bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparative study of the essential oils of the genus Plumeria Linn. from Malaysia
Authors: Tohar Norsita , Mohd Mustafa A. , Jantan Ibrahim , Awang Khalijah
Published: June 2006

The chemical composition of the flower oils of three Malaysian Plumeria Linn. species, P. acuminata Ait. (white flower), P. rubra Linn. (reddish‐orange flower) and P. rubra Linn. (red flower), were determined by gas chromatography on two columns of different polarity, GC–MS and Kováts retention indices. The oil of P. acuminata Ait. (white flower) was made up predominantly of benzyl salicylate (39.0%), benzyl benzoate (17.2%), trans‐nerolidol (10.6%), neryl phenylacetate (10.5%) and linalool (8.9%). Phenylethyl benzoate at 12.3% was the most abundant compound in the oil of P. rubra Linn. (reddish‐orange flower), followed by dodecanoic acid at 11.8% concentration. Hexadecanoic acid constituted 9.3% and 27.2% of the oils of P. rubra Linn. (reddish‐orange flower) and P. rubra Linn. (red flower), respectively. Copyright © 2006 John Wiley & Sons, Ltd.
Composition and antimicrobial activity of the volatile oil of Artemisia kopetdaghensis Krasch., M.Pop. & Linecz ex Poljak from Iran
Authors: Ramezani M. , Behravan J. , Yazdinezhad A.
Published: June 2006

Artemisia kopetdaghensis Krasch., M.Pop. & Linecz ex Poljak (Asteraceae) is a common perennial herb growing wild in north‐eastern parts of Iran. The essential oil of A. kopetdaghensis was isolated by hydrodistillation in 2.14% (v/w) yield. The chemical composition of the essential oil was examined by GC and GC–MS. Thirty‐three compounds were identified, representing 86.8% of the total oil. The major constituents were methyleugenol (24.4%), geranial (13.6%), davanone (11.1%), camphor (9.8%) and neral (7.4%). Minimum inhibitory concentration was determined, using the agar dilution method, against eight bacteria and two fungal strains. The essential oil showed a moderate antimicrobial activity. Copyright © 2006 John Wiley & Sons, Ltd.
Essential oil composition of Leucas milanjiana Guerke
Authors: Moody J. O. , Gundidza M. , Wyllie G.
Published: June 2006

A hydrodistilled oil obtained from the leaves of Leucas milanjiana Gurke (Lamiaceae) was analysed by capillary GC and GC‐MS. The leaf volatile oil contained 30 components, out of which 26 were identified. The predominant components were found to be β‐cubebene (38.15%), α‐pinene (19.71%), trans‐caryophyllene (7.41%) and α‐terpinolene (5.34%). The results are qualitatively and quantitatively at variance with data on other Leucas species and may therefore be of some chemotaxonomic significance for the genus. Copyright © 2006 John Wiley & Sons, Ltd.
Volatile compounds after spontaneous fermentation of musts from Vitis vinifera cv. Albariño grapes cultivated in different origins from Rías Baixas AOC, Spain
Authors: Zamúz S. , Vilanova M.
Published: June 2006

White wines experimentally produced from the white grape variety Albariño from three different areas from Rias Baixas AOC, north‐western Spain, have been analysed in this study. The contents of terpenes, C13‐norisoprenoids, alcohols, acetates and ethyl esters were determined by GC–MS. The Albariño wines from O Rosal are characterized by a high content of higher alcohols, while wines from Val do Salnés show the highest concentrations of free terpenes, acetates and ethyl esters; and wines of Condado do Tea show the highest concentrations of C13‐norisoprenids, principally due to the α‐ionone. Two principal components accounting for 90.7% of the total variance were calculated by means of a principal components analysis (PCA), and the graphical representation of these two components allows grouping the wines according their respective origins. Volatile compounds with fruity and floral odours showed the highest odour activity values, contributing in a great measure to the aroma of Albariño wines. Copyright © 2006 John Wiley & Sons, Ltd.
Higher‐resolution hyperbolic‐coupled‐elliptic flux‐continuous CVD schemes on structured and unstructured grids in 2‐D
Authors: Edwards Michael G.
Published: June 2006

Higher‐order convection schemes have been developed for the essentially hyperbolic systems of reservoir simulation and can significantly enhance solution quality. Locally conservative full‐tensor flux‐continuous finite‐volume schemes have also been developed for the porous medium pressure equation with general geometry and permeability tensors on structured and unstructured grids. These schemes removeO(1) errors induced by standard methods, and are now recognized as an essential component of any numerical method designed for reservoir simulation and modelling flow in porous media.

In this paper, novel higher‐resolution hyperbolic conservation law schemes, designed for convective flux approximation on unstructured grids are coupled with general full‐tensor continuous Darcy flux approximations. The schemes are developed for multi‐phase flow in porous media. Benefits in terms of improved front resolution are demonstrated. Comparisons with current methods including the control‐volume finite element (CVFE) method highlight the advantages of the new formulation for flow resolution in reservoir simulation. Copyright © 2006 John Wiley & Sons, Ltd.
Higher‐resolution hyperbolic‐coupled‐elliptic flux‐continuous CVD schemes on structured and unstructured grids in 3‐D
Authors: Edwards Michael G.
Published: June 2006

Novel three‐dimensional unstructured grid higher order convection schemes are presented. The schemes are coupled with locally conservative flux continuous control‐volume distributed (CVD) finite‐volume schemes for the porous medium general tensor pressure equation on structured and unstructured grids in 3‐D.

