bluuebunny/crossref_metadata_2025 huggingface dataset:
First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage
Authors: Bérard Anick , Ramos Élodie , Rey Évelyne , Blais Lucie , St.‐André Martin , Oraichi Driss
Published: December 2006

BACKGROUND: Conflicting findings with regard to the teratogenic risks of first trimester use of paroxetine have prompted the FDA, Health Canada, and the manufacturer of the drug to issue warnings against its use during pregnancy. Given that untreated depression during pregnancy can lead to deleterious effect on the mother and her unborn fetus, data on the relationship between the dose and the range of malformations is warranted. This study attempts to quantify the association between first trimester exposure to paroxetine and congenital cardiac malformations, adjusting for possible confounders, and to quantify the dose–response relationship between paroxetine use and cardiac defects. METHODS: The Medication and Pregnancy registry was used. This population‐based registry was built by linking three administrative databases (RAMQ, Med‐Écho, and ISQ), and includes all pregnancies in Quebec between 01/01/1997 and 06/30/2003. Date of entry in the registry is the date of the first day of the last menstrual period. To be eligible for this study, women had to: 1) be 15–45 years of age at entry; 2) be covered by the RAMQ drug plan ≥12 months before and during pregnancy; 3) be using only one type of antidepressant during the first trimester; and 4) have a live birth. Two nested case‐control studies were carried out comparing the prevalence of paroxetine use in the first trimester of pregnancy to the prevalence of other antidepressant exposures during the same time period. Cases were defined as: 1) any major malformations; or 2) any cardiac malformations diagnosed in the first year of life; controls were defined as no major or minor malformations. Multivariate logistic regression techniques were used to analyze data. RESULTS: Among the 1,403 women meeting inclusion criteria, 101 infants with major congenital malformations were identified; 24 had cardiac malformations. Adjusting for possible confounders, the use of paroxetine (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 0.49–3.92), and the use of other SSRIs (OR = 0.89, 95% CI = 0.28–2.84) during the first trimester of pregnancy did not increase the risk of congenital cardiac malformations compared with the use of non‐SSRI antidepressants. When considering the dose, however, a dose–response relationship was observed, thus women exposed to >25 mg/day of paroxetine during the first trimester of pregnancy were at increased risk of having an infant with major congenital malformations (adjusted [adj] OR = 2.23, 95% CI = 1.19, 4.17), or major cardiac malformations (adj OR = 3.07, 95% CI = 1.00, 9.42). CONCLUSIONS: Gestational exposure to paroxetine is associated with major congenital malformations and major cardiac malformations for only first trimester exposure above 25 mg/day. Birth Defects Res (Part B). © 2006 Wiley‐Liss, Inc.
Coupled positive and negative feedback circuits form an essential building block of cellular signaling pathways
Authors: Kim Dongsan , Kwon Yung‐Keun , Cho Kwang‐Hyun
Published: December 2006

Cellular circuits have positive and negative feedback loops that allow them to respond properly to noisy external stimuli. It is intriguing that such feedback loops exist in many cases in a particular form of coupled positive and negative feedback loops with different time delays. As a result of our mathematical simulations and investigations into various experimental evidences, we found that such coupled feedback circuits can rapidly turn on a reaction to a proper stimulus, robustly maintain its status, and immediately turn off the reaction when the stimulus disappears. In other words, coupled feedback loops enable cellular systems to produce perfect responses to noisy stimuli with respect to signal duration and amplitude. This suggests that coupled positive and negative feedback loops form essential signal transduction motifs in cellular signaling systems. BioEssays 29: 85–90, 2007. © 2006 Wiley Periodicals, Inc.
Biomechanical properties of intermediate filaments: from tissues to single filaments and back
Authors: Kreplak Laurent , Fudge Douglas
Published: December 2006

The animal cell cytoskeleton consists of three interconnected filament systems: actin‐containing microfilaments (MFs), microtubules (MTs), and the lesser known intermediate filaments (IFs). All IF proteins share a common tripartite domain structure and the ability to assemble into 8–12 nm wide filaments. Electron microscopy data suggest that IFs are built according to a completely different plan from that of MFs and MTs. IFs are known to impart mechanical stability to cells and tissues but, until recently, the biomechanical properties of single IFs were unknown. However, with the discovery of naturally occurring micrometer‐wide IF bundles and the development of new methodologies to mechanically probe single filaments, it is now possible to propose a more unified view of IF biomechanics. Unlike MFs and MTs, single IFs can now be described as flexible, extensible and tough, which has important implications for our understanding of cell and tissue mechanics. Furthermore, the molecular mechanisms at play when IFs are deformed point toward a pivotal role for them in mechanotransduction. BioEssays 29: 26–35, 2007. © 2006 Wiley Periodicals, Inc.
The trick of the tail: protein–protein interactions of metabotropic glutamate receptors
Authors: Enz Ralf
Published: December 2006

