bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual Investors’ Sentiment and Temporary Stock Price Pressure
Authors: Chan Siu Y. , Fong Wai‐Ming
Published: July 2004

Using data for the Hong Kong stock market, where individual investors’ sentiment is likely to be influential, this study finds that the publication of individual investors’ sentiment temporarily affects stock prices regardless of the publication's incompetence in predicting stock returns. Specifically, when the publication reports that more and more investors are optimistic, the return on the day just after the publication is higher and the return several days later is lower. Furthermore, the results are strongest for small stocks, and weakest for large stocks. It seems that some individual investors buy (sell) stocks when others, as reported by the publication, are optimistic (pessimistic), and that the trading causes temporary buying (selling) pressure initially and price reversals afterwards.
Managing a Portfolio of Interdependent New Product Candidates in the Pharmaceutical Industry
Authors: Blau Gary E. , Pekny Joseph F. , Varma Vishal A. , Bunch Paul R.
Published: July 2004

Highly regulated industries such as pharmaceuticals and agrochemicals face the challenge of maintaining a 0continuous stream of new products. This is difficult because of low probabilities of technical success, high development costs, uncertain market impact, a scarcity of good new product ideas, and limited human and capital resources available to develop them. The problem of evaluating and selecting which new products to develop and then of sequencing or of scheduling them is complicated further by the presence of dependencies between products both in the market place and in the development process itself.

This study proposes a portfolio management approach that selects a sequence of projects, which maximizes the expected economic returns at an acceptable level of risk for a given level of resources in a new product development pipeline. A probabilistic network model of distinct activities is used to capture all the activities and resources required in the “process” of developing a new drug. A prioritization scheme suggesting sequences for developing new independent drug candidates with unlimited resources is generated with a conventional bubble chart approach. These sequences initiate a genetic algorithm (GA)‐based search for the optimal sequence in the presence of product dependencies and limited resources. By statistically evaluating the sequences generated during the GA search using a discrete event simulation model, it is possible to construct an economic reward‐risk frontier that illustrates the trade‐offs between expected rewards and risks. The model ideally is suited to answer various “what if” questions relative to changes in the resource level on pipeline performance.

The methodology is illustrated with an industrially motivated case study, involving nine interdependent new product candidates targeting three diseases. The dramatic results yield a candidate sequence with an expected return 28 percent higher than the sequence suggested by the bubble chart approach at almost the same level of risk. The synergism among the candidate dependencies, pipeline resources, and economic and technical uncertainties demonstrates the necessity of a computationally intensive approach if the best development strategy is to be realized.
Disruptive Technology Reconsidered: A Critique and Research Agenda
Authors: Danneels Erwin
Published: July 2004

The popular work by Clayton Christensen and colleagues on disruptive technology serves as a springboard to examine five key issues concerning the effect of technological change on firms and industries. This article challenges and integrates current theory in this domain, and raises questions to initiate new work. The discussion is organized around the following themes: the definition of disruptive technology, the predictive use of the theory of technological disruption, explaining the success of incumbents, the implications of the theory for the merits of being customer‐oriented, and the merits of creating a spin‐off to commercialize the disruptive technology. Examination of these themes shows the relationship of the disruptive technology work with research in a variety of related areas. Many of these links have not been made explicit before, and several of them have been misunderstood. This article is intended to encourage further research on disruptive technology and spur debate by practitioners and scholars alike.
Visualizing the Self: Exploring the Potential Benefits and Drawbacks for New Product Evaluation
Authors: Dahl Darren W. , Hoeffler Steve
Published: July 2004

This study examines the role of visual processing in new product evaluation. The primary goal of this research was to provide insights into the role of visualization content (self‐related versus others‐related images) in product evaluation as it differentially relates to two separate types of products—incremental products and really new products. This study's results show that for incremental products, visualizing with self‐related images (versus others‐related images) led to higher evaluations. In this context, it seems that familiarity with the product category from which an incremental product extension is generated enables individuals to produce images easily where they can see themselves using the new product. In some sense, self‐related visualization might be thought of as a form of surrogate experience with the new product. The ability to self‐reference during evaluation provides positive benefits to the evaluation outcome.

Contrasting this result, this study's findings showed that for really new product introductions the previously identified benefits of self‐visualization were not realized. Confirming this study's prediction, the advantage of self‐visualization over others‐related visualization was lost. This is attributed to consumer difficulty in visualizing the full application of a really new product to their current consumption behavior. Of further interest, this study's results also showed that in the case of really new products others‐related visualization facilitated higher evaluations than self‐visualization.

