bluuebunny/crossref_metadata_2025 huggingface dataset:
Osteopenia and cancer in children and adolescents
Authors: Sala Alessandra , Barr Ronald D.
Published: February 2007

The attainment of a satisfactory peak bone mass, which is accomplished largely by the end of adolescence, is the best protection against excessive bone mineral loss in late adulthood. Factors that influence this process include age, race, sex, body size, pubertal status, diet, physical activity, and other lifestyle elements. Cancer and its treatment in children and teenagers adversely impact bone mineralization. In particular, chemotherapy (especially glucocorticosteroids and methotrexate) and cranial irradiation (apparently by reducing growth hormone secretion and by causing hypogonadotropic hypogonadism) interfere with normal bone turnover. Resorption often exceeds formation, resulting in net bone mineral loss and providing a rational basis for the use of antiresorptive drugs. Such osteopenia may be symptomatic, with pain and abnormal gait, and increases the risk of fractures several fold. The disorder is compounded by reduced physical activity, so programs to reduce this deficit are of measurable benefit. All of those engaged in the care of children and adolescents with cancer have an opportunity to improve the bone health of these young people and to limit their risk of developing osteoporosis and fragility fractures in adult life. Cancer 2007;. © 2007 American Cancer Society.
High incidence of hepatitis B virus infection in B‐cell subtype non‐Hodgkin lymphoma compared with other cancers
Authors: Wang Feng , Xu Rui‐hua , Han Bing , Shi Yan‐xia , Luo Hui‐yan , Jiang Wen‐qi , Lin Tong‐yu , Huang Hui‐qiang , Xia Zhong‐jun , Guan Zhong‐zhen
Published: February 2007

BACKGROUND.

The authors investigated the prevalence of hepatitis B virus (HBV) infection by using serologic markers in non‐Hodgkin lymphoma (NHL) compared with other types of cancers in Chinese patients.

METHODS.

In this case‐control study, HBV and other hepatitis markers were compared between a study group and a control group. The study group included 587 patients with NHL (age range, 16–86 years), and the control group included 1237 patients (age range, 16–89 years) who were diagnosed with other cancers except liver cancer. An enzyme‐linked immunosorbent assay was used to test serum samples from both groups for HBV markers and other hepatitis markers.

RESULTS.

Logistic regression analysis showed that there was a higher prevalence of HBV infection in patients with the B‐cell subtype of NHL (30.2%) than in patients with other cancers (14.8%; odds ratio [OR], 2.6; 95% confidence interval [95% CI], 2.0–3.4); however, in patients with the T‐cell subtype of NHL, the HBV infection rate (19.8%) was similar to that among patients with other cancers (OR, 1.2; 95% CI, 0.8–1.8). A significant difference in HBV prevalence was found between B‐cell and T‐cell NHL (OR, 2.3; 95% CI, 1.4–3.6). In the patients with B‐cell NHL, those who were infected with HBV had a significantly earlier disease onset (9.5 years) than those who were not infected with HBV.

CONCLUSIONS.

The current results demonstrated that patients with B‐cell NHL, but not patients with T‐cell NHL, had a higher prevalence of HBV infection. HBV infection was associated with a significantly earlier disease onset (P < .001), a finding that suggested the possibility that HBV may play an etiologic role in the induction of B‐cell NHL. Cancer 2007. © 2007 American Cancer Society.
Proposal of a new concept for color‐appearance modeling
Authors: Nayatani Yoshinobu , Sakai Hideki
Published: February 2007

A new type of color‐appearance model (CAM) is proposed together with its concept and flow of formulations. The topics described are: (1) The existence of two kinds of color‐appearance models, CAMs previously used and CAMs newly proposed. (2) All the CAMs, previously developed and used, do not predict color‐appearance attribute of perceived lightness of object colors under any illuminations. They may be adequately called “the model for predicting color‐appearance match between object colors under different adapting conditions.” (3) Newly improved CAMs take the Helmholtz–Kohlrausch effect in the VCC method into account. They can determine object colors with the same Tone (equi‐perceived lightness, equi‐whiteness‐blackness, and equi‐perceived chroma) irrespective of hues under reference illuminant. The newly improved models can be named Integrated CAMs. Their applicable fields are described in detail. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 113–120, 2007
Spectral adaptation
Authors: Fairchild Mark D.
Published: February 2007

Chromatic adaptation refers to the ability of the human visual system to adjust to the color of the illumination, or other prevailing stimuli, such that perceived object colors vary far less with changes in illumination than would be expected from simple radiometry or colorimetry. Models of chromatic adaptation are generally formulated as extensions of the von Kries hypothesis of some sort of independent gain control mechanisms operating on the three types of cone, or similar signals. This article introduces a new way to model the phenomenon with no requirement for the first stage chromatic processing. This model is referred to as a spectral adaptation model since it acts upon spectra rather than chromatic signals such as tristimulus values. The spectral adaptation model was compared with other models of adaptation both computationally and through limited psychophysical data. It is shown to have reasonable and flexible performance and could be of practical value in applications such as spectral image reproduction. A limiting case of the spectral model, a model of perfect color constancy, is also described and compared with traditional colorimetric chromatic adaptation models. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 100 – 112, 2007
Proposed modification to the CIECAM02 colour appearance model to include the simultaneous contrast effects
Authors: Wu Ray‐Chin , Wardman Roger H.
Published: February 2007

