bluuebunny/crossref_metadata_2025 huggingface dataset:
The accuracy of endoscopic ultrasound for restaging esophageal carcinoma after chemoradiation therapy
Authors: Kalha Ishaan , Kaw Madhukar , Fukami Norio , Patel Mihir , Singh Sandeep , Gagneja Harish , Cohen Deborah , Morris Jeffrey
Published: July 2004

BACKGROUND

Endoscopic ultrasound (EUS) is an accurate staging modality for esophageal malignancy. Studies have determined that EUS does not retain this accuracy after chemoradiation and that it should not be used as a restaging tool for esophageal carcinoma. In this study, the authors examined their experience with esophageal carcinoma and restaging after neoadjuvant therapy with EUS.

METHODS

A retrospective chart review was conducted that included 83 patients with locoregional esophageal adenocarcinoma who were treated with chemoradiation under protocol. All patients underwent surgical resection. EUS was performed for restaging, and the results were compared with findings at surgical pathology using the TNM classification system.

RESULTS

All 83 patients identified underwent surgery. There were 77 males, and the mean patient age was 59 years. At restaging, the tumor status (T classification) was assessed correctly by EUS in 22 of 83 patients (29%). The sensitivity of EUS for the individual T classifications were 0% for T0 tumors, 19% for T1 tumors, 27% for T2 tumors, 52% for T3 tumors, and 0% for T4 tumors. In 19 of 83 patients, the tumor classification was correct, whereas 42 of 83 patients were over classified, and 15 of 83 patients were under classified when the EUS results were compared with the surgical pathology results. The lymph node status (N classification) was assessed correctly by EUS in 41 of 83 patients. The sensitivity of EUS for N classification was 48% for N0 disease and 52% for N1 disease. Twenty‐two patients were restaged with residual disease according to the EUS results but had no evidence of residual tumor or lymph node involvement according to the surgical pathology results.

CONCLUSIONS

EUS did not retain its usefulness as a restaging modality after neoadjuvant chemoradiation for esophageal adenocarcinoma when the standard TNM classification system was used. Cancer 2004. © 2004 American Cancer Society.
Tumor lymphangiogenesis in head and neck squamous cell carcinoma
Authors: Franchi Alessandro , Gallo Oreste , Massi Daniela , Baroni Gianna , Santucci Marco
Published: July 2004

BACKGROUND

Tumor metastasis to regional lymph nodes via the lymphatic system represents the first step of dissemination in head and neck squamous cell carcinoma (HNSCC) and serves as a major prognostic indicator for disease progression and as a guide for therapeutic strategies. In the current study, the authors investigated whether tumor lymphangiogenesis may be related to the risk of lymph node metastasis and to clinical outcome in patients with HNSCC.

METHODS

Immunostaining for the lymphatic marker D2‐40 was used, and lymphangiogenesis was quantified within the tumor and in the peritumoral area in 52 HNSCC specimens using computer‐assisted morphometric analysis.

RESULTS

Lymphatic vessels were found to be significantly more numerous and larger in the peritumoral area compared with within the tumor, and the number and relative area of intratumoral and peritumoral lymphatics was significantly higher in HNSCC cases with lymph node metastasis. Multivariate analysis demonstrated that high peritumoral lymphangiogenesis (above the median value) was associated with an increased risk of developing lymph node metastasis. No correlation was found between tumor lymphangiogenesis and the disease‐free or overall survival in the current series.

CONCLUSIONS

The results indicate that peritumoral lymphangiogenesis may be an indicator of the risk of lymph node metastasis in patients with HNSCC. Cancer 2004. © 2004 American Cancer Society.
The toppler mouse: A novel mutant exhibiting loss of Purkinje cells
Authors: Duchala Cynthia S. , Shick H. Elizabeth , Garcia Jessica , Deweese Dannette M. , Sun Xiaoyan , Stewart Valerie J. , Macklin Wendy B.
Published: July 2004

We describe the genetic and neurological features of toppler, a spontaneous autosomal mutation that appeared in a colony of FVB/N mice and that manifests as severe ataxia appearing at around 12 days of age, worsening with age. The lifespan of affected mice is 8–12 months, with occasional mice living longer. Both homozygous males and females are fertile, and females are able to nurture litters. Histological examination of brain revealed no striking abnormalities other than the loss of cerebellar Purkinje cells. The toppler mutation was mapped to mouse chromosome 8, and to assess whether it was novel or a recurrence of a previously described chromosome 8 mouse mutant, toppler mice were crossed with the nervous and tottering mouse mutants. These studies demonstrate that toppler is a unique mouse mutation. Purkinje cell abnormalities in toppler mice were obvious around postnatal day (P) 14, i.e., toppler Purkinje cells already exhibited abnormal morphology. Staining for calbindin, a calcium binding protein enriched in Purkinje cells, showed altered dendritic morphology. Between P14 and P30, dramatic Purkinje cell loss occurred, although there were differences in the degree of Purkinje cell loss in each lobule. At P30, the surviving Purkinje cells expressed zebrin II. From P30 through 6 months, many of the remaining Purkinje cells gradually degenerated. Purkinje cell loss was analyzed by terminal deoxynucleotidyl transferase‐mediated biotinylated UTP nick end labeling (TUNEL), and Purkinje cells were TUNEL‐positive most abundantly at P21. In addition, Bergmann glia were TUNEL positive at P21, and they expressed activated caspase‐3 at earlier time points. Interestingly, despite the apparent death of some Bergmann glia, there was up‐regulation of glial fibrillary acidic protein, expressed in astrocytes as well as Bergmann glia. Given the changes in both Purkinje cells and glia in toppler cerebellum, this may be a very useful model in which to investigate the developmental interaction of Purkinje cells and Bergmann glia. J. Comp. Neurol. 476:113–129, 2004. © 2004 Wiley‐Liss, Inc.
Evidence for the disproportionate mapping of olfactory airspace onto the main olfactory bulb of the hamster
Authors: Schoenfeld Thomas A. , Knott Thomas K.
Published: July 2004