The mediating role of visualization‐based evaluation difficulty provides further explanation for these findings. Self‐related images are shown to be difficult to imagine in a really new product context, whereas imagining others utilizing the really new product is shown to be significantly easier. Perhaps individuals can see the benefits and better understand the novel applications of a really new product when visually simulating someone else using it but have more trouble imagining the applicability of the innovation in their own life. These findings are integrated into a discussion of the managerial implications and the potential avenues for future research in the area.
Organizational Learning and New Product Introductions
Authors: Michael Steven C. , Palandjian Tracy Pun
Published: July 2004

Organizational learning widely is believed to be important to competitive performance of companies. The purpose of this article is to examine how organizations learn from their experiences in new product introductions. Theory suggests that organizations will display a “competency trap” that reduces their ability to learn from organizational experience. Often initial success can cause a firm to rely on a single or a few experiences to develop routines, discounting later experiences. Therefore it is expected that organizations will have trouble learning from experience.

The theory was tested by examining all new product introductions in the U.S. shampoo industry from 1974–1987. The dynamic nature of the business—the average brand survives about two years—made this an attractive research venue. Using the econometric technique of survival time modeling, a model was fitted of survival of brands as a function of organizational experience and organizational experience squared. The model also included controls for financial resources available to the firm and the level of first year's advertising. The model confirmed the general hypothesis that firms' brands are less successful the more experience they have. This study interprets this as evidence of a competency trap in new product introductions.

The results broadly are supportive of the hypothesis that organizations find it harder to learn from experience as experience grows. Untangling the source of this problem is a goal of further research. For practice, the article suggests caution to brand managers in experienced companies. There is no guarantee that firms grow in their ability to build brands; results here suggest the opposite. Formal reviews of the new product, its process, and its performance by senior managers for lessons learned is desirable. Management of individuals and organizations may facilitate learning from experience. For managing individuals, often product success brings about a reassignment of successful personnel; care should be taken to insure that individuals' learning is captured by the new product organization before reassignment. On the organizational level, formal brand management may be a highly effective method for managing an ongoing stable of long‐lived brands but may be a poor choice in a dynamic market like shampoo. Companies may explore new organizational structures and departments to conceive and to develop new products since the skills required for managing ongoing brands may be different from creating new ones.
Cultural discourse in the Corpus of East African English and beyond: possibilities and problems of lexical and collocational research in a one million‐word corpus
Authors: Schmied Josef
Published: July 2004

Abstract:  This contribution discusses content as well as methodology. As far as content is concerned, it looks at culture‐specific lexemes in East African English and compares it with the international reference varieties of English, British and American. As far as methodology is concerned, it uses the East African component of the International Corpus of English (ICE‐EA) and explores to what extent culture‐specific lexemes (East Africanisms or Kenyanisms/Tanzanianisms) can be explored and described on the basis of these data and suggests other methods to complement them.1
Comparing world Englishes: a research guide
Authors: Fallon Helen
Published: July 2004

Abstract:  This paper presents a practical research guide to world English, with particular emphasis on comparative studies of varieties of English. Part I is a select bibliography of journal articles, books, and book chapters relating to comparative studies of English dating from 1992 to 2002. Part II lists the journals included in Part I, and includes details such as contact information and frequency of publication. Part III deals with electronic resources. Specifically, it provides information about currently available electronic corpora of contemporary English, together with contact details and ordering information.
A Cognitive-Process Taxonomy for Sex Differences in Cognitive Abilities
Authors: Halpern Diane F.
Published: July 2004

Females and males show different average patterns of academic achievement and scores on cognitive ability tests. Females obtain higher grades in school, score much higher on tests of writing and content-area tests on which the questions are similar to material that was learned in school, attain a majority of college degrees, and are closing the gap in many careers that were traditionally male. By contrast, males score higher on standardized tests of mathematics and science that are not directly tied to their school curriculum, show a large advantage on visuospatial tests (especially those that involve judgments of velocity and navigation through three-dimensional space), and are much more knowledgeable about geography and politics. A cognitive-process taxonomy can shed light on these differences.
Genetic Influence on Human Psychological Traits
Authors: Bouchard Thomas J.
Published: July 2004

There is now a large body of evidence that supports the conclusion that individual differences in most, if not all, reliably measured psychological traits, normal and abnormal, are substantively influenced by genetic factors. This fact has important implications for research and theory building in psychology, as evidence of genetic influence unleashes a cascade of questions regarding the sources of variance in such traits. A brief list of those questions is provided, and representative findings regarding genetic and environmental influences are presented for the domains of personality, intelligence, psychological interests, psychiatric illnesses, and social attitudes. These findings are consistent with those reported for the traits of other species and for many human physical traits, suggesting that they may represent a general biological phenomenon.
Children's Exposure to Violence in the Family and Community
Authors: Margolin Gayla , Gordis Elana B.
Published: July 2004

Exposure to family and community violence is linked with aggression, depression, posttraumatic stress symptoms, and academic and cognitive difficulties. It has the potential to permeate many dimensions of children's day-to-day lives and to erode possible sources of social support. Although the literature focuses on deleterious outcomes, many children fare well in the face of exposure to violence. Research attending to developmental processes, the co-occurrence of multiple forms of violence, and psychobiological mechanisms will clarify why outcomes are better for some children than for others. Greater understanding of children's risk and resilience in the face of such exposure will inform intervention efforts.
Parental School Involvement and Children's Academic Achievement
Authors: Hill Nancy E. , Taylor Lorraine C.
Published: July 2004