The schemes are developed for multi‐phase flow in porous media. Benefits of the schemes in terms of improved front resolution and medium discontinuity resolution are demonstrated. Comparisons with current methods including the control‐volume finite element method highlight the advantages of the new formulation for three‐dimensional reservoir simulation. Copyright © 2006 John Wiley & Sons, Ltd.
The effect of reduction in cross‐validation intervals on the performance of multifactor dimensionality reduction
Authors: Motsinger Alison A. , Ritchie Marylyn D.
Published: June 2006

Multifactor Dimensionality Reduction (MDR) was developed to detect genetic polymorphisms that present an increased risk of disease. Cross‐validation (CV) is an important part of the MDR algorithm, as it prevents over‐fitting and allows the predictive ability of a model to be evaluated. CV is a computationally intensive step in the MDR algorithm. Traditionally, MDR has been implemented using 10‐fold CV. In order to reduce computation time and therefore allow MDR analysis to be applied to larger datasets, we evaluated the possibility of eliminating or reducing the number of CV intervals used for analysis. We found that eliminating CV made final model selection impossible, but that reducing the number of CV intervals from ten to five caused no loss of power, thereby reducing the computation time of the algorithm by half. The validity of this reduction was confirmed with data from an Alzheimer's disease (AD) study. Genet. Epidemiol. 2006. © 2006 Wiley‐Liss, Inc.
Molecular evolution of 5′ flanking regions of 87 candidate genes for atherosclerotic cardiovascular disease
Authors: Ding Keyue , Kullo Iftikhar J.
Published: June 2006

Inter‐individual variation in quantitative traits as well as in disease susceptibility may be due to differences in the level and spatio‐temporal pattern of gene expression. An evolutionary model of genetic variation in cis‐regulatory regions may help identify loci of interest for the study of the genetic basis of complex diseases such as atherosclerotic cardiovascular disease (ASCVD). We studied the molecular evolution of 87 candidate genes for ASCVD to detect signatures of selection in 5′ flanking regions. Resequenced data for these genes were available in 24 African‐Americans, 23 European‐Americans, and 1 chimpanzee (Pan troglodytes). Statistical tests of evolutionary neutrality (Tajima's D and Fay and Wu's H) were performed using coalescent simulations under a standard neutral model and a population structure model to differentiate selection from human demographic history. Evidence suggestive of selection was present in 5′ flanking regions of 15 genes. A modified McDonald‐Kreitman test was used to compare the ratio of putative functional and non‐functional sites between and within species in 5′ flanking regions. A significant excess or deficit of fixed changes over polymorphisms was noted in 16 genes. Of the 26 genes showing deviation from evolutionary neutrality based on the above two tests, 13 genes showed an unusual haplotype pattern in 5′ flanking regions, providing supportive evidence of selection. These results indicate that selection may play a role in establishing variation in 5′ flanking regions of a subset of candidate genes for ASCVD and motivate further studies of these loci in determining inter‐individual susceptibility to ASCVD. Genet. Epidemiol. 2006. © 2006 Wiley‐Liss, Inc.
Subtle myelin defects in PLP‐null mice
Authors: Rosenbluth Jack , Nave Klaus‐Armin , Mierzwa Amanda , Schiff Rolf
Published: June 2006

This study explores subtle defects in the myelin of proteolipid protein (PLP)‐null mice that could potentially underlie the functional losses and axon damage known to occur in this mutant and in myelin diseases including multiple sclerosis. We have compared PLP‐null central nervous system (CNS) myelin with normal myelin using ultrastructural methods designed to emphasize fine differences. In the PLP‐null CNS, axons large enough to be myelinated often lack myelin entirely or are surrounded by abnormally thin sheaths. Short stretches of cytoplasm persist in many myelin lamellae. Most strikingly, compaction is incomplete in this mutant as shown by the widespread presence of patent interlamellar spaces of variable width that can be labeled with ferricyanide, acting as an aqueous extracellular tracer. In thinly myelinated fibers, interlamellar spaces are filled across the full width of the sheaths. In thick myelin sheaths, they appear filled irregularly but diffusely. These patent spaces constitute a spiral pathway through which ions and other extracellular agents may penetrate gradually, possibly contributing to the axon damage known to occur in this mutant, especially in thinly myelinated fibers, where the spiral path length is shortest and most consistently labeled. We show also that the “radial component” of myelin is distorted in the mutant (“diagonal component”), extending across the sheaths at 45° instead of 90°. These observations indicate a direct or indirect role for PLP in maintaining myelin compaction along the external surfaces of the lamellae and to a limited extent, along the cytoplasmic surfaces as well and also in maintaining the normal alignment of the radial component. © 2006 Wiley‐Liss, Inc.
TIP30 inhibits growth of HCC cell lines and inhibits HCC xenografts in mice in combination with 5-FU
Authors: Zhao Jian , Zhang Xia , Shi Mei , Xu Hao , Jin Jun , Ni Haidong , Yang Silei , Dai Jianxin , Wu Mengchao , Guo Yajun
Published: June 2006

Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The specific cellular gene alterations responsible for hepatocarcinogenesis are not well known. Previous works showed that loss of

TIP30

, also called

CC3

, a putative tumor suppressor, increased the incidence of hepatocellular carcinoma in mice, and some clinical samples of human HCC tissues had aberrant expression of

TIP30

. Here, we report that the introduction of

TIP30

by an adenovirus vector into HCC cell lines that had decreased expressions of

TIP30

inhibited cell proliferation, decreased anchorage-dependent growth, suppressed invasion through the extracellular matrix, and inhibited tumorigenesis in nude mice. Moreover, exogenous expression of

Tip30

sensitized HCC cells to cytotoxic drugs and to apoptosis induced by tumor necrosis factor–related ligands

in vitro.