A modified CIECAM02 colour appearance model, named CIECAM02‐m2, is proposed to enable CIECAM02 to predict the simultaneous contrast effect. The structure of the CIECAM02‐m2 is a development from CIECAM02, and contains two different procedures for modifying the reference white; one is for lightness and the other is for hue. The model was tested using a data set accumulated in this study and the LUTCHI data. The CV values for three colour attributes between predictions and experimental data were used to evaluate the accuracy of the model. The low CV values obtained show the performance of the CIECAM02‐m2 model to predict the simultaneous contrast effect satisfactorily. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 121 – 129, 2007
Work week productivity, visual complexity, and individual environmental sensitivity in three offices of different color interiors
Authors: Kwallek Nancy , Soon Kokyung , Lewis Carol M.
Published: February 2007

This report is the fourth in a series from a large scale study that examines the effects of three office color interiors (white, predominately red, and predominately blue‐green) on worker productivity. Matched on relevant variables, participants were assigned to one of three offices and performed simulated office tasks for four consecutive days. Productivity was measured through workers' task performance and task accuracy, taking into account individual differences in environmental sensitivity (i.e., stimulus screening). The findings suggested that the influences of interior colors on worker productivity were dependent upon individuals' stimulus screening ability and time of exposure to interior colors. Implications of office workers' long‐term productivity are discussed in relation to issues concerning the visual complexity of interior environments. © 2007 Wiley Periodicals, Inc. Col Res Appl, 32, 130 – 143, 2007
A three‐symbol code for organized proteomes based on cyclical imaging of protein locations
Authors: Schubert Walter
Published: February 2007

Background:

A major challenge in the post genomic era is to map and decipher the functional molecular networks of proteins directly in a cell or a tissue. This task requires technologies for the colocalization of random numbers of different molecular components (e.g. proteins) in one sample in one experiment.

Methods:

Multi‐epitope‐ligand‐“kartographie” (MELK) was developed as a microscopic imaging technology running cycles of iterative fluorescence tagging, imaging, and bleaching, to colocalize a large number of proteins in one sample (morphologically intact routinely fixed cells or tissue).

Results:

In the present study, 18 different cell surface proteins were colocalized by MELK in cells and tissue sections in different compartments of the human immune system. From the resulting sets of multidimensional binary vectors the most prominent groups of protein–epitope arrangements were extracted and imaged as protein “toponome” maps providing direct insight in the higher order topological organization of immune compartments uncovering new tissue domains. The data sets suggest that protein networks, topologically organized in proteomes in situ, obey a unique protein‐colocation and ‐anticolocation code describable by three symbols.

Conclusion:

The technology has the potential to colocalize hundreds of proteins and other molecular components in one sample and may offer many applications in biology and medicine. © 2007 International Society for Analytical Cytology.
Clonal expansions of CD4+ B helper T cells in autoimmune myasthenia gravis
Authors: Tackenberg Björn , Kruth Jens , Bartholomaeus Johanna E. , Schlegel Kerstin , Oertel Wolfgang H. , Willcox Nicholas , Hemmer Bernhard , Sommer Norbert
Published: February 2007

The weakness in myasthenia gravis (MG) is mediated by T helper cell (Th)‐dependent autoantibodies against neuromuscular epitopes. So far, analyzing Th phenotypes or antigen specificities has yielded very few clues to pathogenesis. Here we adopt an alternative antigen‐independent approach, analyzing T cell receptor (TCR) Vβ usage/expansions in blood from 118 MG patients. We found major expansions (⩾ five standard deviations above the mean of 118 healthy, individually age‐ and sex‐matched controls) in diverse Vβ in 21 patients (17.6%, p<0.001) among CD4+ T cells, and in 45 patients (38.1%, p<0.001) among CD8+ T cells. In informative probands, the expanded CD4+ cells consistently showed a Th cell phenotype (CD57+CXCR5+) and expressed Th1 cytokines. Furthermore, their expression of markers for activation, lymphocyte trafficking and B cell‐activating ability persisted for ⩾3 years. Surprisingly, we noted a selective decline in the expansions/their CD57 positivity while the probands’ MG was improving. CDR3 spectratyping suggested mono‐ or oligoclonal origins, which were confirmed by the prevalent TCR Vβ CDR3 sequences of Th cells cloned from repeat bleeds. Thus, our data provide evidence for persistent clonally expanded CD4+ B helper T cell populations in the blood of MG patients. These unexpected CD4+ expansions might hold valuable clues to MG immunopathogenesis.
Platinum(II) and Palladium(II) Complexes with N‐Aminoguanidine
Authors: Aitken David J. , Albinati Alberto , Gautier Arnaud , Husson Henri‐Philippe , Morgant Georges , Nguyen‐Huy Dung , Kozelka Jiří , Lemoine Pascale , Ongeri Sandrine , Rizzato Silvia , Viossat Bernard
Published: February 2007

N‐Aminoguanidine (Amgu) was examined for its behaviour as a ligand for platinum(II) and palladium(II). Protonated AmguH+ can coordinate platinum as a monodentate ligand bound via the N4 amino group. Deprotonated, electrically neutral Amgu forms chelate complexes with both PtII and PdII; in these complexes Amgu is coordinated to the metal by the N4 amino group and the deprotonated N1 imino group, forming a five‐membered ring. K[PtCl3(dmso)] reacted with Amgu·HCl to yield a chelate complex with N1 bound trans to S, suggesting that an exchange between the N1 and N4 binding sites followed the primary nucleophilic attack of N4 on platinum. Whereas reactions between K2PdCl4 and Amgu·HCl were rapid and straightforward, K2PtCl4 was easily reduced to metallic platinum by Amgu·HCl, especially in stoichiometric conditions. Solution NMR and X‐ray crystallographic characterization is presented for five new complexes: trans‐[PtCl2(AmguH‐N4)2]Cl2·21/2H2O (3), trans‐[Pt(Amgu‐N1,N4)2](NO3)2 (4), [PtCl(Amgu‐N1,N4)(dmso)]Cl·2H2O (5), [PdCl2(AmguH‐N1,N4)] (6), and trans‐[Pd(Amgu‐N1,N4)2]Cl2 (7). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Nickel(II)‐Carbene Intermediates in Reactions of Geminal Dihaloalkanes with Nickel(0) Reagents and the Corresponding Carbene Capture as the Phosphonium Ylide
Authors: Eisch John J. , Qian Yun , Rheingold Arnold L.
Published: February 2007