Developing collaborations between families and schools to promote academic success has a long-standing basis in research and is the focus of numerous programs and policies. We outline some of the mechanisms through which parental school involvement affects achievement and identify how patterns and amounts of involvement vary across cultural, economic, and community contexts and across developmental levels. We propose next steps for research, focusing on the importance of considering students' developmental stages, the context in which involvement takes place, and the multiple perspectives through which involvement may be assessed. Finally, we discuss enhancing involvement in diverse situations.
Contents
Authors: Keast David H. , Bowering C. Keith , Evans A. Wayne , Mackean Gerald L. , Burrows Catherine , D'Souza Lincoln
Published: July 2004

The effective management of nonhealing wounds is based on a complete patient history, a detailed initial assessment of the wound, and an analysis of probable causative factors. This information is used to individualize a management strategy to the underlying pathophysiology preventing healing and to implement appropriate wound interventions. Regular reassessment of progress toward healing and appropriate modification of the intervention are also necessary. Accurate and clinically relevant wound assessment is an important clinical tool, but this process remains a substantial challenge. Wound assessment terminology is nonuniform, many questions surrounding wound assessment remain unanswered, agreement has yet to be reached on the key wound parameters to measure in clinical practice, and the accuracy and reliability of available wound assessment techniques vary. This article, which resulted from a meeting of wound healing experts in June 2003, reviews clinically useful wound measurement approaches, provides an overview of the principles and practice of chronic wound assessment geared to a clinical audience, and introduces a simple mnemonic, MEASURE. MEASURE encapsulates key wound parameters that should be addressed in the assessment and management of chronic wounds: Measure (length, width, depth, and area), Exudate (quantity and quality), Appearance (wound bed, including tissue type and amount), Suffering (pain type and level), Undermining (presence or absence), Reevaluate (monitoring of all parameters regularly), and Edge (condition of edge and surrounding skin). This article also provides some preliminary recommendations targeted to developing best practice guidelines for wound assessment.
Theorising economic nationalism*
Authors: Nakano Takeshi
Published: July 2004

Abstract.Economic nationalism has been regarded as a set of attitudes rather than a coherent theory. However, by using Durkheim's analytical framework and bringing the concept of the nation into political economy, the author argues that economic nationalism can be provided with a systematic theory. This theory for economic nationalism helps us to grasp the reciprocal relationship between the political and economic power of the nation‐state. Economic modernisation, especially industrialisation, needs the powerful state, and the state derives its power from the nation. Economic development can amplify the social imaginary of the nation by expanding mobilisation and communication. Protectionism, industrial policy and Keynesian policy can strengthen not only the economy but also nationalism. The proposed theory for economic nationalism thus paves the way for understanding the role of nationalism in political economy.
Nationalism, primitivism and the golden age in Othon Friesz's Autumn Work (1908)*
Authors: Roy Nina
Published: July 2004

Abstract. This paper focuses on a detailed analysis of the Fauve artist Othon Friesz's painting Autumn Work (1908) within the contextual juncture of nationalism and primitivism. The painting occupies a unique position within this framework as it elucidates a point a convergence between nationalist ideologies and the primitivist turn towards peasant cultures as a repository of the past. This interpretation also identifies how Friesz's fusion of the Virgilian golden age with the contemporary, rural myth disrupts the Self/Other framework of primitivism via the lens of national identity. Friesz's employment of classically influenced and avant‐grade aesthetics further underscores the ways in which the painting references not only his personal artistic negotiation between tradition and modernity, but also the significance of ancestral myths and temporal oppositions in both nationalist and primitivist discourse.
A bargain between the secular state and Turkish Islam: politics of ethnicity in Central Asia
Authors: Turam Berna
Published: July 2004

Abstract. This paper reveals and analyses the ethnic politics mobilised by a fast‐growing Islamic movement, the Gülen movement, which emerged in the 1980s in Turkey and expanded to Central Asia in the mid‐1990s. Following the micro‐sites, where nationness is reproduced as an everyday practice, my ethnographic research in Almaty‐Kazakhstan explored the emergent Islamic sensibilities for the nation and ethnic identity. Revivalist Islam has often been essentialised as incompatible with nationalism, since it has been widely associated with the Muslim community rather than nations and nation‐states. I argue that this bias is facilitated and maintained by the deep division in the literature. Scholarly work on both Islam and nationalism are split into two opposing approaches, state‐centered and culture‐centered. The findings of the present study challenge the binary thinking that juxtaposes politics against culture and dichotomises ethnic and state‐framed base of nationalism and nationhood. My major finding is that the Gülen movement has not only inherited the symbols and myths of descent from the founding fathers of the Turkish state, but it is also currently reproducing the related ethnic politics in cooperation with–not in opposition to–the secular states in the post‐Soviet Turkic world. The study reconciles ethno‐symbolic and state‐centered approaches in explaining the convergence between Islamic and secular nationalism in the formation of ethnic politics in Almaty‐Kazakhstan.
Magnaporthe grisea interactions with the model grass Brachypodium distachyon closely resemble those with rice (Oryza sativa)
Authors: ROUTLEDGE ANDREW P. M. , SHELLEY GREG , SMITH JOEL V. , TALBOT NICHOLAS J. , DRAPER JOHN , MUR LUIS A. J.
Published: July 2004

