bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Word Processing and Short‐term Memory Deficits on Verbal Learning: Evidence from Aphasia
Authors: Martin Nadine , Saffran Eleanor M.
Published: July 2002

We report two experiments that investigate the abilities of aphasic subjects with lexical and short‐term memory impairments to learn supraspan lists of 10 words. We examined effects of stimulus factors (characteristics of words and lists to be learned) and subject factors (verbal and nonverbal STM span, nature of language impairment). Learning ability was influenced by the imageability and frequency of the words to be learned (Experiment 1) and by the linguistic relationship among words in a list (Experiment 2). Additionally, learning ability was affected by the nature of a subject's word processing deficit (whether it involved semantic and/or phonological processes). Phonological ability was positively associated with learning in both experiments, and semantic ability was associated with learning when words in a list were high in both frequency and imageability (Experiment 1) or were contextually related to one another (Experiment 2). Finally, verbal STM span was positively related to learning performance, but the effect was more pronounced for word span than digit span. These relationships among word processing ability, verbal STM span, and learning ability are discussed with reference to learning in aphasia and to models of learning more generally.
The Effects of Region on the Welfare and Monetary Income of Spanish Families
Authors: García Inmaculada , Molina José Alberto
Published: July 2002

In this paper, we carry out a regional study aimed at measuring the effects of different regions on the welfare and income of Spanish families. This has, in turn, allowed us to calculate the inequality in welfare and income that exists between these households. The results confirm the relation between welfare and monetary income for those Spanish households in which both spouses work. Furthermore, we find that the welfare level in the east and Madrid regions is higher than elsewhere, with the lowest welfare level being found in the south. The comparison between regions allows us to rank them from the lowest to the highest welfare levels, with this ranking adopting the order north, centre, east, south and Madrid.
Negotiating about the Residential Environment: It is Not Only Money that Matters
Authors: Verhage Roelof , Needham Barrie
Published: July 2002

In the housing development process, negotiations take place between public and private parties about who is going to finance projects that should improve residential quality. In this paper, an analytical framework is developed for understanding these negotiations in different forms which the development process can take. Part of the expenditure on the residential environment is fixed by quality standards. Another part is directly related to the development: the developer pays for the 'on-site' services. Both forms of expenditure can be seen as costs. They influence the development gain remaining. Projects aimed at increasing the residential quality have to be paid out of this remaining gain (i.e. they do not raise the price of the housing). Therefore, the negotiations are about the use of the development gain. For the outcome of these negotiations, three things are of central importance: How much money is available? Who has the money? And who has power to influence the use to which the money is put? This is illustrated by a comparison of the development process in Great Britain and the Netherlands. The value of the framework is demonstrated by applying it to recent changes in the Netherlands.
Conceptualising Computer Use in Education: Introducing the Computer Practice Framework (CPF)
Authors: Twining Peter
Published: July 2002

Abstract There is a growing need to be able to enhance the impact of investing in computer use in education at all levels. The article suggests that one way to approach this problem is through looking at the impact of such investments on educational practice. This necessitates the use of a coherent framework for conceptualising the educational practice surrounding computer use. A number of important problems with existing frameworks for thinking about the educational practice surrounding computer use are identified and a set of criteria for evaluating such frameworks is presented. A new framework, the Computer Practice Framework (CPF), is then described and its scope and limitations are discussed in the light of these evaluation criteria.
Adventures of Feminism: Simone de Beauvoir's Autobiographies, Women's Liberation, and Self-Fashioning
Authors: Curthoys Ann
Published: July 2002

While The Second Sex is usually taken as Simone de Beauvoir's major theoretical contribution to feminism, in the 1960s and 1970s it was very often through her autobiographies – especially Memoirs of a Dutiful Daughter, The Prime of Life, and Force of Circumstance, along with novels such as She Came to Stay and The Mandarins – that her feminist ideas were most thoroughly absorbed. The autobiographies became nothing less than a guide for the fashioning of a new kind of feminine self. Where The Second Sex had intimated that a significant aspect of human liberation lay in women not losing their identity or their sense of self in those of men, it was the autobiographies which suggested and demonstrated in great detail how this might be done. In them, the rejection of conventional marriage and children was no mere slogan, but the foundation of what seemed to young female readers to be a fascinating and challenging life. In this paper, I reflect on de Beauvoir and her historical and contemporary relevance: first through reminiscence and re-reading of the autobiographies themselves; then with an historical examination of how they were read, taking Sydney, Australia, as my example; and finally by offering some reflections on subsequent feminist critique.
Contextualizing the Construction and Social Organization of the Commercial Male Sex Industry in London at the Beginning of the Twenty-first Century
Authors: Gaffney Justin , Beverley Kate
Published: July 2002

Feminist theories are concerned to analyse how women can transform society so that they are no longer subordinated, by understanding how patriarchal relations control and constrict them.

(Abbott and Wallace, 1997: 284)

Feminisms start from the position that women are oppressed within a society, which is patriarchal and socially constructed within knowledge which is malestream. This traditionally defines men such that they are rendered subordinate, within a social world constructed by men. Feminisms are engaged with making transparent patriarchal constructs, and illuminating the ‘spaces’ within which women-realities can become more visible.