In a previous study of geminal bond cleavages of substrates of the type R2CE2 [E2 = X2, O, S, Li(SO2Ph)] by nickel(0) reagents [LnNi, Ln = (Cod)2, (Et4P)4], leading to R2C=CR2 as products, the tentative hypothesis had been proposed that such reactions likely proceed via nickel(0)‐carbene intermediates (J. J. Eisch, Y. Qian, M. Singh, J. Organomet. Chem. 1996, 512, 207). Because such proposed nickel(0)‐carbenes do not satisfactorily account for reactions encountered with such α‐eliminations, a detailed reexamination of the reaction of these nickel(0) reagents with geminal dihalides has been undertaken. For example, two reactions of such presumed nickel(0)‐carbenes remained anomalous: (1) the failure of 5,5‐dibromotetraphenylcyclopentadiene to form its expected dimer, octaphenylphenylfulvalene and instead the formation of triethylphosphonium tetraphenylcyclopentadienide in its reaction with (Et3P)4Ni; and (2) the presumed capture of intermediate R2C=Ni0 in presence of the trapping agent (benzaldehyde or benzophenone). As to the first anomaly, a detailed study has shown that no trace of octaphenylfulvalene was formed. As to the second anomaly, the R2C fragment could be trapped by the carbonyl reagents only in reactions involving (Et3P)4Ni, but not in reactions with (Cod)2Ni. This finding compels one to conclude that the carbonyl reagent is capturing the Wittig reagent, R2C=PEt3, and not R2C=Ni0. Based upon all present data, the mechanism of such C=C bond dimerizations is best explicable in terms of nickel(II)‐carbenes. The triethylphosphonium tetraphenylcyclopentadienide formed here has by single‐crystal X‐ray structure determination, complemented by 13C NMR spectroscopic data, been found to have the zwitterionic structure Ph4Cp––+PEt3 as its paramount resonance contributor.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
The advent of mineralized skeletons in Neoproterozoic Metazoa—new fossil evidence from the Gaojiashan Fauna
Authors: Hong Hua , Zhe Chen , Xunlai Yuan
Published: February 2007

The terminal Neoproterozoic (Ediacaran) Dengying Formation in southern Shaanxi, China, hosts two types of conical fossils: one is the so‐called Conotubus, found in siliciclastic rocks in the lower and middle part of the Gaojiashan Member; the other is the renowned Cloudina in carbonate rocks of the upper Gaojiashan Member and succeeding Beiwan Member. Conotubus are conical and gently curved tubular fossils, with a variable rate of expansion. They are built of multiple thin, steep, eccentrically nested funnels set one within the next. A detailed comparison of the two conical fossils suggests that the organic tubes of Conotubus may be the precursor of the mineralized Cloudina tubes; this inference is consistent with their similarities in both wall structure and life style. Our research thus suggests that the organic skeleton preceded the rise of the mineralized skeleton in Cloudina‐like fossils. Sophisticated hypotheses have been advocated, some linking the skeletal genesis to increasing levels of Ca2+ in the seas, others to the enlargement of body sizes of animals. Yet our findings have supported the ‘arms race’ hypothesis: skeletons evolved primarily through selective predation pressure. Copyright © 2007 John Wiley & Sons, Ltd.
Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients
Authors: Olde Damink Steven W. M. , Jalan Rajiv , Deutz Nicolaas E. P. , Dejong Cornelis H. C. , Redhead Doris N. , Hynd Paula , Hayes Peter C. , Soeters Peter B.
Published: February 2007

Upper gastrointestinal (GI) bleeding in cirrhotic patients has a high incidence of mortality and morbidity. Postbleeding catabolism has been hypothesized to be partly due to the low biological value of hemoglobin, which lacks the essential amino acid isoleucine. The aims were to study the metabolic consequences of a “simulated” upper GI bleed in patients with cirrhosis of the liver and the effects of intravenous infusion of isoleucine. Portal drained viscera, liver, muscle, and kidney protein kinetics were quantified using a multicatheterization technique during routine portography. Sixteen overnight-fasted, metabolically stable patients who received an intragastric infusion of an amino acid solution mimicking hemoglobin every 4 hours were randomized to saline or isoleucine infusion and received a mixture of stable isotopes (L-[ring-2H5]phenylalanine, L-[ring-2H4]tyrosine, and L-[ring-2H2]tyrosine) to determine organ protein kinetics. This simulated bleed resulted in hypoisoleucinemia that was attenuated by isoleucine infusion. Isoleucine infusion during the bleed resulted in a positive net balance of phenylalanine across liver and muscle, whereas renal and portal drained viscera protein kinetics were unaffected. In the control group, no significant effect was shown.