Germplasm of Brachypodium distachyon was inoculated with Magnaporthe grisea using either rice‐ (Guy11) or grass‐adapted (FAG1.1.1, PA19w‐06, PA31v‐01) host‐limited forms of the fungus, and interactions with varying degrees of susceptibility and resistance were identified. Ecotype ABR5 was resistant to each M. grisea strain whereas ABR1 was susceptible to all but P31vi‐01. Mendelian segregation in ABR1 × ABR5 crosses suggested that a single dominant resistance gene conferred resistance to Guy11. Microscopic analyses revealed that the aetiology of Guy11 fungal development and disease progression in ABR1 closely resembled that of rice infections. In ABR5, Guy11 pathogenesis was first suppressed at 48 h post‐inoculation, at the secondary hyphal formation stage and was coincident with cytoplasmic granulation. Resistance to strains PA31v‐01 and FAG1.1.1 was associated with a localized cell death with little callose deposition. 3,3‐Diaminobenzidine staining indicated the elicitation of cell death in B. distachyon was preceded by oxidative stress in the interacting epidermal cells and the underlying mesophyll cells. Northern blot hybridization using probes for barley genes (PR1, PR5 and PAL) indicated that each was more rapidly expressed in ABR5 challenged with Guy11 although the B. distachyon defence genes BD1 and BD8 were more quickly induced in ABR1. Such data show that B. distachyon is an appropriate host for functional genomic investigations into M. grisea pathology and plant responses.
MicroRNAs: more than a role in plant development?
Authors: LLAVE CESAR
Published: July 2004

Eukaryotic small RNA comprises several classes of 21–25 nucleotide non‐coding RNA, of which microRNA (miRNA) has gained a great deal of attention because it is directly involved in controlling growth and development in plants. miRNAs are processed by the RNase III‐like Dicer, although recent studies have implicated additional gene products in the step‐wise maturation of miRNAs from their primary nuclear transcripts. They function as sequence‐specific guides to trigger cleavage or translational repression of target mRNAs that have complementary sequences. Natural miRNA targets encode members of large families of transcription factors, which are collectively required for a number of developmental processes. In addition to developmental regulation, some miRNAs might be involved in specific physiological responses to several types of stresses, such as those induced by pathogen infections. Strikingly, the potyviruses, the largest group of plant RNA viruses, are able to interfere with miRNA‐guided cleavage of multiple regulatory targets in plants, thus modulating gene expression of the host cell.
Expression of a modified nucleocapsid‐protein of Tomato spotted wilt virus (TSWV) confers resistance against TSWV and Groundnut ringspot virus (GRSV) by blocking systemic spread
Authors: SCHWACH FRANK , ADAM GÜNTER , HEINZE CORNELIA
Published: July 2004

Tobacco transformed with a construct comprising the nucleocapsid‐protein (N) gene of Tomato spotted wilt virus (TSWV) and the 5′ non‐translated leader sequence of Plum pox virus (PPV) as a translation enhancer displays unusually broad resistance against tospoviruses. Contrary to expectations, the transgenic plants did not express a higher level of TSWV N protein than control plants harbouring the N gene without the PPV enhancer. Instead, expression of an N‐terminally elongated N protein, due to the presence of an in‐frame start codon in the PPV leader, was detected. This modified N protein was present in nucleocore and virion preparations and appears to confer resistance by interfering with systemic spread of the virus in the aerial parts of the transgenic plants, while not having an effect on primary replication.
Gene expression in germinated cysts of Phytophthora nicotianae
Authors: SHAN WEIXING , MARSHALL JERRY S. , HARDHAM ADRIENNE R.
Published: July 2004