It was initially believed that G‐protein‐coupled receptors, such as metabotropic glutamate receptors, could simply be described as individual proteins that are associated with intracellular signal cascades via G‐proteins. This view is no longer tenable. Today we know that metabotropic glutamate receptors (mGluRs) can dimerize and bind to a variety of proteins in addition to trimeric G‐proteins. These newly identified protein interactions led to the discovery of new regulatory mechanisms that are independent of and sometimes synergistic with the classical G‐protein‐coupled second messenger pathways. Notably, several of these mechanisms connect mGluR‐mediated signaling to other receptor classes, thereby creating a network of different receptor types and associated signal cascades. The intracellular C‐termini of mGluRs play a key role in the regulation of these networks, and various new protein interactions of these domains were described recently. Because mGluRs are involved in a variety of physiological and pathophysiological processes, some of the proteins interacting with this receptor class have potential as valuable pharmaceutical targets. This review will give a comprehensive overview of proteins interacting with mGluR C‐termini, highlight new evolving regulatory mechanisms for glutamatergic signal transduction and discuss possibilities for future drug development. BioEssays 29: 60–73, 2007. © 2006 Wiley Periodicals, Inc.
Enhancement of Relaxivity Rates of Gd–DTPA Complexes by Intercalation into Layered Double Hydroxide Nanoparticles
Authors: Xu Zhi Ping , Kurniawan Nyoman D. , Bartlett Perry F. , Lu Gao Qing
Published: December 2006

In this paper we report the preparation and characterization of [Gd(dtpa)]2− intercalated layered double hydroxide (LDH) nanomaterials. [Gd(dtpa)]2− (gadolinium(III) diethylene triamine pentaacetate) was transferred into LDH by anionic exchange. The intercalation of [Gd(dtpa)]2− into LDH was confirmed by X‐ray diffraction for the new phase with the interlayer spacing of 3.5–4.0 nm and by FTIR for the characteristic vibration peaks of [Gd(dtpa)]2−. The morphology of the nanoparticles was influenced by the extent of [Gd(dtpa)]2− loading, in which the poly‐dispersity quality decreased as the [Gd(dtpa)]2− loading was increased. Compared with the morphology of the original Mg2Al–Cl–LDH nanoparticles (hexagonal plate‐like sheets of 50–200 nm), the modified LDH–Gd(dtpa) nanoparticles are bar‐like with a width of 30–60 nm and a length of 50–150 nm. LDH–Gd(dtpa) was expected to have an increased water proton magnetic resonance relaxivity due to the intercalation of [Gd(dtpa)]2− into the LDH interlayer that led to slower molecular anisotropic tumbling compared with free [Gd(dtpa)]2− in solution. Indeed, LDH–nanoparticle suspension containing ≈1.6 mM [Gd(dtpa)]2− exhibits a longitudinal proton relaxivity r1 of ≈16 mM−1 s−1 and a transverse proton relaxivity r2 of ≈50 mM−1 s−1 at room temperature and a magnetic field of 190 MHz, which represents an enhancement four times (r1) and 12 times (r2) that of free [Gd(dtpa)]2− in solution under the same reaction conditions. We have thus tailored LDH–nanoparticles into a novel contrast agent with strong relaxivity, promising for great potential applications in magnetic resonance imaging.
Oligothiophene‐Linked Bisnaphthopyrans: Sequential and Temperature‐Dependent Photochromism
Authors: Zhao Weili , Carreira Erick M.
Published: December 2006

Photochromic bisnaphthopyrans linked with oligothiophenes were synthesized and their photochromic behavior studied. Sequential and temperature‐dependent photochromism was observed in the oligothiophene linked bisnaphthopyrans. The kinetics of photo and thermal processes in bisnaphthopyrans in comparison with naphthopyrans were studied. Substituent and linking effects on the photochromic properties are discussed. We demonstrate that the cross‐talk between the two photochromophores is dependent on the length of the oligothiophene linker. The presence of the bithiophene linker led to high colorability and high quantum yield of coloration.
Pt0 and Pd0 Olefin Complexes of the Metalloid N‐Heterocyclic Carbene Analogues [EI(ddp)] (ddp=2‐{(2,6‐diisopropylphenyl)amino}‐4‐{(2,6‐diisopropylphenyl)imino}‐2‐pentene; E=Al, Ga): Ligand Substitution, HH and SiH Bond Activation, and Cluster Formation
Authors: Kempter Andreas , Gemel Christian , Fischer Roland A.
Published: December 2006

Various products of the reaction of [E(ddp)] (ddp=2‐{(2,6‐diisopropylphenyl)amino}‐4‐{(2,6‐diisopropylphenyl)imino}‐2‐pentene; E=Al, Ga) with Pt0 and Pd0 olefin complexes are reported. Thus, the reaction of [Pt(cod)2] (cod=1,5‐cyclooctadiene) with two equivalents of [Ga(ddp)] yields [Pt(1,3‐cod){Ga(ddp)}2] (1), whereas treatment of [Pd2(dvds)3] (dvds=1,1,3,3‐tetramethyl1,3‐divinyldisiloxane) with [E(ddp)] leads to the monomeric compounds [(dvds)Pd{E(ddp)}] (E=Ga (2 a), Al (2 b)) by substitution of the bridging dvds ligand. Both 1 and 2 a readily react with strong π‐acceptor ligands such as CO or tBuNC to give the dimeric compounds [M{μ2‐Ga(ddp)}(L)] (L=CO, tBuNC; M=Pt (3 a, 5 a), Pd (3 b, 5 b)), respectively. Based on 1H NMR spectroscopic data, [Pt{Ga(ddp)}2(CO)] is likely to be an intermediate in the formation of 3 a. Furthermore, reactions of 1 with H2 and HSiEt3 yield the monomeric compounds [Pt{Ga(ddp)}2(H)2] (7) and [Pt{Ga(ddp)}2(H)(SiEt3)] (8). Finally, the reaction of [Pt(cod)2] with one equivalent of [Ga(ddp)] in the presence of H2 in hexane gives the new dimeric cluster [Pt{μ2‐Ga(ddp)}(H)2]2 (9).
Lightness and hue contrast effects in surface (fabric) colours
Authors: Wu Ray‐Chin , Wardman R. H.
Published: December 2006