Conclusion:

The present study investigated hepatic and portal drained viscera protein metabolism selectively in humans. The data show that hepatic and muscle protein synthesis is stimulated by improving the amino acid composition of the upper GI bleed by simultaneous intravenous isoleucine administration. (Hepatology 2007;45:560–568.)
Impairment of hepatic Stat-3 activation and reduction of PPARα activity in fructose-fed rats
Authors: Roglans Núria , Vilà Laia , Farré Mireia , Alegret Marta , Sánchez Rosa María , Vázquez-Carrera Manuel , Laguna Juan Carlos
Published: February 2007

Fructose makes up a significant proportion of energy intake in westernized diets; its increased consumption has paralleled the growing prevalence of obesity and metabolic syndrome over the past two decades. In the current study, we demonstrate that fructose administration (10% wt/vol) in the drinking water of rats reduces the trans-activating and trans-repressing activity of the hepatic peroxisome proliferator-activated receptor α (PPARα). As a consequence, fructose decreases hepatic fatty oxidation and increases pro-inflammatory transcription factor nuclear factor κB (NF-κB) activity. These changes were not observed in glucose-administered rats (10% wt/vol), although both carbohydrates produced similar changes in plasma adiponectin and in the hepatic expression of transcription factors and enzymes involved in fatty acid synthesis. Fructose-fed, but not glucose-fed, rats were hyperleptinemic and exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) transcription factor, although they did not present a similar increase in the serine phosphorylation of nuclear STAT3. Thus, an impairment in the hepatic transduction of the leptin signal could be responsible for the observed alterations in PPARα activity in fructose-fed rats. Because PPARα activity is lower in human than in rodent liver, fructose ingestion in humans should cause even worse effects, which would partly explain the link between increased consumption of fructose and widening epidemics of obesity and metabolic syndrome.

Conclusion

: Hypertriglyceridemia and hepatic steatosis induced by fructose ingestion result from a reduction in the hepatic catabolism of fatty acids driven by a state of leptin resistance. (Hepatology 2007;45:778–788.)
SgIGSF is a novel biliary–epithelial cell adhesion molecule mediating duct/ductule development
Authors: Ito Akihiko , Nishikawa Yuji , Ohnuma Kazuhiro , Ohnuma Ikuyo , Koma Yu-ichiro , Sato Ayuko , Enomoto Katsuhiko , Tsujimura Tohru , Yokozaki Hiroshi
Published: February 2007

Spermatogenic immunoglobulin superfamily (SgIGSF) is an intercellular adhesion molecule of the nectin-like family. While screening its tissue distribution, we found that it was expressed in fetal liver but not adult liver. In the present study, we examined which cells in developing and regenerating liver express SgIGSF via immunohistochemistry and Western blot analysis. In developing mouse liver, SgIGSF expression was transiently upregulated at perinatal ages and was restricted to the lateral membrane of biliary epithelial cells (BECs). In regenerating rat livers from the 2-acetylaminofluorene/partial hepatectomy model, SgIGSF was detected exclusively in oval cells that aligned in ductal and trabecular patterns by the second week posthepatectomy. In human livers, fetal and newborn bile ducts and cirrhotic bile ductules were clearly positive for SgIGSF, whereas disease-free adult bile ducts were negative. To investigate the role of SgIGSF in bile duct/ductule formation, we used an

in vitro

model in which rat hepatocyte aggregates embedded in collagen gels containing insulin and epidermal growth factor extend epithelial sheets and processes in the first week and form ductules within a month. The process and ductular cells were continuously positive for SgIGSF and cytokeratin 19, a BEC marker. When the aggregate culture was started in the presence of a function-blocking anti-SgIGSF antibody, the number of epithelial processes per aggregate was reduced by 80%.

Conclusion:

We propose that SgIGSF is a novel and functional BEC adhesion molecule that is expressed for a limited time during active bile duct/ductule formation. (Hepatology 2007;45:684–694.)
Cardiotrophin-1 is an essential factor in the natural defense of the liver against apoptosis
Authors: Marquès Juan M. , Belza Idoia , Holtmann Bettina , Pennica Diane , Prieto Jesus , Bustos Matilde
Published: February 2007

We previously reported that exogenous cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, exerts hepatoprotective effects. Because CT-1 is expressed in the normal liver, we hypothesized that this cytokine may constitute an endogenous defense of the liver against proapoptotic stimuli. Here, we found that CT-1−/− mice died faster than wild-type animals after challenge with a lethal dose of the Fas agonist Jo-2. At sublethal doses of Jo-2, all wild-type mice survived whereas CT-1−/− animals developed extensive hepatocyte apoptosis with 50% mortality at 24 hours. Pretreatment with CT-1 improved survival and reduced injury in both CT-1−/− and wild-type animals. Upon Fas ligation the activation of STAT-3, a molecule that defends the liver against apoptosis, was lower in CT-1−/− mice than in wild-type animals despite similar IL-6 up-regulation in the 2 groups. Analysis of liver transcriptome in CT-1−/− and wild-type mice showed that 9 genes reported to be associated with cell survival/death functions were differentially expressed in the 2 groups. Four of these genes [IGFBP1, peroxiredoxin3, TNFR1, and calpastatin (endogenous inhibitor of calpain)] could be validated by real-time PCR. All of them were down-regulated in CT-1−/− mice and were modulated by CT-1 administration. Treatment of CT-1−/− animals with the calpain inhibitor MDL28170 afforded significant protection against Fas-induced liver injury.