The life cycle of Phytophthora species contains several distinct asexual developmental stages that are important for plant infection and disease development. These include vegetative growth of filamentous hyphae, production of multinucleate sporangia, motile, uninucleate zoospores and germinated cysts, the stage at which plant colonization is initiated. To understand mechanisms regulating molecular and cellular processes in germinated cysts, differential hybridization analysis of a cDNA library was used to identify genes up‐regulated after cyst germination in P. nicotianae. Arrays of 12 288 random cDNA clones derived from a germinated cyst cDNA library were screened with 32P‐labelled cDNA probes synthesized from mRNA isolated from four different developmental stages and tobacco tissues infected with P. nicotianae. The resultant expression profiles for each cDNA clone led to the identification of over 300 clones showing up‐regulated expression in germinated cysts compared with the other three stages. Sequencing of the 5′ end of 382 selected clones yielded 355 sequences representing 146 putative unigenes. Sequence analysis revealed similarities to genes encoding proteins involved in energy production, protein biosynthesis, signalling, cell‐wall biogenesis and transcription regulation. Novel genes putatively involved in cell adhesion, cell‐wall biogenesis and transcriptional regulation were identified. Thirty‐one cDNA clones were analysed by Northern blotting and for 28 the pattern of expression in the Northern blots was the same as that indicated by the macroarray screening, verifying the fidelity of the colony hybridization data.
Fungal dimorphism regulated gene expression in Ustilago maydis: II. Filament down‐regulated genes
Authors: GARCÍA‐PEDRAJAS MARÍA D. , GOLD SCOTT E.
Published: July 2004

Ustilago maydis displays dimorphic growth alternating between a budding haploid form and a filamentous dikaryon resulting from mating of two haploid cells. This morphological switch plays a critical role in pathogenicity because only the filamentous dikaryon can infect corn plants. Previously, we identified a role for the cAMP signal transduction pathway in dimorphism and pathogenicity. The repression of a subset of genes in filamentous cells may be critical for programming virulence. To identify these filament down‐regulated genes and to understand better the role of wild‐type budding cells in the life and disease cycle of U. maydis in nature, we used suppression subtractive hybridization. We arrayed a library of approximately 5500 cDNA clones and showed by reverse Northern blot analysis that most, as expected, are down‐regulated during filamentous growth. By an iterative sequencing and hybridization process to eliminate previously determined sequences, we showed that > 88% of the clones detected as differential in the reverse Northern blot screening harbour sequences corresponding to 48 different genes. Differential expression was confirmed for 37 of these genes by Northern blot analysis. For eight of these confirmed differential genes, expression could only be detected in budding cells. For genes expressed in both growth forms, levels of differential expression varied from as much as 65‐fold to only two‐fold higher levels in budding cells. Twenty‐seven of the 37 genes confirmed to be differential had similarity to database sequences, and fell into several putative functional categories. In future studies we will produce deletion mutants in several highly differentially expressed genes to study their roles in morphogenesis and pathogenesis.
Identification of a lipopolysaccharide responsive erk‐like MAP kinase in tobacco leaf tissue
Authors: PIATER LIZELLE ANN , NÜRNBERGER THORSTEN , DUBERY IAN A.
Published: July 2004

Lipopolysaccharides (LPS) are indispensable cell surface components of Gram‐negative bacteria and have diverse roles in plant–microbe interactions. Treatment of Nicotiana tabacum with the LPS of an endophytic strain of Burkholderia cepacia results in an enhanced defensive capacity in the tissue. In this study the rapid and transient phosphorylation of an extracellular signal‐regulated (ERK)‐like mitogen‐activated protein (MAP) kinase in response to LPS from B. cepacia (LPSB.cep.) elicitation is reported. Based on in‐gel kinase assays it was found that this 43‐kDa LPSB.cep.‐responsive kinase is optimally activated following 7 min elicitation with 100 µg/mL LPS. Its identity as an ERK MAPK was supported by tyrosine‐phosphorylated association with induction, immunodetection with pTEpY‐specific MAPK antibodies and inhibition of phosphorylation by U0126, an upstream MAPKK inhibitor. The kinase utilized myelin basic protein, but not casein or histone, as substrate. Ca2+ did not modulate the phosphorylation, nor did wounding. To date, other MAP kinases have been shown to act either independently or upstream from reactive oxygen intermediates produced during the oxidative burst. It was found that hydrogen peroxide is either not generated in leaf tissue in response to LPS elicitation or, if generated, does not trigger the phosphorylation of the kinase. Physicochemical characterization of the ERK‐like MAPK indicated a molecular mass of 43 kDa and a pI of 6.3; two‐dimensional gel analysis indicated two charge isomers. This is the first demonstration of such an LPS‐responsive MAP kinase phosphorylation in plants.
Risk of vascular disease in adults with diagnosed coeliac disease: a population‐based study
Authors: West J. , Logan R. F. A. , Card T. R. , Smith C. , Hubbard R.
Published: July 2004

Background : It has been suggested that vascular disease mortality may be reduced in coeliac disease because of lower levels of blood pressure, cholesterol and body mass.

Aim : To examine whether people with coeliac disease are at reduced risk of various vascular diseases.

Methods : We identified 3790 adults with diagnosed coeliac disease and 17 925 age‐ and sex‐matched controls in the General Practice Research Database. We estimated odds ratios for diagnosed hypertension, hypercholesterolaemia and atrial fibrillation and hazard ratios for myocardial infarction and stroke.

