bluuebunny/crossref_metadata_2025 huggingface dataset:
Skeletal elements in the vertebrate eye and adnexa: Morphological and developmental perspectives
Authors: Franz‐Odendaal Tamara A. , Vickaryous Matthew K.
Published: February 2006

Although poorly appreciated, the vertebrate eye and adnexa are relatively common sites for skeletogenesis. In many taxa, the skeleton contributes to internal reinforcement in addition to the external housing of the eye (e.g., the circumorbital bones and eyelids). Eyeball elements such as scleral cartilage and scleral ossicles are present within a broad diversity of vertebrates, albeit not therian mammals, and have been used as important models for the study of condensations and epithelial–mesenchymal interactions. In contrast, other elements invested within the eye or its close surroundings remain largely unexplored. The onset and mode of development of these skeletal elements are often variable (early versus late; involving chondrogenesis, osteogenesis, or both), and most (if not all) of these elements appear to share a common neural crest origin. This review discusses the development and distribution of the skeletal elements within and associated with the developing eye and comments on homology of the elements where these are questionable. Developmental Dynamics 235:1244–1255, 2006. © 2006 Wiley‐Liss, Inc.
A 3D Manganese Coordination Polymer [Mn3(IMDC)2(H2O)4] Constructed from [Mn2(IMDC)2(H2O)2] Layers and [Mn(H2O)2] Pillars (IMDC = 4,5‐imidazoledicarboxylate)
Authors: Zhang Man‐Bo , Chen Yong‐Mei , Zheng Shou‐Tian , Yang Guo‐Yu
Published: February 2006

A novel three‐dimensional coordination polymer[Mn3(IMDC)2(H2O)4] (1) (IMDC = 4,5‐imidazoledicarboxylate),consisting of [Mn2(IMDC)2(H2O)2] layers and [Mn(H2O)2]pillars, was synthesized hydrothermally and characterized by IR spectroscopy, elemental analysis, TGA, and magnetic measurements. It is the first example of a 3D framework containing 4,5‐imidazoledicarboxylate in the family of manganese complexes. Variable‐temperature magnetic susceptibility measurements show a weak antiferromagnetic coupling interaction between the MnII ions of the dimeric units. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Block Copolymer Assemblies as Templates for the Generation of Mesoporous Inorganic Materials and Crystalline Films
Authors: Smarsly Bernd , Antonietti Markus
Published: February 2006

This Microreview presents the synthesis of mesoporous, crystalline inorganic materials using self‐assembled block copolymer mesostructures as templates. The advances in this field are discussed in light of the progress in the development of suitable polymer templates. Particular emphasis is placed on the special conditions and demands to transform the primary sol–gel films into mesoporous, aligned crystalline films for functional applications. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Synthesis of New Palladium(II) Complexes Containing Hemilabile N‐(Alkylamino)pyrazole Ligands: Spectroscopic Analysis and Crystal Structure of [PdCl(ddae)]Cl·H2O {ddae = Bis[2‐(3,5‐dimethyl‐1‐pyrazolyl)ethyl]ethylamine}
Authors: Pañella Anna , Pons Josefina , García‐Antón Jordi , Solans Xavier , Font‐Bardia Mercè , Ros Josep
Published: February 2006

Treatment of the tridentate (NN′N) N‐alkylaminopyrazoleligands bis[2‐(3,5‐dimethyl‐1‐pyrazolyl)ethyl]ethylamine (ddae), bis[2‐(3,5‐dimethyl‐1‐pyrazolyl)ethyl]isopropylamine (ddai) and bis[2‐(3,5‐dimethyl‐1‐pyrazolyl)ethyl]tert‐butylamine (ddat) with [PdCl2(CH3CN)2] in a 1:1 M/L ratio in CH2Cl2 produces [PdCl2(NN′N)]. Treatment of the corresponding ligand with [PdCl2(CH3CN)2] in a 1:2 M/L ratio in the presence of AgBF4 in CH2Cl2/methanol (6:1) gives [PdCl(NN′N)](BF4). The complexes [PdCl2(NN′N)] were again obtained when the complexes [PdCl(NN′N)](BF4) were heated under reflux in a solution of NEt4Cl in acetonitrile, which means that ligands ddae, ddai and ddat in complexes 1–6 are hemilabile. These PdII complexes have been characterised by elemental analyses, conductivity measurements and IR and 1H and 13C{1H} NMR spectroscopy. The 1H NMR spectroscopic studies for compounds [PdCl2(NN′N)] give evidence of κ2(Npz,Npz) coordination in acetonitrile and κ3(Npz,Namino,Npz) coordination in methanol. The X‐ray structure of the complex [PdCl(ddae)]Cl·H2O has been determined. The PdII is coordinated to the ddae ligand by two nitrogen atoms of the pyrazolyl groups and one nitrogen atom of the amine, along with one chlorine atom, in a slightly distorted square‐planar geometry. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Interrill erosion on cultivated Greek soils: modelling sediment delivery
Authors: Dimoyiannis D. , Valmis S. , Danalatos N. G.
Published: February 2006