Conclusion

: CT-1−/− mice are highly sensitive to Fas-mediated apoptosis due in part to deficient STAT-3 activation and inadequate control of calpain activity during the apoptotic process. Our data show that CT-1 is a natural defense of the liver against apoptosis. This cytokine may have therapeutic potential. (Hepatology 2007;45:639–648.)
Novel aspects of PPARα-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study
Authors: Martin Pascal G. P. , Guillou Hervé , Lasserre Frédéric , Déjean Sébastien , Lan Annaig , Pascussi Jean-Marc , SanCristobal Magali , Legrand Philippe , Besse Philippe , Pineau Thierry
Published: February 2007

Peroxisome proliferator-activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism. It is activated by diverse chemicals such as fatty acids (FAs) and regulates the expression of numerous genes in organs displaying high FA catabolic rates, including the liver. The role of this nuclear receptor as a sensor of whole dietary fat intake has been inferred, mostly from high-fat diet studies. To delineate its function under low fat intake conditions (4.8% w/w), we studied the effects of five regimens with contrasted FA compositions on liver lipids and hepatic gene expression in wild-type and PPARα-deficient mice. Diets containing polyunsaturated FAs reduced hepatic fat stores in wild-type mice. Only sunflower, linseed, and fish oil diets lowered hepatic lipid stores in PPARα−/− mice, a model of progressive hepatic triglyceride accumulation. These beneficial effects were associated, in particular, with dietary regulation of Δ9-desaturase in both genotypes, and with a newly identified PPARα-dependent regulation of lipin. Furthermore, hepatic levels of 18-carbon essential FAs (C18:2ω6 and C18:3ω3) were elevated in PPARα−/− mice, possibly due to the observed reduction in expression of the Δ6-desaturase and of enoyl-coenzyme A isomerases. Effects of diet and genotype were also observed on the xenobiotic metabolism-related genes Cyp3a11 and CAR.

Conclusion:

Together, our results suggest that dietary FAs represent—even under low fat intake conditions—a beneficial strategy to reduce hepatic steatosis. Under such conditions, we established the role of PPARα as a dietary FA sensor and highlighted its importance in regulating hepatic FA content and composition. (Hepatology 2007;45:767–7777.)
Hepatic abnormalities in patients with chronic granulomatous disease
Authors: Hussain Nadeem , Feld Jordan J. , Kleiner David E. , Hoofnagle Jay H. , Garcia-Eulate Reyes , Ahlawat Sushil , Koziel Deloris E. , Anderson Victoria , Hilligoss Dianne , Choyke Peter , Gallin John I. , Liang Jake T. , Malech Harry L. , Holland Steven M. , Heller Theo
Published: February 2007

Chronic granulomatous disease (CGD) is a rare congenital disorder characterized by repeated bacterial and fungal infections. Aside from a high incidence of liver abscess, little is known about hepatic involvement in CGD. The aim of this study was to describe the spectrum of liver abnormalities seen in CGD. The charts of 194 patients with CGD followed at the NIH were reviewed, with a focus on liver abnormalities. Liver enzyme elevations occurred on at least one occasion in 73% of patients during a mean of 8.9 years of follow-up. ALT elevations were generally transient. Although transient alkaline phosphatase (ALP) elevations were also common, persistent ALP elevations lasting up to 17.6 years were seen in 25% of patients. Liver abscess occurred in 35% of patients. Drug-induced hepatotoxicity was documented in 15% of patients but likely occurred more frequently. Hepatomegaly was found in 34% and splenomegaly in 56% of patients. Liver histology showed granulomata in 75% and lobular hepatitis in 90% of specimens. Venopathy of the portal vein was common (80%) and associated with splenomegaly. Venopathy of the central vein was also common (63%) and was associated with the number of abscess episodes. Nodular regenerative hyperplasia (NRH) was seen in 9 patients, including 6 of 12 autopsy specimens.

Conclusion:

Liver enzyme abnormalities occur frequently in patients with CGD. In addition to liver abscesses and granulomata, drug hepatotoxicity is likely underappreciated. Vascular lesions such as venopathy and—to a lesser extent—NRH are common. The cause and clinical consequences of venopathy await prospective evaluation. (Hepatology 2007;45:675–683.)
Prevention of hepatocyte allograft rejection in rats by transferring adenoviral early region 3 genes into donor cells
Authors: Mashalova Elena V. , Guha Chandan , Roy-Chowdhury Namita , Liu Laibin , Fox Ira J. , Roy-Chowdhury Jayanta , Horwitz Marshall S.
Published: February 2007

Hepatocyte transplantation is being evaluated as an alternative to liver transplantation for metabolic support during liver failure and for definitive treatment of inherited liver diseases. However, as with liver transplantation, transplantation of allogeneic hepatocytes requires prolonged immunosuppression with its associated untoward effects. Therefore, we explored strategies for the genetic modification of donor hepatocytes that could eliminate allograft rejection, obviating the need for immunosuppression. Products of early region 3 (

AdE3

) of the adenoviral genome are known to protect infected cells from immune recognition and destruction. In the present study we showed that immortalized rat hepatocytes that had been stably transduced with AdE3 before transplantation into fully MHC-mismatched rats are protected from allograft rejection. Quantitative real-time PCR analysis showed that a similar number of engrafted AdE3-transfected hepatocytes had survived in syngeneic and allogeneic recipients. AdE3 expression did not reduce expression of MHC class I on the surfaces of donor hepatocytes. Consistent with this, the

in vivo

cytotoxic cell–mediated alloresponse was attenuated but not abolished in recipients of AdE3-transfected allogeneic hepatocytes. In contrast, graft survival correlated with a marked reduction in cell-surface localization of Fas receptor in the transplanted cells and inhibition of Fas-mediated apoptosis, which are related to the antiapoptotic functions of the AdE3 proteins.