Olfactory receptor neurons (ORNs) project to the rodent main olfactory bulb (MOB) from spatially distinct air channels in the olfactory recesses of the nose. The relatively smooth central channels of the dorsal meatus map onto the dorsal MOB, whereas the highly convoluted peripheral channels of the ethmoid turbinates project to the ventral MOB. Medial and lateral components of each projection stream innervate the medial and lateral MOB, respectively. To ascertain whether such topography entails the disproportionate representation seen in other sensory maps, we used disector‐based stereological techniques in hamsters to estimate the number of ORNs associated with each channel in the nose and the number of their targets (glomeruli and mitral and tufted cells) in corresponding divisions of the MOB. Each circumferential half of the MOB (dorsal/ventral, medial/lateral) contained about 50% of the 3,100 glomeruli and about 50% of the 160,000 mitral and tufted cells per bulb. We found equivalent numbers of ORNs with dendritic knobs in the medial and lateral channels (4.5 million each). However, the central channels had only 2 million knobbed ORNs, whereas the peripheral channels had 7 million. Thus, there is a disproportionate mapping of the central‐peripheral axis of olfactory airspace onto the dorsal‐ventral axis of the MOB, encompassing a greater than threefold variation in the average convergence of ORNs onto MOB secondary neurons. We hypothesize that the disproportionate projections help to optimize chemospecific processing by compensating, with differing sensitivity, for significant variation in the distribution and concentration of odorant molecules along the olfactory air channels during sniffing. J. Comp. Neurol. 476:186–201, 2004. © 2004 Wiley‐Liss, Inc.
Active caspase‐3 expression during postnatal development of rat cerebellum is not systematically or consistently associated with apoptosis
Authors: Oomman Sowmini , Finckbone Velvetlee , Dertien Janet , Attridge Jennifer , Henne William , Medina Margarita , Mansouri Bobbak , Singh Hema , Strahlendorf Howard , Strahlendorf Jean
Published: July 2004

Development is a dynamic process that includes an intricate balance between an increase in cell mass and an elimination of excess or defective cells. Although caspases have been intimately linked to apoptotic events, there are a few reports suggesting that these cysteine proteases can influence the differentiation and proliferation of cells. Specifically, the active form of caspase‐3, which has been classified as an executor of apoptosis, recently has been implicated in a nonapoptotic role in the regulation of the cell cycle, cell proliferation, and cell differentiation. This study investigated the nonapoptotic function and phenotypic expression of active caspase‐3‐positive cells in the external granule cell layer (EGL) of the postnatal rat cerebellum by using biochemical and immunohistochemical analyses, respectively. Evidence that negates an apoptotic function for the caspase‐3‐positive EGL cells includes a failure to exhibit chromatin condensation (assessed with TOPRO), phosphatidyl serine externalization (Annexin V labeling), or DNA fragmentation (TUNEL labeling). Proliferative (Ki67‐positive) and differentiated (TUJ1‐positive) cells within the EGL exhibited a cytosolic expression of caspase‐3, whereas terminally differentiated granule cells (NeuN‐positive) in the internal granular layer and the migrating granule cells did not express active caspase‐3. Thus, this study supports a nonapoptotic role for active caspase‐3 in cells residing in the EGL and suggests a possible involvement in EGL proliferation and differentiation. J. Comp. Neurol. 476:154–173, 2004. © 2004 Wiley‐Liss, Inc.
On the bounded rationality of gender stereotyping in fame judgments
Authors: Steffens Melanie C. , Mecklenbräuker Silvia , Buchner Axel , Mehl Bettina
Published: July 2004

The false‐fame effect is the phenomenon that familiar names are falsely judged famous more often than unfamiliar names. M.R. Banaji and A.G. Greenwald (1995) demonstrated a gender bias in the false‐fame effect: In line with existing gender stereotypes, the false‐fame effect was larger for male than for female names. A more general explanation for gender biasing in fame judgments is based on cognitive availability. Name gender could be used as an ecologically valid cue when making fame judgments. If the relevant universe of famous names contained more male than female names, a gender bias in fame judgments should be observed, if it contained more female names, the gender bias should be reversed. Indeed, this pattern could be demonstrated experimentally, and we argue that it is not compatible with an account that draws on gender stereotyping but with one based on cognitive availability. Copyright © 2004 John Wiley & Sons, Ltd.
Counterfactual thinking and stereotypes: The nonconformity effect
Authors: Catellani Patrizia , Alberici Augusta I. , Milesi Patrizia
Published: July 2004