Ectopic expression of TIP30 in HCC cells enhanced p53 expression and decreased Bcl-2/Bcl-xL expression. Treatment of nude mice bearing subcutaneously established HCC tumors with a combination of an adenovirus expressing

TIP30

and the cytotoxic drug 5-fluorouracil completely suppressed tumor growth and prolonged survival.

In conclusion

,

TIP30

may play an important role in the suppression of hepatocarcinogenesis by acting as a tumor suppressor. Overexpression of TIP30 might be a promising candidate as a treatment for HCC that would increase sensitivity to chemotherapeutic drugs.

Supplementary material for this article can be found on the HEPATOLOGY website
(http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Actin organization and hepatocyte differentiation are regulated by extracellular matrix via PI-4,5-bisphosphate in the rat
Authors: Kimata Takayuki , Nagaki Masahito , Ogiso Tomio , Naiki Takafumi , Kato Tomohiro , Moriwaki Hisataka
Published: June 2006

Cell adhesion to the extracellular matrix (ECM) plays vital roles in both morphogenesis and regulation of gene expression in cells of adult organisms. How intracellular, cytoskeletal, and signaling factors connect and communicate with the ECM is a fundamental question. Using a cDNA microarray analysis, we identified phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) phosphatase mRNA as being up-regulated in hepatocytes cultured on a basement membrane matrix, Engelbreth-Holm-Swarm (EHS) gel, which led to the finding that the PI(4,5)P2 levels of hepatocytes decreased on EHS gel. These changes in hepatocytes on EHS gel were accompanied by promotion of actin depolymerization and differentiated phenotypes of the hepatocytes. Treatment with PI(4,5)P2 or a phospholipase C inhibitor, U73122, resulted in decreased mRNA expressions of albumin and hepatocyte nuclear factor 4 (HNF-4) in hepatocytes. In contrast, actin-disrupting agent gelsolin increased mRNA expressions of albumin and HNF-4.

In conclusion

, organization of the actin cytoskeleton via PI(4,5)P2 is involved in the regulation of hepatocyte differentiation by the ECM.
Hepatitis B virus genotype G monoinfection and its transmission by blood components
Authors: Chudy Michael , Schmidt Michael , Czudai Volker , Scheiblauer Heinrich , Nick Sigrid , Mosebach Mira , Hourfar Michael Kai , Seifried Erhard , Roth Kurt W. , Grünelt Elke , Nübling Micha C.
Published: June 2006

An acute hepatitis B virus (HBV) infection was diagnosed in a regular apheresis (plasma/platelet) donor by the hepatitis B surface antigen (HBsAg) assay and minipool nucleic acid amplification technology (NAT). The acute infection was confirmed by detection of anti-HBc (IgM) and anti-HBs 2 weeks later. The donor showed no clinical symptoms and had normal alanine aminotransferase levels. He had a history of weekly apheresis plasma or platelet donations. Archived material from the donor and the respective recipients was investigated by sensitive HBV NATs as part of a look-back procedure. HBV DNA was detectable in previous donations as well as in two recipients transfused with platelet concentrates. The rare HBV genotype G was identified in all HBV-DNA-positive samples. Strong evidence of genotype G monoinfection was obtained by clonal sequencing, HBV genotype line probe assay, genotype-specific NATs, and restriction pattern analysis. In contrast to previously described genotype G infections, which all appeared as coinfections with genotype A, neither the hepatitis B e antigen (HBeAg) nor anti-HBe was detectable in any of the samples. This shows that HBeAg is dispensable for viral replication. The delay in detecting HBsAg in both the donor and recipient samples may be explained by either decreased genotype G–specific synthesis of incomplete viral forms in early HBV infection or the lower sensitivity to genotype G of the current HBsAg assays.

In conclusion

, this reported case of an HBV infection was caused exclusively by genotype G.
Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell–mediated hepatitis
Authors: Kremer Michael , Hines Ian Neil , Milton Richard Jameson , Wheeler Michael Daryl
Published: June 2006

Steatohepatitis enhances the severity of liver injury caused by acute inflammation. The purpose of this study was to test the hypothesis that fatty liver due to chronic choline-deficient diet exacerbates concanavalin A (ConA)-induced liver hepatitis, which is predominantly facilitated by T cells. Male C57BL/6 mice were fed either control choline-sufficient diet (CSD) or choline-deficient diet (CDD) for 6 weeks before ConA administration. Mice were sacrificed 3, 9, and 24 hours after ConA injection. Liver injury measured by aspartate aminotransferase (AST), alanine aminotransferase (ALT), pathology, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining was minimal in mice fed either diet before ConA exposure. However, ConA-induced liver injury was significantly greater in CDD-fed mice compared with control-fed mice. Liver cytokines were assessed by quantitative real-time polymerase chain reaction (PCR). The expression of T helper (Th) 1 cytokines tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), and interferon gamma (IFN-γ) were dramatically elevated after ConA in CDD-fed mice compared with control-fed mice. CDD also enhanced ConA-induced STAT4 activation, but not STAT6. Notably, regulators of T-cell differentiation were strongly shifted toward a predominant Th1 profile. T-bet, regulator of the Th1 response, was up-regulated in CDD-fed mice, whereas Th2 regulator GATA-3 was significantly suppressed in CDD-fed mice after ConA. Moreover, the expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3, and repressor of GATA-3 (ROG) favored a predominant Th1 cytokine response in CDD-fed mice.