Simultaneous contrast effects on lightness and hue in surface colours were investigated. Test colours, surrounded by induction colours, were matched by colours surrounded by neutral gray. The matching colours were selected from a series of samples that varied in either lightness or hue respectively. The lightness experiments were carried out by a panel of 20 observers on 135 test/induction colour combinations. The hue experiments were conducted on 51 test/induction colour combinations by a panel of eight observers. The lightness of the test colour was found to decrease linearly with the lightness of the induction colour, regardless of the hue of the induction colour. The magnitude of the lightness contrast effect in fabric colours was found to be about one‐quarter of that found in CRT display colours in a previous study. The hue contrast effect found in this study followed the opponent‐colour theory. Two distinctly different regions could be identified when the hue difference was plotted against hue‐angle difference between the induction colour and the test colour. The slope of the line in the region where the hue of the induction colour is close to the test colour was much larger than the slope in the other region, indicating that the hue contrast effect was more obvious when the induction colour was close to the test colour. © 2006 Wiley Periodicals, Inc. Col Res Appl, 32, 55–64, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/col.20285
Growth and characterization of KBi(WO4)2 single crystals
Authors: Xie H. D. , Shen D. Z. , Wang X. Q. , Shen G. Q.
Published: December 2006

Potassium bismuth tungstate [KBi(WO4)2] single crystals with dimensions up to 20 mm × 15 mm × 15 mm have been successfully grown by using the top‐seeded solution growth technique and K2W2O7 as solvent. Experiments show that this crystal is unstable in a strong acid or alkali environment and has a blue fluorescence emission. The density, hardness, melting point, absorption edge, transparency range, prominent Raman shift frequency are 7.57 g/cm3, 238 kg/mm2, 800 °C, 380 nm, 400–5450 nm, 868 cm–1 respectively. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Subcellular compartmentalization of aromatase is sexually dimorphic in the adult zebra finch brain
Authors: Rohmann Kevin N. , Schlinger Barney A. , Saldanha Colin J.
Published: December 2006

The vertebrate brain is a source of estrogen (E) via the expression of aromatase (E‐synthase). In the zebra finch (Taeniopygia guttata), despite documented dimorphisms in E‐action, no differences are detectable in circulating E, or the neural levels of aromatase transcription, activity, or somal protein expression. Studies of aromatase expression at the light‐ and electron‐microscope levels reveal greater numbers of fibers and presynaptic boutons in adult males relative to females. We assayed aromatase activity and content in synaptosomes and microsomes from the anterior [containing lMAN and Area X (males)] and posterior telencephalon (containing HVC and RA) of adult birds. In contrast to non‐song birds and mammals, both cell fractions contain abundant aromatase measurable in terms of activity (enzyme assays) and content (Western blots) with minimal enrichment in microsomes. From brain homogenates of identical concentration, aromatase activity was higher in the synaptosomal relative to the microsomal fraction, in males relative to females, and in the posterior compared to anterior telencephalon. These effects were driven by high levels of synaptosomal aromatase in the male posterior telencephalon. These data suggest that males possess more aromatase per presynaptic bouton, or a greater number of aromatase‐containing presynaptic boutons than females in the posterior telencephalon. Further, the present report reveals synaptic aromatization as a considerable source of E in the zebra finch brain, and supports the idea that telencephalic synapses in and around the adult male song production nuclei may be exposed to higher levels of E compared to the female brain. © 2006 Wiley Periodicals, Inc. J Neurobiol 67: 1–9, 2007
Neuropilin 2/semaphorin 3F signaling is essential for cranial neural crest migration and trigeminal ganglion condensation
Authors: Gammill Laura S. , Gonzalez Constanza , Bronner‐Fraser Marianne
Published: December 2006

In the head of vertebrate embryos, neural crest cells migrate from the neural tube into the presumptive facial region and condense to form cranial ganglia and skeletal elements in the branchial arches. We show that newly formed neural folds and migrating neural crest cells express the neuropilin 2 (npn2) receptor in a manner that is highly conserved in amniotes. The repulsive npn2 ligand semaphorin (sema) 3F is expressed in a complementary pattern in the mouse. Furthermore, mice carrying null mutations for either npn2 or sema3F have abnormal cranial neural crest migration. Most notably, “bridges” of migrating cells are observed crossing between neural crest streams entering branchial arches 1 and 2. In addition, trigeminal ganglia fail to form correctly in the mutants and are improperly condensed and loosely organized. These data show that npn2/sema3F signaling is required for proper cranial neural crest development in the head. © 2006 Wiley Periodicals, Inc. J Neurobiol 67: 47–56, 2007
Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice
Authors: Zheng Yanyan , Chen Wen-ling , Louie Stan G. , Yen Benedict T. S. , Ou Jing-hsiung James
Published: December 2006

HBV is a major risk factor for hepatocellular carcinoma (HCC). However, whether HBV can directly cause HCC or only indirectly via the induction of chronic liver inflammation has been controversial. By using transgenic mice carrying the entire HBV genome as a model, we now demonstrate that HBV by itself is an inefficient carcinogen. However, it can efficiently promote hepatocarcinogenesis initiated by the carcinogen diethylnitrosamine (DEN). This effect of HBV does not involve chronic liver inflammation, is apparently due to enhanced hepatocellular apoptosis and compensatory regeneration following DEN treatment, and does not require the HBV X protein.