This paper presents research undertaken by two key services working with male sex workers in central London. The insights gained from this research are discussed, as they allow comparison between the traditionally subordinate position of women and the contextual experiences of the ‘hidden’ population of male sex industry workers. It demonstrates, that like women, for male sex workers, hegenomic and heterosexist constructs ensure that they also occupy a subordinated position within society.
Masculinity and the Dance of the Dragon: Reading Lovelace Discursively
Authors: Lewis Linden
Published: July 2002

The exploration and examination of the construction of masculinity is increasingly emerging as an integrated part of the study of gender in society in general, and in the Caribbean in particular. We are constantly in search for new sources of material which tell us about the ways in which men construct their masculinity in Caribbean society. In this paper I draw on the imagery and ideas provided by the literary text. I interrogate the novel The Dragon Can't Dance, written by Trinidadian novelist Earl Lovelace. The writer uses the metaphor of the dragon, the costume donned by the main protagonist Aldrick in the yearly Carnival masquerade, as a mask which disguises the need for Aldrick to confront his own masculinity under poor, urban conditions in Trinidad. In the struggles and confrontations between urban working–class men and women in the community of Calvary in Trinidad, the novelist teases out the different constructions of masculinity in the various characters he portrays. I explore the novel, focusing particularly on the ways in which this construction is embedded in the struggles over issues of identity, ethnicity, reputation and honor. While the novelist is clearly able to read into the mind of the male in society, his renditions of the female are not so incisive. However, this is not a shortcoming as the women, though not as well-rounded characters in the novel, play key roles in the definition and shaping of masculinities. This reading of the novel illustrates that the literary text suggests itself as a critical site for further explorations of the illusive data on gender and especially that on masculinity.
Feminist Recoveries in My Father's House
Authors: Clegg Christine
Published: July 2002

One of the achievements of feminist politics, in a range of disciplines and practices, has been to secure a hearing for traumatic narratives of incest. Recently, however, the debate in the public domain seems overwhelmed by what has come to be known as ‘the memory wars’. Fathers accused by adult daughters have dismissed the possibility that traumatic childhood memories can be recovered, largely on the grounds of science and reason. This response of accused fathers would seem to drive out other ways of reading and interpreting the traumatic histories of the cultures we inhabit. On the other hand, feminist responses to narratives of incest are complicated by the desire for appropriate endings. Taking Sylvia Fraser's autobiography, My Father's House: A Memoir of Incest and Healing (1989, 1992) as an exemplary text, this article explores the difficult implications for adult women who commit to literary writing their memories of incest. In particular, how can feminism respond to an incest survivor who wants to forgive her father?
Sexual Abuse and Troubled Feminism: A Reply to Camille Guy
Authors: Atmore Chris
Published: July 2002

In a recent issue of Feminist Review Camille Guy argued, focusing on selected controversies in New Zealand and Australia, that radical feminists have had a prescriptive hegemony in defining issues of sexual abuse, and that this has resulted in injustices and a censorious climate in which people who disagreed were too intimidated to speak out. This article replies to Guy's assertions and, while disagreeing with much of her argument, also suggests that it does point to more broadly sig-nificant issues for feminists trying to analyse and oppose sexual violences at the end of the twentieth century. These include the legacy of the western feminist sex wars in a frequently polarized set of approaches to sexual abuse controversies, and the usefulness of postmodern/poststructuralist theories in helping feminists to make sense of the increasing complexities of the relationship between the mass media and feminist discourses against rape and child sexual abuse.
Social group membership and perceptions of the self in Northern Irish children
Authors: Muldoon Orla T. , Trew Karen
Published: July 2002

Social disadvantage and minority group membership are believed to have an adverse effect on the development of the self-concept. However, the exact effects of such factors on children’s self-competence and self-esteem are still subject to debate, with some authors arguing that it is not until later in life that the adverse psychological effects of social disadvantage become apparent. This study therefore examined the relationship between gender, ethnicity, socioeconomic status (SES), and age on self-competence and self-esteem in childhood. Eight- to eleven-year-old children ( N = 689) completed the Harter Self-Perception Profile for Children (Harter, 1985) and the results were analysed using MANOVA. Substantial gender differences in self-perceptions across several domains, including global self-esteem, were evident. The analysis also indicated that children of lower SES and from the Roman Catholic (minority) community in Northern Ireland had significantly less positive self-perceptions than middle SES and Protestant (majority group) children in a range of domains. These differences, however, were generally only evidenced at ages 10 and 11. Discussion of these results highlights the influence of group memberships on children’s social development, particularly at the preadolescent stage, and points to the need to consider the combined effects of psychosocial identities and socioeconomic background on the development of self-perceptions.
Measuring it Core Capabilities for Electronic Commerce
Authors: van der Heijden Hans
Published: July 2002

