in the rosiglitazone group (P = 0.28). Forty percent of men in the in the placebo group and 38% of men in the rosiglitazone group had a posttreatment PSADT > 150% of the baseline PSADT and no new metastases (P = 1.00). In exploratory analyses, the rate of a positive outcome remained higher than expected in the placebo group, even when a positive outcome was redefined using more stringent criteria. The time to disease progression was similar between the groups.

CONCLUSIONS

Rosiglitazone did not increase PSADT or prolong the time to disease progression more than placebo in men with a rising PSA level after radical prostatectomy and/or radiation therapy. The unexpected discordance between baseline and posttreatment PSADT in the placebo group reinforced the importance of randomized controlled trials in this setting. Cancer 2004. © 2004 American Cancer Society.
Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma
Authors: Chen Wendy Y. , Hankinson Susan E. , Schnitt Stuart J. , Rosner Bernard A. , Holmes Michelle D. , Colditz Graham A.
Published: August 2004

BACKGROUND

Observational studies and randomized trials have demonstrated that hormone replacement therapy (HRT) increases the recipient's risk of developing breast carcinoma. Because it is known that some breast malignancies are hormonally responsive and that others are not, it has been hypothesized that HRT may be associated with the development of estrogen receptor (ER)‐positive/progesterone receptor (PR)‐positive breast carcinoma more so than with the development of ER‐negative/PR‐negative breast carcinoma.

METHODS

The Nurses' Health Study is a prospective cohort study that enrolled 121,700 female registered nurses ages 30–55 years in 1976. In the current study, the authors analyzed 2548 malignancies that developed among eligible postmenopausal women in that cohort between 1980 and 2000 and for which data on ER and PR status were available.

RESULTS

Compared with women who had never used HRT, current long‐term users of HRT were more likely to develop ER‐positive/PR‐positive breast carcinoma (multivariate risk ratio [RR], 1.80; 95% confidence interval [CI], 1.52–2.12) but were not any more likely to develop ER‐negative/PR‐negative disease (multivariate RR, 1.00; 95% CI, 0.72–1.39). This effect grew stronger with increasing duration of current HRT use and was also more pronounced among women with body mass index < 25 kg/m2. Furthermore, the association between HRT use and ER‐positive/PR‐positive disease was stronger among patients receiving combined HRT (CHRT) regimens, which included estrogen and progesterone, than among users of estrogen alone (ERT). In addition, tumors tended to develop more quickly in current users of CHRT than in ERT users.

CONCLUSIONS

The finding that current users of HRT were more likely to develop ER‐positive/PR‐positive tumors than they were to develop ER‐negative/PR‐negative ones suggests that both endogenous and exogenous hormonal factors may influence breast tumor characteristics. In analyses of the effects of hormonal factors on breast tumor development, ER‐positive/PR‐positive tumors and ER‐negative/PR‐negative tumors should be considered separately from each other Cancer 2004. © 2004 American Cancer Society.
Clinical relevance of immunophenotype in a retrospective comparative study of 297 peripheral T‐cell lymphomas, unspecified, and 496 diffuse large B‐cell lymphomas
Authors: Morabito Fortunato , Gallamini Andrea , Stelitano Caterina , Callea Vincenzo , Guglielmi Cesare , Neri Santo , Lazzaro Antonio , Orsucci Lorella , Ilariucci Fiorella , Sacchi Stefano , Vitolo Umberto , Federico Massimo
Published: August 2004

BACKGROUND

To assess the impact of T‐cell/B‐cell phenotype on clinical outcome, the authors retrospectively compared patients who had peripheral T‐cell lymphoma, unspecified (PTCL‐U), with patients who had diffuse large B‐cell lymphoma (DLBCL).

METHODS

Two hundred ninety‐seven cases of PTCL‐U and 496 cases of DLBCL that had been transferred from the files of the Intergruppo Italiano Linfomi or the Gruppo Italiano Linfomi were integrated into a unique working file and reviewed by the authors.

RESULTS

The PTCL‐U group and the DLBCL group had significantly different distribution patterns with respect to patient age, gender, disease stage, performance status (PS), the presence or absence of systemic “B” symptoms, the presence or absence of bulky disease, lactic acid dehydrogenase (LDH) levels, and number of extranodal sites (ENS). A significantly greater number of patients in the DLBCL group experienced complete remission (P < 0.0001). Multinomial logistic regression analysis confirmed that immunophenotype, PS, LDH concentration, and number of ENS were independent predictors of response. At a median follow‐up duration of 43 months, there was no observable difference in disease‐free survival (DFS) between patients with DLBCL and patients with PTCL‐U; however, multivariate analysis did reveal that poorer PS and bone marrow involvement were significantly associated with shorter DFS. Furthermore, although the overall survival (OS) curves associated with the T‐cell and B‐cell immunophenotypes were significantly different from each other at a median follow‐up duration of 37 months (P = 0.0012), Cox multivariate analysis excluded immunophenotype from the final OS model.