Past research has shown that counterfactual thinking (‘if only…’) is related to judgements of responsibility for negative events. It has also shown that behaviours deviating from the target's own behavioural standard (intrapersonal norm) are likely to trigger counterfactuals—the so‐called exceptional‐routine effect. In the present research, we demonstrate that behaviours deviating from a social category's behavioural standard (social norm) are also likely to trigger counterfactuals—what may be called the nonconformity effect. Two studies investigated counterfactual thinking regarding a rape case, classifying counterfactuals according to their conformity versus nonconformity to relevant social norms, and their focus on actions versus inactions. In Study 1, participants with higher endorsement of the rape victim stereotype generated more counterfactuals on the victim's non‐conforming inactions than did participants with lower stereotype endorsement. The presence of a nonconformity effect was confirmed in Study 2, where participants rated their agreement with externally generated counterfactuals. Moreover, in Study 2, counterfactuals focused on the victim's non‐conforming inactions predicted responsibility attribution to the victim through the mediating role of perceived avoidability of the event. Copyright © 2004 John Wiley & Sons, Ltd.
When prototypicality makes ‘maybes’ look more certain: Another look at targets' vigilance towards prejudice cues
Authors: Morera Maria D. , Dupont Emmanuelle , Leyens Jacques‐Philippe , Désert Michel
Published: July 2004

In previous research, targets' sensitivity to prejudice cues has been assessed on the basis of two types of information. Prototypical information renders the situation representative of discrimination encountered by the ingroup. Diagnostic information is a direct indication that prejudice possibly is operating in a given situation. We hypothesize that, when available and processed at the onset of an evaluation situation, prototypical information shapes targets' understanding of subsequent diagnostic information. In three experiments, participants were informed that they were to be evaluated by relevant outgroup members either before or after having performed a task. Diagnostic information was always provided at the same moment, i.e. after the task was completed, and was either uncertain (prejudice may bias the evaluation) or certain (prejudice certainly biases the evaluation). In the before condition, attributions to prejudice were as elevated whatever participants were told that prejudice might, or certainly did, bias the evaluation. Furthermore, in the case of uncertain diagnostic information, those who were readily informed of the evaluator(s)' identity attributed their failure to prejudice to a greater extent than those who received this information later. Copyright © 2004 John Wiley & Sons, Ltd.
Cognitive adaptation and mental health: A motivational analysis
Authors: Ratelle Catherine F. , Vallerand Robert J. , Chantal Yves , Provencher Pierre
Published: July 2004

The present study tested a motivational model where the beneficial impact that processes of cognitive adaptation have on mental health takes place through self‐determined motivation. The model proposes that the components of cognitive adaptation theory (positive self‐perceptions, perceptions of control, and optimism) foster a self‐determined motivation. In turn, self‐determined motivation predicts positive indices of mental health. In addition, the model posits that the beneficial role of cognitive adaptation on mental health is mediated by motivational processes. The model was tested using a 1‐year prospective design with a random sample from the general population. Results from structural equation modelling analysis provided empirical support for the proposed model. Results are discussed with regards to Taylor's (1983) cognitive adaptation theory, self‐determination theory (Deci & Ryan, 1991), and the Hierarchical Model of Intrinsic and Extrinsic Motivation (Vallerand, 1997). Copyright © 2004 John Wiley & Sons, Ltd.
The liberating role of conflict in group creativity: A study in two countries
Authors: Nemeth Charlan J. , Personnaz Bernard , Personnaz Marie , Goncalo Jack A.
Published: July 2004

Researchers of group creativity have noted problems such as social loafing, production blocking, and especially, evaluation apprehension. Thus, brainstorming techniques have specifically admonished people ‘not to criticize’ their own and others' ideas, a tenet that has gone unexamined. In contrast, there is research showing that dissent, debate and competing views have positive value, stimulating divergent and creative thought. Perhaps more importantly, we suggest that the permission to criticize and debate may encourage an atmosphere conducive to idea generation. In this experimental study, traditional brainstorming instructions, including the advice of not criticizing, were compared with instructions encouraging people to debate—even criticize. A third condition served as a control. This study was conducted both in the United States and in France. Results show the value of both types of instruction, but, in general, debate instructions were superior to traditional brainstorming instructions. Further, these findings hold across both cultures. Results are discussed in terms of the potential positive value of encouraging debate and controversy for idea generation. Copyright © 2004 John Wiley & Sons, Ltd.
In case of death, cling to the ingroup
Authors: Castano Emanuele
Published: July 2004

An experiment investigated whether the enhanced importance of the ingroup as a consequence of the salience of death thoughts is a unconscious defense mechanism. Scottish participants were subliminally primed with either the word death or field. Subsequently, they were asked to classify a series of pictures as either English or Scottish, and to state whether a series of negative traits applied to the English or not. Results showed that participants primed with the word death were more likely to exclude targets that looked more like outgroup than ingroup members, than participants in the field (control) prime condition. The pattern observed on the categorization‐latency also supported the claim that death‐prime participants are more careful in classifying targets. Finally, death‐prime participants also conveyed more negative, stereotypical judgments of the English in a trait attribution task. The implications of the results are discussed in relation to terror management theory and social identification phenomena. Copyright © 2004 John Wiley & Sons, Ltd.
Question/statement judgments: An fMRI study of intonation processing
Authors: Doherty Colin P. , West W. Caroline , Dilley Laura C. , Shattuck‐Hufnagel Stefanie , Caplan David
Published: July 2004