Conclusion

: Our results demonstrate a direct role of HBV in a hepatocarcinogenesis pathway that involves the interaction between this virus and a dietary carcinogen. (Hepatology 2007;45:16–21.)
Regulation of the UGT1A1 bilirubin-conjugating pathway: Role of a new splicing event at the UGT1A locus
Authors: Lévesque Eric , Girard Hugo , Journault Kim , Lépine Johanie , Guillemette Chantal
Published: December 2006

UDP-glucuronosyltransferase 1A1 (UGT1A1) is involved in a wide range of biological and pharmacological processes because of its critical role in the conjugation of a diverse array of endogenous and exogenous compounds. We now describe a new UGT1A1 isoform, referred to as isoform 2 (UGT1A1_i2), encoded by a 1495-bp complementary DNA isolated from human liver and generated by an alternative splicing event involving an additional exon found at the 3′ end of the

UGT1A

locus. The

N

-terminal portion of the 45-kd UGT1A1_i2 protein is identical to UGT1A1 (55 kd, UGT1A1_i1); however, UGT1A1_i2 contains a unique 10-residue sequence instead of the 99–amino acid C-terminal domain of UGT1A1_i1. RT-PCR and Western blot analyses with a specific antibody against UGT1A1 indicate that isoform 2 is differentially expressed in liver, kidney, colon, and small intestine at levels that reach or exceed, for some tissues, those of isoform 1. Western blots of different cell fractions and immunofluorescence experiments indicate that UGT1A1_i1 and UGT1A1_i2 colocalize in microsomes. Functional enzymatic data indicate that UGT1A1_i2, which lacks transferase activity when stably expressed alone in HEK293 cells, acts as a negative modulator of UGT1A1_i1, decreasing its activity by up to 78%. Coimmunoprecipitation of UGT1A1_i1 and UGT1A1_i2 suggests that this repression may occur via direct protein–protein interactions.

Conclusion:

Our results indicate that this newly discovered alternative splicing mechanism at the

UGT1A

locus amplifies the structural diversity of human UGT proteins and describes the identification of an additional posttranscriptional regulatory mechanism of the glucuronidation pathway. (Hepatology 2007;45:128–138.)
Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation
Authors: Nguyen Lananh N. , Furuya Momoko H. , Wolfraim Lawrence A. , Nguyen Anthony P. , Holdren Matthew S. , Campbell Jean S. , Knight Belinda , Yeoh George C. T. , Fausto Nelson , Parks Tony W.
Published: December 2006

Oval cells are hepatocytic precursors that proliferate in late-stage cirrhosis and that give rise to a subset of human hepatocellular carcinomas. Although liver regeneration typically occurs through replication of existing hepatocytes, oval cells proliferate only when hepatocyte proliferation is inhibited. Transforming growth factor-β (TGF-β) is a key inhibitory cytokine for hepatocytes, both

in vitro

and

in vivo

. Because TGF-β levels are elevated in chronic liver injury when oval cells arise, we hypothesized that oval cells may be less responsive to the growth inhibitory effects of this cytokine. To examine TGF-β signaling

in vivo

in oval cells, we analyzed livers of rats fed a choline-deficient, ethionine-supplemented (CDE) diet for phospho-Smad2. Phospho-Smad2 was detected in more than 80% of hepatocytes, but staining was substantially reduced in oval cells. Ki67 staining, in contrast, was significantly more common in oval cells than hepatocytes. To understand the inverse relationship between TGF-β signaling and proliferation in oval cells and hepatocytes, we examined TGF-β signaling

in vitro

. TGF-β caused marked growth inhibition in primary hepatocytes and the AML12 hepatocyte cell line. Two oval cell lines, LE/2 and LE/6, were less responsive. The greater sensitivity of the hepatocytes to TGF-β–induced growth inhibition may result from the absence of Smad6 in these cells.

Conclusion

: Our results indicate that oval cells, both

in vivo

and

in vitro

, are less sensitive to TGF-β–induced growth inhibition than hepatocytes. These findings further suggest an underlying mechanism for the proliferation of oval cells in an environment inhibitory to hepatocytic proliferation. (Hepatology 2007;45:31–41.)
Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein
Authors: Visvanathan Kumar , Skinner Narelle A. , Thompson Alex J.V. , Riordan Stephen M. , Sozzi Vitini , Edwards Roslyn , Rodgers Sally , Kurtovic Jelica , Chang Judy , Lewin Sharon , Desmond Paul , Locarnini Stephen
Published: December 2006

Toll-like receptors (TLRs) play a key role in the innate immune response. The aim of this study was to examine the expression of TLR2 and TLR4 in chronic hepatitis B (CHB). The TLR2 and TLR4 expression on hepatocytes and Kupffer cells from fresh liver biopsies was measured from 21 patients with untreated hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. Parallel studies were also undertaken on monocytes from their peripheral blood. Expression of TLR2 on hepatocytes, Kupffer cells, and peripheral monocytes was significantly reduced in patients with HBeAg-positive CHB in comparison with HBeAg-negative CHB and controls, whereas it was significantly increased in HBeAg-negative CHB compared with controls. The level of TLR4 expression did not differ significantly between the groups. These results were confirmed

in vitro

using hepatic cell lines transduced with recombinant HBV baculovirus expressing wild-type HBV (HBeAg-positive), precore stop codon (G1896A) mutant HBV (HBeAg-negative). The functional relevance of these findings was established by the demonstration of significantly reduced cytokine production (TNF-α) and phospho-p38 kinase expression in the presence of the HBeAg. In the absence of HBeAg, HBV replication was associated with up-regulation of the TLR2 pathway leading to increased TNF-α production.

