bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo studies of the anticancer action of terbinafine in human cancer cell lines: G0/G1 p53‐associated cell cycle arrest
Authors: Lee Wen‐Sen , Chen Rong‐Jane , Wang Ying‐Jan , Tseng How , Jeng Jiiang‐Huei , Lin Shyr‐Yi , Liang Yu‐Chih , Chen Chien‐Ho , Lin Chien‐Huang , Lin Jen‐Kun , Ho Pei‐Yin , Chu Jan‐Show , Ho Wei‐Lu , Chen Li‐Ching , Ho Yuan‐Soon
Published: June 2003

Terbinafine (TB) (Lamisil®), a promising oral antifungal agent used worldwide, has been used in the treatment of superficial mycosis. In our study, we demonstrated that TB dose‐dependently decreased cell number in various cultured human malignant cells. Flow cytometry analysis revealed that TB interrupts the cell cycle at the G0/G1 transition. The TB‐induced cell cycle arrest in colon cancer cell line (COLO 205) occurred when the cyclin‐dependent kinase (cdk) system was inhibited just as the levels of p53, p21/Cip1 and p27/Kip1 proteins were augmented. In the TB‐treated COLO 205, the binding between p53 protein and p53 consensus binding site in p21/Cip1 promoter DNA probe was increased. Pretreatment of COLO 205 with p53‐specific antisense oligodeoxynucleotide decreased the TB‐induced elevations of p53 and p21/Cip1 proteins, which in turn led to arrest in the cell cycle at the G0/G1 phase. Moreover, in the p53 null cells, HL60, TB treatment did not induce cell cycle arrest. Taken together, these results suggest an involvement of the p53‐associated signaling pathway in the TB‐induced antiproliferation in COLO 205. We further examined whether administration of TB could affect the growth of tumors derived from human colon cancer cells in an in vivo setting. COLO 205 cells implanted subcutaneously in nude mice formed solid tumor; subsequent intraperitoneal injections of TB (50 mg/kg) led to obvious decline in tumor size, up to 50–60%. In these tumors, increases in the p21/Cip1, p27/Kip1 and p53 proteins and the occurrence of apoptosis were observed. Combined treatment with TB and nocodazole (ND), a clinically used anticancer agent, potentiated the apoptotic effect in COLO 205. These findings demonstrate for the first time that TB can inhibit the proliferation of tumor cells in vitro and in vivo. © 2003 Wiley‐Liss, Inc.
Malignant tumors in first‐degree relatives of cancer patients aged 0–25 years (province of Trieste, Italy)
Authors: Brunetti Davide , Tamaro Paolo , Cavallieri Furio , Stanta Giorgio
Published: June 2003

To determine whether the occurrence of first and second primary malignancies in first‐degree relatives of cancer patients aged 0–25 years (probands) differed from that in the general population, a cohort study was carried out on 860 relatives of 265 probands living in the province of Trieste, Italy. During the follow‐up period (median duration = 28 years, 25th–75th percentile = 20–34), the relatives developed 103 first primary cancers vs. 88.9 expected for a standardized incidence ratio (SIR) of 1.2 (p = 0.2). Significantly elevated risks were found for melanoma in the parents of probands aged 15–25 years with melanoma (SIR = 15.0, p = 0.002), for hemolymphatic malignancies in the fathers of probands aged 0–14 years with brain tumors (SIR = 13.3, p = 0.0005) and for hemolymphatic cancers in relatives as a whole of probands aged 15–25 years with lymphomas (SIR = 4.5, p = 0.01). During the follow‐up period, 7 relatives with a first primary cancer had a subsequent malignancy vs. 4.2 expected for an SIR of 1.7 (p = 0.3). Our results indicate that young cancer patients per se should not to be considered as a factor that usually increases the risk of developing malignant tumors among their first‐degree relatives, except when a known cancer family syndrome or predisposition is recognized. © 2003 Wiley‐Liss, Inc.
Exclusion of BRAFV599E as a melanoma susceptibility mutation
Authors: Meyer Peter , Klaes Ruediger , Schmitt Christina , Boettger Melanie Barbara , Garbe Claus
Published: June 2003

Very recently, BRAF mutations were found in about 2/3 of malignant melanomas and at lower frequencies in other human cancers. The BRAF gene codes for a protein in the mitogen‐activated protein kinase (MAPK) pathway. All mutations identified to date are within the kinase domain, with a single missense mutation (V599E) accounting for 80%. We investigated the hypothesis that this common somatic BRAF mutation (V599E) would contribute to melanoma predisposition in familial and polygenic malignant melanoma if occuring as a germ‐line mutation. We performed comprehensive mutational screening of exon 15 of BRAF using DHPLC (denaturing high‐performance liquid chromatography) and DNA sequencing techniques. No V599E mutation could be detected in 172 melanoma patients comprising 46 familial cases, 21 multiple melanoma patients and 106 cases with at least one first‐degree relative suffering from other cancers. We therefore conclude that the common somatic BRAF mutation V599E does not contribute to polygenic and familial melanoma predisposition. © 2003 Wiley‐Liss, Inc.
Vitamin D enhances caspase‐dependent and ‐independent TNFα‐induced breast cancer cell death: The role of reactive oxygen species and mitochondria
Authors: Weitsman Gregory E. , Ravid Amiram , Liberman Uri A. , Koren Ruth
Published: June 2003