Results : Adults with coeliac disease, compared with controls, were less likely to have had a diagnosis of hypertension [11% vs. 15%, odds ratio 0.68 (95% confidence interval: 0.60–0.76)] or hypercholesterolaemia [3.0% vs. 4.8%, odds ration 0.58 (95% confidence interval: 0.47–0.72)] but slightly more likely to have had atrial fibrillation [2.1% vs. 1.7%, odds ratio 1.26 (95% confidence interval: 0.97–1.64)]. The hazard ratio for myocardial infarction was 0.85 (95% confidence interval: 0.63–1.13), while the hazard ratio for stroke was 1.29 (95% confidence interval: 0.98–1.70).

Conclusions : Although rates of myocardial infarction and stroke were not substantially different, adults with coeliac disease do have a lower prevalence of hypertension and hypercholesterolaemia compared with the general population. The effect of a gluten‐free diet on cardiovascular risk factors should be determined before any screening programmes for coeliac disease are instituted.
Azathioprine dose escalation in inflammatory bowel disease
Authors: Rayner C. K. , Hart A. L. , Hayward C. M. M. , Emmanuel A. V. , Kamm M. A.
Published: July 2004

Background : Forty per cent of patients with inflammatory bowel disease fail to respond to standard dose azathioprine (2 mg/kg/day).

Aims : To evaluate the efficacy and safety of increasing the azathioprine dose according to a fixed schedule and guided by clinical response and adverse effects.

Methods : We reviewed the records of all patients with inflammatory bowel disease treated by a single clinician over 6 years, unresponsive to at least 3 months treatment with standard dose azathioprine, and whose dose was subsequently increased.

Results : Forty patients (27 male; 24 Crohn's, 16 ulcerative colitis) with chronic active disease or recurrent flares despite standard dose azathioprine for a median 8 months (range 3–114) increased their dose from a median 2.02 (1.61–3.19) mg/kg/day to 2.72 (2.37–3.99) mg/kg/day in one to four increments of 0.5 mg/kg/day, and were followed over a median6 (0.5–54) months. Eleven of the 40 patients (seven Crohn's, four ulcerative colitis) responded or had reduced frequency of flare‐ups at the end of follow‐up, while 17 of the 40 patients had no benefit. Response was more likely for maximum doses ≤2.5 mg/kg/day (six of 11 patients) than for doses >2.5 mg/kg/day (five of 29 patients) (P = 0.042). Twelve patients (11 of whom received maximum doses >2.5 mg/kg/day) were unable to maintain an increased azathioprine dose because of leukopenia in eight, nausea in three, and raised liver enzymes in one (all transient and reversible).

Conclusions : Increasing the azathioprine dose up to 2.5 mg/kg/day appears beneficial in patients who have not responded to 2 mg/kg/day. Further increase above 2.5 mg/kg/day is less likely to be efficacious, and is associated with a substantial risk of adverse reactions.
Clinical and histological features of non‐alcoholic fatty liver disease in Hong Kong Chinese
Authors: Wong V. W.‐S. , Chan H. L.‐Y. , Hui A. Y. , Chan K.‐F. , Liew C.‐T. , Chan F. K.‐L. , Sung J. J.‐Y.
Published: July 2004

Background: Non‐alcoholic fatty liver disease is prevalent in affluent countries and is a cause of cirrhosis and possibly hepatocellular carcinoma.

Aim: To examine the clinical and histological features of biopsy‐proven non‐alcoholic fatty liver disease and investigate the predictors of severe histological disease in Chinese patients.

Methods: Electronic records of all patients (n = 247) who underwent liver biopsy between 1996 and 2003 in our hospital were retrieved. Patients who had histological features of non‐alcoholic fatty liver disease were identified. The demographic, clinical, laboratory and histological (Brunt's criteria) parameters of these patients were analysed.

Results: Forty‐two patients had histology‐proven non‐alcoholic fatty liver disease. The median age was 47 years (range 23–69). All except one patient had features of metabolic syndrome. The median alanine aminotransferase was 93 (range 24–270) IU/L. Thirty‐six (85.7%) patients had steatohepatitis and 11 (26.1%) also had fibrosis. Only one patient had stage 3 fibrosis. The presence of diabetes mellitus predicted higher grade steatohepatitis and fibrosis (P = 0.019) whereas alanine aminotransferase level had no correlation with histological severity of steatohepatitis. After a median follow‐up of 42 months, no patient developed hepatic decompensation.

Conclusions: Most Chinese patients with non‐alcoholic fatty liver disease had features of the metabolic syndrome. Histological activity was generally mild. Diabetes mellitus was the most important predictor of severe histological disease.
Masking of 13C urea breath test by proton pump inhibitors is dependent on type of medication: comparison between omeprazole, pantoprazole, lansoprazole and esomeprazole
Authors: Levine A. , Shevah O. , Shabat‐Sehayek V. , Aeed H. , Boaz M. , Moss S. F. , Niv Y. , Avni Y. , Shirin H.
Published: July 2004

Background : The need to withhold acid suppression therapy while awaiting urea breath test results is a common clinical problem in symptomatic patients. It is unclear at present if the dose or type of proton pump inhibitor or the type of test meal govern the apparent masking effect of proton pump inhibitors on the urea breath test.