Conclusion

: This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response. (Hepatology 2007;45:102–110.)
Participation in management training in a transitioning context: A case of China
Authors: Wang Jia , Wang Greg G.
Published: December 2006

This phenomenological study explores critical issues related to participation in human resource development (HRD) interventions. Specifically focusing on master of business administration (M.B.A.) training programs in China, we conducted in‐depth individual interviews with twelve middle‐level managers to understand their perceptions and experience of this academic program during the country's recent transitional period. The findings suggest that HRD participation in a specific transitioning cultural context may present features that have not been explored by previous learning participation studies in either HRD or adult education. In the light of the transitioning nature of the Chinese cultural context, we derived three propositions for future research on HRD learning participation. Practical implications for learning participation are also drawn based on the results of the study.
Critical role for matrix metalloproteinase‐9 in platelet‐activating factor‐induced experimental tumor metastasis
Authors: Ko Hyun‐Mi , Kang Jee‐Hae , Jung Bongnam , Kim Han‐A , Park Sung Jun , Kim Kyoung‐Jin , Kang Yeong‐Rim , Lee Hern‐Ku , Im Suhn‐Young
Published: December 2006

In this study, the roles of matrix metalloproteinase (MMP)‐2 and MMP‐9 in platelet‐activating factor (PAF)‐induced experimental pulmonary metastasis of the murine melanoma cell, B16F10, were investigated. An injection of PAF resulted in increases in mRNA expression, protein levels and the activities of both MMP‐2 and MMP‐9 in the lungs. The overall expression of MMP‐9 was stronger than that of MMP‐2. The increased MMP‐9 expression was inhibited by both NF‐κB and AP‐1 inhibitors, whereas the increased MMP‐2 expression was inhibited by only AP‐1 inhibitors. Immunohistochemical analysis revealed that MMP‐9 was expressed in bronchial epithelial cells as well as in the walls of blood vessels, whereas MMP‐2 expression was observed only in bronchial epithelial cells. PAF significantly enhanced the pulmonary metastasis of B16F10, which was inhibited by both NF‐κB and c‐jun inhibitors. MMP‐9 inhibitor, but not that of MMP‐2, completely inhibited PAF‐induced B16F10 metastasis. These data indicate that MMP‐9, the expression of which was regulated by NF‐κB and AP‐1, plays a critical role in PAF‐induced enhancement of pulmonary melanoma metastasis. © 2006 Wiley‐Liss, Inc.
The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases
Authors: Ou Di‐Peng , Tao Yi‐Ming , Tang Fa‐Qing , Yang Lian‐Yue
Published: December 2006

The hepatitis B virus (HBV) is a major cause of human hepatocellular carcinoma (HCC) which has a very high mortality rate due to high incidence of metastasis. It is unknown whether HBV contributes to HCC metastasis. In this report, we present clinical data obtained from HCC patients indicating that the expression of hepatitis B virus X protein (HBx) in HCC is associated with an increased expression of membrane‐type 1 matrix metalloproteinase (MT1‐MMP), and matrix metalloproteinase‐2(MMP‐2), which correlates with a poor prognosis. We further demonstrate experimentally that HBx upregulates MT1‐MMP, which in turn induces MMP‐2. Significantly, HBx‐mediated MMP activation is associated with a marked increase of cell migration, as revealed by both wound‐healing and transwell migration assays, suggesting that HBx may facilitate tumor cell invasion by upregulation of MMPs and subsequent destruction of the extracellular matrix. Together, our results support a model in which HBx contributes to HCC metastasis by upregulation of MMPs. © 2006 Wiley‐Liss, Inc.
Competitive inhibition of carcinogen‐activating CYP1A1 and CYP1B1 enzymes by a standardized complex mixture of PAH extracted from coal tar
Authors: Mahadevan Brinda , Marston Charis P. , Luch Andreas , Dashwood Wan‐Mohaiza , Brooks Eric , Pereira Cliff , Doehmer Johannes , Baird William M.
Published: December 2006

A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, the Standard Reference Material (SRM) 1597, was recently shown to decrease the levels of DNA binding of the 2 strong carcinogens benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) in the human mammary carcinoma‐derived cell line MCF‐7 (Mahadevan et al., Chem Res Toxicol 2005;18:224–231). The present study was designed to further elucidate the biochemical mechanisms involved in this inhibition process. We examined the effects of SRM 1597 on the metabolic activation of BP and DBP toward DNA‐binding derivatives in Chinese hamster cells expressing either human cytochrome P450 (CYP) 1A1 or CYP1B1. SRM 1597 inhibited BP‐DNA adduct formation through the entire exposure time in cells expressing human CYP1A1, while it significantly inhibited adduct formation only up to 48 hr when co‐treated with DBP. Conversely, human CYP1B1‐expressing cells were unable to catalyze PAH‐DNA adduct formation on treatment with SRM 1597 alone, and on co‐treatment with BP or DBP. The data obtained from biochemical experiments revealed that SRM 1597 competitively inhibited the activity of both human enzymes as analyzed by 7‐ethoxyresorufin O‐deethylation assays. While the Michaelis‐Menten constant (KM) was <0.4 μM in the absence of SRM 1597, this value increased up to 1.12 (CYP1A1) or 4.45 μM (CYP1B1) in the presence of 0.1 μg/ml SRM 1597. Hence the inhibitory effects of the complex mixture on human CYP1B1 were much stronger when compared to human CYP1A1. Taken together, the decreases in PAH‐DNA adduct formation on co‐treatment with SRM 1597 revealed inhibitory effects on the CYP enzymes that convert carcinogenic PAH into DNA‐binding metabolites. The implications for the tumorigenicity of complex environmental PAH mixtures are discussed. © 2006 Wiley‐Liss, Inc.
Effects of methyl paraben on skin keratinocytes
Authors: Ishiwatari S. , Suzuki T. , Hitomi T. , Yoshino T. , Matsukuma S. , Tsuji T.
Published: December 2006