Calcitriol, the hormonal form of vitamin D, potentiates the activity of some common anticancer drugs and agents of the anticancer immune system, including tumor necrosis factor α (TNFα). TNFα‐induced cytotoxicity is due to both caspase‐dependent and ‐independent pathways. Cotreatment with calcitriol enhanced both modes of TNFα‐induced death in MCF‐7 breast cancer cells. It increased caspase‐3‐like activity as assayed by the cleavage of poly‐(ADP‐ribose)polymerase and of the fluorogenic substrate ac‐DEVD‐AMC. It also enhanced TNFα‐induced caspase‐independent cytotoxicity in the presence of the pan‐caspase inhibitor zD‐2,6‐dichlorobenzoyloxymethylketone. The antioxidants N‐acetylcysteine, reduced glutathione, lipoic acid and ascorbic acid markedly reduced the enhancing effect of the hormone on TNFα‐induced caspase activation. N‐acetylcysteine and reduced glutathione also decreased caspase‐independent cytotoxicity in the presence or absence of calcitriol, indicating that reactive oxygen species (ROS) have a key role in the cross talk between TNFα and calcitriol. Mitochondrial damage is common to both TNFα‐induced caspase‐dependent and ‐independent pathways and may underlie excessive production of ROS. Mitochondrial membrane potential (ΔΨ) was assessed by the specific potential‐sensitive fluorescent probe JC‐1. The hormone augmented the drop in ΔΨ and release of cytochrome c from mitochondria, induced by TNFα. The effect of calcitriol on ΔΨ was mimicked by rotenone, which increased both the drop in ΔΨ and caspase activation induced by TNFα. It is possible that the interaction of TNFα and calcitriol on the level of the mitochondria is the underlying mechanism responsible for the enhancement of TNFα‐induced, ROS‐mediated caspase‐dependent and ‐independent cell death. © 2003 Wiley‐Liss, Inc.
Induction of apoptosis and chemosensitization of mesothelioma cells by Bcl‐2 and Bcl‐xL antisense treatment
Authors: Hopkins‐Donaldson Sally , Cathomas Richard , Simões‐Wüst A. Paula , Kurtz Stefanie , Belyanskya Larisa , Stahel Rolf A. , Zangemeister‐Wittke Uwe
Published: June 2003

Our study was designed to investigate the role of the anti‐apoptotic proteins Bcl‐2 and Bcl‐xL in the chemoresistance of cells derived from malignant pleural mesothelioma. First, we determined the basal expression levels of Bcl‐2 and Bcl‐xL in mesothelioma cells and examined the effect of their downregulation by antisense oligonucleotides. Bcl‐xL mRNA and protein could be readily detected in mesothelioma cell lines, whereas only low levels of Bcl‐2 mRNA and protein were found. Preferential downregulation of either Bcl‐xL alone or of Bcl‐xL and Bcl‐2 simultaneously was achieved by treatment with antisense oligonucleotides 4259 and 4625, respectively, whereas the expression of other apoptosis‐relevant genes remained unaffected. Treatment with oligonucleotides 4259 or 4625 lowered the apoptosis threshold in ZL34 mesothelioma cells, as indicated by an increase in cell death accompanied by increased caspase‐3‐like activity, a decrease of the mitochondrial transmembrane potential and the cleavage of procaspase‐7 and ICAD. In addition to the direct induction of apoptosis, antisense treatment sensitized ZL34 cells to the cytostatic effect of cisplatin and gemcitabine, with the combination of 4625 and cisplatin being the most effective. Our results demonstrate that Bcl‐2 and Bcl‐xL antisense treatment facilitates apoptosis in mesothelioma cells and suggest the use of Bcl‐2/Bcl‐xL bispecific antisense treatment in combination with cisplatin or gemcitabine for therapy of malignant pleural mesothelioma. © 2003 Wiley‐Liss, Inc.
Childhood exposure to simian virus 40‐contaminated poliovirus vaccine and risk of AIDS‐associated non‐Hodgkin's lymphoma
Authors: Engels Eric A. , Rodman Leonard H. , Frisch Morten , Goedert James J. , Biggar Robert J.
Published: June 2003

Persons with acquired immunodeficiency syndrome (AIDS) have increased risk for non‐Hodgkin's lymphoma (NHL). Recent studies have reported the detection of DNA sequences from simian virus 40 (SV40), a macaque polyomavirus that contaminated early poliovirus vaccines, in a large proportion of AIDS‐associated NHLs. To examine the association between SV40 exposure and NHL risk, we analyzed data from a U.S. registry‐based cohort study of persons with AIDS (1980–96). We calculated NHL incidence in persons born in 1958–61 (exposed to SV40‐contaminated poliovirus vaccine as children, n = 39,468) and in 1964–67 (born after vaccines were cleared of SV40 and thus unexposed, n = 17,340). Among persons with AIDS, NHL incidence was 11.7 per 1,000 person‐years in SV40‐exposed individuals (616 NHL cases) and 10.1 per 1,000 person‐years in SV40‐unexposed individuals (230 cases; unadjusted relative risk 1.15, 95% CI 0.99–1.34, p = 0.06). Because of differences in cohorts' birth years and the evolving demographics of the AIDS epidemic, SV40‐exposed subjects were older at AIDS onset than unexposed subjects (mean age 32.0 vs. 27.2 years, p < 0.0001), and the cohorts differed by sex (p < 0.0001) and ethnic group (p < 0.0001). Since NHL incidence was relatively high among whites (p < 0.0001) and homosexual males (p < 0.0001) and increased with age (p = 0.09), comparisons required adjustments for these factors. After adjustment, SV40 exposure was not associated with NHL incidence (adjusted relative risk 0.97, 95% CI 0.79–1.20, p = 0.80). We conclude that childhood exposure to SV40 through receipt of contaminated poliovirus vaccine was not associated with increased risk for AIDS‐associated NHL. Our findings do not support a role for SV40 in lymphomagenesis among immunosuppressed persons. © 2003 Wiley‐Liss, Inc.
Familial brain tumours—genetics or environment? A nationwide cohort study of cancer risk in spouses and first‐degree relatives of brain tumour patients
Authors: Malmer Beatrice , Henriksson Roger , Grönberg Henrik
Published: June 2003