For interrill erosion, raindrop‐induced detachment and transport of sediment by rainfall‐disturbed sheet flow are the predominant processes, while detachment by sheet flow and transport by raindrop impact are negligible. In general, interrill subprocesses are inter‐actively affected by rainfall, soil and surface properties. The objective of this work was to study the relationships among interrill runoff and sediment loss and some selected para‐meters, for cultivated soils in central Greece, and also the development of a formula for predicting single storm sediment delivery. Runoff and soil loss measurement field experiments have been conducted for a 3·5‐year period, under natural storms. The soils studied were developed on Tertiary calcareous materials and Quaternary alluvial deposits and were textured from sandy loam to clay. The second group of soils showed greater susceptibility to sealing and erosion than the first group. Single storm sediment loss was mainly affected by rain and runoff erosivity, being significantly correlated with rain kinetic energy (r= 0·64***), its maximum 30‐minute intensity (r= 0·64***) and runoff amount (r= 0·56***). Runoff had the greatest correlation with rain kinetic energy (r= 0·64***). A complementary effect on soil loss was detected between rain kinetic energy and its maximum 30‐minute intensity. The same was true for rain kinetic energy and topsoil aggregate instability, on surface seal formation and thus on infiltration characteristics and overland flow rate. Empirical analysis showed that the following formula can be used for the successful prediction of sediment delivery (Di):Di= 0·638βEI30tan(θ) (R2= 0·893***), whereβis a topsoil aggregate instability index,Ethe rain kinetic energy,I30the maximum 30‐minute rain intensity andθthe slope angle. It describes soil erodibility using a topsoil aggregate instability index, which can be determined easily by a simple laboratory technique, and runoff through the product of this index and rain kinetic energy. Copyright © 2006 John Wiley & Sons, Ltd.
Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC
Authors: Zucman-Rossi Jessica , Jeannot Emmanuelle , Van Nhieu Jeanne Tran , Scoazec Jean-Yves , Guettier Catherine , Rebouissou Sandra , Bacq Yannick , Leteurtre Emmanuelle , Paradis Valérie , Michalak Sophie , Wendum Dominique , Chiche Laurence , Fabre Monique , Mellottee Lucille , Laurent Christophe , Partensky Christian , Castaing Denis , Zafrani Elie Serge , Laurent-Puig Pierre , Balabaud Charles , Bioulac-Sage Paulette
Published: February 2006

Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1α (HNF1α) and β-catenin were sequenced. No tumors were mutated in both HNF1α and β-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1α mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (

P

< 10−4), lack of cytological abnormalities (

P

< 10−6), and no inflammatory infiltrates (

P

< 10−4). In contrast, the group of tumors defined by β-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (

P

< 10−5). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (

P =

10−3), ductular reaction (

P

< 10−2), and dystrophic vessels (

P =

.02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the β-catenin–mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1α mutated tumors (

P =

.004).

In conclusion

, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype–phenotype correlations and suggests that adenomas with β-catenin activation have a higher risk of malignant transformation. (Hepatology 2006;43:515–524.)
Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity
Authors: Levy Gary A. , Adamson Gord , Phillips James M. , Scrocchi Louise A. , Fung Laisum , Biessels Pieter , Ng Nancy F. , Ghanekar Anand , Rowe Andrea , Ma Max Xuezhong , Levy Adam , Koscik Cheryl , He William , Gorczynski Reginald , Brookes Steve , Woods Caroline , McGilvray Ian D. , Bell David
Published: February 2006

Side effects of interferon–ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin–ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) by macrophages.

In vivo

, untreated MHV-3–infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203–treated mice with a marked reduction in biochemical [ALTmax 964 ± 128 IU/L (ribavirin); 848 ± 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203–treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture.

In conclusion

, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines

in vitro

. (Hepatology 2006;43:581–591.)
Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver
Authors: Zwingmann Claudia , Bilodeau Marc
Published: February 2006

The hepatoprotective mechanisms of N-acetylcysteine (NAC) in non–acetaminophen-induced liver injury have not been studied in detail. We investigated the possibility that NAC could affect key pathways of hepatocellular metabolism with or without changes in glutathione (GSH) synthesis. Hepatocellular metabolites and high-energy phosphates were quantified from mouse liver extracts by 1H- and 31P-NMR (nuclear magnetic resonance) spectroscopy. 13C-NMR-isotopomer analysis was used to measure [U-13C]glucose metabolism through pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC). NAC (150-1,200 mg/kg) increased liver concentrations of GSH from 8.60 ± 0.48 to a maximum of 12.95 ± 1.03 μmol/g ww, whereas hypotaurine (HTau) concentrations increased from 0.05 ± 0.02 to 9.95 ± 1.12 μmol/g ww. The limited capacity of NAC to increase GSH synthesis was attributed to impaired glucose metabolism through PC. However, 300 mg/kg NAC significantly increased the fractional 13C-enrichment in Glu (from 2.08% ± 0.26% to 4.00% ± 0.44%) synthesized through PDH, a key enzyme for mitochondrial energy metabolism. This effect could be uncoupled from GSH synthesis and was associated with the prevention of liver injury induced by tert-butylhydroperoxide and 3-nitropropionic acid.