CONCLUSIONS

The findings made in the current study indicate that the natural history of PTCL‐U may differ from that of DLBCL. Patients with PTCL‐U tended to have less favorable clinical outcomes, although the observed difference in outcome was only partially attributable to immunophenotype, which was independently associated with response, but not with survival. Differences in prognostic factor distributions between patients with PTCL‐U and patients with DLBCL may account for some portion of the expected phenotype‐associated risk. Cancer 2004. © 2004 American Cancer Society
Glucocorticoid administration in antiemetic therapy
Authors: Münstedt Karsten , Borces Dennis , Bohlmann Michael K. , Zygmunt Marek , von Georgi Richard
Published: August 2004

BACKGROUND

Although glucocorticoids are often used in cancer therapy, in particular to enhance the effectiveness of antiemetic therapy, they have been associated with impaired tumor apoptosis and an increased frequency of metastases in some reports. The current study aimed to determine whether glucocorticoid treatment had an adverse effect on outcomes in patients with ovarian carcinoma.

METHODS

Records of patients with ovarian carcinoma who were scheduled to receive at least six courses of systemic chemotherapy were reviewed. Patients were grouped into those who had or had not received corticosteroid medication as a part of general antiemetic prophylaxis before chemotherapy, and details of hematologic parameters during treatment and disease recurrence‐free and overall survival were recorded.

RESULTS

Altogether, 245 patients with ovarian carcinoma had received chemotherapy. Of these, 62 had been given concurrent glucocorticoid treatment and 183 had not. The two patient groups were well balanced with respect to disease stage and other prognostic factors. Kaplan–Meier analyses showed no significant differences in survival between the groups. Patients who received glucocorticoid treatment had significantly higher leukocyte values in the days immediately after chemotherapy, higher nadir leukocyte values, and higher counts before subsequent courses of chemotherapy (P < 0.01; Levene test, t test) compared with patients who did not receive glucocorticoid treatment. As a result, the initial treatment targets were achieved significantly more often in the glucocorticoid group (P = 0.007; chi‐square test).

CONCLUSIONS

There was no evidence that glucocorticoid treatment had a negative effect on outcomes in these patients. Glucocorticoids may exert protective effects on the bone marrow. Cancer 2004. © 2004 American Cancer Society.
Lung adenocarcinoma and human papillomavirus infection
Authors: Chen Yen‐Ching , Chen Jen‐Hau , Richard Kradin , Chen Pao‐Yang , Christiani David C.
Published: August 2004

Over the past three decades, the incidence of lung adenocarcinoma has increased worldwide. Most individuals with lung adenocarcinoma (especially women) are nonsmokers. Reported risk factors for the development of lung adenocarcinoma include cigarette smoking; exposure to cooking fumes, air pollution, second‐hand smoke, asbestos, and radon; nutritional status; genetic susceptibility; immunologic dysfunction; tuberculosis infection; and asthma. Human papillomavirus (HPV) infection is a known risk factor for the development of squamous cell carcinoma (SCC), but it has not been thoroughly assessed as a potential risk factor for the development of pulmonary adenocarcinoma. More than 50% of people are infected with HPV during their lifetimes, either via intrauterine or postnatal infection. Recent studies involving Taiwanese patients have demonstrated a possible association between HPV infection and the risk of developing pulmonary adenocarcinoma. HPV transmission pathways have not yet been conclusively identified. The observation of certain types of HPV in association with cervical and oral SCC raises the possibility of sexual transmission of HPV from the cervix to the oral cavity, with subsequent transmission to the larynx and then to the lung. HPV infection and metaplasia in lung tissue may increase an individual's susceptibility to the tumorigenesis of pulmonary adenocarcinoma. Further epidemiologic and pathologic investigations will be necessary to establish a causal relation. Cancer 2004. © 2004 American Cancer Society.
Assessing fatigue in persons with cancer
Authors: Wu Horng‐Shiuann , McSweeney Maryellen
Published: August 2004

BACKGROUND

Cancer‐related fatigue (CRF) is a highly prevalent, subjective experience of patients with and survivors of cancer. Effective assessment of the attributes of CRF from the patient's perspective is essential. The current study developed a measure of CRF from the patient's perspective and determined its psychometric properties for patients with cancer undergoing chemotherapy.