Some ingredients of dermatological formulations result in skin irritation and allergy. In particular, preservatives have been reported extensively as a cause of allergic contact dermatitis. The study focused on parabens which have been used extensively as antimicrobial preservatives in foods, drugs and cosmetics. The aim of this study was to clarify the effects of the daily use of methyl paraben (MP) on human skin.

The concentrations of MP in the stratum corneum (SC) of the human forearm were measured using the cup method and GC‐MS after daily applications of MP containing formulations. The study also investigated the effects of long‐term exposure to MP on keratinocytes in vitro. Normal human keratinocytes and the skin equivalents were cultured in the medium containing MP. The following changes were analysed: proliferating ability, apoptotic cells, morphological changes, mRNA and protein expressions.

After 1 month of daily applications of MP containing formulations, MP remained unmetabolized and persisted slightly in the SC. MP decreased the proliferating ability of keratinocytes and changed the cell morphology. MP also decreased the expressions of hyaluronan synthase 1 and 2 mRNAs and type IV collagen. In contrast, it increased the expressions of involucrin and HSP27. Furthermore, MP influenced the epidermal differentiation of the skin equivalent.

These results suggest that MP exposure through application of dermatological formulations results in MP persistence and accumulation in the SC, and that MP might influence the aging and differentiation of keratinocytes. Copyright © 2006 John Wiley & Sons, Ltd.
Nanomechanical analysis of bone tissue engineering scaffolds
Authors: Kaufman Jessica D. , Song Jie , Klapperich Catherine M.
Published: December 2006

Copolymers of (2‐hydroxyethyl methacrylate) (HEMA) and methacrylamide monomers conjugated with amino acids were synthesized and crosslinked with ethylene glycol dimethacrylate. The resulting library of copolymers was mineralized in vitro using two distinct methods. In the first mineralization method, the copolymers were polymerized in the presence of a sub‐micron hydroxyapatite (HA) suspension. In the second method, copolymers were mineralized with HA using a urea‐mediated process. The mechanical properties of all of the copolymers, both mineralized and not, were determined using nanoindentation under both load and displacement control. A power law fit to the initial unloading curve was used to determine a reduced elastic modulus for each material. Between 30 and 300 indentations were performed on each material, and ANOVA analysis was run to determine the statistical significance of differences in modulus between samples. Using nanoindentation, the 22 different samples had reduced modulus values ranging from 840 MPa to 4.14 GPa. Aspartic acid‐methacrylate (Asp‐MA) copolymers were not distinguishable from the pHEMA control material. Polymerization in the presence of HA created a more uniform material than the urea method of mineralization. Several challenges and solutions encountered in the nanomechanical testing of soft, heterogeneous materials are discussed. These results demonstrate that with proper experimental design, the mechanical properties of tissue engineering scaffold materials based on polymer‐ceramic composite materials can be determined using small samples and nanoindentation techniques. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res 80A:, 2007
Enhanced antigen‐specific primary CD4+ and CD8+ responses by codelivery of ovalbumin and toll‐like receptor ligand monophosphoryl lipid A in poly(D,L‐lactic‐co‐glycolic acid) nanoparticles
Authors: Hamdy Samar , Elamanchili Praveen , Alshamsan Aws , Molavi Ommoleila , Satou Tadaaki , Samuel John
Published: December 2006

The purpose of this research was to investigate the use of biodegradable poly(D,L‐lactic‐co‐glycolic acid) nanoparticles (PLGA‐NP) as a vaccine delivery system to codeliver antigen, ovalbumin (OVA) along with monophosphoryl lipid A (MPLA) as adjuvant for induction of potent CD4+ and CD8+ T cell responses. The primary CD4+ T responses to OVA/MPLA NP were investigated using OVA‐specific T cells from DO11.10 transgenic mice. Following adoptive transfer of these cells, mice were immunized s.c. by NP formulations. For assessing the CD8+ responses, bone marrow derived dendritic cells (DCs) were pulsed with different OVA formulations, then, cocultured with CD8+ T cells from OT‐1 mice. T cell proliferation/activation and IFN‐γ secretion profile have been examined. Particulate delivery of OVA and MPLA to the DCs lead to markedly increase in in vitro CD8+ T cell T cell proliferative responses (stimulation index >3000) and >13‐folds increase in in vivo clonal expanded CD4+ T cells. The expanded T cells were capable of cytokine secretion and expressed an activation and memory surface phenotype (CD62Llo, CD11ahi, and CD44hi). Codelivery of antigen and MPLA in PLGA‐NP offers an effective method for induction of potent antigen specific CD4+ and CD8+ T cell responses. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res 80A:, 2007
PLGA nanometer surface features manipulate fibronectin interactions for improved vascular cell adhesion
Authors: Miller Derick C. , Haberstroh Karen M. , Webster Thomas J.
Published: December 2006