We examined changes in fMRI BOLD signal associated with question/statement judgments in an event‐related paradigm to investigate the neural basis of processing one aspect of intonation. Subjects made judgments about digitized recordings of three types of utterances: questions with rising intonation (RQ; e.g., “She was talking to her father?”), statements with a falling intonation (FS; e.g., “She was talking to her father.”), and questions with a falling intonation and a word order change (FQ; e.g., “Was she talking to her father?”). Functional echo planar imaging (EPI) scans were collected from 11 normal subjects. There was increased BOLD activity in bilateral inferior frontal and temporal regions for RQ over either FQ or FS stimuli. The study provides data relevant to the location of regions responsive to intonationally marked illocutionary differences between questions and statements. Hum Brain Mapping 23:85–98, 2004. © 2004 Wiley‐Liss, Inc.
Effects of antiviral therapy on the cellular immune response in acute hepatitis C
Authors: Rahman Fareed , Heller Theo , Sobao Yuji , Mizukoshi Eishiro , Nascimbeni Michelina , Alter Harvey , Herrine Steven , Hoofnagle Jay , Liang Jake T. , Rehermann Barbara
Published: July 2004

Spontaneous recovery occurs in a minority of patients with acute hepatitis C but is associated with vigorous and long-lasting cellular immune responses. Treatment-induced recovery can be achieved in the majority of patients who are treated in the acute phase, but the kinetics and mechanisms of viral clearance and immune responsiveness are not known. Both direct antiviral effects and indirect immune-mediated effects, such as immune modulation of Th2 to Th1 responses and prevention of exhaustion of cellular responses by rapid reduction of viral titer, have been proposed. To investigate how early antiviral therapy affects hepatitis C virus (HCV)-specific T cell responses, we performed detailed prospective clinical, virological, and immunological studies on 7 patients with acute hepatitis C who received antiviral therapy and were followed at 2 to 4 week intervals for 1 to 2 years. The total CD4+ and CD8+ cell response was analyzed with 600 overlapping HCV peptides and 6 proteins by ex vivo enzyme-linked immunospot (ELISpot), intracellular cytokine staining, and proliferation assays. In contrast to earlier studies with selected HCV epitopes, this extended analysis detected multispecific interferon γ+ (IFN-γ+) responses in each patient, even in the absence of T-cell proliferation. After initiation of antiviral therapy (at a mean of 20 weeks after infection), all sustained responders demonstrated gradually decreasing, then nearly absent HCV-specific T-cell responses, whereas the sole patient who developed viral breakthrough after initial HCV control maintained cellular immune responses. In conclusion, a sustained response to antiviral therapy was not associated with a lasting enhancement of HCV-specific T-cell responsiveness in the blood. (Hepatology 2004;40:87-97.)
Mitochondrial nitric oxide synthase drives redox signals for proliferation and quiescence in rat liver development
Authors: Carreras María C. , Converso Daniela P. , Lorenti Alicia S. , Barbich Mariana , Levisman Damián M. , Jaitovich Ariel , Antico Arciuch Valeria G. , Galli Soledad , Poderoso Juan J.
Published: July 2004

Mitochondrial nitric oxide synthase (mtNOS) is a fine regulator of oxygen uptake and reactive oxygen species that eventually modulates the activity of regulatory proteins and cell cycle progression. From this perspective, we examined liver mtNOS modulation and mitochondrial redox changes in developing rats from embryonic days 17-19 and postnatal day 2 (proliferating hepatocyte phenotype) through postnatal days 15-90 (quiescent phenotype). mtNOS expression and activity were almost undetectable in fetal liver, and progressively increased after birth by tenfold up to adult stage. NO-dependent mitochondrial hydrogen peroxide (H2O2) production and Mn-superoxide dismutase followed the developmental modulation of mtNOS and contributed to parallel variations of cytosolic H2O2 concentration ([H2O2]ss) and cell fluorescence. mtNOS-dependent [H2O2]ss was a good predictor of extracellular signal-regulated kinase (ERK)/p38 activity ratio, cyclin D1, and tissue proliferation. At low 10−11-10−12 M [H2O2]ss, proliferating phenotypes had high cyclin D1 and phospho-ERK1/2 and low phospho-p38 mitogen-activated protein kinase, while at 10−9 M [H2O2]ss, quiescent phenotypes had the opposite pattern. Accordingly, leading postnatal day 2-isolated hepatocytes to embryo or adult redox conditions with H2O2 or NO-H2O2 scavengers, or with ERK inhibitor U0126, p38 inhibitor SB202190 or p38 activator anisomycin resulted in correlative changes of ERK/p38 activity ratio, cyclin D1 expression, and [3H] thymidine incorporation in the cells. Accordingly, p38 inhibitor SB202190 or N-acetyl-cysteine prevented H2O2 inhibitory effects on proliferation. In conclusion, the results suggest that a synchronized increase of mtNOS and derived H2O2 operate on hepatocyte signaling pathways to support the liver developmental transition from proliferation to quiescence. (Hepatology 2004;40:157-166.)
Connexin 32 dominant-negative mutant transgenic rats are resistant to hepatic damage by chemicals
Authors: Asamoto Makoto , Hokaiwado Naomi , Murasaki Toshiya , Shirai Tomoyuki
Published: July 2004