METHODS

Chemotherapy outpatients in a free‐standing metropolitan area cancer clinic participated in the current multiphase study. In the instrument development phase, 42 items were generated from a qualitative study with 10 semistructured individual interviews and 6 daily fatigue diaries. These items were revised based on content evaluation by 20 cancer patient content experts. In the instrument analysis phase, the 30 content‐validated items were pilot tested by 30 patients with breast carcinoma using cognitive interview techniques. The psychometric properties of the resulting 16‐item, 5‐point CRF rating scale were tested with 82 patients with breast carcinoma.

RESULTS

Principal axis factoring gave a one‐factor solution accounting for 59% variance. Coefficient alpha reliability was 0.95 for the final 15‐item scale. Convergent validity with the Schwartz Cancer Fatigue Scale was 0.84, concurrent validity with the Geriatric Depression Scale was 0.61, and predictive validity with the Cancer‐Related Fatigue Distress Scale was 0.83.

CONCLUSIONS

This newly developed instrument to assess the subjective fatigue symptoms of patients with cancer demonstrated effective use of diary and interview methods in instrument development and both cognitive interviewing and traditional psychometric techniques in instrument analysis. The instrument has promising psychometric properties, but confirmatory testing is needed. Cancer 2004. © 2004 American Cancer Society.
A gene signature of inhibitory MHC receptors identifies a BDCA3+ subset of IL‐10‐induced dendritic cells with reduced allostimulatory capacity in vitro
Authors: Velten Florian W. , Duperrier Karine , Bohlender Johannes , Metharom Patraporn , Goerdt Sergij
Published: August 2004

Dendritic cells (DC) are crucial gatekeepers in regulating immunity. Whereas mature immunostimulatory myeloid DC (DCims) potently promote immune responses, IL‐10‐induced myeloid DC (DC‐IL‐10) counteract T cell activation. To elucidate the molecular repertoire by which DC‐IL‐10 secure reduced T cell activation, comparative gene expression profiling was done using Affymetrix U133A microarrays. Among the genes overexpressed in DC‐IL‐10, eight immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐containing inhibitory molecules (ILT2, ILT3, ILT4, ILT5, DCIR, PILRA, FcγRIIB, SLAM) were found. Phenotypic analysis of DC‐IL‐10 defined an ILThigh DC subset further characterized by expression of CD14, TLR2, DC‐SIGN, and CD123 and the lack of lymphocyte, monocyte/macrophage, and plasmacytoid DC markers such as CD3, CD8, and CD68. A unique feature of the ILThigh DC subset was expression of the novel DC marker BDCA3, which was not detected on monocytes, immature DC, DCims, or ILTlow DC‐IL‐10. While the allogeneic T cell proliferation induced by the entire DC‐IL‐10 population was approximately 30% of that stimulated by DCims, allogeneic MLR responses driven by the ILThigh DC subset were reduced to 8% of the allostimulatory capacity of DCims, although secretion of the inhibitory cytokine IL‐10 and other Th1/Th2‐associated cytokines was similar in these cells.
Expression of housekeeping and immunoproteasome subunit genes is differentially regulated in positively and negatively selecting thymic stroma subsets
Authors: Nil Ahmed , Firat Elke , Sobek Vera , Eichmann Klaus , Niedermann Gabriele
Published: August 2004

The expression of housekeeping and/or immunoproteasomes in isolated thymic stroma subsets has so far not been analyzed but may have important consequences for self peptide repertoires presented by MHC class I molecules during positive and negative thymic selection. Here we determined the expression of housekeeping and immunoproteasome β subunits and of PA28 in positively and negatively selecting stroma subsets. Positively selecting cortical thymic epithelial cells (cTEC) expressed only housekeeping but no immunoproteasome β subunit mRNA and proteins. However, immunoproteasome β subunits could be induced in cTEC by infection withListeria monocytogenesor injection of IFN‐γ. In negatively selecting stroma including medullary epithelial cells and dendritic cells, incomplete and low representation of housekeeping β subunit proteins but high and complete expression of immunoproteasome β subunit proteins suggests absence of proper housekeeping proteasomes and predominance of immunoproteasomes. Expression of immunoproteasome β subunits in negatively selecting stroma was independent of IFN‐γ receptor as shown in knockout (KO) mice. Absence of LMP2 altered thymic selection of the MHC class I‐restricted transgenic P14 TCR in KO mice. The data suggest that negative selection may primarily involve immunoproteasome peptide repertoires and that peripheral infection may influence peptide repertoires involved in positive selection.
Detection of low‐frequency human antigen‐specific CD4+ T cells using MHC class II multimer bead sorting and immunoscope analysis
Authors: Lemaître Fabrice , Viguier Manuelle , Cho Min‐Sun , Fourneau Jean‐Marie , Maillère Bernard , Kourilsky Philippe , van Endert Peter M. , Ferradini Laurent
Published: August 2004