In conclusion

, NAC (1) has a limited capacity to elevate GSH synthesis; (2) increases HTau formation linearly; and (3) improves mitochondrial tricarboxylic acid (TCA) cycle metabolism by stimulation of carbon flux through PDH. This latter effect is independent of the capacity of NAC to replete GSH stores. These metabolic actions, among other yet unknown effects, are critical for NAC's therapeutic value and should be taken into account when deciding on a wider use of NAC.

Supplementary material for this article can be found on the HEPATOLOGY website (

http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html

).

(Hepatology 2006;43:454–463.)
Chronic hepatitis B in children after e antigen seroclearance: Final report of a 29-year longitudinal study
Authors: Bortolotti Flavia , Guido Maria , Bartolacci Samuela , Cadrobbi Paolo , Crivellaro Carlo , Noventa Franco , Morsica Giulia , Moriondo Maria , Gatta Angelo
Published: February 2006

Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long-term prognosis remains unsettled. This report describes the results of a 29-year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg-positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 ± 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg-negative hepatitis and the other 84 became inactive carriers. During a mean follow-up of 14.5 ± 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg-negative hepatitis at the last follow-up. Of the 8 initially HBeAg-negative children, 2 had HBeAg-negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg-negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow-up, 15 of the 89 initially HBeAg-positive patients and 2 of 8 initially HBeAg-negative children had cleared hepatitis B surface antigen.

In conclusion

, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg-negative hepatitis. Long-term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse. (Hepatology 2006;43:556–562.)
Improved prognosis for patients hospitalized with esophageal varices in Sweden 1969–2002
Authors: Stokkeland Knut , Brandt Lena , Ekbom Anders , Hultcrantz Rolf
Published: February 2006

Liver cirrhosis may be complicated by the development of esophageal varices. The treatment of esophageal varices has changed radically during the last 30 years. Our aim was to study whether the prognosis for patients with esophageal varices had improved in Sweden between 1969 and 2002. We linked register data from the Hospital Discharge Register and from the Causes of Death Register at The National Board of Health in Sweden between 1969 and 2002 to identify and follow-up all patients with esophageal varices according to International Classification of Diseases—8, —9, and —10. There were 12,281 patients hospitalized with esophageal varices, and for all patients there was an increase in the 5-year survival in the years between 1969 and 1979 as opposed to the years between 1990 and 2002. Better survival occurred for women compared with men, for younger patients compared with older, and for patients hospitalized in the latest decade compared with the earlier decades. We found a significant decrease in the mortality caused by esophageal varices during the years studied but no decrease attributable to other causes.

In conclusion,

mortality for patients hospitalized with esophageal varices in Sweden decreased between 1969 and 2002. The decrease is seen for both 1- and 5-year mortality, and this suggests that the use of new treatment strategies both for acute variceal hemorrhage and secondary prophylaxis has had an impact on prognosis. (Hepatology 2006;43:500–505.).
Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation
Authors: Blasco Alejandro , Forns Xavier , Carrión José A. , García-Pagán Juan Carlos , Gilabert Rosa , Rimola Antoni , Miquel Rosa , Bruguera Miquel , García-Valdecasas Juan-Carlos , Bosch Jaime , Navasa Miquel
Published: February 2006

Liver biopsy is essential in the follow-up of HCV-infected liver transplant recipients. The aim of this study was to prospectively compare percutaneous (PLB) versus transjugular liver biopsy (TLB) in the assessment of liver damage. We also explored the diagnostic value of hepatic venous pressure gradient (HVPG) to identify patients at risk of severe HCV disease recurrence after liver transplantation (LT). One hundred sixteen paired PLB and TLB (with HVPG measurement) were performed 3 or 12 months after LT in 80 patients. Concordance for necroinflammation and fibrosis was fair or good, particularly 1 year after LT (kappa ≥ 0.6). At this point, a significant positive association was seen between the median HVPG and the fibrosis stage (2.5 mm Hg for F0; 5 mm Hg for F1, 6 mm Hg for F2, and 11.5 mm Hg for F3; Kruscal-Wallis < 0.001). Despite this strong association, portal hypertension (HVPG ≥ 6 mm Hg) was detected in 1 (5%) of 22, 4 (16%) of 25, and 6 (60%) of 10 patients with fibrosis stages 0, 1, and 2, respectively. After a median follow-up of 38 months, clinical decompensation occurred in 15 (19%) of 80 patients. Although the presence of significant fibrosis (F2-F3) 1 year after transplantation was good to predict clinical decompensation (AUC: 0.80), an HVPG of 6 mm Hg or greater was extremely accurate at identifying patients at risk of disease progression (AUC: 0.96).