This paper reports on the theoretical development and empirical validation of a measurement instrument for three information technology (IT) core capabilities in an electronic commerce context. The instrument is based on the work of Feeny and Willcocks (1998) and includes the capabilities ‘information systems (IS)/IT governance’, ‘business system thinking’ and ‘relationship building’. It was validated using a sample consisting of 179 respondents, all of whom were IT managers or chief information officers. The results demonstrate that the constructs are reliable (a coefficients > 0.8) and valid. A confirmatory factor analysis on the data set yielded a moderately acceptable model fit. The model also demonstrated highly significant factor loadings (p > 0.001). The paper shows that a respecification of a competing model in which IS/IT governance is split into ‘business IT strategic thinking’ and ‘IT management’ provides better measures of fit. The paper concludes that the core capabilities of IT departments are useful constructs for incorporating into future research. They are successfully able to predict behaviours that have relatively little overlap. Recommended further research includes the relationship between capabilities and governance structures as well as further investigation into how IT core capabilities are formed and strengthened in organizations.
Cultural Influences on it use Amongst Factory Managers: A UK-Japanese Comparison
Authors: Kambayashi Norio , Scarbrough Harry
Published: July 2002

This paper seeks to analyse the influence of national cultural factors on the use of information technology (IT) by managers. An analysis of the existing literature on the interplay between technology, culture and organizational context indicates that the influence of national culture needs to be carefully specified if it is to be differentiated from institutional and organizational factors. Moreover, insofar as such influence operates at all, it is subsumed within, and not exterior to, a dynamic and emergent process of interaction between technology design and organizational practices. In this light, the study presented here seeks to avoid a simplistic approach in which national culture is viewed as an exogenous force directly conditioning action, but rather posits such influence as a critical element of the wider context which enframes action. These considerations were reflected in the research design of the empirical study presented here. This involved a survey of managers in over 1400 firms across five industrial sectors in the UK and Japan. These countries were chosen because previous studies had indicated that they exhibit distinctive cultural differences in their management practices. By conducting a large-scale survey across a range of sectors, the study aimed to abstract the diffuse effect of these cultural differences from the specific impact of sectorial and organizational contingencies. In particular, questions within the survey sought to explore the extent to which managerial preferences and practices in IT use could be interpreted in terms of two key dimensions of national cultural difference. The latter were operationalized in this study as a control orientation to IT use, and an individualistic orientation to IT use, respectively. The overall analysis of the survey data suggests that the effect of national culture is significant and seems to operate across industry boundaries. Managers in Japanese factories do in fact exhibit the hypothesized stronger orientation towards a control orientation in the use of IT, while managers in British factories show a relatively stronger orientation towards individualistic use of IT at the management level.
The effects of real price and a change in the distribution system on alcohol consumption
Authors: ZHANG JIA‐FANG , CASSWELL SALLY
Published: July 2002

Time–series analysis of alcohol consumption data has shown an impact of real price on alcohol consumption in NZ in the decade 1984–96. Beer consumption was reduced by real price increases and wine consumption was increased by real price decreases. By contrast, during this period spirits were price inelastic. A further influence on alcohol consumption was the introduction of wine into grocery stores, which led to a sudden permanent increase in wine consumption 3 months after the legislation came into force. Beer and spirits were not introduced into supermarkets at this time and while there was no effect on beer consumption there was a significant decrease in spirits consumption. [Zhang J‐F, Casswell S. The effects of real price and a change in the distribution system an alcohol consumption. Drug Alcohol Rev 1999; 18: 371–378]
Lipopolysaccharide and silica‐stimulated mononuclear cell prostaglandin production in ulcerative colitis
Authors: Punchard Neville A. , Cason John , Mullins Jonathan , Chander Chaman , Thompson Richard P. H.
Published: July 2002

Basal, lipopolysaccharide (LPS) and silica‐stimulated prostaglandin (PG) production were compared between peripheral blood mononuclear cells (PBMNC) from UC patients and healthy subjects (HS). Basal and LPS‐stimulated PBMNC PGI2, but not PGE2, production was greater in UC. LPS stimulated both PGE2 and PGI2 by PBMNC from HS and UC patients. Silica stimulated production of both PGs by cells from HS but only
PGE2 by cells from UC patients. The differences in responses to silica and LPS may result from differences in activation of NFκB or, alternatively, prior sensitisation to one of these agents. That PBMNC PGE2 production is not increased in UC, as it is in Crohn’s disease, suggests that there are differences in PBMNC behaviour between these two diseases.
Administration of isoferulic acid improved the survival rate of lethal influenza virus pneumonia in mice
Authors: Sakai Shinya , Ochiai Hiroshi , Mantani Naoki , Kogure Toshiaki , Shibahara Naotoshi , Terasawa Katsutoshi
Published: July 2002

Background: Isoferulic acid (IFA) is a main active ingredient of the rhizoma of Cimicifuga heracleifolia, which is used frequently in Japanese traditional medicine as an anti‐inflammatory drug. It has been revealed that IFA inhibits the production of macrophage inflammatory protein‐2 (MIP‐2), which is a murine counterpart of the chemokine family that may contribute to the pathogenesis of inflammatory diseases through the chemotactic activity for inflammatory and immune effector cells.

Aim of the study: In this study, we investigated the therapeutic effect of IFA on the progression of lethal influenza virus pneumonia in mice by comparison with that of dexamethasone (DX), a potent inhibitor for various inflammatory cytokines including MIP‐2.

Methods: Mice were infected by intranasal inoculation of influenza virus under ether anesthesia. The IFA or DX was given by oral administration once daily for 4 days after infection. After infection, the survival rate and the change in body weight were daily monitored.