In conclusion

, these data support the hypothesis that hepatosteatosis caused by CDD is associated with more severe ConA-induced hepatitis due to a predominant shift toward Th1 response.
Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytes in vivo
Authors: Zschemisch Nils-Holger , Liedtke Christian , Dierssen Uta , Nevzorova Yulia A. , Wüstefeld Torsten , Borlak Jürgen , Manns Michael P. , Trautwein Christian
Published: June 2006

Cyclin E1 controls G1/S phase transition of the eukaryotic cell cycle. We report the impact of alternative spliced cyclin E1 isoforms on cell cycle regulation in hepatocytes. We show that expression of new cyclin E1 mRNA variants IN3, Δ4, and Δ5 is associated with retarded proliferation in murine hepatocellular carcinoma. Additionally, we demonstrate that a new cyclin E1 isoform Δ3/8 lacking the central part of wild-type mRNA is expressed predominantly in nonproliferating murine hepatocytes. Following partial hepatectomy, Δ3/8 is downregulated when hepatocytes enter the cell cycle from quiescence. The Δ3/8 protein does not exhibit any cyclin box motif but binds cyclin-dependent kinase 2 without stimulating kinase activity. We demonstrate that Δ3/8 lacks any nuclear localization signal and is exclusively located in the cytoplasm. Overexpression of Δ3/8 in cultured cells leads to a delayed G0-G1 transition, indicating that this splice variant helps to maintain a quiescent state of hepatocytes.

In conclusion

, we identified an isoform of cyclin E1 involved in G0 maintenance and suggest an additional mechanism for cell cycle control.
The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis
Authors: Matei Vasilica , Rodríguez-Vilarrupla Aina , Deulofeu Ramon , Colomer Dolors , Fernández Mercedes , Bosch Jaime , Garcia-Pagán Juan-Carlos
Published: June 2006

In cirrhosis, intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension. Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH4) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis. Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl4 cirrhosis. Thereafter, rats were treated with tetrahydrobiopterin, and eNOS activity, NO bioavailability, assessed with a functional assay, and the vasodilator response to acetylcholine (endothelial function) were evaluated. Livers with cirrhosis showed reduced BH4 levels and decreased GTP-cyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine. Tetrahydrobiopterin supplementation increased BH4hepatic levels and eNOS activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis.

In conclusion

, the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the eNOS cofactor, tetrahydrobiopterin. Tetrahydrobiopterin supplementation improved the endothelial dysfunction of cirrhotic livers.
Multiple polymorphic loci determine basal hepatic and splenic iron status in mice
Authors: Grant Gemma R. , Robinson Susan W. , Edwards Richard E. , Clothier Bruce , Davies Reginald , Judah David J. , Broman Karl W. , Smith Andrew G.
Published: June 2006

Polymorphisms of genes linked to iron metabolism may account for individual variability in hemochromatosis and iron status connected with liver and cardiovascular diseases, cancers, toxicity, and infection. Mouse strains exhibit marked differences in levels of non-heme iron, with C57BL/6J and SWR showing low and high levels, respectively. The genetic basis for this variability was examined using quantitative trait loci (QTL) analysis together with expression profiling and chromosomal positions of known iron-related genes. Non-heme iron levels in liver and spleen of C57BL/6J × SWR F2 mice were poorly correlated, indicating independent regulation. Highly significant (

P

< .01) polymorphic loci were found on chromosomes 2 and 16 for liver and on chromosomes 8 and 9 for spleen. With sex as a covariate, additional significant or suggestive (

P

< 0.1) QTL were detected on chromosomes 7, 8, 11, and 19 for liver and on chromosome 2 for spleen. A gene array showed no clear association between most loci and differential iron-related gene expression. The gene for transferrin and a transferrin-like gene map close to the QTL on chromosome 9. Transferrin saturation was significantly lower in C57BL/6J mice than in SWR mice, but there was no significant difference in the serum level of transferrin, hepatic expression, or functional change in cDNA sequence. β2-Microglobulin, which, unlike other loci, was associated with C57BL/6J alleles, is a candidate for the chromosome 2 QTL for higher iron.

In conclusion

, the findings show the location of polymorphic genes that determine basal iron status in wild-type mice. Human equivalents may be pertinent in predisposition to hepatic and other disorders.
Phenobarbital regulates nuclear expression of HNF-4α in mouse and rat hepatocytes independent of CAR and PXR
Authors: Bell Aaron W. , Michalopoulos George K.
Published: June 2006

Phenobarbital is a lipophilic molecule used as a sedative and antiepileptic drug that elicits a multitude of effects in the liver, including gross liver enlargement, hepatocyte hypertrophy, and induced expression of drug-metabolizing enzymes and other liver-specific genes. The constitutive androstane receptor (CAR; NR1I3) and to a lesser extent the pregnane X receptor (PXR; NR1I2) are responsible for mediating induction of many phenobarbital-responsive genes. However, CAR-mediated transcriptional control of some genes is critically dependent on hepatocyte nuclear factor 4 alpha (HNF-4α; NR2A1), which itself regulates multiple liver-specific genes involved in hepatic growth, metabolism, and differentiation. We studied the effects of phenobarbital on HNF-4α expression in hepatocytes and provide evidence that HNF-4α nuclear expression is regulated in response to phenobarbital. Real-time polymerase chain reaction analyses revealed that HNF-4α mRNA is modestly up-regulated by phenobarbital. In addition, nuclear expression of HNF-4α protein is significantly elevated 3 hours after the administration of phenobarbital in wild-type, CAR−/−, and CAR−/−/PXR−/− mice.