CONCLUSION:

AdE3

gene products prevent hepatocyte allograft rejection mainly by protecting the cells from the effector limb of the host immune response and could be used as a tool to facilitate allogeneic hepatocyte transplantation. (Hepatology 2007;45:755–766.)
Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy
Authors: Prasad Srinivasa , Dhiman Radha K. , Duseja Ajay , Chawla Yogesh K. , Sharma Arpita , Agarwal Ritesh
Published: February 2007

Minimal hepatic encephalopathy (MHE) has a negative effect on patients' daily functioning. Thus far, no study has investigated the effect of treatment-related improvement in cognitive functions on health-related quality of life (HRQOL). We measured psychometric performance by number and figure connection tests parts A and B, picture completion, and block design tests and HRQOL by the Sickness Impact Profile (SIP) of 90 patients with cirrhosis on inclusion into the study and 3 months later. A

Z

score less than −2 on the neuropsychological (NP) tests was considered abnormal. Sixty-one (67.7%) patients had MHE. They were randomly assigned in a 1:1 ratio to receive treatment (lactulose) for 3 months (n = 31) or no treatment (n = 30) in a nonblinded design. The mean number of abnormal NP tests decreased significantly in patients in the treated group (baseline, 2.74 [95% CI 2.40-3.08]; after 3 months, .75 [95% CI .36-1.16]) compared with patients in the untreated group (baseline, 2.47 [95% CI 2.19-2.74]; after 3 months, 2.55 [95% CI 2.16-2.94]); multivariate analysis of variance (MANOVA) for time and treatment,

P

= 0.001. The mean total SIP score improved among patients in the treated group (baseline, 10.39 [95% CI 9.36-11.43]; after 3 months, 3.77 [95% CI 2.52-5.02]) compared with patients in the untreated group (baseline, 10.36 [95% CI 8.98-11.73]; after 3 months, 10.39 [95% CI 8.36-12.42]); MANOVA for time and treatment,

P

= 0.002. Improvement in HRQOL was related to the improvement in psychometry.

Conclusion

: Treatment with lactulose improves both cognitive function and HRQOL in patients with cirrhosis who have MHE. (Hepatology 2007;45:549–559.)
Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection
Authors: Penna Amalia , Pilli Massimo , Zerbini Alessandro , Orlandini Alessandra , Mezzadri Sergio , Sacchelli Luca , Missale Gabriele , Ferrari Carlo
Published: February 2007

The functional impairment of HCV-specific T cell responses is believed to be an important determinant of HCV persistence, but the functional T cell defects of patients with chronic hepatitis C (CH-C) are only partially defined. CD8 responses to HLA-A2–restricted epitopes of HCV and other unrelated viruses were studied in 23 HLA-A2–positive patients both

ex vivo

and after

in vitro

culture. Degranulation capacity, intracellular perforin, and granzyme-A content and cytokine production (IFN-γ, TNF-α) by HCV- and non–HCV-specific CD8 cells were tested both

ex vivo

and

in vitro

, whereas cytolytic activity was studied after 10 days' expansion

in vitro

. Memory maturation and role of exhaustion were assessed

ex vivo

by HCV-specific CD8 staining for CD127 and PD-1, and

in vitro

after peripheral blood mononuclear cells (PBMC) culture in the presence of anti–PD-L1 monoclonal antibodies. IFN-γ production and cytolytic activity were expressed less efficiently by HCV-specific than by non–HCV specific CD8 cells derived from the same CH-C patients. The amount of stored granzyme-A within single cells was always lower in HCV-specific CD8 cells, which were less efficient also in the release of lytic granules and in the production of TNF-α. The CD8 dysfunction was associated with high PD-1 expression by most HCV-specific CD8 cells, and PD-1/PD-L1 blockade by anti–PD-L1 antibodies

in vitro

was able to improve the HCV-specific CD8 function.

Conclusion:

Our study characterizes CD8 defects that may be important in maintaining HCV persistence; identification of strategies to correct these defects may help to define novel approaches to treat HCV infection. (Hepatology 2007;45:588–601.)
TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer-specific apoptosis within a therapeutic window
Authors: Koschny Ronald , Ganten Tom M. , Sykora Jaromir , Haas Tobias L. , Sprick Martin R. , Kolb Armin , Stremmel Wolfgang , Walczak Henning
Published: February 2007

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a novel promising anticancer biotherapeutic. However, TRAIL-resistant tumor cells require combinatorial regimens to sensitize tumor but not normal cells for TRAIL-induced apoptosis. Here, we investigated the mechanism of the synergistic antitumor effect of bortezomib in combination with TRAIL in hepatoma, colon, and pancreatic cancer cells in comparison to the toxicity in primary human hepatocytes (PHH). TRAIL cotreatment at high but clinically relevant concentrations of bortezomib caused toxicity in PHH which potentially limits the clinical applicability of bortezomib/TRAIL cotreatment. However, at low concentrations of bortezomib TRAIL-resistant hepatoma, colon and pancreatic cancer cell lines but not PHH were efficiently sensitized for TRAIL-induced apoptosis. RNA interference and TRAIL receptor blockage experiments revealed that in bortezomib-treated hepatoma cells TRAIL-R1/TRAIL-R2 up-regulation, enhanced TRAIL DISC formation and cFLIPL down-regulation in addition to accumulation of Bak cooperatively sensitized for TRAIL. Bim, although accumulated upon bortezomib treatment, did not play a causal role for TRAIL sensitization in Hep3b cells. Combined treatment with bortezomib and TRAIL massively reduced the clonogenic capacity of hepatoma cells

in vitro.

Surviving clones could be resensitized for repeated TRAIL treatment.