Our study investigated whether the familial aggregation of glioma is due to environmental or genetic effects and it investigated and compared the risk to spouses and first‐degree relatives (FDR) of patients with primary brain tumours (PBT) for developing both PBT and the risk for other types of cancer. All PBT patients identified in Sweden from 1958–97 in The Swedish Cancer Registry (SCR) were linked to the nationwide Swedish Family Database, including persons in Sweden born from 1932–97. The cohorts of spouses and FDR were linked to the SCR to identify observed cases of PBT and other cancer. Standardised incidence ratios (SIR) were calculated using the incidence rates from SCR as the reference. We found that there were no increased risks for any specific type of PBT in the cohort of spouses. In the FDR cohort, generally the risk for a PBT was significantly increased by 2 to 3 times for the same histopathology as the probands. Spouses of PBT patients had an increased risk of skin cancer. We conclude that FDR, not spouses, have a significantly increased risk, which indicates a genetic origin of the familial aggregation of brain tumours. © 2003 Wiley‐Liss, Inc.
Ectopic chromosome around centrosome in metaphase cells as a marker of high‐risk human papillomavirus–associated cervical intraepithelial neoplasias
Authors: Furuta Reiko , Hirai Yasuo , Katase Katsuyoshi , Tate Shinichi , Kawaguchi Tokuichi , Akiyama Futoshi , Kato Yo , Kumada Kazuki , Iwasaka Tsuyoshi , Yaegashi Nobuo , Kanazawa Koji , Yoshikawa Hiroyuki , Kitagawa Tomoyuki
Published: June 2003

This report describes the appearance of ectopic chromosome around centrosome (ECAC) in metaphase cell nuclei of high‐risk HPV‐associated cervical neoplasms. ECAC are clearly visible on HE‐stained sections as a tiny (approx. 0.7 μ), round, dark structure or an aggregate of filamentous chromosome, often symmetrical at bilateral centrosomes. They appear in CINs from an early stage (CIN I), with the highest incidence in HPV16‐associated CIN II–III (75%), and are less common in HPV‐related invasive carcinomas (21%) and in lesions associated with high‐risk HPV types other than 16. Rates for ECAC‐positive nuclei in metaphase preparations (ECAC rate) for each lesion ranged 3.6–30%, the average being 14.5%. ECAC appeared very rarely in CINs associated with intermediate‐risk HPVs and was never encountered in HPV6/11‐induced condylomas or HPV‐unrelated neoplasms in other organs. ECAC may be morphologic evidence of HPV‐induced chromosomal instability working as a background mechanism in cervical carcinogenesis and also a useful marker for the histopathologic differentiation of high‐risk CINs. © 2003 Wiley‐Liss, Inc.
Selective expression of HLA‐G in malignant and premalignant skin specimens in kidney transplant recipients
Authors: Aractingi Sélim , Kanitakis Jean , Euvrard Sylvie , Le Danff Caroline , Carosella Edgardo D.
Published: June 2003

The HLA‐G molecule has been implicated in the escape from the host antitumor immune response. Besides, this molecule appears also to be detected in transplant recipient's tissues, mainly those with fewer rejection episodes. Since skin carcinomas develop frequently in organ transplant recipients, we asked whether HLA‐G could be expressed in these lesions, therefore allowing tumor development in such patients. Immunohistochemical analysis of kidney transplant recipients presenting various types of epithelial malignant tumor and benign cutaneous lesion was done using a specific anti‐HLA‐G antibody. HLA‐G was expressed in 35% of specimens of SCC, 47% of in situ carcinoma, 27% of AK and 14% of BCC but never in the 24 benign lesions studied. Many benign specimens were obtained from the same patients who had tumors, demonstrating that HLA‐G expression was restricted to the malignant sites. Interestingly, HLA‐G was expressed by proliferative keratinocytes, inflammatory infiltrates and even endothelial cells. Cytokines triggered in the course of organ transplantation include IL‐10. This molecule may induce expression of HLA‐G, which in turn may be implicated in tumor development in transplanted recipients. © 2003 Wiley‐Liss, Inc.
Little evidence for involvement of MLH3 in colorectal cancer predisposition
Authors: Hienonen Tuija , Laiho Päivi , Salovaara Reijo , Mecklin Jukka‐Pekka , Järvinen Heikki , Sistonen Pertti , Peltomäki Päivi , Lehtonen Rainer , Nupponen Nina N. , Launonen Virpi , Karhu Auli , Aaltonen Lauri A.
Published: June 2003

Mutations in the DNA MMR genes MSH2, MLH1, MSH6 and PMS2 underlie a large subset of HNPCC cases, and a hallmark of the tumors is MSI. In many HNPCC families, however, a causative mutation has not been found. Therefore, the involvement of additional, thus far unknown, genes in MSI as well as MSS colorectal tumor predisposition is possible. The role of a relatively recently cloned MMR gene, MLH3, in familial CRC has been studied; but the results appear somewhat conflicting. To further evaluate the role of MLH3 in CRC predisposition, we analyzed 30 Finnish CRC cases for germline mutations by sequencing. These cases were selected from a large series of Finnish CRC patients, to match features previously proposed to associate with MLH3 germline defects. We found 5 missense variants, 4 of which were also found in Finnish cancer‐free controls. The only remaining variant does not appear to be an attractive candidate for a disease‐associated mutation because the amino acid change is located outside the conserved residues. We also screened for the previously reported variants, including a frameshift change, the most likely pathogenic MLH3 mutation observed so far. The frameshift was not present in the 30 CRC cases or in 700 cancer‐free controls. While it is a difficult task to exclude a role of MLH3 in HNPCC, our study could not confirm a role for MLH3 in CRC predisposition. © 2003 Wiley‐Liss, Inc.
Increasing use of seat belts among kindergarten children: Skills beyond awareness
Authors: Gidron Yori , Hochberg Ronny
Published: June 2003