Connexins are subunits of gap junction channels, which allow direct transfer of ions, secondary messenger molecules, and other metabolites between contacting cells. Gap junctions are believed to be involved in tissue homeostasis, embryonic development, and control of cell proliferation. Several studies have shown that cell damage signals are transmitted through gap junctions when cells are irradiated or when cells bearing the herpes simplex virus-thymidine kinase (HSV-TK) gene are treated with ganciclovir. We established 2 lines of transgenic rats with a dominant-negative mutant of connexin 32 gene under control of the albumin promoter. In the livers of transgenic rats, membrane localization of normal endogenous connexin 32 protein is disturbed, and gap junction capacity measured by scrape dye-transfer assay in vivo is markedly decreased when compared with wild-type rats. The present investigation concerned susceptibility to the liver-toxic substances D-galactosamine and carbon tetrachloride. These toxicants induced massive liver cell death and elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the wild-type rats; however, much fewer liver cells were damaged and serum enzyme elevation was much lower in the transgenic rats. In conclusion, gap junctional intercellular communication (GJIC) plays an important role in toxic effects of chemicals; damage or death signals may pass through gap junctions in the rat liver in vivo. (Hepatology 2004;40:205-210.)
Usefulness of dried blood samples for quantification and molecular characterization of HBV-DNA
Authors: Jardi Rosendo , Rodriguez-Frias Francisco , Buti Maria , Schaper Melanie , Valdes Auristela , Martinez Mariano , Esteban Rafael , Guardia Jaime
Published: July 2004

The purpose of this study was to assess the use of dried blood spot (DBS) samples for hepatitis B virus (HBV) DNA quantification, HBV genotyping, and detection of G1896A precore mutants and variants in the YMDD polymerase motif. We studied DBS and serum samples from 82 patients with chronic HBV infection (23 hepatitis B e antigen [HBeAg]-positive and 39 HBeAg-negative), 20 HBeAg-inactive carriers, and 15 HBeAg-negative patients under lamivudine therapy (selected from chronic HBV patients). DBS samples consisted of approximately 20 μL of blood applied to 5-mm paper disks. HBV DNA quantification and HBV precore mutant detection were done using real-time polymerase chain reaction, HBV genotyping using restriction fragment length polymorphism, and YMDD variant detection by Inno-lipa assay. DBS and serum results were compared. HBV DNA was detected in a range of 102-108 copies/mL, with low intra-assay and inter-assay variation (<10%). Median DBS HBV DNA (copies/mL) was: 3.7 × 106 in HBeAg-positive, 6.2 × 105 in HBeAg-negative, and 5.5 × 102 in inactive carriers (P < .05). HBV DNA was positive in serum (median 5 × 103 copies/mL) but negative in DBS for five inactive carriers. The correlation coefficient between HBV DNA concentration in DBS versus serum samples was r
2 = 0.96 (P < .001). The sensitivity of HBV DNA detection in DBS samples was 1 log10 lower than in serum samples. Concordance between DBS and serum for HBV genotyping, and for precore mutant and YMDD variant detection was optimal. DBS storage for 7 days at room temperature and 21 days at −20°C revealed no decrease in HBV DNA levels or integrity. In conclusion, the DBS sample is useful for HBV DNA quantification, genotyping, and detection of precore mutant and YMDD variants. All four determinations can be completed with a single drop of dried blood. (Hepatology 2004;40:133-139.)
Adiponectin protects LPS-induced liver injury through modulation of TNF-α in KK-Ay obese mice
Authors: Masaki Takayuki , Chiba Seiichi , Tatsukawa Hiroshi , Yasuda Tohru , Noguchi Hitoshi , Seike Masataka , Yoshimatsu Hironobu
Published: July 2004

Adiponectin, an adipocytokine, has been identified in adipose tissue, and its receptors are widely distributed in many tissues, including the liver. The present study was performed to clarify the role of adiponectin in lipopolysaccharide (LPS)-induced liver injury using KK-Ay obese mice. We analyzed the effects of adiponectin pretreatment on liver injury induced by d-galactosamine/LPS (GalN/LPS) in KK-Ay obese mice. GalN/LPS treatment induced significant increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the blood, apoptotic and necrotic changes in hepatocytes, and/or showed a high degree of lethality. The GalN/LPS-induced liver injury was more pronounced in KK-Ay obese mice than in lean controls. Pretreatment with adiponectin ameliorated the GalN/LPS-induced elevation of serum AST and ALT levels and the apoptotic and necrotic changes in hepatocytes, resulting in a reduction in lethality. In addition, pretreatment with adiponectin attenuated the GalN/LPS-induced increases in serum and hepatic tumor necrosis factor α (TNF-α) levels and increased peroxisome proliferator-activated receptor (PPAR) α messenger RNA expression in the liver. Furthermore, abdominal macrophages from KK-Ay obese mice pretreated with adiponectin in vitro exhibited decreased LPS-induced TNF-α production compared with controls. Finally, adiponectin pretreatment also ameliorated TNF-α-induced liver injury. In conclusion, these findings suggest that adiponectin prevents LPS-induced hepatic injury by inhibiting the synthesis and/or release of TNF-α of KK-Ay obese mice. (Hepatology 2004;40:177-184.)
Identification of the leukocyte cell-derived chemotaxin 2 as a direct target gene of β-catenin in the liver
Authors: Ovejero Christine , Cavard Catherine , Périanin Axel , Hakvoort Theodorus , Vermeulen Jacqueline , Godard Cécile , Fabre Monique , Chafey Philippe , Suzuki Kazuo , Romagnolo Béatrice , Yamagoe Satoshi , Perret Christine
Published: July 2004