In conclusion

, HVPG determination is a valuable tool for follow-up in patients with HCV recurrence after LT. (Hepatology 2006;43:492–499.)
E2F1 identified by promoter and biochemical analysis as a central target of glioblastoma cell‐cycle arrest in response to ras inhibition
Authors: Blum Roy , Nakdimon Itay , Goldberg Liat , Elkon Ran , Shamir Ron , Rechavi Gideon , Kloog Yoel
Published: February 2006

Active Ras contributes to the malignant phenotype of glioblastoma multiforme. Recent studies showed that the Ras inhibitor farnesyl thiosalicylic acid downregulates the transcription factor hypoxia‐inducible factor‐1α, causing shutdown of glycolysis in U87 glioblastoma cells. Farnesyl thiosalicylic acid also inhibited the growth of U87 cells. The way in which Ras inhibition affects U87 cell proliferation was not clear. Here we applied a computational method in which gene expression profile clustering is combined with promoter sequence analysis to obtain global dissection of the transcriptional response to farnesyl thiosalicylic acid in U87 cells. The analysis revealed a prominent Ras‐dependent cell‐cycle arrest response, in which a major component is highly enriched for the binding‐site signature of the transcription factor E2F1. Electrophoretic mobility shift assays together with E2F‐luciferase reporter assays showed that E2F1 was inactivated by the Ras inhibitor. Inhibition of Ras by farnesyl thiosalicylic acid promoted proteasomal degradation of cyclin D1, with a concomitant decrease in phosphorylated retinoblastoma protein accompanied by downregulation of E2F1 and decreased expression of key E2F1‐regulated genes critical for cell‐cycle progression. U87 cell growth arrest induced by farnesyl thiosalicylic acid was overridden by constitutive expression of E2F1. Thus, downregulation of E2F1 and of hypoxia‐inducible factor‐1α represents 2 distinct arms of the antioncogenic effect of Ras inhibitors in glioblastoma. © 2006 Wiley‐Liss, Inc.
L‐type amino acid transporter 1 as a potential molecular target in human astrocytic tumors
Authors: Nawashiro Hiroshi , Otani Naoki , Shinomiya Nariyoshi , Fukui Shinji , Ooigawa Hidetoshi , Shima Katsuji , Matsuo Hirotaka , Kanai Yoshikatsu , Endou Hitoshi
Published: February 2006

L‐type amino acid transporter 1 (LAT1) is a Na+‐independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan‐Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p < 0.0001) and for those with glioblastoma multiforme in particular (p = 0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2‐aminobicyclo‐2 (2,2,1)‐heptane‐2‐carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose‐dependent manner. Kaplan‐Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy. © 2006 Wiley‐Liss, Inc.
Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer
Authors: Lind Helge , Zienolddiny Shanbeh , Ekstrøm Per Olav , Skaug Vidar , Haugen Aage
Published: February 2006

Lung cancer is the leading cause of cancer mortality in the world. Although exposure to carcinogens is considered to be the main cause, genetic variation may contribute to lung cancer risk. Murine double minute 2, MDM2, is a key regulator of p53 activity and recently a polymorphism in the promoter region of the MDM2 gene was characterized. This single nucleotide polymorphism, SNP309, was shown to influence MDM2 transcription, MDM2 protein levels and p53 activity. The aim of this study was to investigate whether this functionally important SNP is associated with risk of nonsmall cell lung cancer. The study consisted of 341 nonsmall cell lung cancer cases and 412 healthy controls of Norwegian origin. Our results indicate that the G/G genotype of SNP309 is associated with lung cancer risk with an odds ratio of 1.62 (95% CI: 1.06–2.50). Interestingly, the strongest effect of the polymorphism was seen among women. Females homozygous for SNP309 G/G had associated odds ratio 4.06 (1.29–12.8). We also explored the MDM2 SNP309 in relation to TP53 gene mutations and age at nonsmall cell lung cancer diagnosis. Our results indicate that the G/G genotype of SNP309 is associated with higher age at diagnosis in individuals with TP53 mutations (p = 0.037). © 2006 Wiley‐Liss, Inc.
Cigarette smoking and colorectal cancer risk in Germany: A population‐based case–control study
Authors: Verla‐Tebit Emaculate , Lilla Carmen , Hoffmeister Michael , Brenner Hermann , Chang‐Claude Jenny
Published: February 2006