Conclusion:

Bortezomib/TRAIL cotreatment bears the risk of severe hepatotoxicity at high but clinically relevant concentrations of bortezomib. However, within a wide therapeutic window bortezomib sensitized different cancer cells but not PHH for TRAIL-induced apoptosis. (Hepatology 2007;45:649–658.)
Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes
Authors: Casado Marta , Mollá Belén , Roy Rosa , Fernández-Martínez Amalia , Cucarella Carme , Mayoral Rafael , Boscá Lisardo , Martín-Sanz Paloma
Published: February 2007

Cyclooxygenase-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE2 found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals. However, Tg animals were resistant to Fas-mediated liver injury, as demonstrated by low levels of plasmatic aminotransferases, a lesser caspase-3 activation, and Bax levels and an increase in Bcl-2, Mcl-1, and xIAP proteins, when compared with the Wt animals. Moreover, the resistance to Fas-mediated apoptosis is suppressed in the presence of COX-2–selective inhibitors, which prevented prostaglandin accumulation in the liver of Tg mice.

Conclusion:

These results demonstrate that expression of COX-2–dependent prostaglandins exerted a protection against liver apoptosis. (Hepatology 2007;45:631–638.)
Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver
Authors: Zhou Hongchao , Rogler Leslie E. , Teperman Lewis , Morgan Glyn , Rogler Charles E.
Published: February 2007

Hepatocyte function and regeneration are severely compromised in severe liver disease, and a common sequela is cirrhosis. Structural changes caused by cirrhosis create a cellular environment conducive to the formation of ductular reactions (DRs). Ductular reactions are primarily composed of oval cells also known as “intermediate hepatobiliary cells”. We have conducted single, double, and triple staining to study lineages of oval cells present in DRs. Staining with NCAM, CK19, and HepPar1 has revealed a distinctly bipolar structure to DRs that are embedded in cirrhotic tissue. Spatial analysis of cells that are singly HepPar1-positive, or CK19-positive, has revealed hepatocytic and biliary poles, respectively, in the DRs. Also, the location of singly NCAM-positive cells in DRs suggests that they may be bipotent liver stem/progenitor cells. The locations of other intermediate hepatobiliary cells, which have combinations of markers, suggest that CK19+/NCAM+ cells are transitional cells in the biliary lineage and that rare cells that are negative for all three markers are transitional cells in the hepatocytic lineage. A working cell lineage model for DRs is presented. (Hepatology 2007;45:716–724.)
Decreased hepatocyte membrane potential differences and GABAa-β3 expression in human hepatocellular carcinoma
Authors: Minuk Gerald Y. , Zhang Manna , Gong Yuewen , Minuk Leonard , Dienes Hans , Pettigrew Norman , Kew Michael , Lipschitz Jeremy , Sun Dongfeng
Published: February 2007

To determine whether hepatocyte membrane potential differences (PDs) are depolarized in human HCC and whether depolarization is associated with changes in GABAA receptor expression, hepatocyte PDs and γ-aminobutyric acid (GABA)A receptor messenger RNA (mRNA) and protein expression were documented in HCC tissues via microelectrode impalement, real-time reverse-transcriptase polymerase chain reaction, and Western blot analysis, respectively. HCC tissues were significantly depolarized (−19.8 ± 1.3 versus −25.9 ± 3.2 mV, respectively [

P

< 0.05]), and GABAA-β3 expression was down-regulated (GABAA-β3 mRNA and protein expression in HCC; 5,693 ± 1,385 and 0.29 ± 0.11 versus 11,046 ± 4,979 copies/100 mg RNA and 0.62 ± 0.16 optical density in adjacent tumor tissues, respectively [

P

= 0.002 and

P

< 0.0001, respectively]) when compared with adjacent nontumor tissues. To determine the physiological relevance of the down-regulation, human malignant hepatocytes deficient in GABAA-β3 receptor expression (Huh-7 cells) were transfected with GABAA-β3 complementary DNA (cDNA) or vector alone and injected into nu/nu nude mice (n = 16-17 group). Tumors developed after a mean (± SD) of 51 ± 6 days (range: 41-60 days) in 7/16 (44%) mice injected with vector-transfected cells and 70 ± 12 days (range: 59-86 days) in 4/17 (24%) mice injected with GABAA-β3 cDNA-transfected cells (

P

< 0.005).

Conclusion:

The results of this study indicate that (1) human HCC tissues are depolarized compared with adjacent nontumor tissues, (2) hepatic GABAA-β3 receptor expression is down-regulated in human HCC, and (3) restoration of GABAA-β3 receptor expression results in attenuated

in vivo

tumor growth in nude mice. (Hepatology 2007;45:735–745.)
Developing an alginate/chitosan hybrid fiber scaffold for annulus fibrosus cells
Authors: Shao Xinxin , Hunter Christopher J.
Published: February 2007

A fibrous scaffold made of alginate or alginate/chitosan was fabricated for annulus fibrosus (AF) cell culture using a wet‐spinning and lyophilization technique. The scaffolds were evaluated using several in vitro tests. Scanning electron microscopy showed the scaffold fibers generally aligned in one direction with individual fiber diameters varying between 40–100 μm. The alginate/chitosan hybrid scaffold exhibited a slower degradation rate, while both scaffold types did not display any cyto‐toxicity to 3T3 fibroblasts and could maintain canine AF cell growth. The AF cells retained their spherical shape within the fibrous scaffold at the beginning of the culture period and formed into cell clusters at later times. Specific extracellular matrix molecules, including collagen I, collagen II, and aggrecan, could be detected in the AF cell clusters. These results demonstrate the feasibility of using this hybrid alginate/chitosan scaffold for AF cell culture, and the potential application for intervertebral disc tissue engineering. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007
Fibrin glue mixed with gelatin/hyaluronic acid/chondroitin‐6‐sulfate tri‐copolymer for articular cartilage tissue engineering: The results of real‐time polymerase chain reaction
Authors: Chou Cheng‐Hung , Cheng Winston T.K. , Kuo Tzong‐Fu , Sun Jui‐Sheng , Lin Feng‐Huei , Tsai Jui‐Che
Published: February 2007