To clarify molecular mechanisms underlying liver carcinogenesis induced by aberrant activation of Wnt pathway, we isolated the target genes of β-catenin from mice exhibiting constitutive activated β-catenin in the liver. Adenovirus-mediated expression of oncogenic β-catenin was used to isolate early targets of β-catenin in the liver. Suppression subtractive hybridization was used to identify the leukocyte cell-derived chemotaxin 2 (LECT2) gene as a direct target of β-catenin. Northern blot and immunohistochemical analyses demonstrated that LECT2 expression is specifically induced in different mouse models that express activated β-catenin in the liver. LECT2 expression was not activated in livers in which hepatocyte proliferation was induced by a β-catenin-independent signal. We characterized by mutagenesis the LEF/TCF site, which is crucial for LECT2 activation by β-catenin. We further characterized the chemotactic property of LECT2 for human neutrophils. Finally, we have shown an up-regulation of LECT2 in human liver tumors that expressed aberrant activation of β-catenin signaling; these tumors constituted a subset of hepatocellular carcinomas (HCC) and most of the hepatoblastomas that were studied. In conclusion, our results show that LECT2, which encodes a protein with chemotactic properties for human neutrophils, is a direct target gene of Wnt/β-catenin signaling in the liver. Since HCC develops mainly in patients with chronic hepatitis or cirrhosis induced by viral or inflammatory factors, understanding the role of LECT2 in liver carcinogenesis is of interest and may lead to new therapeutic perspectives. (Hepatology 2004;40:167-176.)
Risk of diabetes in HIV infected veterans pre- and post-HAART and the role of HCV coinfection†
Authors: Butt Adeel A. , Fultz Shawn L. , Kwoh Kent C. , Kelley David , Skanderson Melissa , Justice Amy C.
Published: July 2004

We examined the association of hepatitis C virus (HCV) infection with diabetes in veterans infected with human immunodeficiency virus (HIV) before and after the institution of highly active antiretroviral therapy (HAART). The role of age, race, liver disease, alcohol, and drug diagnoses upon the risk of diabetes was also determined. Male veterans with HIV who entered care between 1992 and 2001 were identified from the Veterans Affairs (VA) administrative database. Demographic and disease data were extracted. Kaplan-Meier curves were plotted to determine the incidence of diabetes. Unadjusted and adjusted hazards ratios for diabetes were determined using Cox regression method. A total of 26,988 veterans were studied. In multivariate Cox regression analysis, factors associated with a diagnosis of diabetes included increasing age (HR, 1.44 per 10-year increase in age; 95% CI, 1.39-1.49), minority race (African American: HR, 1.35; 95% CI, 1.24-1.48; Hispanic: HR, 1.63; 95% CI, 1.43-1.86), and care in the HAART era (HR, 2.35; 95% CI, 2.01-2.75). There was a significant interaction between care in the HAART era and HCV infection, with HCV infection being associated with a significant risk of diabetes in the HAART era (HR, 1.39; 95% CI, 1.27-1.53) but not in the pre-HAART era (HR, 1.01; 95% CI, 0.75-1.36). In conclusion, HIV-infected veterans in the HAART era are at a higher risk for diabetes compared with those in the pre-HAART era. HCV coinfection is associated with a significantly higher risk of diabetes in the HAART era, but not in the pre-HAART era. HCV-HIV coinfected patients should be aggressively screened for diabetes. (Hepatology 2004;40:115-119.)
Long-term follow-up after successful interferon therapy of acute hepatitis C
Authors: Wiegand Johannes , Jäckel Elmar , Cornberg Markus , Hinrichsen Holger , Dietrich Manfred , Kroeger Julian , Fritsch Wolfgang P. , Kubitschke Anne , Aslan Nuray , Tillmann Hans L. , Manns Michael Peter , Wedemeyer Heiner
Published: July 2004

Early treatment of acute hepatitis C infection with interferon alfa-2b (IFN-α-2b) prevents chronicity in almost all patients. So far, no data are available on the long-term outcome after interferon (IFN) therapy of acute hepatitis C. The aim of this study was to assess the clinical, virological, and immunological long-term outcome of 31 successfully treated patients with acute hepatitis C infection who were followed for a median of 135 weeks (52-224 weeks) after end of therapy. None of the individuals had clinical evidence of liver disease. Alanine aminotransferase (ALT) levels were normal in all but 1 patient. Serum hepatitis C virus (HCV) RNA was negative throughout follow-up, even when investigated with the highly sensitive transcription-mediated amplification (TMA) assay (cutoff 5-10 IU/mL). In addition, no HCV RNA was detected in peripheral blood mononuclear cells (PBMC) of 15 cases tested. The patients’ overall quality-of-life scores as determined by the SF-36 questionnaire did not differ from the German reference control cohort. Ex vivo interferon gamma (IFN-γ) ELISPOT analysis detected HCV-specific CD4+ T-helper cell reactivity in only 35% of cases, whereas HCV-specific CD8+ T-cell responses were found in 4 of 5 HLA-A2-positive individuals. Anti-HCV antibody levels decreased significantly during and after therapy in all individuals. In conclusion, early treatment of symptomatic acute hepatitis C with IFN-α-2b leads to a long-term virological, biochemical, and clinical response. Waning of anti-HCV humoral immunity and presence of HCV-specific CD8+ (but not CD4+) T cells highlights the complexity of T-cell and B-cell memory to HCV, which might be significantly altered by IFN treatment. (Hepatology 2004;40:98-107.)
The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: Hype or hope?
Authors: Trauner Michael , Jaeschke Hartmut , Mullen Kevin , Moradpour Darius
Published: July 2004