Aim : To prospectively evaluate Helicobacter pylori detection rates during treatment with four different proton pump inhibitors, utilizing a high‐dose citric acid‐based 13C urea breath test.

Methods : Patients positive for Helicobacter pylori by urea breath test were randomized to receive either omeprazole 20 mg/day, pantoprazole 40 mg/day, lansoprazole 30 mg/day or esomeprazole 40 mg/day for 14 days. A repeat breath test was performed on day 14 of treatment.

Results : One hundred and seventy‐nine patients, mean age 45.8 ± 16.8, completed the study. Treatment with omeprazole or pantoprazole prior to urea breath test (UBT) was associated with low false negative results, while lansoprazole and esomeprazole caused clinically unacceptable high false negative rates (pantoprazole 2.2% vs. lansoprazole 16.6%, P = 0.02, vs. esomeprazole 13.6%, P = 0.05; omeprazole 4.1% vs. lansoprazole 16.6%, P = 0.05).

Conclusions : Proton pump inhibitor‐induced false negative results on high‐dose citric acid based urea breath test vary with the type of proton pump inhibitor used. Selection of the appropriate test meal and proton pump inhibitor may allow symptomatic individuals to continue their proton pump inhibitors prior to performing a urea breath test.
Treatment of acute hepatitis C with interferon α‐2b: early initiation of treatment is the most effective predictive factor of sustained viral response
Authors: Delwaide J. , Bourgeois N. , Gérard C. , De Maeght S. , Mokaddem F. , Wain E. , Bastens B. , Fevery J. , Géhénot M. , Le Moine O. , Martinet J. P. , Robaeys G. , Servais B. , Van Gossum M. , Van Vlierberghe H. ,   the Belgian Association for the Study of the Liver (BASL)
Published: July 2004

Aim : To evaluate the efficacy of early interferon α‐2b in non‐post‐transfusion acute hepatitis C virus: a prospective study with historical comparison.

Patients : Group A: 28 patients prospectively treated for acute hepatitis C virus with daily regimen of interferon 5 million units for 2 months. Group B: historical series of 16 patients with untreated acute hepatitis C virus.

Results : There was no significant difference between the two groups with regard to gender, age, icterus, alanine aminotransferase, or genotypes. In group B, hepatitis spontaneously resolved in three of 16 (19%) patients (follow‐up 1–7 years). In group A, 21 of 25 patients became sustained viral responders (75%; P = 0.0003 vs. group B). Factors include not predictive of sustained viral response: age, gender, sources of infection, presence of icterus, alanine aminotransferase peak, bilirubin peak, incubation period, presence of hepatitis C virus antibodies at presentation, or genotypes. The time from presentation to the start of therapy was, however, significantly shorter in sustained viral responders (43 ± 31 days) than in relapsers or non‐responders (88 ± 52 days) (P = 0.016).

Conclusions : Early treatment of acute hepatitis C virus with interferon prevents chronicity. A short waiting time from presentation to treatment appears as the most relevant predictive factor for sustained response.
Therapeutic Arthritis Research and Gastrointestinal Event Trial of lumiracoxib – study design and patient demographics
Authors: Hawkey C. J. , Farkouh M. , Gitton X. , Ehrsam E. , Huels J. , Richardson P.
Published: July 2004

Background : Cyclooxygenase‐2 selective inhibitors were developed in order to reduce the incidence of life‐threatening gastrointestinal ulcer complications compared with non‐selective non‐steroidal anti‐inflammatory drugs. Previous outcomes studies have, variously, lacked power to investigate this endpoint, focused on broader outcomes, or been too small to quantify the influence of aspirin.

Aim : To evaluate lumiracoxib, a novel cyclooxygenase‐2 selective inhibitor, vs. non‐selective non‐steroidal anti‐inflammatory drugs in an outcomes study of considerably increased size. This paper describes the study's methodology.

Methods and patients : The Therapeutic Arthritis Research and Gastrointestinal Event Trial was a randomized, double‐blind, 52‐week study of lumiracoxib 400 mg once daily (two to four times the recommended dose for osteoarthritis) versus naproxen 500 mg twice daily or ibuprofen 800 mg three‐times daily in patients with osteoarthritis. Randomization was stratified for low‐dose aspirin use and age (≤ 64, 65–74, ≥ 75 years). The study was powered to investigate upper gastrointestinal ulcer complications (primary endpoint) in patients not taking aspirin and in the overall study population; other endpoints included cardiovascular, renal and hepatic measures.