Studies have shown fairly consistent positive relationships between smoking and risk of colorectal adenomas, but have yielded inconsistent results for colorectal cancer. Issues relating to the duration, cumulative dose of smoking and the effect of smoking cessation on colorectal cancer risk still need clarification. In a population‐based case–control study in Germany, we recruited 540 incident cases of colorectal cancer and 614 controls matched to cases by sex, 5‐year age groups and county of residence from January 2003 to June 2004. Subjects were aged ≥30 years, and provided information on risk factors of colorectal cancer, including lifetime cigarette smoking habits, in personal interviews. Odds ratios (OR) and 95% confidence intervals (CI) were computed using conditional logistic regression models, adjusting for potential confounders. Compared with nonsmokers, there was an increased risk for smoking for ≥30 years (OR: 1.25, 95% CI: 0.90–1.75) and a significant risk increase for ≥40 pack‐years of smoking (OR: 1.92, 95% CI: 1.13–3.28). Stratification by sex yielded higher risk estimates among females than that among males, with adjusted ORs of 3.5 (95% CI: 1.29–9.52) and 1.15 (0.69–1.91) for women and men, respectively, following ≥30 pack‐years of smoking (pinteraction = 0.18). Among smokers, risk reduction was observed after ≥20 years of quitting smoking and was significant for ≥40 years (OR: 0.46; 95% CI: 0.21–0.98), when compared to current smokers (p for linear trend = 0.05). This study supports the hypothesis that smoking for a long duration at a high cumulative dose increases the risk for colorectal cancer, particularly among women, and suggests that there is risk reduction after longterm smoking cessation. © 2006 Wiley‐Liss, Inc.
Basic fibroblast growth factor endows dorsal telencephalic neural progenitors with the ability to differentiate into oligodendrocytes but not γ‐aminobutyric acidergic neurons
Authors: Abematsu Masahiko , Kagawa Tetsushi , Fukuda Shinji , Inoue Toshihiro , Takebayashi Hirohide , Komiya Setsuro , Taga Tetsuya
Published: February 2006

Basic fibroblast growth factor (bFGF) is commonly used to enrich and maintain neural stem cells in vitro. Olig2 is an essential transcription factor for oligodendrocyte lineage specification and is expressed predominantly in ventral neuroepithelial cells in the medial and lateral ganglionic eminence (GE), where oligodendrocyte progenitors originate. Here we report significant induction of Olig2 expression in dorsal neuroepithelium‐derived cells cultured in the presence of bFGF, in which Olig2‐expressing cells were initially negligible. Among Olig2‐expressing cells appearing after a 5‐day treatment with bFGF, 99.8% coexpressed nestin. There was no significant difference in proliferation or apoptosis in dorsal and ventral neuroepithelial cultures in the presence of bFGF, suggesting that bFGF induces ectopic expression of Olig2 in dorsal “cortical” neuroepithelial cells. Similarly, expression of Mash1, another ventral neuroepithelial cell marker gene, was also induced in cultured dorsal neuroepithelial cells in the presence of bFGF. Conversely, in this culture, expression of dorsal neuroepithelial cell markers, such as Neurogenin1, Neurogenin2, Pax6, and Emx2, was down‐regulated. These results suggested a possible ventralizing activity of bFGF. In fact, bFGF‐treated dorsal neuroepithelial cells acquired the potential to generate O4‐positive oligodendrocytes with efficacy comparable to that observed with GE‐derived cells. In marked contrast, bFGF did not enable dorsal neuroepithelial cells to generate γ‐aminobutyric acid (GABA) neurons, which normally develop only from GE in vivo. Thus, bFGF endows dorsal telencephalic neural progenitors with the ability to differentiate into oligodendrocytes but not GABAergic neurons, suggesting the presence of different mechanisms governing specification of dorsoventral cell identities of neuronal and glial cell lineages. © 2006 Wiley‐Liss, Inc.
Increased glia‐specific transgene expression with glial fibrillary acidic protein promoters containing multiple enhancer elements
Authors: de Leeuw Bertie , Su Mu , Horst Maarten ter , Iwata Shingo , Rodijk Mark , Hoeben Rob C. , Messing Albee , Smitt Peter Sillevis , Brenner Michael
Published: February 2006

The ability to direct transgene expression to astrocytes has become increasingly important as the roles for these cells continue to expand. Promoters consisting of the 5′‐flanking region of the human or mouse glial fibrillary acidic protein (GFAP) gene have generally proved satisfactory. However, a more powerful promoter would be advantageous for several applications, such as expression of dominant negative RNAs or proteins, or for gene therapy. We investigated the possibility of increasing the transcriptional activity of the human GFAP promoter by inserting into it one or three additional copies of putative GFAP enhancer regions. The promoters enhanced with three additional copies gave 75‐fold higher LacZ expression levels upon plasmid transfection into GFAP‐expressing U251 cells than the parental gfa2 promoter. Surprisingly, in a transgenic mouse model, the enhanced promoters resulted in no or only very low expression of marker genes, probably caused by toxicity. When various cell lines were infected with replication‐deficient adenoviral vectors, the enhanced promoters gave LacZ expression levels that were approximately 10‐fold higher than those with the parental gfa2 promoter, while retaining specificity for GFAP‐expressing cells. Injection of the adenoviral vectors carrying the enhanced promoters into nude mouse brain showed that LacZ expression was limited to GFAP‐positive cells. We conclude that gfa2 enhanced promoters are useful for production of short‐term, glia‐specific, high expression levels of genes in an adenoviral context. Adenoviral vectors containing these enhanced promoters may be useful in glioma gene therapy. © 2006 Wiley‐Liss, Inc.
Huperzine a attenuates mitochondrial dysfunction in β‐amyloid‐treated PC12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism
Authors: Gao Xin , Tang Xi Can
Published: February 2006