Participatory learning was previously found to increase seat belt use by children. However, cross‐cultural generalizability, effects of intervention beyond enhancing awareness, and risk factors for nonuse of seat belts, were not addressed. This study examined the effects of such an intervention on seat belt use, and addressed these issues in an Israeli kindergarten. One week, and 1 day before the intervention, 29 and 20%, respectively, of children were fastened by parents. Significant increases were seen 1 day (71%) and 1 month after the intervention (65%). The intervention's effects generalize to an Israeli sample, are not merely due to enhancing awareness, and maintain over time. © 2003 Wiley Periodicals, Inc. J Comm Psychol 31: 315–319, 2003.
Client choice of treatment and client outcomes
Authors: Calsyn Robert J. , Morse Gary A. , Yonker Robert D. , Winter Joel P. , Pierce Kathy J. , Taylor Matthew J.
Published: June 2003

Participants in this study suffered from severe mental illness and were homeless at baseline. They were given their choice of five different treatment programs. The current study investigated two major questions: (1) what is the impact of positive expectancies about the efficacy of the chosen program on number of contacts with the chosen program and client outcomes; and (2) what is the impact of positive views about nonchosen programs (alternative choice variables) on contact with the chosen program and client outcomes. Client outcomes assessed were psychotic symptoms, days homeless, and client satisfaction. Positive expectancy variables were the number of reasons for choosing a program and confidence that the program would help. Alternative choice variables were the number of nonchosen programs visited and the attractiveness of a nonchosen program. Only the number of reasons for choosing the program was significantly related to program contact with the chosen program. Both of the positive expectancy variables and program contact were significantly correlated with consumer satisfaction. In general, neither the positive expectancy variables nor the alternative choice variables predicted changes in psychotic symptoms nor days homeless. © 2003 Wiley Periodicals, Inc. J Comm Psychol 31: 339–348, 2003.
Changing contexts? The effects of a primary prevention program on classroom levels of peer relational and physical victimization
Authors: Leadbeater Bonnie , Hoglund Wendy , Woods Tom
Published: June 2003

Whereas school‐based prevention programs often target deficits in individual children's social skills in order to limit their aggression or exposure to peer victimization, there is increasing evidence that school‐wide and classroom‐level factors can also affect the success of these programs. This short‐term longitudinal study involved 432 elementary school students from 44 classrooms in 17 urban schools. We investigated whether classroom characteristics (average levels of social competence, emotional problems, and behavioral problems) and school‐wide characteristics (proportion of children on income assistance and implementation of a peer victimization prevention program—the Walk away, Ignore, Talk, and Seek help [W.I.T.S.] program) experienced in Grade 1 influences changes in children's reports of relational and physical victimization at the end of Grade 2. Findings showed that classroom levels of emotional problems predicted increases in relational victimization (beyond individual differences in emotional and behavioral problems). Classroom levels of behavioral problems predicted reports of increases in physical victimization (beyond individual differences). Classroom levels of social competence also interacted with individual levels of emotional problems such that children with higher levels of emotional problems in classes with more socially competent children reported more relational and physical victimization. Higher school levels of poverty and lack of program involvement also predicted higher levels of physical victimization, beyond individual and classroom effects. The capacity of the W.I.T.S. program to influence classroom level characteristics and the moderating effects of school poverty on victimization were also assessed. © 2003 Wiley Periodicals, Inc. J Comm Psychol 31: 397–418, 2003.
Depletion of mitochondrial DNA in HIV‐1‐infected patients and its amelioration by antiretroviral therapy
Authors: Miura Toshiyuki , Goto Mieko , Hosoya Noriaki , Odawara Takashi , Kitamura Yoshihiro , Nakamura Tetsuya , Iwamoto Aikichi
Published: June 2003

Mitochondrial DNA (mtDNA) of peripheral blood mononuclear cells (PBMCs) collected from Human immunodeficiency virus 1 (HIV‐1)‐infected patients and healthy controls were measured longitudinally using real‐time polymerase chain reaction to evaluate the effects of antiretroviral agents on mtDNA synthesis in vivo and to assess the value of monitoring mtDNA in PBMCs to predict adverse events amongst these patients. MtDNA levels in PBMCs were significantly decreased in treatment‐naive HIV‐1‐infected patients compared with healthy people. MtDNA levels were not only significantly correlated with CD4+ T‐cell count, but also inversely correlated with HIV‐1 viral load. MtDNA levels in untreated patients and healthy controls were stable during the period of observation. On the other hand, amongst patients treated with regimens containing AZT/3TC or d4T/3TC, mtDNA increased during treatment and recovered to levels comparable to healthy controls. In contrast, mtDNA decreased immediately after the initiation of an AZT/ddC‐containing regimen. We did not find a correlation between mtDNA levels and changes in clinical parameters. There was no significant difference in mtDNA levels between patients with and those without lipoatrophy. Furthermore, there was no obvious difference in mtDNA levels amongst those patients exhibiting signs and symptoms of peripheral neuropathy. In conclusion, the decrease in mtDNA levels in PBMCs amongst HIV‐1‐infected patients and its amelioration by antiretroviral therapy may suggest the influence of direct effects on mitochondria or mtDNA by HIV‐1 infection. Further investigations are needed to elucidate the mechanisms contributing to decreased mtDNA and the value of mtDNA measurement in the care of HIV‐1‐infected individuals. J. Med. Virol. 70:497–505, 2003. © 2003 Wiley‐Liss, Inc.
Saccharomyces cerevisiae‐derived HBsAg preparations differ in their attachment to monocytes, immune‐suppressive potential, and T‐cell immunogenicity
Authors: Vanlandschoot Peter , Van Houtte Freya , Hoek Frans , Nieuwland Rienk , Leroux‐Roels Geert
Published: June 2003