Results: IFA administration markedly improved the survival rate and body weight loss of influenza virusinfected mice in a suitable dose range (0.5 mg/day). However, DX administration did not show a beneficial effect at any dose.

Conclusion: These data suggested that IFA is a novel tool not only for the intervention therapy, but also for the studies on the pathogenesis of influenza virusinduced pneumonia.
Cancer immunotherapy: potential involvement of mediators
Authors: Ben-Efraim S.
Published: July 2002

The description of a cell‐free soluble anti‐tumour factor by Carswell et al. in 1975 (Proc Natl Acad Sci USA, 72: 3666–3670) was followed by a long series of experimental and clinical investigations into the role of cell‐free mediators in cancer immunotherapy. These investigations included research on the effects of macrophage–derived eicosanoids (cycloxygenase and lipoxygenase derivates of arachidonic acid) and of monokines such as tumour necrosis factor‐α, interleukin‐1 and granulocyte–monocyte–macrophage–colony stimulating factor) and of lymphocyte products: interleukins and interferons. The investigations yielded information on the effects of various factors on macrophage and T‐cell activation in vitro, determination of direct anti‐tumour properties on animal and human tumour cells in vitro and on therapeutic effectiveness in tumour‐bearing individuals either alone or in combination with other therapeutic factors and their production by tumour cells. During recent years much effort has been dedicated towards the use of the tumour cells transfected with cytokine genes in the preparation of cancer vaccines. Cycloxygenase products (prostaglandins) were usually assumed to inhibit expression of anti‐tumour activity by macrophages and an increase in their production in cancer patients was considered as a poor prognostic index. Lipoxygenase (leukotrienes) products were assumed to exhibit antitumour activity and to induce production of IL‐1 by macrophages. Interleukins 2, 4, 6, 7, 12 and the interferons were extensively tested for their therapeutic effectiveness in experimental tumour models and in cancer clinical trials. The general conclusion on the use of cell‐free mediators for cancer immunotherapy is that much still has to be done in order to assure effective and reproducible therapeutic effectiveness for routine use in the treatment of human neoplasia.
Decreased levels of serum platelet‐activating factor acetylhydrolase in patients with rheumatic diseases
Authors: Vergne P. , Praloran V. , Treves R. , Denizot Y.
Published: July 2002

PAF is a potent inflammatory compound known to stimulate the release of various cytokines involved in rheumatic diseases. Elevated blood PAF levels are reported in these patients. We report that serum PAF acetylhydrolase activity (AHA) levels are decreased in patients with rheumatoid arthritis or osteoarthritis as compared to healthy controls. Serum and synovial fluid AHA levels were correlated in these patients. The present study suggests the potential role of AHA in controling systemic and/or local PAF levels in patients with rheumatic diseases.
The effect of interleukin‐10 and transforming growth factor β‐1 on HLA‐DR expression in colonic epithelial cells
Authors: Zimmerman M. J. , Radford-Smith G. R. , Jewell D. P.
Published: July 2002

The aim of this study was to assess whether interleukin‐10 (IL‐10) and/or transforming growth factor β‐1 (TGF β1) downregulate HLA‐DR expression using the HT29 cell line as a model of colonic epithelial cells. HLA‐DR expression was induced in HT29 cells with γ‐interferon. The effects of IL‐10 alone, TGF β1 alone, and IL‐10 and TGF β1 in combination were studied. HLA‐DR expression was assessed using flow cytometric analysis. γ‐Interferon induced HLA‐DR expression in a dose‐dependent fashion. In the absence of γ‐interferon, neither IL‐10 nor TGF β1 induced HLA‐DR expression. In isolation, neither IL10 nor TGF β1 downregulated HLA‐DR expression. When IL‐10 and TGF β1 were added in combination, small (6‐30%) statistically significant reductions in HLA‐DR expression were seen. The biological significance is unclear.
Role of the epithelial layer in the generation of superoxide anion by the guinea‐pig isolated trachea
Authors: Sadeghi-Hashjin G. , Henricks P. A. J. , Folkerts G. , Muis T. , Garssen J. , Nijkamp F. P.
Published: July 2002

The lucigenin‐dependent chemiluminescence generation by guinea‐pig isolated tracheal two rings preparations was studied. Tracheal preparations stimulated with phorbol myristate acetate (PMA) or opsonized zymosan generated chemiluminescence. The total amount of chemiluminescence generated in 120 min was 754 ± 63 mV × min for PMA and 4832 ±396 mV × min for zymosan. Generation of chemiluminescence was decreased by more than 50% when the tissues were co‐incubated with superoxide dismutase (100 U/ml). Also, addition of direct donors of nitric oxide diminished chemiluminescence generation by zymosan‐activated tracheal rings significantly by about 50%. However, the presence of the precursor or of inhibitors of nitric oxide synthase did not influence zymosan‐induced chemiluminescence. Removal of the epithelial layer from tracheal rings caused an approximately 90% decrease in chemiluminescence response. However, isolated epithelial cell suspensions did not generate chemiluminescence. Histologic examination showed that the number of eosinophils in the tracheal tissue was reduced from 56 ± 7 to 18 ± 8 per mm basal membrane when the epithelial layer was removed. These results indicated that (1) superoxide anion formation can take place in the guinea‐pig trachea, (2) eosinophils in the epithelial and submucosal layers of guinea‐pig trachea are likely candidates for superoxide generation although other cell types can also be involved, and (3) besides relaxing airway smooth muscle, nitric oxide donors may also affect superoxide in the airways.
Serum Levels of IL‐6 Type Cytokines and Soluble IL‐6 Receptors in Active B‐Cell Chronic Lymphocytic Leukemia and in Cladribine Induced Remission
Authors: Robak T. , Wierzbowska A. , Błasińska-Morawiec M. , Korycka A. , Błoński J. Z.
Published: July 2002