The largest cause of mortality in the Western world is atherosclerotic vascular disease. Many of these diseases require synthetic vascular grafts; however, their patency rate is only 30% in small (<6 mm) diameter vascular grafts after 5 years of implantation. In an effort to increase small diameter vascular graft success, researchers have been designing random nanostructured surface features which enhance vascular cell functions. However, for the present study, highly‐controllable, nanostructured features on poly(lactic‐co‐glycolic acid) (PLGA) surfaces were formulated. To create ordered nanostructured roughness on PLGA surfaces, either 500, 200, or 100 nm polystyrene nanospheres were separately placed onto mica. These were then used as a template for creating an inverse poly(dimethylsiloxane) mold which was utilized to cast PLGA. Compared to all other PLGA films formulated, AFM results demonstrated greater initial fibronectin spreading on PLGA which possessed spherical 200 nm features. Compared to smooth PLGA, PLGA with 500 or 100 nm surface features, results further showed that PLGA with 200 nm spherical features promoted vascular cell (specifically, endothelial, and smooth muscle cell) adhesion. In this manner, the present study demonstrated a specific nanometer surface feature size that promoted fibronectin spreading and subsequent vascular cell adhesion; criteria critical to vascular graft success. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res 80A:, 2007
Spanning trees with leaf distance at least four
Authors: Kaneko Atsushi , Kano M. , Suzuki Kazuhiro
Published: December 2006

For a graph G, we denote by i(G) the number of isolated vertices of G. We prove that for a connected graph G of order at least five, if i(G–S) < |S| for all ∅︁ ≠ S ⊆ V(G), then G has a spanning tree T such that the distance in T between any two leaves of T is at least four. This result was conjectured by Kaneko in “Spanning trees with constrains on the leaf degree”, Discrete Applied Math, 115 (2001), 73–76. Moreover, the condition in the result is sharp in a sense that the condition i(G–S) < |S| cannot be replaced by i(G–S) ≤ |S|. © 2006 Wiley Periodicals, Inc. J Graph Theory 55: 83–90, 2007
Bayesian strategies for dynamic pricing in e‐commerce
Authors: Cope Eric
Published: December 2006

E‐commerce platforms afford retailers unprecedented visibility into customer purchase behavior and provide an environment in which prices can be updated quickly and cheaply in response to changing market conditions. This study investigates dynamic pricing strategies for maximizing revenue in an Internet retail channel by actively learning customers' demand response to price. A general methodology is proposed for dynamically pricing information goods, as well as other nonperishable products for which inventory levels are not an essential consideration in pricing. A Bayesian model of demand uncertainty involving the Dirichlet distribution or a mixture of such distributions as a prior captures a wide range of beliefs about customer demand. We provide both analytic formulas and efficient approximation methods for updating these prior distributions after sales data have been observed. We then investigate several strategies for sequential pricing based on index functions that consider both the potential revenue and the information value of selecting prices. These strategies require a manageable amount of computation, are robust to many types of prior misspecification, and yield high revenues compared to static pricing and passive learning approaches. © 2006 Wiley Periodicals, Inc. Naval Research Logistics, 2007
Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis
Authors: Hajj R , Lesimple P , Nawrocki‐Raby B , Birembaut P , Puchelle E , Coraux C
Published: December 2006

Cystic fibrosis (CF) at an advanced stage of the disease is characterized by airway epithelial injury and remodelling. Whether CF remodelling is related to infection and inflammation or due to an abnormal regenerative process is still undecided. We have recently established the expression and secretion profiles of interleukin (IL)‐8, matrix metalloproteinase (MMP)‐7, MMP‐9, and tissue inhibitor of metalloproteinase (TIMP)‐1 during non‐CF airway epithelial regeneration in a humanized nude mouse xenograft model. To enhance our understanding of CF remodelling, we compared the regeneration process of non‐infected human CF and non‐CF nasal epithelia. In both CF and non‐CF situations, epithelial regeneration was characterized by successive steps of cell adhesion and migration, proliferation, pseudostratification, and terminal differentiation. However, histological examination of the grafts showed a delay in differentiation of the CF airway epithelium. Cell proliferation was higher in the regenerating CF epithelium, and the differentiated CF epithelium exhibited a pronounced height increase and basal cell hyperplasia in comparison with non‐CF epithelium. In addition, while the number of goblet cells expressing MUC5AC was similar in CF and non‐CF regenerated epithelia, the number of MUC5B‐immunopositive goblet cells was lower in CF grafts. The expression of human IL‐8, MMP‐7, MMP‐9, and TIMP‐1 was enhanced in CF epithelium, especially early in the regenerative process. Together, our data strongly suggest that the regeneration of human CF airway surface epithelium is characterized by remodelling, delayed differentiation, and altered pro‐inflammatory and MMP responses. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Identification of nucleated red blood cells in maternal circulation: A second step in screening for fetal aneuploidies and pregnancy complications
Authors: Mavrou A. , Kouvidi E. , Antsaklis A. , Souka A. , Kitsiou Tzeli S. , Kolialexi A.
Published: December 2006

Background

Identification of fetal nucleated red blood cells (NRBCs) in maternal circulation can facilitate non‐invasive prenatal diagnosis, but technical difficulties still exist. An increase in the number of circulating NRBCs, however, could indicate fetal aneuploidies or pregnancy complications.

Materials and Methods

The number of NRBCs was determined from 20 mL peripheral blood in 351 women in the second trimester of pregnancy after isolation by magnetic cell sorting (MACS) with anti‐CD71 antibody and identification with May‐Grunwald/Giemsa staining.