In vitro

analysis revealed that phenobarbital-induced HNF-4α expression is both time- and dose dependent. In addition, the phosphatase inhibitor okadaic acid and the Ca2+/calmodulin-dependent protein kinase II inhibitor KN62 block nuclear induction of HNF-4α by phenobarbital. Furthermore, HNF-4α nuclear expression is enhanced by inhibition of cyclic AMP–dependent protein kinase A.

In conclusion

, induced nuclear expression of HNF-4α and CAR is an integral part of the phenobarbital response, aimed at coordinated regulation of genes involved in drug metabolism and detoxification as well as maintenance of liver function.
Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure
Authors: Antoniades Charalambos Gustav , Berry Philip A. , Davies Edward T. , Hussain Munther , Bernal William , Vergani Diego , Wendon Julia
Published: June 2006

Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non–acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n = 26) and spontaneous survivors (AALF-S, n = 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%,

P

< .001) and NAALF (22 %,

P

< .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%,

P

< .001) and higher levels of IL-4, IL-6, IL-10 and TNF-α (

P

< .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r = −0.8 to −0.5,

P

< .01), IL-10 (r = −0.8,

P

< .0001), TNF-α (r = −0.4,

P

= .02). HLA-DR percentage level ≤15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis.

In conclusion

, the strong relationship of monocyte HLA-DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis.
Enhancement by pyrazole of lipopolysaccharide-induced liver injury in mice: Role of cytochrome P450 2E1 and 2A5
Authors: Lu Yongke , Cederbaum Arthur I.
Published: June 2006

The mechanisms by which alcohol causes liver injury are still not certain. Either LPS or CYP2E1 are considered independent risk factors involved in alcoholic liver disease, but mutual relationships or interactions between them are unknown. In the present study, the possible synergistic action of CYP2E1 and LPS in liver injury was investigated by evaluating the effects of pyrazole (inducer of CYP2E1), Chlormethiazole (CMZ), an inhibitor of CYP2E1, and CYP2E1-knockout mice. Mice were injected with pyrazole (150 mg/kg, ip) daily for 2 days, followed by LPS injection (4 mg/kg, ip). CMZ (50mg/kg, ip) was administered 15 h before and 30 min after LPS treatment, respectively. LPS-induced liver injury was enhanced by pyrazole, as indicated by pathological changes and increases in ALT and AST, and positive TUNEL staining. LPS-induced oxidative stress was also enhanced by pyrazole as indicated by increases in 4-hydroxy-2-nonenal and 3-nitrotyrosine adduct formation. CMZ protected against the pyrazole enhanced LPS liver injury and oxidative stress. CYP2E1 but also CYP2A5 were increased by the pyrazole/LPS treatment. CMZ decreased the elevated CYP2E1 activity by 90%, but CYP2A5 activity was also lowered (30%-50%). CYP2E1-knockout mice exhibited only minor liver injury after treatment with pyrazole/LPS, but wild-type mice exhibited severe liver injury. While no CYP2E1 was present in the CYP2E1 knockout mice, CYP2A5 activity was also lower.

In conclusion

, induction of CYP2E1 plays an important role in the enhancement of LPS liver injury by pyrazole, but some contribution by CYP2A5 cannot be excluded.

Supplementary material for this article can be found on the HEPATOLOGY website
(http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Lack of chemokine receptor CCR5 promotes murine fulminant liver failure
Authors: Tiegs Gisa
Published: June 2006

Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-γ, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.
Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences
Authors: Blackard Jason T. , Kemmer Nyingi , Sherman Kenneth E.
Published: June 2006

An estimated 170 million persons are infected with the hepatitis C virus (HCV) worldwide. While hepatocytes are the major site of infection, a broad clinical spectrum of extrahepatic complications and diseases are associated with chronic HCV infection, highlighting the involvement of HCV in a variety of non-hepatic pathogenic processes. There is a growing body of evidence to suggest that HCV can replicate efficiently in extrahepatic tissues and cell types, including peripheral blood mononuclear cells. Nonetheless, laboratory confirmation of HCV replication in extrahepatic sites is fraught with technical challenges, and

in vitro

systems to investigate extrahepatic replication of HCV are severely limited. Thus, future studies of extrahepatic replication should combine innovative

in vitro

assays with a prospective cohort design to maximize our understanding of this important phenomenon to the pathogenesis and treatment response rates of HCV.
Studies towards a Conjugate Vaccine for Anthrax: Synthesis of the Tetrasaccharide Side Chain of the Bacillus anthracis Exosporium
Authors: Adamo Roberto , Saksena Rina , Kováč Pavol
Published: June 2006

The first synthesis of β‐L‐glycoside 17 of the tetrasaccharide β‐Ant‐(1 → 3)‐α‐L‐Rhap‐(1 → 3)‐α‐L‐Rhap‐(1 → 2)‐L‐Rhap is described (Schemes 1–3). Its spacer can be functionalized to make it amenable to conjugation to proteins by different conjugation methods. The synthesis was performed in a stepwise manner starting from the aglycon‐bearing terminal saccharide with thioglycosides as glycosyl donors. To attach the upstream terminal anthrose residue, the assembled linker‐equipped trisaccharide was glycosylated with ethyl 4‐azido‐3‐O‐benzyl‐2‐O‐(bromoacetyl)‐4,6‐dideoxy‐1‐thio‐β‐D‐glucopyranoside (11). Further functionalization of the tetrasaccharide thus obtained, followed by deprotection gave the target substance 17. Synthesis of substructures of 17 equipped with the same spacer, namely β‐L‐Rhap‐1‐O‐(CH2)5COOMe (21), α‐L‐Rhap‐(1 → 2)‐β‐L‐Rhap‐1‐O‐(CH2)5COOMe (22), and α‐L‐Rhap‐(1 → 3)‐α‐L‐Rhap‐(1 → 2)‐β‐L‐Rhap‐1‐O‐(CH2)5COOMe (23), is also described (Scheme 4).
Synthesis, Olfactory Evaluation, and Determination of the Absolute Configuration of the 3,4‐Didehydroionone Stereoisomers
Authors: Serra Stefano , Fuganti Claudio , Brenna Elisabetta
Published: June 2006