MHC class II tetramers are attractive tools to study antigen‐specific CD4+ T cell responses in various clinical situations in humans. HLA‐DRA1*0101/DRB1*0401 MHC class II heterodimers were produced as empty molecules using the Drosophila melanogaster expression system. Peptide binding experiments revealed that these molecules could be loaded efficiently with appropriate MHC class II tumor epitopes. Interestingly, MHC class II tetramer staining was influenced by modifications in membrane lipid rafts, and could in itself induce activation changes of stained CD4+ T cells at 37°C. In order to increase the threshold of detection of poorly represented peripheral antigen‐specific CD4+ T cells, we combined cell sorting using MHC class II multimer beads together with TCR analysis using the immunoscope technology. This strategy greatly increased the sensitivity of detection of specific CD4+ T cells to frequencies as low as 4×10–6 among peripheral blood mononuclear cells. Such a combined approach may have promising applications in the immunomonitoring of patients under vaccination protocols to tightly follow induced antigen‐specific CD4+ T cells expressing previously identified TCR.
Frequent expression of the natural killer cell receptor KLRG1 in human cord blood T cells: correlation with replicative history
Authors: Marcolino Isabel , Przybylski Grzegorz K. , Koschella Marie , Schmidt Christian A. , Voehringer David , Schlesier Michael , Pircher Hanspeter
Published: August 2004

The killer cell lectin‐like receptor G1 (KLRG1) belongs to the family of inhibitory C‐type lectins that are encoded in the NK gene complex. Similar to other inhibitory NK cell receptors, KLRG1 expression in adult peripheral blood lymphocytes is restricted to NK cells and to antigen‐experienced T cells. Umbilical cord blood T cells are thought to represent an homogenous pool of naive T cells. Surprisingly, we identified substantial subsets of CD4 (∼ 30%) and CD8 (∼ 20%) αβ T cells in cord blood that expressed KLRG1. In contrast to T cells in adult, KLRG1+ T cells in cord blood exhibited predominantly a naive CCR7+CD45RA+ and CD11alow phenotype. After birth, KLRG1 expression in T cells from peripheral blood decreased rapidly to reappear in effector/memory T cells in adults. KLRG1+ T cells in cord blood expressed a diverse T cell receptor β (TCRβ) repertoire and the cells proliferated normally, in contrast to KLRG1+ T cells from adults. Finally, examination of T cell receptor excision circles (TREC) indicated that KLRG1 expression discriminated between cord blood T cells that differed in their post‐thymic expansion rate. Thus, analysis of KLRG1 expression in cord blood revealed an unexpected heterogeneity of human T cells in newborns.
A unique pattern of up‐ and down‐regulation of chemokine receptor CXCR3 on inflammation‐inducing Th1 cells
Authors: Chen Jun , Vistica Barbara P. , Takase Hiroshi , Ham Don II , Fariss Robert N. , Wawrousek Eric F. , Chan Chi‐Chao , DeMartino Julie A. , Farber Joshua M. , Gery Igal
Published: August 2004

Chemokine receptor CXCR3 and its CXC ligands play major roles in Th1 cell‐induced inflammatory processes. Here, we examined the expression of CXCR3 by TCR‐transgenic Th1 lymphocytes that induce ocular inflammation in mice expressing the target antigen in their lenses. The essential role of CXCR3 in this model was indicated by the observation that the ocular inflammation was significantly blocked by an antibody against this receptor. CXCR3 expression by Th1 cells was elevated during their initial activation in culture and further increased during the consecutive incubation with IL‐2. However, CXCR3 expression declined dramatically during the ensuing antigenic reactivation, in parallel with down‐regulation of its mRNA. Yet, reactivated Th1 cells exhibited the highest degree of pathogenicity when adoptively transferred into recipients. Transferred reactivated Th1 cells proliferated vigorously and re‐expressed CXCR3 while residing in the spleen of recipient mice, reaching ∼85% positivity 4 days post cell transfer when their massive migration to the target eyes began. Importantly, infiltrating Th1 cells underwent profound phenotypic changes in the eye that closely resembled those seen during reactivation of Th1 cells in vitro and included down‐regulation of CXCR3. These observations thus show that expression of CXCR3, a major participant in Th1‐induced inflammation, fluctuates profoundly during cell activation and migration and is down‐regulated upon re‐exposure of these cells to the antigen, in vitro or in the target organ.
Methyl Substitution of Aluminum−Hydride Bonds in a Carbaalane and an Aluminum Imide
Authors: Stasch Andreas , Shravan Kumar S. , Jancik Vojtech , Roesky Herbert W. , Magull Jörg , Noltemeyer Mathias
Published: August 2004