Autologous fibrin glue has been demonstrated as a potential scaffold with very good biocompatibility for neocartilage formation. However, fibrin glue has been reported not to provide enough mechanical strength, but with many growth factors to interfere the tissue growth. Gelatin/hyaluronic acid/chondroitin‐6‐sulfate (GHC6S) tri‐copolymer sponge has been prepared as scaffold for cartilage tissue engineering and showed very good results, but problems of cell seeding and cell distribution troubled the researchers. In this study, GHC6S particles would be added into the fibrin glue to provide better mechanical strength, better cell distribution, and easier cell seeding, which would be expected to improve cartilage regeneration in vitro. Porcine cryo‐precipitated fibrinogen and thrombin prepared from prothrombin activated by 10% CaCl2 solution were used in two groups. One is the fibrin glue group in which porcine chondrocytes were mixed with thrombin–fibrinogen solution, which was then converted into fibrin glue. The other is GHC6S‐fibrin glue in which GHC6S particles were added into the thrombin–fibrinogen solution with porcine chondrocytes. After culturing for 1–2 weeks, the chondrocytes cultured in GHC6S‐fibrin glue showed a round shape with distinct lacuna structure and showed positive in S‐100 protein immunohistochemical stain. The related gene expressions of tissue inhibitor of metalloproteinases‐1, matrix metalloproteinase‐2, MT1‐MMP, aggrecan, decorin, type I, II, X collagen, interleukin‐1 β, transforming growth factor‐β 1 (TGF‐β1), and Fas‐associating death domain were checked by real‐time PCR. The results indicated that the chondrocytes cultured in GHC6S‐fibrin glue would effectively promote extracellular matrix (ECM) secretion and inhibit ECM degradation. The evidence could support that GHC6S‐fibrin glue would be a promising scaffold for articular cartilage tissue engineering. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2007
Synthesis of the anxiolytic agent [14C] 6‐hydroxy‐buspirone for use in a human ADME study
Authors: Bonacorsi Samuel J. , Burrell Richard C. , Luke George M. , DePue Jeffrey S. , Kent Rinehart J. , Balasubramanian Balu , Christopher Lisa J. , Iyer Ramaswamy A.
Published: February 2007

A reliable synthesis of 14C labeled 6‐hydroxy‐buspirone is described. The molecule belongs to a unique class of compounds with the potential for anxiolytic activity. A radiolabeled analog was prepared to support the development of 6‐hydroxy‐buspirone. Specifically, a labeled variant was designed to meet the requirements of a human adsorption‐distribution‐metabolism‐elimination (ADME) study. Multiple 14C labels were needed to fully track the potential metabolic transformation of the molecule. Labeled 6‐hydroxy‐buspirone was prepared by oxidation of separately labeled versions of [14C]buspirone. The final product was isolated in reasonable yield with a radiochemical purity of 99.8%. Copyright © 2007 John Wiley & Sons, Ltd.
Synthesis of 18F‐labelled stilbenes from 4‐[18F]fluorobenz‐aldehyde using the Horner–Wadsworth–Emmons reaction
Authors: Gester Sven , Pietzsch Jens , Wuest Frank R.
Published: February 2007

The first application of the Horner–Wadsworth–Emmons reaction in 18F‐chemistry is described. This carbonyl‐olefination reaction was performed via a ‘multi‐step/one‐pot’ reaction by the coupling of benzylic phosphonic acid esters (3,5‐bis‐methoxymethoxybenzyl)‐phosphonic acid diethyl ester 2e, (4‐methoxy‐methoxybenzyl)‐phosphonic acid diethyl ester 3e and (4‐dimethyl‐aminobenzyl)phosphonic acid diethyl ester 4d) with 4‐[18F]fluorobenzaldehyde to give the corresponding 18F‐labelled stilbenes [18F]2g, [18F]3g and [18F]4e exclusively as the expected E‐isomers. The radiochemical yields ranged from 9% to 22% (based upon [18F]fluoride, including HPLC purification). The specific activity reached up to 90 GBq/µmol. Copyright © 2007 John Wiley & Sons, Ltd.
Reexamining the quantification of perfusion MRI data in the presence of bolus dispersion
Authors: Ko Linda , Salluzzi Marina , Frayne Richard , Smith Michael
Published: February 2007

Purpose

To determine the true impact of dispersion upon cerebral blood flow (CBF) quantification by removing an algorithm implementation‐induced systematic error.

Materials and Methods

The impact of dispersion on the arterial input function (AIF) between measurement and entry into the tissue of interest on CBF estimates was simulated assuming: 1) contralateral circulation flow that introduces a true arterial tissue delay (ATD)‐related dispersive component; and 2) the presence of an arterial stenosis that disperses and shifts the AIF peak entering the tissue; increasing the apparent ATD relative to the original AIF.

Results

Previously reported CBF estimates for the stenosis dispersion model were found to be a mixture of true dispersive effects and an algorithm implementation‐induced systematic error. The true CBFMEASURED/CBFNO‐DISPERSION ratios for short mean transit times (MTT) (normal) and long MTT (infarcted) tissue were similar for both dispersion models evaluated; this was an unanticipated result. The CBF quantification inaccuracies induced through the dispersion model truly related to ATD were lower than for the local stenosis‐based dispersion for small ATD values.

Conclusion

Correcting the systematic error present in a previous deconvolution study removes the reported ATD‐related impact on CBF quantification. The impact of dispersion was smaller than half that reported in previous simulation studies. J. Magn. Reson. Imaging 2007;25:639–643. © 2007 Wiley‐Liss, Inc.