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. FXR-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.
Bile acid-induced negative feedback regulation of the human ileal bile acid transporter
Authors: Neimark Ezequiel , Chen Frank , Li Xiaoping , Shneider Benjamin L.
Published: July 2004

Ileal expression of the apical sodium-dependent bile acid transporter (ASBT) in the rat is unaffected by bile salts, yet in the mouse it is under negative-feedback regulation. The bile acid responsiveness of human ASBT is unknown. The human ASBT promoter linked to a luciferase reporter was studied in Caco-2 cells treated with chenodeoxycholic acid (CDCA) and transfected with expression plasmids for farnesoid X-receptor (FXR), short heterodimer partner (SHP), and retinoic acid receptor/retinoid X receptor (RAR/RXR). CDCA treatment of Caco-2 cells led to a 75% reduction in steady-state ASBT messenger RNA levels and a 78% reduction in human ASBT promoter activity. A dominant negative FXR abrogated the response to CDCA. Site-directed mutagenesis of an RAR/RXR cis element in the human ASBT promoter reduced its activity by 50% and eliminated the bile acid response. Retinoic acid activated the human ASBT promoter fourfold. SHP repressed the activity of the ASBT promoter and reduced activation by retinoic acid. Antisense mediated knock-down of SHP in Caco-2 cells partially offset the bile acid mediated repression of ASBT promoter activity. In conclusion, the human ASBT is positively regulated by retinoic acid. Bile acids induce a negative feedback regulation of human ASBT via an FXR-mediated, SHP-dependent effect upon RAR/RXR activation of ASBT. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (Hepatology 2004;40:149-156.)
Cartilage tissue engineering on the surface of a novel gelatin–calcium‐phosphate biphasic scaffold in a double‐chamber bioreactor
Authors: Chang Chih‐Hung , Lin Feng‐Huei , Lin Chien‐Cheng , Chou Cheng‐Hung , Liu Hwa‐Chang
Published: July 2004

Tissue engineering is a new approach to articular cartilage repair; however, the integration of the engineered cartilage into the host subchondral bone is a major problem in osteochondral injury. The aim of the present work, therefore, was to make a tissue‐engineered osteochondral construct from a novel biphasic scaffold in a newly designed double‐chamber bioreactor. This bioreactor was designed to coculture chondrocytes and osteoblasts simultaneously. The aim of this study was to prove that engineered cartilage could be formed with the use of this biphasic scaffold. The scaffold was constructed from gelatin and a calcium‐phosphate block made from calcined bovine bone. The cartilage part of the scaffold had a uniform pore size of about 180 μm and approximate porosity of 75%, with the trabecular pattern preserved in the bony part of the scaffold. The biphasic scaffolds were seeded with porcine chondrocytes and cultured in a double‐chamber bioreactor for 2 or 4 weeks. The chondrocytes were homogeneously distributed in the gelatin part of the scaffold, and secretion of the extracellular matrix was demonstrated histologically. The chondrocytes retained their phenotype after 4 weeks of culture, as proven immunohistochemically. After 4 weeks of culture, hyaline‐like cartilage with lacuna formation could be clearly seen in the gelatin scaffold on the surface of the calcium phosphate. The results show that this biphasic scaffold can support cartilage formation on a calcium‐phosphate surface in a double‐chamber bioreactor, and it seems reasonable to suggest that there is potential for further application in osteochondral tissue engineering. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 313–321, 2004
Physicochemical factors influencing bacterial transfer from contact lenses to surfaces with different roughness and wettability
Authors: Vermeltfoort Pit B. J. , van der Mei Henny C. , Busscher Henk J. , Hooymans Johanna M. M. , Bruinsma Gerda M.
Published: July 2004

The aim of this study was to determine the transfer of Pseudomonas aeruginosa No. 3 and Staphylococcus aureus 835 from contact lenses to surfaces with different hydrophobicity and roughness. Bacteria were allowed to adhere to contact lenses (Surevue, PureVision, or Focus Night & Day) by incubating the lenses in a bacterial suspension for 30 min. The contaminated lenses were put on a glass, poly(methylmethacrylate), or silicone rubber substratum, shaped to mimic the eye. After 2 and 16 h, lenses were separated from the substrata and bacteria were swabbed off from the respective surfaces and resuspended in saline. Appropriate serial dilutions of these suspensions were made, from which aliquots were plated on agar for enumeration. Bacterial transfer varied between 4 and 60%, depending on the combination of strain, contact time, contact lens, and substratum surface. For P. aeruginosa No. 3, transfer was significantly higher after 16 h than after 2 h, whereas less increase with time was seen for S. aureus 835. Bacterial transfer from all tested contact lenses was least to silicone rubber, the most hydrophobic and roughest substratum surface included. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 71B: 336–342, 2004
Classical force field parameters for the heme prosthetic group of cytochrome c
Authors: Autenrieth Felix , Tajkhorshid Emad , Baudry Jerome , Luthey‐Schulten Zaida
Published: July 2004