The synthesis of 3,4‐didehydroionone isomers 4, (+)‐6, and (−)‐6 and of 3,4‐didehydro‐7,8‐dihydroionone isomers 5, (+)‐7, and (−)‐7 was accomplished starting from commercially available racemic α‐ionone (1). Their preparation of the racemic forms 4–7 was first achieved by mean of a number of chemo‐ and regioselective reactions (Schemes 1 and 2). The enantio‐ and diastereoselective lipase‐mediated kinetic acetylation of 4‐hydroxy‐γ‐ionone (10a/10b) provided 4‐hydroxy‐γ‐ionone (+)‐10a/(±)‐10b and (+)‐4‐(acetyloxy)‐γ‐ionone ((+)12b) (Scheme 3). The latter compounds were used as starting materials to prepare the 3,4‐didehydro‐γ‐ionones (+)‐ and (−)‐6 and the 3,4‐didehydro‐7,8‐dihydro‐γ‐ionones (+)‐ and (−)‐7 in enantiomer‐enriched form. The absolute configuration of (+)‐12b was determine by chemical correlation with (+)‐(6S)‐γ‐ionone ((+)‐3) and with (−)‐(6S)‐α‐ionone ((−)‐1) therefore allowing to assign the (S)‐configuration to (+)‐6 and (+)‐7. Olfactory evaluation of the above described 3,4‐didehydroionone isomers shows a significant difference between the enantiomers and regioisomers both in fragrance feature and in detection threshold (Table).
Synthesis and Electronic Spectroscopy of Bromocarbazoles. Direct Bromination of N‐ and C‐Substituted Carbazoles by N‐Bromosuccinimide or a N‐Bromosuccinimide/Silica Gel System
Authors: Ponce María B. , Cabrerizo Franco M. , Bonesi Sergio M. , Erra‐Balsells Rosa
Published: June 2006

The preparation, isolation and characterization by elemental analysis and 1H‐NMR, 13C‐NMR, and MS data of the bromo derivatives of N‐substituted carbazoles, i.e., of 9‐methyl‐9H‐carbazole (1), 9‐phenyl‐9H‐carbazole (2), 9‐benzyl‐9H‐carbazole (3), 2‐methoxy‐9‐methyl‐9H‐carbazole (4), and of C‐substituted carbazoles, i.e., of 2‐(acetyloxy)‐9H‐carbazole (5) and 3‐nitro‐9H‐carbazole (6), are reported, in part for the first time. As brominating reagents, N‐bromosuccinimide (NBS) or NBS/silica gel in CH2Cl2, NBS in AcOH, KBrO3/KBr in EtOH doped with a catalytic amount of H2SO4, or KBrO3/KBr in AcOH were employed, and their uses were compared. Semi‐empirical PM3 calculations were performed to predict the reactivity of the N‐substituted and C‐substituted carbazoles and of their bromo derivatives and found to verify the experimental results. The UV‐absorption and fluorescence and phosphorescence emission spectra of the bromocarbazole derivatives in MeCN solution at 298 K and in a solid matrix at 77 K were compared with those of the corresponding carbazoles 1–6. The dynamic properties of the lowest excited singlet and triplet states (τf, τp, ϕf, and ϕp) were measured under the same experimental conditions. The intramolecular spin–orbital‐coupling effect of the Br‐atom and NO2 group on the spectroscopic data, photophysical parameters, and on the photo reactivity were also briefly analyzed.
A New Synthesis of Pteridines
Authors: Xu Ming , Vasella Andrea
Published: June 2006

A new synthesis of pteridines possessing a (substituted) (Z)‐3‐hydroxyprop‐1‐enyl group at C(6) is based on the acylation of 4‐amino‐5‐nitrosopyrimidines with dienoic acid chlorides, followed by a high‐yielding intramolecular hetero‐Diels–Alder cycloaddition and cleavage of the NO bond leading to 4. Thermolysis of the resulting pteridines 4 possessing a benzyloxy group at C(4) led to the products 5, resulting from isomerisation of the 3‐hydroxyprop‐1‐enyl to an 3‐oxopropyl side chain, while the analogous pteridine 8 possessing an NH2 group at C(4) remained unaffected.
Three Novel Terpenoids from Schisandra pubescens var. pubinervis
Authors: Huang Sheng‐Xiong , Yang Jing , Xiao Wei‐Lie , Zhu Yan‐Ling , Li Rong‐Tao , Li Li‐Mei , Pu Jian‐Xin , Li Xian , Li Sheng‐Hong , Sun Han‐Dong
Published: June 2006