Results

An average of eight NRBCs (range 1–12) were identified among 282 women with chromosomally normal fetuses. In cases known to carry aneuploid fetuses the mean number was 35 (range 7–113), but when the fetus had trisomy 21 (n = 17) an average of 71 NRBCs were identified. Among 26 carriers of β‐thalassemia, 42 NRBCs (range 22–158) were isolated. In pregnancies with abnormal Doppler findings in both uterine arteries (n = 20), 15 NRBCs (range 2–75) were isolated.

Conclusion

Determining the number of NRBCs in maternal circulation could represent an additional screening step for fetal aneuploidies, as long as the anemic status of the mother is taken into consideration. However, more cases with abnormal Doppler results must be investigated before this test is used for in the prediction of pregnancy complications. Copyright © 2006 John Wiley & Sons, Ltd.
Three‐vessel view of the fetal heart: In utero development of the great vessels
Authors: Moon Min Hoan , Cho Jeong Yeon , Park Eun Jung , Min Jee Yeon , Kim Jeong‐Ah , Jung Sung Il , Song Mi Jin
Published: December 2006

Objectives

The purpose of our study is to provide reference values for the great vessels obtained from images of the three‐vessel view of the fetal heart, with an emphasis on the size discrepancy of the great vessels.

Methods

From February 2003 to May 2003, the main pulmonary artery (MPA), ascending aorta (AA), and SVC were measured in well‐dated, nonanomalous fetuses scanned at 14–38 weeks of gestation.

Results

The size of each great vessel had a significant positive relationship with advance in gestation (P < 0.001); MPA (mm) = − 2.76 + 0.34 × GA, ascending aorta (AA) (mm) = − 1.73 + 0.26 × GA − 1.18E − 05 × GA3, and SVC (mm) = 0.33 + 0.01 × GA2 − 4.12E − 05 × GA3. The AA/MPA ratio was significantly decreased with advance in gestation, while the SVC/AA ratio was significantly increased; AA/MPA ratio = − 1.24 − 0.03 × GA + 3.88E − 04 × GA2; P < 0.001, SVC/AA ratio = 0.63 − 5.43E − 03 × GA + 1.96E − 04 × GA2; P < 0.001.

Conclusion

On the three‐vessel view of the fetal heart, the interpretation of the size discrepancy of the great vessels needs to be adjusted according to fetal growth. Copyright © 2006 John Wiley & Sons, Ltd.
Magnetic resonance imaging and histopathological characterization of prostate tumors in TRAMP mice as model for pre‐clinical trials
Authors: Degrassi Anna , Russo Micaela , Scanziani Eugenio , Giusti Anna , Ceruti Roberta , Texido Gemma , Pesenti Enrico
Published: December 2006

BACKGROUND

The Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) develops progressive forms of prostate cancer. Due to the lack of a validated non‐invasive methodology, pathology has been so far the most common parameter evaluated in efficacy studies.

METHODS

We studied by magnetic resonance imaging (MRI) 210 mice that were repeatedly measured up to 33 weeks of age in order to stage prostate tumors and follow pathological progression in single animals. A pre‐clinical trial with doxorubicin was also performed.

RESULTS

Progressive forms of cancer (well and poorly differentiated (PD) adenocarcinomas) were easily recognized on MR images and MRI findings were validated against histopathological analysis. Age at tumor onset was different for the two tumoral forms. Doxorubicin treatment caused a strong reduction in tumor volume.

CONCLUSIONS

Prostate cancer in TRAMP mice is multifocal and heterogeneous: a non‐invasive methodology such as MRI facilitates the rational design of translational pre‐clinical trials in this widely used animal model. Prostate 67: 396–404, 2007. © 2006 Wiley‐Liss, Inc.
Active capping demonstration in the Anacostia river, Washington, D.C.
Authors: Reible Danny , Lampert David , Constant David , Mutch Jr. Robert D. , Zhu Yuewei
Published: December 2006

An active capping demonstration project in Washington, D.C., is testing the ability to place sequestering agents on contaminated sediments using conventional equipment and evaluating their subsequent effectiveness relative to conventional passive sand sediment caps. Selected active capping materials include: (1) AquaBlokTM, a clay material for permeability control; (2) apatite, a phosphate mineral for metals control; (3) coke, an organic sequestration agent; and (4) sand material for a control cap. All of the materials, except coke, were placed in 8,000‐ft test plots by a conventional clamshell method during March and April 2004. Coke was placed as a 1.25‐cm layer in a laminated mat due to concerns related to settling of the material. Postcap sampling and analysis were conducted during the first, sixth, and eighteenth months after placement. Although postcap sampling is expected to continue for at least an additional 24 months, this article summarizes the results of the demonstration project and postcap sampling efforts up to 18 months. Conventional clamshell placement was found to be effective for placing relatively thin (six‐inch) layers of active material. The viability of placing high‐value or difficult‐to‐place material in a controlled manner was successfully demonstrated with the laminated mat. Postcap monitoring indicates that all cap materials effectively isolated contaminants, but it is not yet possible to differentiate between conventional sand and active cap layer performance. Monitoring of the permeability control layer indicated effective reductions in groundwater seepage rates through the cap, but also showed the potential for gas accumulation and irregular release. All of the cap materials show deposition of new contaminated sediment onto the surface of the caps, illustrating the importance of source control in maintaining sediment quality. © 2006 Wiley Periodicals, Inc.