Accurate force fields are essential for describing biological systems in a molecular dynamics simulation. To analyze the docking of the small redox protein cytochrome c (cyt c) requires simulation parameters for the heme in both the reduced and oxidized states. This work presents parameters for the partial charges and geometries for the heme in both redox states with ligands appropriate to cyt c. The parameters are based on both protein X‐ray structures and ab initio density functional theory (DFT) geometry optimizations at the B3LYP/6‐31G* level. The simulations with the new parameter set reproduce the geometries of the X‐ray structures and the interaction energies between water and heme prosthetic group obtained from B3LYP/6‐31G* calculations. The parameter set developed here will provide new insights into docking processes of heme containing redox proteins. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1613–1622, 2004
The Perugino's palette: integration of an extended in situ XRF study by Raman spectroscopy
Authors: Ricci C. , Borgia I. , Brunetti B. G. , Miliani C. , Sgamellotti A. , Seccaroni C. , Passalacqua P.
Published: July 2004

Throughout the years, a large number of paintings by Perugino have been investigated using the in situ non‐destructive x‐ray fluorescence (XRF) technique. Three anomalous characteristics were frequently identified, concerning a brown earth pigment containing zinc, the presence of manganese in some red lakes and the association of the presence of copper and tin with grey–blue regions. In an effort to understand these anomalies better, five micro‐samples, taken from selected easel paintings by Perugino at the Galleria Nazionale dell'Umbria and a fresco at the Monastero di Sant'Agnese in Perugia, were studied by micro‐Raman spectroscopy and scanning electron microscopy (SEM). Micro‐Raman spectroscopy was a useful tool to investigate the molecular nature of such uncommon pigments and SEM provided useful information on the stratigraphy of the paint layers. The brown earth pigments, used by the master in the last period of his production, were definitely confirmed to be characterized by zinc impurities. The manganese contained in red lakes was shown to be due to ground alkaline glass, with a small quantity of manganese and iron, probably added to the oil binder in an attempt to speed up drying. Finally, in the sampled paintings, the grey–blue colour characterized by copper and tin was not present. Copyright © 2004 John Wiley & Sons, Ltd.
A Raman spectroscopic study of pollution‐induced glass deterioration
Authors: Robinet Laurianne , Eremin Katherine , Cobo del Arco Belén , Gibson Lorraine T.
Published: July 2004

White crystalline deposits were present on a large number of 19th and 20th century British glass artefacts in the National Museums of Scotland collections. Analysis of these deposits by ion chromatography showed that sodium and formate were the dominant ions. Raman spectroscopy identified sodium formate anhydrate phase II as the main phase, with sodium formate phase I′, sodium sulfate decahydrate and possibly potassium formate present at minor levels. Minor levels of sodium, chloride and potassium were detected by scanning electron microscopy, suggesting the presence of sodium chloride and potassium chloride. Elemental analysis of the glass artefacts by x‐ray fluorescence spectrometry and electron microprobe analysis revealed that most artefacts had high levels of sodium or (more rarely) potassium and low levels of calcium. Measurements and simulation experiments showed that the degradation was caused by the combination of high levels of formic acid, and possibly formaldehyde, generated inside the display cases and storage cupboards and high relative humidity. This study shows that the combination of micro‐Raman spectroscopy, ion chromatography and scanning electron microscopy is ideal for the analysis of glass corrosion products induced by pollutant gases. Copyright © 2004 John Wiley & Sons, Ltd.
Application of Fourier transform Raman spectroscopy to the characterization of parchment and vellum. II—Effect of biodeterioration and chemical deterioration on spectral interpretation
Authors: Edwards Howell G. M. , Perez Fernando Rull
Published: July 2004

Raman spectra of ancient parchment and vellum were recorded and used to characterize materials used in early mediaeval (10th century) and later works. These studies support work on the characterization of pigments used on historiated manuscripts and provide the basis for future studies of the interaction between pigments, binders and parchment or vellum. Examination of the undecorated parts of manuscripts or books has been undertaken to ascertain if there are traces remaining of the procedures used to prepare the materials; in several cases, there is spectroscopic evidence for the presence of sulfates and slaked lime, which were used in the preparation of vellums for scriptoria. The deterioration of vellums and parchments has been related to spectroscopic observation of changes in the protein CONH structures and to the chemical destruction of the CSSC bonds of cysteine. Band broadening resulting from the chemical reactions at these sites was analysed. Copyright © 2004 John Wiley & Sons, Ltd.
Pigments and binders in the wall paintings of Santa Maria della Steccata in Parma (Italy): the ultimate technique of Parmigianino
Authors: Bersani Danilo , Paolo Lottici Pier , Antonioli Gianni , Campani Elisa , Casoli Antonella , Violante Carla
Published: July 2004

Micro‐Raman spectroscopy and gas chromatography combined with mass spectrometry (GC–MS) were employed to investigate the materials used in the wall paintings by the older Parmigianino (Francesco Mazzola, 1503–1540) on the arch over the main altar in the church of Santa Maria della Steccata in Parma, Italy. The pigments used by the artist and those added by later restorations are characterized by micro‐Raman spectroscopy. GC–MS identified the organic binding media in the paint samples and revealed the presence of polysaccharides in the plaster. These investigations may be useful for a comparison with the technique of the young Parmigianino, author of wall paintings in the church of S. Giovanni Evangelista in Parma in the 1520s. Copyright © 2004 John Wiley & Sons, Ltd.