We have investigated the serum concentrations of interleukin‐6 (IL‐6) and two IL‐6 family cytokines‐oncostatin M (OSM) and leukemia inhibitory factor (LIF)‐in 63 patients with B‐cell chronic lymphocytic leukemia (B‐CLL) and 17 healthy controls using the enzyme‐linked immunosorbent assay (ELISA) method. Simultaneously, we measured the serum levels of the soluble forms of two subunits of the IL‐6 receptor complex‐ligand binding glycoprotein 80 (sIL‐6R) and glycoprotein 130 (sgp130). The cytokines and receptors were evaluated in 25 untreated patients and 38 patients treated with cladribine (2‐CdA), as well as in 17 healthy controls. We have correlated the serum levels of these proteins with Rai′s clinical stage of the disease, the response to 2‐CdA treatment and some hematological parameters. We have also evaluated the correlation of the IL‐6 serum level with the concentration of OSM and IL‐6 soluble receptors. IL‐6 was measurable in 62/63 (98.4%), OSM in 20/25 (80%) of untreated and 14/38 (37.8%) of the treated patients. sIL‐6R and sgp130 were detectable in all 63 patients and LIF in none of the CLL patients. IL‐6 serum level in untreated patients was not significantly different as compared to its concentration in the control group (P > 0.05). However, in the patients treated with 2‐CdA the IL‐6 level was significantly lower (P < 0.02), and the lowest concentration was found in the patients with complete remission (CR; median 1.4 pg/ml; P < 0.02). The concentration of sIL‐6R was significantly higher in untreated (median 61.8 ng/ml) and treated (median 50.1 ng/ml) CLL patients when compared to normal persons (median 41.2 ng/ml; P = 0.04; P < 0.001, respectively). There was no difference between the sIL‐6R levels in the patients with CR and the healthy controls. In non‐responders sIL‐6R concentration was the highest and similar to its level in the untreated patients. OSM level was higher in the untreated patients (median 1.8 pg/ml) than in the normal controls (median 0.0 pg/ml; P < 0.001) and in the CR patients (median 0.0 pg/ml; P < 0.03). The serum concentration of sgp130 was similar in the untreated (median 480 pg/ml) and treated (median 470 pg/ml) patients, as well as in the healthy persons (median 420 pg/ml; P > 0.05). We have found significant positive correlation between the levels of sIL6R and the lymphocytes count in CLL patients (Ρ=0.423; P < 0.001). In addition, sIL‐6R and OSM serum concentrations correlated also with CLL Rai stage. In conclusion, the serum level of IL‐6, OSM and sIL‐6R, but not LIF and sgp130, are useful indicators of CLL activity.
A 12‐Year Follow‐Up of a Methadone Medical Maintenance Program
Authors: Schwartz Robert P. , Brooner Robert K. , Montoya Ivan D. , Currens Marian , Hayes Michael
Published: July 2002

Methadone Medical Maintenance (MDM) is an alternative for treatment of stable methadone maintained individuals. It involves a monthly physician's visit, at which methadone take‐home doses are dispensed to last until the next appointment. The safety and efficacy of this treatment modality is currently under investigation. The purpose of this study was to evaluate the long‐term safety and efficacy of MDM in a methadone program in Baltimore. A sample of 21 patients was enrolled in the study and followed for 12 years. They were evaluated once a month by a primary care physician affiliated with a methadone clinic who collected urine toxicology samples and dispensed the monthly methadone dose. The results showed that only 6 (28.6%) patients dropped out during the 12 years of the study. Twelve (0.5%) of 2,290 urine samples collected were positive for drugs. No methadone overdose or diversion was observed. Participants reported significant improvement in their quality of life. The results of this study support the safety and efficacy of medical maintenance of stable methadone maintained individuals.
The Disabling Nature of Comorbid Depression Among Older DUI Recipients
Authors: Oslin David W. , O'Brien Charles P. , Katz Ira R.
Published: July 2002

Alcoholism and depression are two of the most common and disabling mental illnesses in late life. This study is a descriptive report of a sample of 49 adults who had recently been convicted of Driving Under the Influence of alcohol (DUI). A lifetime history of alcohol abuse or dependence was present in 48 subjects (98%), while a depressive disorder occurred in 24 (49%) of the subjects. Concurrent alcoholism and depression, present in 12 subjects (24.5%), produced greater self‐reported disability compared to those subjects with alcoholism alone. One‐year longitudinal follow‐up was available on 31 subjects (63.3%). Over the course of one year, there were no changes in drinking behavior, depressive symptoms, or self‐reported quality of life. These data support previous studies that suggest greater disability inpatients with concurrent mental illnesses.
Preventing disulfiram hepatitis in alcohol abusers: inappropriate guidelines and the significance of nickel allergy
Authors: BREWER COLIN , HARDT FINN
Published: July 2002