We observed previously that huperzine A (HupA), a selective acetylcholinesterase inhibitor, can counteract neuronal apoptosis and cell damage induced by several neurotoxic substances, and that this neuroprotective action somehow involves the mitochondria. We investigated the ability of HupA to reduce mitochondrial dysfunction in neuron‐like rat pheochromocytoma (PC12) cells exposed in culture to the amyloid β‐peptide fragment 25–35 (Aβ25–35). After exposure to 1 μM Aβ25–35for various periods, cells exhibited a rapid decline of ATP levels and obvious disruption of mitochondrial membrane homeostasis and integrity as determined by characteristic morphologic alterations, reduced membrane potential, and decreased activity of ion transport proteins. In addition, Aβ25–35treatment also led to inhibition of key enzyme activities in the electron transport chain and the tricarboxylic acid cycle, as well as an increase of intracellular reactive oxygen species (ROS). Pre‐incubation with HupA for 2 hr not only attenuated these signs of cellular stress caused by Aβ, but also enhanced ATP concentration and decreased ROS accumulation in unharmed normal cells. Those results indicate that HupA protects mitochondria against Aβ‐induced damages, at least in part by inhibiting oxidative stress and improving energy metabolism, and that these protective effects reduce the apoptosis of neuronal cells exposed to this toxic peptide. © 2006 Wiley‐Liss, Inc.
Long‐term effects of stroke on neuronal rest activity in rolandic cortical areas
Authors: Tecchio F. , Zappasodi F. , Pasqualetti P. , Tombini M. , Caulo M. , Ercolani M. , Rossini P.M.
Published: February 2006

To understand the relationship between neuronal function and clinical state in the framework of stroke, the long‐term poststroke rolandic spontaneous neuronal activity was studied by means of magnetoencephalography. Fifty‐six patients who had suffered a unilateral stroke within the middle cerebral artery were enrolled. Median time since stroke was 2.8 years. In association with lesion features and clinical picture, total and relative band powers and the spectral entropy were analyzed in the affected (AH) and unaffected (UH) hemispheres in comparison with an age‐matched control group. An increase of absolute and relative slow band powers and a reduction of relative fast band powers were found in patients' AH with respect to both UH and control values. Absolute delta band was higher than in controls also in UH. New findings were the increase of rolandic rest activity power also in the alpha band and the decrease of spectral entropy in AH with respect to both UH and control values. Moreover, our results in chronic stroke patients indicate frequency‐selective alterations related to specific dysfunctions: global clinical status was mostly impaired in patients with larger lesions and increased total and slow band activity powers, whereas hand functionality was mostly disrupted in patients with subcortical involvement and reduction of high‐frequency rhythms and spectral entropy. Total power increase and spectral richness decrease are in agreement with a higher synchrony of local neuronal activity, a reduction of the intracortical inhibitory network's efficiency, and an increase of neuronal excitability. © 2006 Wiley‐Liss, Inc.
Transplantation of hNT neurons into the ischemic cortex: Cell survival and effect on sensorimotor behavior
Authors: Bliss T.M. , Kelly S. , Shah A.K. , Foo W.C. , Kohli P. , Stokes C. , Sun G.H. , Ma M. , Masel J. , Kleppner S.R. , Schallert T. , Palmer T. , Steinberg G.K.
Published: February 2006

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory‐motor function. hNT‐transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors. © 2006 Wiley‐Liss, Inc.
Extracellular signal‐regulated kinases 1/2 are required for adult retinal ganglion cell axon regeneration induced by fibroblast growth factor‐2
Authors: Sapieha Przemyslaw S. , Hauswirth William W. , Di Polo Adriana
Published: February 2006

The intracellular signaling mechanisms used by neurotrophic factors to promote axon growth in the mature, injured central nervous system are not well understood. Here we investigated the signaling cascades that control fibroblast growth factor‐2 (FGF‐2)‐mediated retinal ganglion cell (RGC) axon extension in vivo. For this purpose, a novel adeno‐associated virus (AAV) was used to deliver the FGF‐2 gene to RGCs, providing a sustained source of this neurotrophic factor. FGF‐2 gene transfer led to an approximately ten‐fold increase in the number of axons that extended past the lesion site compared with control nerves. Axon growth correlated with FGF‐2‐induced activation of the extracellular signal‐regulated kinases 1/2 (Erk1/2), but not phosphoinositide 3‐kinase or protein kinase C. Pharmacological inhibition of Erk1/2 activation resulted in an ∼80% decrease in the number of axons that regenerated in the injured optic nerve. Our data demonstrate that the Erk1/2 pathway is an essential signaling component in FGF‐2‐mediated axon regeneration in the mature, injured visual system. © 2006 Wiley‐Liss, Inc.
The Rho‐family guanine nucleotide exchange factor GEFT enhances retinoic acid‐ and cAMP‐induced neurite outgrowth
Authors: Bryan Brad A. , Cai Yi , Liu Mingyao
Published: February 2006