Expression of the hepatitis B virus S protein results in the formation of a lipoprotein particle, the hepatitis B surface antigen (HBsAg). Such particles, produced in Saccharomyces cerevisiae, bind to the cell surface of monocytes through interaction with the lipopolysaccharide binding protein and the lipopolysaccharide receptor, CD14. This attachment is suggested to depend on the presence of charged phospholipids in the particles. In addition, such particles interfere with the lipopolysaccharide and interleukin‐2‐induced activation of monocytes. In the present study, it is reported that of three Saccharomyces cerevisiae‐derived HBsAg preparations, two have a reduced capacity to bind to monocytes. A correlation with a reduced potential to inhibit the lipopolysaccharide‐induced activation of monocytes and an increased potential to stimulate HBsAg‐specific T‐cell proliferation is observed. Surprisingly, differences in phospholipid content that might explain these observations, were not detected. J. Med. Virol. 70:513–519, 2003. © 2003 Wiley‐Liss, Inc.
Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease
Authors: Sugauchi Fuminaka , Ohno Tomoyoshi , Orito Etsuro , Sakugawa Hiroshi , Ichida Takafumi , Komatsu Masafumi , Kuramitsu Tomoyuki , Ueda Ryuzo , Miyakawa Yuzo , Mizokami Masashi
Published: June 2003

Hepatitis B virus (HBV) mutants with deletions in the preS region have not been evaluated for association with viral genotypes. In a case‐control study, HBV DNA samples collected from 80 each of carriers infected with HBV genotype B or C were examined for preS deletions. PreS deletion mutants were found in a total of 37 of 160 (23%) HBV carriers. Carriers with preS deletion mutants were older (56.0 ± 12.7 vs 49.3 ± 16.9 years, P < 0.05), were infected more frequently with HBV genotype C (84% vs 40%, P < 0.05), and had more advanced disease, such as liver cirrhosis and hepatocellular carcinoma (54% vs 31%; P < 0.05), than did those without such mutants. In a multivariate analysis, genotype C (odds ratio [OR] = 9.3, P < 0.001) and advanced liver disease (OR = 3.1, P < 0.01) were the most significant variables in association with preS deletions. A direct repeat sequence (TCAGG) was found at the start or at the end of preS1 deletions in 6 of the 20 (30%) cases examined, and preS2 deletions in these cases were clustered over the 5′‐terminal half of this region. These results indicate that the development of preS deletion mutants depends on HBV genotypes and that it may be associated with progressive liver disease. J. Med. Virol. 70:537–544, 2003. © 2003 Wiley‐Liss, Inc.
Expression of the chemokine IP‐10 correlates with the accumulation of hepatic IFN‐γ and IL‐18 mRNA in chronic hepatitis C but not in hepatitis B
Authors: Mihm Sabine , Schweyer Stefan , Ramadori Giuliano
Published: June 2003

The pathogenesis of hepatitis C virus‐induced chronic liver disease is still poorly understood. Previous studies revealed enhanced hepatic expression of the Th1 prototype cytokine IFN‐γ in individuals with chronic hepatitis C. In accordance with several animal models of experimentally induced hepatitis, a Th1 lymphocyte driven inflammatory process, which involves newly infiltrated as well as resident monocytes/macrophages, has been proposed. An involvement of the interferon‐γ‐inducible chemokine IP‐10, which is chemoattractive for stimulated Th1 cells and monocytes, is also suggested. Using an HBV transgenic mouse model, a reduction of hepatic infiltration and liver disease was achieved recently by administration of antibodies directed against the interferon‐γ‐inducible chemokine Mig and against IP‐10. In the present study, expression of IP‐10 was investigated both in serum and in the liver of patients with chronic hepatitis C and hepatitis B. Patients with liver diseases of non‐viral etiologies served as controls. IP‐10 expression was highest in hepatitis C. In chronic hepatitis C, but not in chronic hepatitis B nor in liver disorders unrelated to viral infections, IP‐10 expression was strongly correlated with the amount of transcripts for IFN‐γ and to the amount of transcripts for the constitutively expressed macrophage derived cytokine IL‐18. Hepatic inflammatory activity, however, was found to be associated more closely with IFN‐γ than with IP‐10 or IL‐18 mRNA expression. The data support the hypothesis that IP‐10 is responsible for the recruitment of Th cells and monocytes in chronic hepatitis C, and suggest that its role in chronic hepatitis B is less determining. Moreover, they deliver additional support for the view that IFN‐γ still has to be considered as a mediator that determines the outcome of inflammation, e.g., via its ability to activate IL‐18 expressing cells and to initiate a delayed type hypersensitivity reaction. J. Med. Virol. 70:562–570, 2003. © 2003 Wiley‐Liss, Inc.
Distribution of hepatitis B virus in the liver of chronic hepatitis C patients with occult hepatitis B virus infection
Authors: Rodríguez‐Iñigo Elena , Mariscal Luisa , Bartolomé Javier , Castillo Inmaculada , Navacerrada Cristina , Ortiz‐Movilla Nuria , Pardo Margarita , Carreño Vicente
Published: June 2003