Disulfiram hepatitis, although sometimes fatal, is a very rare complication of alcoholism treatment. A disproportionate number of cases are associated with disulfiram treatment for nickel allergy and unrecognized nickel sensitivity may partly explain the surprisingly high proportion of female victims‐ about 60%. US guidelines formulated in 1988 suggest that alcoholic patients should not be started on disulfiram unless liver toxicity tests have been done and, if elevated, returned to normal. This advice is unsound and contrasts with medical attitudes to the prevention of other rare side effects. It has led to significant delays in starting treatment which are probably much more hazardous than the very slight risks of hepatotoxicity. We recommend that the guidelines be modified in favour of an approach which emphasizes the education of patients and their carers and clinical rather than laboratory monitoring.
Retroperitoneal Sarcoma With Infected Necrosis: An Unfavourable Prognostic Factor
Authors: Spillane Andrew J. , Thomas J. Meirion
Published: July 2002

Purpose. To report the phenomenon of infected retroperitoneal sarcoma (RPS).

Method. Two case reports.

Results. Both patients died soon after laparotomy.

Discussion. Infected RPS is identified as an entity not clearly documented in the literature. It should probably be added to the list of poor prognostic factors when planning the management of patients with RPS.
Pulmonary Tumour Embolism Complicating a Case of Leiomyosarcoma
Authors: Gentle Stephen , Fisher Cyril , Soni Neil , Hill Sue , Thomas J. Meirion
Published: July 2002

Patient. A case of peripheral leiomyosarcoma presenting with features of pulmonary thromboembolism is described.

Discussion. Persistence of the embolus despite triple‐armed thrombolytic therapy and the presence of intravascular tumour invasion suggest the rare entity of pulmonary tumour embolism from a leiomyosarcoma.
Progress in the Molecular Biology of Ewing Tumors
Authors: Kovar Heinrich
Published: July 2002

Purpose/results/discussion. Rearrangement of the EWS gene with an ETS oncogene by chromosomal translocation is a hallmark of the Ewing family of tumors (EFT). Detectability, incidence, tumor specificity and variability of this aberration have been matters of intense investigation in recent years. A number of related alterations have also been found in other malignancies. The common consequence of these gene rearrangements is the generation of an aberrant transcription factor. In EFT, the ETS partner is responsible for target recognition. However, synergistic and possibly tissue‐restricted transcription factors interacting with either the EWS or the ETS portion may influence target selection. Minimal domains of both fusion partners were defined that have proved necessary for the in vitro transformation of murine fibroblasts. These functional studies suggest a role for aberrant transcriptional regulation of transforming target genes by the chimeric
transcription factors. Also, fusion of the two unrelated protein domains may affect overall protein conformation and consequently DNA binding specificity. Recent evidence suggests that EWS, when fused to a transcription factor, interacts with different partners than germ‐line EWS. Variability in EWS–ETS gene fusions has recently been demonstrated to correlate with clinical outcome. This finding may reflect functional differences of the individual chimeric transcription
factors. Alternatively, type and availability of specific recombinases at different time‐points of stem cell development or in different stem cell lineages may determine fusion type. Studies on EFT cell lines using EWS–ETS antagonists do suggest a rate‐limiting essential role for the gene rearrangement in the self‐renewal capacity of EFT cells. The presence of additional aberrations varying in number and type that may account for immortalization and full transformation is
postulated. Knowledge about such secondary alterations may provide valuable prognostic markers that could be used for treatment stratification.
Oncogenic Osteomalacia as a Harbinger of Recurrent Osteosarcoma
Authors: Lamont Elizabeth B. , Cavaghan Melissa K. , Brockstein Bruce E.
Published: July 2002

Discussion. Oncogenic osteomalacia is a rare paraneoplastic syndrome
of skeletal demineralization from renal phosphate loss. Patients with this disorder have the
characteristic clinical, laboratory, and radiographic findings of hyperphosphaturic
osteomalacia. Although the pathophysiology has not yet been clearly delineated, a humoral
factor produced by the tumor is suspected to be the cause.

Purpose. We report the first case of oncogenic osteomalacia that
improved with chemotherapy, discuss this paraneoplastic syndrome, and review the
medical literature regarding its etiology.
Clear Cell Chondrosarcoma of Bone
Authors: Ayoub Khalid S. , Grimer Robert J. , Carter Simon R. , Mangham David C. , Davies A. M. , Tillman Roger M.
Published: July 2002

Purpose. Clear cell chondrosarcoma is a rare variant of chondrosarcoma. Six cases
are herein reported.

Subjects. We have treated six patients with clear cell chondrosarcoma in the past 28
years, representing 1.6% of all chondrosarcomas seen in this time period.

Results and Discussion. Half the patients had been initially underdiagnosed and
inappropriately treated.