The Rho GTPases are important regulators of neurite outgrowth and pathfinding. We have recently reported that a Rho‐family guanine nucleotide exchange factor, GEFT, modulates dendrite spine morphology and basal neurite outgrowth in primary hippocampal neurons and Neuro2A cells, respectively. Here we demonstrate that GEFT protein is highly expressed in all regions of the brain and is highly up‐regulated upon treatment of Neuro2A cells with retinoic acid and dibutyric cAMP, which promote dendrite and axon‐like neurite extensions, respectively. Within retinoic acid‐induced neurite extensions, GEFT is localized to actin‐enriched regions in the primary neurites, with little or no expression from secondary branches. Dibutyric cAMP‐induced neurite extensions are highly concentrated for GEFT at the actin‐rich distal tip of the growth cone. Additionally, we demonstrate that GEFT promotes neurite outgrowth in undifferentiated as well as differentiated Neuro2A cells. Together, our data provide new evidence suggesting that GEFT is an important regulator of multiple processes involved in axon and dendrite formation. © 2006 Wiley‐Liss, Inc.
Raman, FT‐IR and DFT studies of ortho‐, meta‐ and para‐pyridinomethylene substituted di(4‐hydroxy‐coumarin) and their Ce(III), La(III) and Nd(III) complexes
Authors: Georgieva I. , Kostova I. , Trendafilova N. , Rastogi V. K. , Bauer G. , Kiefer W.
Published: February 2006

Vibrational spectra of ortho‐, meta‐ and para‐pyridinomethylene substituted di(4‐hydroxycoumarin) (o‐, m‐, p‐PyDC, (PyDCs)) and their Ce(III), La(III) and Nd(III) complexes were studied by Raman and Fourier transform infrared (FT‐IR) spectroscopies. Density functional theory (DFT) at B3LYP/6‐31G(d) level was used to determine the geometrical and vibrational characteristics of the neutral PyDC isomers and their dianionic forms. The experimental IR and Raman bands of PyDCs were assigned to the corresponding normal modes on the basis of DFT calculations. The effect of the intramolecular H‐bonds in PyDCs as well as of the PyDCs deprotonation on the vibrational mode positions was estimated by comparison with the molecular vibrations of the H‐bonding‐free 4‐hydroxycoumarin and PyDC dianionic forms. The characteristic IR and Raman bands of o‐, m‐ and p‐PyDC were specified and discussed. The comparative vibrational analysis of the neutral and the dianionic PyDCs and their Ln(III) complexes gave evidence that the PyDC ligands bound the lanthanide(III) through the carbonylic oxygens and the deprotonated hydroxylic oxygens. Copyright © 2006 John Wiley & Sons, Ltd.
Lymphoscintigraphic drainage of acral limb skin to interval sentinel lymph nodes in healthy subjects
Authors: Aydin Mustafa Asim , Okudan Berna , Nasir Serdar , Özbek Meltem , Karagöz Arif , Altuntaş Selman
Published: February 2006

Background and Objectives

In the literature, drainage to epitrochlear and popliteal sentinel lymph nodes (SLN) are analyzed for whole or distal extremity (below elbow or knee) melanomas that are not topographically homogeneous with respect to tendency of drainage to interval SLNs. We hypothesize that acral (hand and foot) skin has a uniform frequency of drainage to interval SLNs, which is higher than reported for distal extremity melanomas.

Methods

One hundred healthy subjects were enrolled. Fifty subjects had standard four extremity lymphoscintigraphies by radiocolloid injection into an interdigital web space as in lymphodynamic studies. On another 50 subjects, either targeted upper (n = 25) or lower (n = 25) extremity lymphoscintigraphies were performed utilizing injection sites that likely drain to interval SLNs. Acral skin drainage to interval SLNs was analyzed for interindividual variability and injection site dependence.

Results

There was considerable interindividual variability in drainage of each injection site to interval SLNs. Hand skin had a uniform 50% frequency of drainage to epitrochlear–midhumeral SLNs with both injection sites. This frequency was higher than the epitroclear SLN frequencies reported for distal extremity melanomas. Foot skin had 10% and 90% frequencies of drainage to popliteal SLNs from standard and targeted injection sites, respectively. Foot skin largely simulates the tendency of drainage reported for distal extremity melanomas while lateral heel represents a limited zone that almost uniformly drains to popliteal SLNs.

Conclusions

Despite dissimilarities between hand and foot, acral skin drainage to interval SLNs is high enough to obligate a thorough interval SLN exploration in acral primaries. J. Surg. Oncol. 2006;93:286–293. © 2006 Wiley‐Liss, Inc.
Transpleurodiaphragmatic cryosurgical ablation for recurrent unresectable colorectal liver metastases
Authors: Stella Mattia , Mithieux François , Meeus Pierre , Kaemmerlen Pierre , Lafon Cyril , Rivoire Michel
Published: February 2006

Background and Objectives

Cryosurgical ablation (CSA) allows the focal destruction of unresectable liver metastases after previous liver resection. The abdominal approach may be difficult for recurrent colorectal cancer metastases located in the upper part of the remaining liver, close to the inferior vena cava (IVC), the hepatic veins, and the diaphragm. A transpleurodiaphragmatic access was assessed for safety and efficacy.