The methylated compounds [(AlMe)6(AlNMe3)2(CCH2Ph)6] (4), [(AlMe)6(AlNMe3)2(CCH2CH2SiMe3)6] (5) and [(AlMe)6(NCH2C4H3S)6] (6) were synthesized in good yields from the corresponding hydride derivatives by treatment with AlMe3 in toluene. The X‐ray single crystal structures of 4·xC7H8, 4·4C7H8 and 6 were determined. In 4·xC7H8 the solvent molecules are arranged in infinite channels along the c axis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
A comparison of temperature density forecasts from GARCH and atmospheric models
Authors: Taylor James W. , Buizza Roberto
Published: August 2004

Density forecasts for weather variables are useful for the many industries exposed to weather risk. Weather ensemble predictions are generated from atmospheric models and consist of multiple future scenarios for a weather variable. The distribution of the scenarios can be used as a density forecast, which is needed for pricing weather derivatives. We consider one to 10‐day‐ahead density forecasts provided by temperature ensemble predictions. More specifically, we evaluate forecasts of the mean and quantiles of the density. The mean of the ensemble scenarios is the most accurate forecast for the mean of the density. We use quantile regression to debias the quantiles of the distribution of the ensemble scenarios. The resultant quantile forecasts compare favourably with those from a GARCH model. These results indicate the strong potential for the use of ensemble prediction in temperature density forecasting. Copyright © 2004 John Wiley & Sons, Ltd.
Forecasting the Treasury's balance at the Fed
Authors: Thornton Daniel L.
Published: August 2004

As part of the Fed's daily operating procedure, the Federal Reserve Bank of New York, the Board of Governors and the Treasury make a forecast of that day's Treasury balance at the Fed. These forecasts are an integral part of the Fed's daily operating procedure. Errors in these forecasts can generate variation in reserve supply and, consequently, the federal funds rate. This paper evaluates the accuracy of these forecasts. The evidence suggests that each agency's forecast contributes to the optimal, i.e., minimum variance, forecast and that the Trading Desk of the Federal Reserve Bank of New York incorporates information from all three of the agency forecasts in conducting daily open market operations. Moreover, these forecasts encompass the forecast of an economic model. Copyright © 2004 John Wiley & Sons, Ltd.
Quality of life in patients with primary biliary cirrhosis
Authors: Poupon Renée Eugénie , Chrétien Yves , Chazouillères Olivier , Poupon Raoul , Chwalow Judith
Published: August 2004

The impact of primary biliary cirrhosis (PBC) on health-related quality of life (HRQOL) is poorly documented. We assessed quality of life in a group of 276 unselected patients with PBC using the Nottingham Health Profile (NHP). This is a generic scale that assesses six major areas commonly associated with HRQOL. Data were compared with those of a sex- and age-matched control group. The associations between NHP scores and the severity of PBC were tested. Patients (86% women) had a median age of 62 years (range 33-87). Most patients were treated with UDCA. PBC patients showed a strong statistically significant difference in energy compared to controls (respectively, 40.6 vs. 22.9, P < .0001) and had worse scores for emotional reactions (22.2 vs. 16.1, P < .005). No other differences were observed. No associations of the dimension subscores were found with biochemical liver tests, histological stages, or duration of the disease. Among the signs or symptoms, fatigue was the finding most often associated with the dimension subscores. In conclusion, patients with PBC feel that their overall quality of life is worse than that of the control population. This difference is mainly due to the decrease in the subscores of energy and emotional reactions, both associated with fatigue. These effects must be taken into account by clinicians when treating these patients, as they constitute the clinical outcomes that have the most impact on patients’ lifestyle and adherence to treatment. (Hepatology 2004;40:489-494.)
Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease
Authors: Toivola Diana M. , Ku Nam-On , Resurreccion Evelyn Z. , Nelson David R. , Wright Teresa L. , Omary Bishr M.
Published: August 2004

Keratin 8 and 18 (K8/18) phosphorylation plays a significant and site-specific role in regulating keratin filament organization, association with binding proteins, and modulation of cell cycle progression. Keratin hyperphosphorylation correlates with exposure to a variety of stresses in cultured cells and in mouse models of liver, pancreatic, and gallbladder injury, and it is found in association with mouse and human Mallory bodies. We asked whether K8/18 phosphorylation correlates with human liver disease progression by analyzing liver explants and biopsies of patients with chronic noncirrhotic hepatitis C virus (HCV) or cirrhosis. We also examined the effect of HCV therapy with interleukin-10 on keratin phosphorylation. Using site-specific antiphosphokeratin antibodies we found keratin hyperphosphorylation on most K8/18 sites in all cirrhotic liver explants tested and in most liver biopsies from patients with chronic HCV infection. Immunofluorescence staining of precirrhotic HCV livers showed focal keratin hyperphosphorylation and limited reorganization of keratin filament networks. In cirrhotic livers, keratin hyperphosphorylation occurred preferentially in hepatic nodule cells adjacent to bridging fibrosis and associated with increased stress kinase activation and apoptosis. Histological and serological improvement after interleukin-10 therapy was accompanied by normalization of keratin hyperphosphorylation on some sites in 7 of 10 patients. In conclusion, site-specific keratin phosphorylation in liver disease is a progression marker when increased and a likely regression marker when decreased. (Hepatology 2004;40:459-466.)
Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice
Authors: McCuskey Robert S. , Ito Yoshiya , Robertson Graham R. , McCuskey Margaret K. , Perry Michael , Farrell Geoffrey C.
Published: August 2004