Conclusions. Our results and our review of the literature highlight the fact that
inadequate initial treatment leads to a high rate of both local recurrence and
metastasis whilst wide initial excision is usually curative.
Sites of Binding and Orientation in a Four‐Location Model for Protein Stereospecificity
Authors: Mesecar Andrew D. , Koshland Daniel E.
Published: July 2002

The stereospecificity of the enzyme isocitrate dehydrogenase was examined by steady‐state kinetics and x‐ray crystallography. The enzyme has the intriguing property that the apoenzyme in the absence of divalent metal showed a selectivity for the inactive l‐enantiomer of the substrate isocitrate, whereas the enzyme containing magnesium showed selectivity for the physiologically active d‐enantiomer. The hydrogen atom on the C2 carbon that is transferred during the reaction was, in both the d‐ and l‐isocitrate complexes, in an orientation very close to that expected for delivery of a hydride ion to the cosubstrate NADPT+. The beta‐carboxylate that is eliminated as a CO2 molecule during the reaction occupied the same site on the protein in both the d‐ and l‐isocitrate complexes. In addition, the C3 carbon was in the same protein site in both the d‐ and l‐enantiomers. Only the fourth group, the OH atom, was in a very different position in the apo enzyme and in the metal‐containing complexes. A four‐location model is necessary to explain the enantiomeric specificity of IDH in contrast to the conventional three‐point attachment model. The thermodynamic and kinetic ramifications of this model are explored.
Direct Pathway from Early/Recycling Endosomes to the Golgi Apparatus Revealed through the Study of Shiga Toxin B-fragment Transport
Authors: Mallard Frédéric , Antony Claude , Tenza Danièle , Salamero Jean , Goud Bruno , Johannes Ludger
Published: July 2002

Shiga toxin and other toxins of this family can escape the endocytic pathway and reach the Golgi apparatus. To synchronize endosome to Golgi transport, Shiga toxin B-fragment was internalized into HeLa cells at low temperatures. Under these conditions, the protein partitioned away from markers destined for the late endocytic pathway and colocalized extensively with cointernalized transferrin. Upon subsequent incubation at 37°C, ultrastructural studies on cryosections failed to detect B-fragment–specific label in multivesicular or multilamellar late endosomes, suggesting that the protein bypassed the late endocytic pathway on its way to the Golgi apparatus. This hypothesis was further supported by the rapid kinetics of B-fragment transport, as determined by quantitative confocal microscopy on living cells and by B-fragment sulfation analysis, and by the observation that actin- depolymerizing and pH-neutralizing drugs that modulate vesicular transport in the late endocytic pathway had no effect on B-fragment accumulation in the Golgi apparatus. B-fragment sorting at the level of early/recycling endosomes seemed to involve vesicular coats, since brefeldin A treatment led to B-fragment accumulation in transferrin receptor–containing membrane tubules, and since B-fragment colocalized with adaptor protein type 1 clathrin coat components on early/recycling endosomes. Thus, we hypothesize that Shiga toxin B-fragment is transported directly from early/recycling endosomes to the Golgi apparatus. This pathway may also be used by cellular proteins, as deduced from our finding that TGN38 colocalized with the B-fragment on its transport from the plasma membrane to the TGN.
Integration of Endothelial Cells in Multicellular Spheroids Prevents Apoptosis and Induces Differentiation
Authors: Korff Thomas , Augustin Hellmut G.
Published: July 2002

Single endothelial cells (EC) seeded in suspension culture rapidly undergo apoptosis. Addition of survival factors, such as VEGF and FGF-2, does not prevent apoptosis of suspended EC. However, when cells are allowed to establish cell–cell contacts, they become responsive to the activities of survival factors. These observations have led to the development of a three-dimensional spheroid model of EC differentiation. EC spheroids remodel over time to establish a differentiated surface layer of EC and a center of unorganized EC that subsequently undergo apoptosis. Surface EC become quiescent, establish firm cell–cell contacts, and can be induced to express differentiation antigens (e.g., induction of CD34 expression by VEGF). In contrast, the unorganized center spheroid cells undergo apoptosis if they are not rescued by survival factors. The responsiveness to the survival factor activities of VEGF and FGF-2 was not dependent on cell shape changes since it was retained after cytochalasin D treatment. Taken together, these findings characterize survival factor requirements of unorganized EC and indicate that polarized surface EC differentiate to become independent of exogenous survival factors. Furthermore, they demonstrate that spheroid cell culture systems are useful not just for the study of tumor cells and embryonic stem cells but also for the analysis of differentiated functions of nontransformed cells.
Absence of Basement Membranes after Targeting the LAMC1 Gene Results in Embryonic Lethality Due to Failure of Endoderm Differentiation
Authors: Smyth Neil , Vatansever H. Seda , Murray Patricia , Meyer Michael , Frie Christian , Paulsson Mats , Edgar David
Published: July 2002