Methods

Between September 1999 and July 2004, 13 patients with recurrent unresectable colorectal liver metastases underwent transpleurodiaphragmatic CSA via limited right thoracotomy. Seventeen lesions were treated; median diameter was 31 mm (range 13–40 mm). One to three cryoprobes were used, depending on the size and location of metastases.

Results

There was no operative death; three patients developed minor complications (23%). Median hospital stay was 10 days (8–14 days). After a median follow‐up of 26 months (range 8–69 months), 9 patients were alive, and 5 were disease‐free. Six patients had liver recurrences outside the cryolesion. Median disease free survival was 12 months with 60% 3‐year survival after CSA and 58% 5‐year survival after first liver surgery.

Conclusions

Transpleurodiaphragmatic CSA is safe and effective in selected patients with unresectable recurrent liver metastases from colorectal cancer. J. Surg. Oncol. 2006;93: 268–272. © 2006 Wiley‐Liss, Inc.
Tumor length as a prognostic factor in esophageal malignancy: Univariate and multivariate survival analyses
Authors: Griffiths Ewen A. , Brummell Zoe , Gorthi Ganesh , Pritchard Susan A. , Welch Ian McL
Published: February 2006

Background and Objectives

Gastrointestinal specialists generally feel that long esophageal tumors carry a worse prognosis and are likely to be more advanced than shorter lesions. Our aim was to investigate the relationship between histologically determined tumor length and aspects of tumor pathology and survival for patients with resected esophageal malignancy.

Methods

Three hundred and nine patients who underwent esophageal resection with curative intent in our unit between 1994 and 2003 were retrospectively analyzed. Pathological details such as TNM stage, differentiation, completeness of surgical resection, and overall stage were collected. Survival data were obtained for each patient and univariate and multivariate analyses were performed. Overall survival was used as the primary endpoint.

Results

There were 225 adenocarcinomas, 72 squamous cell carcinomas, and 12 other tumor types with a median tumor length of 3.5 cm (range 0.5–14 cm). Tumor length greater than 3.5 cm was associated with increasing T stage (P = 0.0001), N stage (P = 0.032), overall stage (P = 0.003), and involvement of the longitudinal resection margins (P = 0.02). Univariate analysis found tumor length greater than 3.5 cm was associated with worse overall survival compared with shorter tumors (P = 0.0002). Tumor length remained a significant prognostic factor on multivariate analysis (P = 0.04). Other prognostic factors on multivariate analysis were age, tumor differentiation, nodal involvement, and resection margin status.

Conclusion

Tumor length greater than 3.5 cm (as determined histologically) is associated with worse disease stage and poor overall patient survival. If preoperative endoscopic tumor length bears a similar relationship, this could assist in patient selection for appropriate treatments. J. Surg. Oncol. 2006;93: 258–267. © 2006 Wiley‐Liss, Inc.
Correlations of oral tongue cancer invasion with matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression
Authors: Kim Se‐Heon , Cho Nam Hoon , Kim Kyubo , Lee Jin Seok , Koo Bon Seok , Kim Jeong Hong , Chang Jung Hyun , Choi Eun Chang
Published: February 2006

Background and Objectives

In oral tongue cancer, the degree of tumor invasion has a significant effect on the prognosis. We hypothesized that the destruction of extracelluar matrix and neovascularization are related to tumor infiltration mechanism. By studying the tissues of early stage oral tongue cancer patients, we are intending to clarify the invasion‐related factors.

Materials and Methods

To demonstrate the invasion process in early T‐stage oral tongue cancer, the expressions of extracellular matrix destruction‐related molecules (MMP‐2, MMP‐9) and neovascularization‐related molecule (VEGF) were observed by immunohistochemical study. Also, staining of CD31 was done for quantification of neovascularization. We analyzed relationship between expression of each substances and tumor invasion depth, tumor free survival rates, and cervical lymph node metastasis rate.

Results

The expression rates of MMP‐2, MMP‐9, VEGF in 38 early oral cancer patients were 52.6%, 78.9%, and 52.6%, respectively. Significant correlation was found between the VEGF expression and microvessel density showed by CD31 immunohistochemical staining (P < 0.001). VEGF expressions were significantly related with tumor invasion depth (P = 0.002). The tumor‐free survival rate of those patients with VEGF‐positive tumors was significantly poorer than in those with VEGF‐negative tumors (P = 0.019).

Conclusions

These results indicate that VEGF is a useful marker for predicting the tumor invasion in patients with early tongue cancer. J. Surg. Oncol. 2006;93: 330–337. © 2006 Wiley‐Liss, Inc.