Conclusions : Therapeutic Arthritis Research and Gastrointestinal Event Trial was designed to provide definitive answers concerning the gastrointestinal safety of lumiracoxib, addressing the controversial issues arising from outcomes studies with other cyclooxygenase‐2 selective inhibitors.
Plasma levels of von Willebrand factor regulate ADAMTS‐13, its major cleaving protease
Authors: Mannucci Pier Mannuccio , Capoferri Cristina , Canciani Maria Teresa
Published: July 2004

ADAMTS‐13, the metalloprotease that disposes physiologically of the most thrombogenic multimers of von Willebrand factor (VWF), tends to be low in plasma when VWF is high. We evaluated the behaviour of these two proteins in naturally occurring, experimental and clinical situations associated with VWF levels spanning from undetectable to supranormal. ADAMTS‐13 was approximately 10% higher (and VWF 35% lower) in 65 healthy individuals of blood group O than in 65 individuals of groups A, B and AB. Thirty‐three patients with type 3 von Willebrand disease (VWD) with undetectable plasma VWF had approximately 35% higher levels of ADAMTS‐13 than a comparable group of healthy individuals with normal VWF. When VWF was raised to supranormal levels by desmopressin (DDAVP) in 10 healthy volunteers, ADAMTS‐13 decreased by approximately 20%, with no change of the protease in three patients with severe VWD who had no post‐DDAVP VWF rise. When VWF was raised from very low to normal levels by the infusion of VWF‐containing plasma concentrates in four patients with type 3 VWD and one with type 1 VWD plasma, ADAMTS‐13 decreased in parallel. These data show that throughout a large spectrum of plasma VWF levels there is a negative association between this protein and the activity of its major cleaving protease.
Haematogones in the peripheral blood of adults: a four‐colour flow cytometry study of 102 patients
Authors: Kroft Steven H. , Asplund Sheryl L. , McKenna Robert W. , Karandikar Nitin J.
Published: July 2004

Haematogones have been extensively characterized in bone marrow, but not in the peripheral blood (PB). We studied 102 PB samples from adult patients with a sensitive flow cytometry method. Sixty‐six of 102 samples (65%) contained detectable haematogones, ranging from 0·01% to 1·3% of white blood cells (median 0·06%, mean 0·13%). Of 66 cases with complete blood count data, 51 had absolute haematogone counts of 0·00037–0·105 × 109/l (median 0·0054 × 109/l, mean 0·012 × 109/l). PB haematogones belonged exclusively to the most mature maturational stage. These findings have implications for PB analysis of minimal residual disease in acute lymphoblastic leukaemia and follicular lymphoma.
Fanconi anaemia and leukaemia – clinical and molecular aspects
Authors: Tischkowitz Marc , Dokal Inderjeet
Published: July 2004

Fanconi anaemia (FA) is an autosomal recessive chromosomal instability disorder, which is characterized by congenital abnormalities, defective haemopoiesis and a high risk of developing acute myeloid leukaemia and certain solid tumours. It can be caused by mutations in at least eight different genes. Molecular studies have established that a common pathway exists, both between the FA proteins and other proteins involved in DNA damage repair such as NBS1, ATM, BRCA1 and BRCA2. This review summarizes the general clinical and specific haematological features and the current management of FA. Recent molecular advances will also be discussed in the context of the cellular and clinical FA phenotype, with particular emphasis on the haematological aspects of the condition.
Identification of protein Sα gene mutations including four novel mutations in eight unrelated patients with protein S deficiency
Authors: Okada Hiromi , Takagi Akira , Murate Takashi , Adachi Tatsuya , Yamamoto Koji , Matsushita Tadashi , Takamatsu Junki , Sugita Kanji , Sugimoto Mitsuhiko , Yoshioka Akira , Yamazaki Tomio , Saito Hidehiko , Kojima Tetsuhito
Published: July 2004

Eight distinct and potentially causative mutations were identified in eight unrelated Japanese patients with protein S (PS) deficiency, by direct DNA sequencing of the protein Sα (PSα) gene‐specific polymerase chain reaction products of all 15 exons and exon/intron boundaries. There were five missense mutations, including two novel mutations (Cys80Tyr and Arg314His), and three showed a major impact on the expected gene products: novel mutations of a 5‐bp deletion (delCTCTG887:Cys206Stop) and a nonsense mutation (Glu208Stop), as well as a previously reported splice site (exon 10 +5 A→G) mutation. One of the patients showed compound heterozygosity for delCTCTG887 and 732A→G. Investigation for the cosegregation state of these two mutations with PS deficiency in the patient's family suggested that the delCTCTG887 mutation was responsible for the abnormal phenotype and that the 732A→G (Lys155Glu) mutation did not appear to play a key role. However, we also identified the same 732A→G (Lys155Glu) mutation in an unrelated patient with apparent PS deficiency with severe pulmonary embolism, and found that this mutation seemed to cosegregate with a PS‐deficient state in her family members. These data implied that unknown factor(s) other than the 732A→G mutation itself might influence phenotypic expression of PS status in different individuals.
Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment
Authors: Hormigo Adília , Abrey Lauren , Heinemann Murk‐Hein , DeAngelis Lisa M.
Published: July 2004

Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P < 0·05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.