In alcoholic steatohepatitis, hepatic microvascular changes have pathogenic significance for hepatocellular function, perisinusoidal fibrosis, and portal hypertension. It is unclear whether similar changes occur in other forms of steatohepatitis. We therefore examined whether hepatic microvascular dysfunction occurs in fibrosing steatohepatitis induced by feeding mice a high-fat methionine- and choline-deficient (MCD) diet. Using in vivo microscopic—as well as histological and electron microscopic—methods, together with measurements of alanine aminotransferase (ALT), lipid content, and oxidative stress, hepatic microvascular structure and function were studied in relation to inflammatory and fibrotic changes during evolution of steatohepatitis. At 3 weeks of MCD diet intake, serum ALT was elevated and hepatic steatosis was pronounced. By 5 weeks, necroinflammatory change was noteworthy, and by 8 weeks perisinusoidal fibrosis was established. Compared with mice receiving the high-fat diet supplemented with methionine and choline (controls), levels of hepatic lipid and lipoperoxides were elevated at 3 weeks and beyond. The numbers of perfused sinusoids were significantly reduced at each time point. Enlarged, fat-laden hepatocytes together with perivascular fibrosis narrowed sinusoidal lumens, making vessels tortuous and impairing sinusoidal perfusion. At 3 and 5 weeks, MCD diet caused significant increases in phagocytic activity of macrophages in centrilobular regions. By 8 weeks, macrophage activity was less striking, but the number of leukocytes adherent to the sinusoidal lining had increased 5-fold compared with controls. In conclusion, these results are consistent with a dysfunctional hepatic microvasculature. Thus, microvascular changes may contribute to progressive liver injury in metabolic and toxic forms of steatohepatitis. (Hepatology 2004;40:386-393.)
High frequency of cholestasis in generalized pustular psoriasis: Evidence for neutrophilic involvement of the biliary tract
Authors: Viguier Manuelle , Allez Matthieu , Zagdanski Anne-Marie , Bertheau Philippe , de Kerviler Eric , Rybojad Michel , Morel Patrice , Dubertret Louis , Lémann Marc , Bachelez Hervé
Published: August 2004

Generalized pustular psoriasis is a rare form of psoriasis that is sometimes associated with extracutaneous manifestations. Evidence for biliary involvement has been suggested in isolated cases. We investigated the prevalence and nature of liver abnormalities occurring in this disease. Twenty-two patients consecutively admitted for generalized pustular psoriasis who underwent liver biological tests at the time of the attack and during the following weeks were included. Twenty patients (90%) had at least one abnormal biological liver parameter. Eleven patients (50%) had pronounced abnormalities: jaundice (4/22), gammaglutamyl transferase higher than 5 times the normal value (10/22), alkaline phosphatase higher than twice the normal value (7/22), and/or aminotransferases higher than 3 times the normal value (7/22). These abnormalities returned to normal range at the time of remission of pustular psoriasis, suggesting that severe liver abnormalities could be associated with severe cutaneous disease. Neutrophilic cholangitis was observed on liver biopsy. Persistent magnetic resonance cholangiopancreatography features similar to those observed in sclerosing cholangitis were found in 3 of the 4 patients studied. No causal factor other than pustular psoriasis could be identified. In conclusion, our results demonstrate the high frequency of liver abnormalities in patients with generalized pustular psoriasis. Biliary involvement related to neutrophilic cholangitis should be added to the spectrum of extracutaneous manifestations of this disease, and physicians should be aware of such a complication. (Hepatology 2004;40:452-458.)
Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1
Authors: de Luján Alvarez María , Ronco María Teresa , Ochoa Elena J. , Monti Juan A. , Carnovale Cristina E. , Pisani Gerardo B. , Lugano María Cristina , Carrillo María Cristina
Published: August 2004