Although occult hepatitis B virus (HBV) infection (HBV‐DNA in serum in the absence of hepatitis B surface antigen [HBsAg]) is common in chronic hepatitis C, its characteristics are not well known. In this work, the presence of HBV‐DNA (by polymerase chain reaction; PCR) and its distribution (by in situ hybridization) in liver biopsies and peripheral blood mononuclear cells (PBMCs) from 32 patients with chronic hepatitis C and occult HBV infection and in 20 HBsAg chronic carriers were determined. The results showed that serum HBV‐DNA levels were statistically lower (P = 0.001) in patients with occult HBV infection than in HBsAg chronic carriers. The HBV infection pattern in liver cells was identical between patients with occult HBV infection and those with chronic hepatitis B. However, the mean percentage of HBV‐infected hepatocytes was significantly lower (P = 0.001) in patients with occult HBV infection (5 ± 4.44%) than in HBsAg chronic carriers (17.99 ± 11.58%). All patients with chronic hepatitis B have HBV‐DNA in their PBMCs while this occurred in 50% of the cases with occult HBV infection. In conclusion, patients with occult HBV infection have a low number of HBV‐infected hepatocytes and this fact could explain the lack of HBsAg detection and low viremia levels found in these cases. J. Med. Virol. 70:571–580, 2003. © 2003 Wiley‐Liss, Inc.
Factors predisposing to the occurrence of cryoglobulinemia in two cohorts of Egyptian and Japanese patients with chronic hepatitis C infection: Ethnic and genotypic influence
Authors: Gad Amal , Tanaka Eiji , Matsumoto Akihiro , el‐Hamid Serwah Abd , Ali Khalil , Makledy Fathy , el‐Gohary Ahmed , Orii Koji , Ijima Akihiro , Rokuhara Akinori , Yoshizawa Kaname , Nooman Zohair , Kiyosawa Kendo
Published: June 2003

The association between cryoglobulinemia and hepatitis C virus (HCV) infection has been reported. However, the factors underlying its wide variation of occurrence have not yet been well identified. To investigate this, cryoglobulinemia was studied in four cohorts of Egyptian and Japanese patients. Fifty Egyptian patients with chronic hepatitis C, infected with genotype 4 (the predominant HCV genotype in Egypt), were compared with 50 age‐ and sex‐matched Japanese patients, infected with HCV genotype 1b (the predominant HCV genotype in Japan). Thirty‐two Egyptian and 30 age‐ and sex‐matched Japanese patients with chronic hepatitis B were included as controls. All patients were noncirrhotic. Antinuclear antibody (ANA), immunoglobulins (Ig), and cryoglubulins were assessed. Results showed a significantly higher prevalence of cryoglobulinemia in chronic hepatitis C Japanese genotype 1b (40%) as compared with Egyptian genotype 4 (14%), P = 0.003, while no difference was found between Japanese (17%) and Egyptian chronic hepatitis B controls (13%). Symptomatic cryoglobulinemia was more prevalent in the Japanese than in the Egyptian chronic hepatitis C group (10% vs. 4%), but the difference was not statistically significant. Univariate analysis showed no association between cryoglobulinemia and either age, sex, alanine aminotransferase level, or HCV viral load in Japanese or Egyptian patients, while the mean IgM level was significantly higher in the cryoglobulin‐positive than in the cryoglobulin‐negative chronic hepatitis C patients in each group (P = 0.003 and 0.017, respectively). Cryoglobulinemia was found to be significantly associated with both high IgG level (P = 0.020), and positive ANA (P < 0.001) in Japanese patients with chronic hepatitis C, genotype 1b but not in Egyptians with genotype 4. Multivariate analysis showed that the only factors predisposing to cryoglobulinemia were Japanese ethnicity with HCV genotype1b (P = 0.002, OR = 2.56), high IgM level of >245 mg/dl (P = 0.018, OR = 2.05) and female gender (P = 0.040, OR = 1/0.66). In conclusion, cryoglobulinemia is prevalent in Japanese patients with chronic hepatitis C infected with genotype 1b, but cryoglobulinemia is not common in Egyptians with HCV genotype 4. Although it was not possible to evaluate ethnicity and HCV genotype separately in this study, HCV genotype 1b appears to predispose more to cryoglobulinemia than does genotype 4. Female gender and high serum IgM level were also related. J. Med. Virol. 70:594–599, 2003. © 2003 Wiley‐Liss, Inc.
Coxsackievirus B3 sequences in the blood of a neonate with congenital myocarditis, plus serological evidence of maternal infection
Authors: Bendig Justin W.A. , Franklin Orla M. , Hebden Anna K. , Backhouse Patricia J. , Clewley Jonathan P. , Goldman Alan P. , Piggott Nick
Published: June 2003

A fatal case of myocarditis in a neonate is described. The clinical features were evident at birth, and enteroviral RNA was detected in the blood of the baby on the day of birth and again 10 days later by a generic enterovirus nested reverse transcription‐polymerase chain reaction (RT‐PCR) assay. The enterovirus RNA was subsequently retested by a separate, newly developed nested RT‐PCR assay yielding a PCR product within the VP1 coding region suitable for sequencing. Identical 239‐base pair sequences were obtained from the RNA of the two blood samples and this sequence most closely resembled coxsackievirus B3 (94% identity). The baby's mother was pyrexial immediately postpartum and an early antenatal serum and a serum sample collected 10 days postpartum tested in parallel for enterovirus IgM antibody showed negative to strong‐positive seroconversion. Infection of the mother was the likely primary event with in utero transfer of the virus to the fetus in the last few days of pregnancy. Neonatal blood is a valuable specimen for enterovirus diagnosis by RT‐PCR. A newly developed nested RT‐PCR assay was successful in typing the enterovirus from stored RNA extracted directly from the blood samples. Serology for enterovirus IgM antibody can be useful for convalescent diagnosis of enterovirus infection in the mother, especially with earlier serum for comparison. J. Med. Virol. 70:606–609, 2003. © 2003 Wiley‐Liss, Inc.
Tissue plasminogen activator induced by dengue virus infection of human endothelial cells
Authors: Huang Ying‐Huey , Lei Huan‐Yao , Liu Hsiao‐Sheng , Lin Yee‐Shin , Chen Shun‐Hua , Liu Ching‐Chuan , Yeh Trai‐Ming
Published: June 2003

Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are severe complications of dengue virus (DV) infection. However, the pathogenesis of hemorrhage induced by dengue virus infection is poorly understood. Since endothelial cells play a pivotal role in the regulation of hemostasis, we studied the effect of DV infection on the production of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI‐1) in vitro using both primary isolated endothelial cells, human umbilical cord veins cells, and a human microvascular endothelial cell line. DV infection significantly induced the secretion of tPA but not PAI‐1 of human endothelial cells. In addition, tPA mRNA of endothelial cells was induced by DV as demonstrated by RT‐PCR. Antibody against IL‐6 but not control antibody inhibited DV‐induced tPA production of endothelial cells. Furthermore, a good correlation between sera levels of IL‐6 and tPA was found in DHF but not DF patients. These results suggest that IL‐6 can regulate DV‐induced tPA production of endothelial cells, which may play important roles in the pathogenic development of DHF/DSS. J. Med. Virol. 70:610–616, 2003. © 2003 Wiley‐Liss, Inc.
Latent and lytic HHV‐8 mRNA expression in PBMCs and Kaposi's sarcoma skin biopsies of AIDS Kaposi's sarcoma patients
Authors: Polstra Abeltje M. , Goudsmit Jaap , Cornelissen Marion
Published: June 2003

Human herpes virus 8 (HHV‐8) is associated with all clinical forms of Kaposi's sarcoma. HHV‐8 DNA is present in Kaposi's sarcoma biopsies and is observed regularly in saliva and less consistently in blood of Kaposi's sarcoma patients. The expression pattern of latent (ORF 73) and lytic (vGCR, vBcl‐2, and vIL‐6) HHV‐8 mRNA was studied in peripheral blood mononuclear cell (PBMC) samples and Kaposi's sarcoma skin biopsies from 11 AIDS Kaposi's sarcoma patients with four different nucleic acid sequence‐based amplification (NASBA) assays. Patients were divided into groups according to the clinical stage of Kaposi's sarcoma (stage I–IV). All biopsies were positive for two or more of the mRNA measured. No clear difference could be seen in the expression pattern in the lesions of the different clinical stages. In the corresponding PBMC samples, very little or no mRNA was measurable in the patients with Kaposi's sarcoma stage I or II, whereas patients with more advanced Kaposi's sarcoma (stage III or IV) had more detectable mRNA in the PBMCs. Thus, the HHV‐8 DNA load in the PBMCs increases in more advanced Kaposi's sarcoma, as does the frequency of mRNA detection in PBMCs. J. Med. Virol. 70:624–627, 2003. © 2003 Wiley‐Liss, Inc.
H1 genotype of measles virus was detected in outbreaks in Japan after 2000
Authors: Zhou Jianhui , Fujino Motoko , Inou Youko , Kumada Atsushi , Aoki Yasuko , Iwata Satoshi , Nakayama Tetsuo
Published: June 2003

We investigated the molecular epidemiology and biological characteristics of wild measles viruses isolated since 1984 in Japan. The circulating measles virus was of genotype C1 before 1985, D3 from 1987 to 1990, and D5 from 1990 to 1997. It was replaced by the same cluster of Chicago‐type D3 strain from 1997 to 1999. In 2000, D5 recirculated with sporadic cases caused by genotype H1. The H1 genotype became dominant in 2001 with a minor distribution of D5. No significant difference was observed in neutralizing titers against C1, D3, D5, and H1 when we used sera having high neutralizing titers. However, some D3 and H1 strains were not completely neutralized with low levels of neutralizing antibody, and maintaining high levels of measles antibodies would be required for the control measles outbreaks. J. Med. Virol. 70:642–648, 2003. © 2003 Wiley‐Liss, Inc.
The structural evolution of the English Channel area
Authors: Lagarde J. L. , Amorese D. , Font M. , Laville E. , Dugué O.
Published: June 2003

The structural evolution of the English Channel area is controlled by structure and particularly by the pre‐existing Cadomian and Variscan crustal discontinuities, which have been reactivated repeatedly in post‐Variscan times. They controlled the crustal subsidence that produced basin development in the Mesozoic, prior to the sea‐floor spreading in the North Atlantic region. They were then reactivated during the Cenozoic compression and basin inversion. The English Channel development is ascribed to mid‐Tertiary differential uplift (Oligocene to Miocene). During late Tertiary to Quaternary times the Channel displays characteristics of a tectonically controlled fluvial basin periodically invaded by the sea. At the lithospheric scale, the Channel can be considered as an active intraplate area influenced by the NW–SE ‘Alpine push’, the NW–SE ‘Atlantic ridge push’ and glacial rebound stresses. Copyright © 2003 John Wiley & Sons, Ltd.
The Pliocene to Early Pleistocene marine to fluviatile succession of the Seuil du Cotentin basins (Armorican Massif, Normandy, France)
Authors: Dugué Olivier
Published: June 2003

Marine and fluvial Plio‐Pleistocene deposits of the Seuil du Cotentin, western Normandy range in age from Late Pliocene to Early Pleistocene. They are preserved in small Cenozoic grabens and are divided into six new formations based on lithology, granulometry, sedimentary structures and associated fossils. The depositional environments of these formations change from marine to fluviatile and represent two transgression–regression cycles. This paper outlines the detailed stratigraphical relationships of the western Normandy Plio‐Pleistocene succession and discusses its correlation with the adjacent eastern area in the Seine River valley (France), in Cornwall and in the southern North Sea basin (East Anglia, Belgium, The Netherlands). Copyright © 2003 John Wiley & Sons, Ltd.
Pleistocene marine and periglacial deposits of the English Channel
Authors: Bates Martin R. , Keen David H. , Lautridou Jean‐Pierre
Published: June 2003

The Pleistocene marine and associated periglacial deposits of the coasts of southern England from Cornwall to Sussex, the British Channel Islands, and northern France from Brittany and Normandy to the Pas de Calais are described. The deposition of almost all marine deposits is ascribed to temperate conditions, although large igneous erratic boulders may have been emplaced by shore‐ice rafting at the end or beginning of cold stages. The balance of the evidence from a variety of dating methods including U‐series dating, amino‐acid geochronology and biostratigraphy of associated terrestrial formations indicates that deposits of the last three pre‐Holocene temperate marine oxygen isotope stages (stages 9, 7 and substage 5e) can readily be identified along much of both coastlines of the Channel. Deposits attributable to stages 11 and 13 are uncommon and best seen in the staircase of marine terraces backing the Hampshire–Sussex coastal plain and perhaps in western Brittany and the Boulonnais. The height above modern sea‐level of the marine deposits is thought to be the result of slow uplift of the coastal zone caused by the isostatic response to sediment unloading during accelerated phases of erosion in cold stages, although deep‐seated tectonics also may have been partly responsible for uplift. However, the height above modern sea‐level of a deposit alone is not on its own an indicator of age.