Three new terpenoids, pubinernoids A–C (1–3), together with six known sesquiterpenoids, were isolated from the leaves and stems of Schisandra pubescens var. pubinervis. The structures of the new compounds were established on the basis of extensive spectroscopic analyses, including application of 2D‐NMR spectroscopic techniques. A plausible formation of the sesquiterpenoid 2 is proposed (Scheme 2), starting from guaianediol (4) as the biogenetic precursor, which was also present in the extract.
Structure Elucidation of Two New Diterpenoids from Isodon phyllostachys: Phyllostacins A and B
Authors: Li Xian , Xiao Wei‐Lie , Huang Sheng‐Xiong , Weng Zhi‐Ying , Shen Yun‐Heng , Han Quan‐Bin , Sun Han‐Dong
Published: June 2006

Two new ent‐kaurane‐derived diterpene derivatives, phyllostacins A (1) and B (2), were isolated from the aerial parts of Isodon phyllostachys, together with two known compounds, irroratin A (3) and serrin B (4). Both 1 and 2 were found to be present as diastereoisomers. In the case of 1, the corresponding diastereoisomeric diacetates 5 and 6 were prepared and separated. The structures of the new compounds were elucidated by extensive 1D‐ and 2D‐NMR spectroscopic methods, in combination with MS experiments. In (D5)pyridine solution, the two epimers of 1 are present in equal amounts, but in CDCl3 or CD3OD, the (S)‐epimer predominates in the mixture of hemiacetals.
New, Diastereoselective One‐Pot Synthesis of Tetrasubstituted Hydantoins
Authors: Alizadeh Abdolali , Masrouri Hassan
Published: June 2006

An effective route to hydantoins is described, based on the 2 : 1 : 1 addition of arylsulfonyl isocyanates, dialkyl acetylenedicarboxylates, and dialkyl trialkylsilyl phosphites. The resulting tetrasubstituted, stable hydantoins 4/4′ (Table) were obtained in excellent yields, and their structures were corroborated spectroscopically (IR, 1H‐, 13C‐, 31P‐NMR, EI‐MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 2).
Synthesis and Characterization of Polypiridine‐Based Rhenium(I) Complexes with Pyrazino[2,3‐f][1,10]phenanthroline
Authors: Díaz Ramiro , Francois Angélica , Leiva Ana María , Loeb Bárbara , Norambuena Ester , Yañez Mauricio
Published: June 2006

A series of tricarbonyl rhenium(I) complexes of the type fac‐[ReI(CO)3(ppl)(L)]0/+, where ppl is pyrazino[2,3‐f][1,10]phenanthroline, and where L is Cl−, TfO−, 4‐(tert‐butyl)pyridine (tBu‐py), 4‐methoxypyridine (MeO‐py), 4,4′‐bipyridyl (bpy), or 10‐(picolin‐4‐yl)phenothiazine (pptz), were synthesized and fully characterized. In all complexes, an increment in the electron‐acceptor properties of ppl compared to the free ligand was observed. This effect was more significant for pyridine‐type ligands, especially for pptz, compared to Cl− or TfO−. The properties of fac‐[Re(CO)3(ppl)(pptz)]PF6 were compared with those of the analogous compound fac‐[Re(CO)3(dppz)(pptz)]PF6, where dppz is dipyrido(3,2‐a : 2′,3′‐c)phenazine, the goal being to generate long‐lived excited charge‐transfer (CT) states. In this respect, fac‐[Re(CO)3(ppl)(pptz)]PF6 seems to be a promising candidate.
Synthesis of Highly Functionalized γ‐Lactones via 1,5‐Electrocyclic Ring Closure
Authors: Anaç Olcay , Güngör F. Şeyma , Merey Gökçe
Published: June 2006

We have investigated 1,5‐electrocyclic ring‐closure reactions of conjugated esters with dimethyl diazomalonate in the presence of [Cu(acac)2] as catalyst. Our new protocol offers an easy entry to various polyfunctionalized γ‐lactones in high yields. Their subsequent derivatives may be used as valuable intermediates, especially in the synthesis of natural products and their analogues.
An Expeditious Synthesis of Methyl Jasmonate
Authors: Chapuis Christian , Cantatore Carole , de Saint Laumer Jean‐Yves
Published: June 2006

We present an efficient three‐step, two‐pot synthesis of methyl jasmonate (trans‐1) based on Diels–Alder cycloaddition of cyclopent‐2‐enone (2) and chloroprene (= 2‐chlorobuta‐1,3‐diene; 3d) in either CHCl3 or CH2Cl2, catalyzed by SnCl4 (0.2 mol‐equiv.) at 20° (75% yield). Subsequent ozonolysis of a cis/trans 55 : 45 mixture of the cycloadduct 4d in either CH2Cl2 or AcOEt at − 78°, followed by addition of Me2S and MeOH in the presence of NaHCO3, afforded, in 64% yield, a cis/trans 40 : 60 mixture of the known aldehyde 5c. The latter was reacted at − 50° under salt‐free conditions with the propyl Wittig reactant to furnish 1 as a cis/trans 20 : 80 mixture ((E/Z) 3 : 97). Alternatively, a cis/trans 7 : 93 mixture ((E/Z) 4 : 96) was obtained in 88% yield from epimerized 5c (AcOH, H2O, 40°; 99%) under usual Wittig conditions at − 20°.
Intrauterine environment and breast cancer risk in a population‐based case‐control study in Poland
Authors: Park Sue Kyung , Garcia‐Closas Montserrat , Lissowska Jolanta , Sherman Mark E. , McGlynn Katherine A. , Pepońska Beata , Bardin‐Mikoajczak Alicja , Zatoński Witold , Szeszenia‐Dąbrowska Neonila , Brinton Louise A.
Published: June 2006