In previous work we showed that interferon alfa-2b (IFN-α2b) increases apoptosis on rat hepatic preneoplastic foci. The aim of this study was to determine if transforming growth factor β1 (TGF-β1) was involved in the programmed cell death on the foci. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine plus 2-acetylaminofluorene) of preneoplasia development (group 1); treated with IFN-α2b during the 2 phases (group 2); treated with IFN-α2b during initiation with diethylnitrosamine (group 3); treated with IFN-α2b during 2-acetylaminofluorene administration (group 4); subjected only to an initiation stage (group 5); and treated with IFN-α2b during the initiation period (group 6). Serum TGF-β1 levels were increased in IFN-α2b-treated rats. Immunohistochemical studies showed that IFN-α2b significantly increased the quantity of TGF-β1-positive hepatocytes in groups 2 to 4. Phosphorylated-Smads-2/3 (p-Smads-2/3) proteins in liver nuclear extracts were significantly elevated. To determine the source of TGF-β1, isolated hepatocytes, Kupffer cells, and peritoneal macrophages from animals in groups 1 and 5 were cultured with or without IFN-α2b. IFN-α2b stimulus induced several-fold increases of TGF-β1 secretion from hepatocytes. Neither Kupffer cells nor peritoneal macrophages secreted detectable TGF-β1 levels when they were treated with IFN-α2b. IFN-α2b-stimulated cultured hepatocytes from preneoplastic livers showed enhanced apoptosis, measured by fluorescence microscopy and caspase-3 activity. They presented higher nuclear accumulation of p-Smads-2/3, indicating increased TGF-β1 signaling. When anti-TGF-β1 was added to the culture media, TGF-β1 activation and apoptosis induced by IFN-α2b were blocked. In conclusion, IFN-α2b-induced production of TGF-β1 by hepatocytes from preneoplastic liver is involved in the apoptotic elimination of altered hepatic foci. (Hepatology 2004;40:394-402.)
Telomeres and telomerase: A dual role in hepatocarcinogenesis
Authors: Satyanarayana Ande , Manns Michael P. , Rudolph Lenhard K.
Published: August 2004

Telomere shortening limits the proliferative capacity of primary human cells and restrains the regenerative capacity of organ systems during chronic diseases and aging. Telomere shortening apparently has a dual role in tumor development and progression. On the one hand, it induces chromosomal instability and the initiation of cancer; on the other hand, tumor progression requires stabilization of telomeres. The predominant mechanism of telomere stabilization in tumor cells is the activation of the telomere-synthesizing enzyme telomerase. The potential use of telomerase activators for the treatment of regenerative disorders will ultimately depend on their effects on tumorigenesis. This review focuses on the role of telomere shortening and telomerase in carcinogenesis with a special focus on hepatocellular carcinoma. (Hepatology 2004;40:276-283.)
Bid-dependent generation of oxygen radicals promotes death receptor activation-induced apoptosis in murine hepatocytes
Authors: Ding Wen-Xing , Ni Hong-Min , DiFrancesca Daniell , Stolz Donna B. , Yin Xiao-Ming
Published: August 2004

Activation of tumor necrosis factor receptor 1 or Fas leads to the generation of reactive oxygen species, which are important to the cytotoxic effects of tumor necrosis factor α (TNF-α) or Fas ligand. However, how these radicals are generated following receptor ligation is not clear. Using primary hepatocytes, we found that TNF-α or anti-Fas antibody-induced burst of oxygen radicals was mainly derived from the mitochondria. We discovered that Bid—a pro-death Bcl-2 family protein activated by ligated death receptors—was the main intracellular molecule signaling the generation of the radicals by targeting to the mitochondria and that the majority of oxygen radical production was dependent on Bid. Reactive oxygen species contributed to cell death and caspase activation by promoting FLICE-inhibitory protein degradation and mitochondrial release of cytochrome c. For the latter part, the oxygen radicals did not affect Bak oligomerization but instead promoted mitochondrial cristae reorganization and membrane lipid peroxidation. Antioxidants could reverse these changes and therefore protect against TNF-α or anti-Fas-induced apoptosis. In conclusion, our studies established the signaling pathway from death receptor engagement to oxygen radical generation and determined the mechanism by which reactive oxygen species contributed to hepatocyte apoptosis following death receptor activation. (Hepatology 2004;40:403-413.)
Association of estrogen receptor α polymorphisms with susceptibility to chronic hepatitis B virus infection
Authors: Deng Guohong , Zhou Gangqiao , Zhai Yun , Li Shuqing , Li Xuhong , Li Ya , Zhang Ruifang , Yao Zhijian , Shen Yan , Qiang Boqing , Wang Yuming , He Fuchu
Published: August 2004