Periglacial head deposits are mainly exposed along the coasts, with the sections showing frost shattered debris moved downslope by cryoreptation (frost‐creep). The age of these deposits is uncertain, although they appear to be principally of marine oxygen isotope stages 4 and 2 in age. Some remnants of marine oxygen isotope stage 6 or 8 head deposits are present both in England and northern France. In a few places with good dating control, head deposits dating to the marine oxygen isotope stage 12 can be recognised. The age of the head deposits in most sections is based on their stratigraphical relationship with loess, palaeosols and on the dating of the underlying raised beaches. Copyright © 2003 John Wiley & Sons, Ltd.
Recent advances in the understanding of Quaternary periglacial features of the English Channel coastlands
Authors: Murton Julian B. , Lautridou Jean‐Pierre
Published: June 2003

Recent advances in the understanding of Quaternary periglaciation of the English Channel coastlands concern laboratory modelling of periglacial processes, dating of periglacial sediments and the distribution of permafrost during marine oxygen isotope stage (MOIS) 2. Modelling studies have successfully simulated (i) ice segregation in chalk in artificial permafrost, (ii) periglacial solifluction of natural slope sediments, and (iii) soft‐sediment deformation during thaw of ice‐rich soil. The resultant structures and deposits in these experiments have similarities with naturally brecciated chalk, solifluction deposits and involutions, respectively, along the English Channel coastlands, providing insights into their genesis and palaeoenvironmental significance.

Dating of periglacial sediments is based on radiocarbon assays of organic material in head deposits, luminescence measurements of loess and coversand, and mammalian biostratigraphy in raised‐beach and associated slope deposits. Most age estimates fall within MOIS 2, although some are within MOIS 6 and possibly other cold stages.

Maps reconstructing the distribution of permafrost during MOIS 2 vary in detail. The precise distribution of permafrost remains to be established owing to problems of (i) imprecise dating in the context of climatic instability, (ii) uncertain palaeoclimatic significance of particular periglacial structures and (iii) sparse data on the age and distribution of relict periglacial features.

The wider significance of periglacial processes to the evolution of the Channel coastlands is speculated to involve rapid valley development by flowing water in areas of moist, frost‐susceptible bedrock that has been brecciated by ice segregation. Copyright © 2003 John Wiley & Sons, Ltd.
The Neogene and Quaternary Clay‐with‐flints north and south of the English Channel: comparisons of distribution, age, genetic processes and geodynamics
Authors: Quesnel Florence , Catt John , Laignel Benoît , Bourdillon Chantal , Meyer Robert
Published: June 2003

Weathered residual accumulations termed Clay‐with‐flints (Argiles à silex) overlying Cretaceous deposits are widespread in southern England and northwestern France. Geological and pedological studies and some field surveys indicate their distribution, nature, age and origin. In France, the microfaunas preserved in the hollow flints of the Clay‐with‐flints demonstrate the preservation of the parent Chalk stratigraphy in the sections studied, i.e. the Clay‐with‐flints corresponds to in situ weathering profiles. However, in England and in France, an important part of the clay component is derived from a thin veneer of basal Tertiary sediment overlying sub‐Tertiary marine erosion surfaces of various Palaeogene transgressions. In England as in France, the youngest generation of Clay‐with‐flints can be dated from Late Pliocene to Quaternary. It formed after removal of different Cenozoic deposits on many plateaus and during the downcutting of Pleistocene rivers. The most visible effect of subsequent weathering profile development is irregular dissolution of the underlying Chalk to produce deep karstic pipes into which the Clay‐with‐flints has slumped; other pedological processes include rubification, clay illuviation and cryoturbation. Clay‐with‐flints also provides evidence of Quaternary palaeoenvironments, Cenozoic continental palaeosurfaces, and their vertical deformation. Copyright © 2003 John Wiley & Sons, Ltd.
The ‘Fleuve Manche’: the submarine sedimentary features from the outer shelf to the deep‐sea fans
Authors: Bourillet Jean‐François , Reynaud Jean‐Yves , Baltzer Agnès , Zaragosi Sébastien
Published: June 2003

Bathymetric, seismic and coring surveys have been carried out since the beginning of the 1990s on the outer shelf, the slope and the continental rise of the Western Approaches margin. Most of the sedimentary features studied belong to a sedimentary system built up since the Oligocene and fed by a palaeoriver, the ‘Fleuve Manche’ that flowed in the English Channel during eustatic lowstands. A geomorphological map details the spatial distributions of the palaeovalleys on the outer shelf, the drainage‐basin‐like organised canyons on the slope and the channel–levee and lobe complexes on the rise. The obvious channel–canyon connections and the assessed palaeovalley–canyon links demonstrate that the ‘Fleuve Manche’ was the single source for terrigeneous fluxes of the Armorican Deep Sea Fan when it was one of two sources of the Celtic Deep Sea Fan. Amongst parameters controlling the sedimentation, two factors play a major role. (i) Subsidence controlled the possibly Messinian riverine incision, the turbidite activities during lowstands, as well as marine infilling of the seawards part of the ‘Fleuve Manche’. (ii) Quaternary sedimentary supplies were influenced by the melting ice‐sheets and the connections with the onshore catchment basins. Copyright © 2003 John Wiley & Sons, Ltd.