High estrogen exposure in utero may increase breast cancer risk later in life. However, studies of the associations between perinatal factors presumed to affect the fetal hormonal environment and breast cancer risk are inconsistent. We used data from a population‐based case‐control study of 2,386 incident breast cancers and 2,502 controls in Poland to evaluate risks associated with various perinatal characteristics. After adjusting for confounders, we found a significant trend (p = 0.01) of breast cancer risk with birth weight (OR = 1.54, 95% CI 1.08–2.19 for birth weights >4,000 g vs. <2,500 g). Subjects with a high birth order (≥6) were at reduced risk (OR = 0.81, 0.61–1.06) when compared with first born subjects. Birth weight was somewhat a stronger risk predictor among subjects whose cancers were diagnosed at 50 years of age or older (OR = 1.84, 1.19–2.85) than among those with cancers diagnosed at younger ages (OR = 1.14, 0.61–2.12). Subjects whose mothers smoked during their pregnancies were at slightly higher risk than those who never smoked (OR = 1.21, 0.99–1.47), but the risk was similar to mothers who only smoked at other times (OR = 1.22, 0.81–1.84). Breast cancer risk was not related to paternal smoking, maternal age, gestational age or twin status. Our results add support to the growing evidence that some perinatal exposures may relate to breast cancer risk. Additional studies are needed to confirm associations and clarify the biologic mechanisms underlying these associations. Published 2006 Wiley‐Liss, Inc.
Structure and function of the components of the human DNA mismatch repair system
Authors: Jascur Thomas , Boland C. Richard
Published: June 2006

DNA mismatch repair (MMR) is one of the several enzyme systems involved in DNA homeostasis. DNA MMR is involved in the repair of specific types of errors that occur during new DNA synthesis; loss of this system leads to an accelerated accumulation of potential mutations, and predisposes to certain types of cancers. Germline mutations in some of the DNA MMR genes cause the hereditary cancer predisposition, Lynch syndrome. This review addresses advances in the biochemistry of DNA MMR and its relationship to carcinogenesis. © 2006 Wiley‐Liss, Inc.
Severe oxidatively damaged DNA after cisplatin treatment of cancer patients
Authors: Siomek Agnieszka , Tujakowski Jerzy , Gackowski Daniel , Rozalski Rafal , Foksinski Marek , Dziaman Tomasz , Roszkowski Krzysztof , Olinski Ryszard
Published: June 2006

There is growing evidence suggesting that cytotoxic activity of cisplatin is closely associated with increased generation of reactive oxygen species (ROS). Therefore, this study was undertaken to examine oxidative DNA damage, which arises as a result of chemotherapy with cisplatin. Using HPLC prepurification/isotope dilution GC/MS methodology, we examined the amount of 8‐oxoGua and 8‐oxodG excreted into urine in cancer patients (n = 66) who received chemotherapy with cisplatin. One day after the infusion of the drug, significant increase in the amount of 8‐oxoGua and 8‐oxodG in urine of the patients was observed, when compared to the initial value (78%, p < 0.0001 and 22%, p = 0.0051). In the “nadir days” (when the most distinct cell death based on hematological cell counts can be observed), the level of modified base and nucleoside decreased in comparison with the aforementioned time point. These results, for the first time, indicate that oxidatively damaged DNA may be, at least in part, responsible for cisplatin induced cytotoxicity. Our results also demonstrate that cell death does not contribute to urinary 8‐oxoGua and 8‐oxodG in humans. © 2006 Wiley‐Liss, Inc.
Variant genotypes of CDKN1A and CDKN1B are associated with an increased risk of breast cancer in Chinese women
Authors: Ma Hongxia , Jin Guangfu , Hu Zhibin , Zhai Xiangjun , Chen Wensen , Wang Shui , Wang Xuechen , Qin Jianwei , Gao Jun , Liu Jiyong , Wang Xinru , Wei Qingyi , Shen Hongbing
Published: June 2006

p21Cip1 and p27Kip1 are cyclin‐dependent kinase inhibitors, which can arrest cell proliferation and serve as tumor suppressors. Reduced protein expression of p21Cip1 and p27Kip1 was frequently observed in a subset of cancers, including breast cancer. In this study, we hypothesized that genetic variants in CDKN1A (encode for p21Cip1) and CDKN1B (encode for p27Kip1) may modulate the risk of breast cancer. To test this hypothesis, we evaluated the associations of the polymorphisms of Ser31Arg and C+20T in CDKN1A and C−79T and Gly109Val in CDKN1B, as well as their combinations, with breast cancer risk in a case‐control study of 368 breast cancer cases and 467 cancer‐free controls in a Chinese population. We found that a significantly increased risk of breast cancer was associated with the variant genotypes of CDKN1B C−79T [adjusted OR = 1.43 (95% CI = 1.03−1.98) for −79TC/TT], compared with the −79CC genotype, but no associations were observed for other variant genotypes. However, the combined variant genotypes of the 4 loci were associated with a significantly increased breast cancer risk (adjusted OR = 1.49, 95% CI = 1.11−2.01 among subjects carrying 3 or more variant alleles), especially among premenopausal women (adjusted OR= 2.30, 95% CI = 1.45−3.66). Furthermore, in premenopausal women, this significant association remained unchanged, after including other individual risk factors in the multivariate logistic regression model, suggesting an independent role of CDKN1A and CDKN1B variants in breast cancer risk. Although the exact biological mechanism remains to be explored, our findings suggest possible involvement of CDKN1A and CDKN1B variants in the etiology of breast cancer. Further large and functional studies are needed to confirm our findings. © 2006 Wiley‐Liss, Inc.