Several studies have demonstrated that estrogen receptor α (ESR1) participates in the pathogenesis of persistent hepatitis B virus (HBV) infection. To examine whether polymorphisms at the ESR1 gene locus are associated with persistent HBV infection, we resequenced ESR1 genomic region for single nucleotide polymorphisms (SNPs) in 27 unrelated Chinese. Two haplotype-tagged SNPs (htSNP), T29C and A252966G, were selected for genotyping in 1,277 persistent HBV-infected cases, 748 spontaneously recovered controls, and 293 nuclear families using polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis. We observed that the subjects bearing ESR1 29T/T genotype had an increased susceptibility to persistent HBV infection compared to those bearing at least one 29C allele (odds ratio 1.41; 95% CI, 1.17-1.71, P < .001). Consistent with the results of population-based association study, a significantly greater than expected transmission of the 29T allele (56.4%) from heterozygous parents to offspring with persistent HBV infection was observed (χ2 = 4.60, P = .033) using the transmission-disequilibrium test (TDT) in 293 nuclear families. Linkage disequilibrium (LD) mapping analysis indicated that the T29C polymorphism contained within a LD block located from promoter region to intron 3 of ESR1, suggesting that the strong association detected with T29C in ESR1 originated from ESR1 itself. In conclusion, our results suggest that the genetic variation at the ESR1 locus influences susceptibility to persistent HBV infection in a Chinese population. (Hepatology 2004;40:318-326.)
Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease
Authors: Abrams Gary A. , Kunde Sachin S. , Lazenby Audrey J. , Clements Ronald H.
Published: August 2004

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4-12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2-6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3-19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6-11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity. (Hepatology 2004;40:475-483.)
Novel peptide-based vaccines efficiently prime murine “help”-independent CD8+ T cell responses in the liver
Authors: Dikopoulos Nektarios , Riedl Petra , Schirmbeck Reinhold , Reimann Jörg
Published: August 2004

Vaccines for the prophylactic and/or therapeutic immunization against hepatotropic pathogens (e.g., hepatitis B and hepatitis C virus) should establish long-lasting, specific antiviral effector/memory CD8+ T cell immunity in the liver. We describe a novel peptide-based vaccine in which antigenic major histocompatibility complex Class I-binding peptides are fused to a cationic (e.g., human immunodeficiency virus tat-derived) domain and complexed to immune-stimulating oligonucleotides. This vaccine formulation efficiently primes liver-homing, Class I-restricted CD8+ effector/memory T cell responses. In different antigen systems, this formulation was more potent in priming liver-homing CD8+ T cell responses than DNA-based vaccines delivering the same epitopes. CD8+ T cell priming was independent of CD4+ T cell “help” but submitted to regulatory control by CD25+ CD4+ T cells. The vaccine efficiently primed memory/effector CD8+ T cells detectable in the liver for more than 3 months after a single injection. With increasing time after priming, the phenotype of these specific memory CD8+ T cells shifted from an effector memory to a central memory type. The vaccine could override T cell tolerance in mice expressing the relevant antigen from a transgene in the liver. The CD8+ T cell immunity in the liver primed by this peptide formulation could be boosted by challenge injections. In conclusion, we describe a simple and potent vaccine formulation that has the potential to generate or reconstitute specific CD8+ T cell immunity to hepatotropic pathogens in the liver. (Hepatology 2004;40:300-309.)
Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats
Authors: Wang Weizheng W. , Smith Darcey L. H. , Zucker Stephen D.
Published: August 2004

The inducible isoform of heme oxygenase (HO), HO-1, has been shown to play an important role in attenuating tissue injury. Because HO-1 catalyzes the rate-limiting step in bilirubin synthesis, we examined the hypothesis that bilirubin is a key mediator of HO-1 cytoprotection, employing a rat model of endotoxemia. Bilirubin treatment resulted in improved survival and attenuated liver injury in response to lipopolysaccharide infusion. Serum levels of NO and tumor necrosis factor α, key mediators of endotoxemia, and hepatic inducible nitric oxide synthase (iNOS) expression were significantly lower in bilirubin-treated rodents versus control animals. Both intraperitoneal and local administration of bilirubin also was found to ameliorate hindpaw inflammation induced by the injection of λ-carrageenan. Consistent with in vivo results, bilirubin significantly inhibited iNOS expression and suppressed NO production in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. In contrast, bilirubin treatment induced a threefold increase in LPS-mediated prostaglandin synthesis in the absence of significant changes in cyclooxygenase expression or activity, suggesting that bilirubin enhances substrate availability for eicosanoid synthesis. Bilirubin had no effect on LPS-mediated activation of nuclear factor κB or p38 mitogen-activated protein kinase, consistent with a nuclear factor κB-independent mechanism of action. Taken together, these data support a cytoprotective role for bilirubin that is mediated, at least in part, through the inhibition of iNOS expression and, potentially, through stimulation of local prostaglandin E2 production. In conclusion, our findings suggest a role for bilirubin in mollifying tissue injury in response to inflammatory stimuli and support the possibility that the phenomenon of “jaundice of sepsis” represents an adaptive physiological response to endotoxemia. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (Hepatology 2004;40:424-433.)