The LAMC1 gene coding for the laminin γ1 subunit was targeted by homologous recombination in mouse embryonic stem cells. Mice heterozygous for the mutation had a normal phenotype and were fertile, whereas homozygous mutant embryos did not survive beyond day 5.5 post coitum. These embryos lacked basement membranes and although the blastocysts had expanded, primitive endoderm cells remained in the inner cell mass, and the parietal yolk sac did not develop. Cultured embryonic stem cells appeared normal after targeting both LAMC1 genes, but the embryoid bodies derived from them also lacked basement membranes, having disorganized extracellular deposits of the basement membrane proteins collagen IV and perlecan, and the cells failed to differentiate into stable myotubes. Secretion of the linking protein nidogen and a truncated laminin α1 subunit did occur, but these were not deposited in the extracellular matrix. These results show that the laminin γ1 subunit is necessary for laminin assembly and that laminin is in turn essential for the organization of other basement membrane components in vivo and in vitro. Surprisingly, basement membranes are not necessary for the formation of the first epithelium to develop during embryogenesis, but first become required for extra embryonic endoderm differentiation.
Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo
Authors: Rogakou Emmy P. , Boon Chye , Redon Christophe , Bonner William M.
Published: July 2002

The loss of chromosomal integrity from DNA double-strand breaks introduced into mammalian cells by ionizing radiation results in the specific phosphorylation of histone H2AX on serine residue 139, yielding a specific modified form named γ-H2AX. An antibody prepared to the unique region of human γ-H2AX shows that H2AX homologues are phosphorylated not only in irradiated mammalian cells but also in irradiated cells from other species, including Xenopus laevis, Drosophila melanogaster, and Saccharomyces cerevisiae. The antibody reveals that γ-H2AX appears as discrete nuclear foci within 1 min after exposure of cells to ionizing radiation. The numbers of these foci are comparable to the numbers of induced DNA double-strand breaks. When DNA double-strand breaks are introduced into specific partial nuclear volumes of cells by means of a pulsed microbeam laser, γ-H2AX foci form at these sites. In mitotic cells from cultures exposed to nonlethal amounts of ionizing radiation, γ-H2AX foci form band-like structures on chromosome arms and on the end of broken arms. These results offer direct visual confirmation that γ-H2AX forms en masse at chromosomal sites of DNA double-strand breaks. The results further suggest the possible existence of units of higher order chromatin structure involved in monitoring DNA integrity.
The Pro-Apoptotic Proteins, Bid and Bax, Cause a Limited Permeabilization of the Mitochondrial Outer Membrane That Is Enhanced by Cytosol
Authors: Kluck Ruth M. , Esposti Mauro Degli , Perkins Guy , Renken Christian , Kuwana Tomomi , Bossy-Wetzel Ella , Goldberg Martin , Allen Terry , Barber Michael J. , Green Douglas R. , Newmeyer Donald D.
Published: July 2002

During apoptosis, an important pathway leading to caspase activation involves the release of cytochrome c from the intermembrane space of mitochondria. Using a cell-free system based on Xenopus egg extracts, we examined changes in the outer mitochondrial membrane accompanying cytochrome c efflux. The pro-apoptotic proteins, Bid and Bax, as well as factors present in Xenopus egg cytosol, each induced cytochrome c release when incubated with isolated mitochondria. These factors caused a permeabilization of the outer membrane that allowed the corelease of multiple intermembrane space proteins: cytochrome c, adenylate kinase and sulfite oxidase. The efflux process is thus nonspecific. None of the cytochrome c-releasing factors caused detectable mitochondrial swelling, arguing that matrix swelling is not required for outer membrane permeability in this system. Bid and Bax caused complete release of cytochrome c but only a limited permeabilization of the outer membrane, as measured by the accessibility of inner membrane-associated respiratory complexes III and IV to exogenously added cytochrome c. However, outer membrane permeability was strikingly increased by a macromolecular cytosolic factor, termed PEF (permeability enhancing factor). We hypothesize that PEF activity could help determine whether cells can recover from mitochondrial cytochrome c release.
β-Arrestin–Dependent Endocytosis of Proteinase-Activated Receptor 2 Is Required for Intracellular Targeting of Activated Erk1/2
Authors: DeFea K.A. , Zalevsky J. , Thoma M.S. , Déry O. , Mullins R.D. , Bunnett N.W.
Published: July 2002

Recently, a requirement for β-arrestin–mediated endocytosis in the activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2) by several G protein–coupled receptors (GPCRs) has been proposed. However, the importance of this requirement for function of ERK1/2 is unknown. We report that agonists of Gαq-coupled proteinase–activated receptor 2 (PAR2) stimulate formation of a multiprotein signaling complex, as detected by gel filtration, immunoprecipitation and immunofluorescence. The complex, which contains internalized receptor, β-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. However, ERK1/2 activity is retained in the cytosol and neither translocates to the nucleus nor causes proliferation. In contrast, a mutant PAR2 (PAR2δST363/6A), which is unable to interact with β-arrestin and, thus, does not desensitize or internalize, activates ERK1/2 by a distinct pathway, and fails to promote both complex formation and cytosolic retention of the activated ERK1/2. Whereas wild-type PAR2 activates ERK1/2 by a PKC-dependent and probably a ras-independent pathway, PAR2(δST363/6A) appears to activate ERK1/2 by a ras-dependent pathway, resulting in increased cell proliferation. Thus, formation of a signaling complex comprising PAR2, β-arrestin, raf-1, and activated ERK1/2 might ensure appropriate subcellular localization of PAR2-mediated ERK activity, and thereby determine the mitogenic potential of receptor agonists.