bluuebunny/crossref_metadata_2025 huggingface dataset:
Did Hayek Commit the Naturalistic Fallacy?
Authors: Angner Erik
Published: November 2004

In promoting spontaneous orders—orders that evolve in a process of cultural evolution—as “efficient,” “beneficial,” and “advantageous,” Friedrich A. Hayek (1899–1992) has often been attributed the belief that there is something desirable about them. For this reason, he has been accused of committing the naturalistic fallacy, that is, of trying to derive an “ought” from an “is.” It appears that Hayek was quite aware of the charge, and vigorously disputed it: “I have no intention to commit what is often called the genetic or naturalistic fallacy” (1988, p. 27).
How We Dapple the World
Authors: Teller Paul
Published: November 2004

This essay endorses the conclusion of Sklar's “Dappled Theories in a Uniform World” that he announces in his abstract, that notwithstanding recent attacks foundational theories are universal in their scope. But Sklar's rejection of a “pluralist ontology” is questioned. It is concluded that so called “foundational” and “phenomenological” theories are on a much more equal footing as sources of knowledge than Sklar would allow, that “giving an ontology” generally involves dealing in idealizations, and that a transfigured “ficitonalism” provides an (in many respects) better model of scientific knowledge than the model of “foundational truths.”
Discussion: Re-solving Irrelevant Conjunction with Probabilistic Independence
Authors: Hawthorne James , Fitelson Branden
Published: November 2004

Naive deductivist accounts of confirmation have the undesirable consequence that if E confirms H, then E also confirms the conjunction H·X, for any X—even if X is completely irrelevant to E and H. Bayesian accounts of confirmation may appear to have the same problem. In a recent article in this journal Fitelson (2002) argued that existing Bayesian attempts to resolve of this problem are inadequate in several important respects. Fitelson then proposes a new-and-improved Bayesian account that overcomes the problem of irrelevant conjunction, and does so in a more general setting than past attempts. We will show how to simplify and improve upon Fitelson's solution.
Gold's Theorem and Cognitive Science
Authors: Johnson Kent
Published: November 2004

A variety of inaccurate claims about Gold's Theorem have appeared in the cognitive science literature. I begin by characterizing the logic of this theorem and its proof. I then examine several claims about Gold's Theorem, and I show why they are false. Finally, I assess the significance of Gold's Theorem for cognitive science.
CRAVE: a database, middleware and visualization system for phenotype ontologies
Authors: Gkoutos Georgios V. , Green Eain C.J. , Greenaway Simon , Blake Andrew , Mallon Ann-Marie , Hancock John M.
Published: November 2004

Motivation: A major challenge in modern biology is to link genome sequence information to organismal function. In many organisms this is being done by characterizing phenotypes resulting from mutations. Efficiently expressing phenotypic information requires combinatorial use of ontologies. However tools are not currently available to visualize combinations of ontologies. Here we describe CRAVE (Concept Relation Assay Value Explorer), a package allowing storage, active updating and visualization of multiple ontologies.

Results: CRAVE is a web-accessible JAVA application that accesses an underlying MySQL database of ontologies via a JAVA persistent middleware layer (Chameleon). This maps the database tables into discrete JAVA classes and creates memory resident, interlinked objects corresponding to the ontology data. These JAVA objects are accessed via calls through the middleware's application programming interface. CRAVE allows simultaneous display and linking of multiple ontologies and searching using Boolean and advanced searches.

Availability: Direct access: http://www.mgu.har.mrc.ac.uk/CRAVE/

Contact:  g.gkoutos@har.mrc.ac.uk
Splenic complications in malaria: report of two cases from Turkey
Authors: Ozsoy M F , Oncul O , Pekkafali Z , Pahsa A , Yenen O S
Published: November 2004

Malaria is still a major health problem in Turkey, where Plasmodium vivax malaria is endemic. Spontaneous rupture of the spleen is an important and life-threatening complication and occurs in up to an estimated 2 % of cases. Hence the small number of case reports suggests under-reporting or underdiagnosis. Review articles have reported only 18 malaria cases with spontaneous splenic rupture in the English language literature since 1960. Two cases of P. vivax malaria with splenic complications are reported here. One of them showed signs and symptoms of acute abdominal pain, then splenic rupture occurred.
Investigation of anti-Toxoplasma gondii antibodies in patients with neoplasia
Authors: Yazar Süleyman , Yaman Ozan , Eser Bülent , Altuntaş Fevzi , Kurnaz Fatih , Şahin Izzet
Published: November 2004

This study aimed to determine the prevalence of anti-Toxoplasma gondii antibodies in patients with neoplasia. One hundred and eight patients with neoplasia and 108 healthy controls were studied for the presence of anti-T. gondii antibodies using a micro ELISA and peroxidase-labelled anti-human IgG (rabbit) and IgM (goat). Anti-T. gondii IgG antibodies were detected in 68 (63.0 %) patients and in 21 (19.4 %) of the controls, which was a statistically significant difference. In addition, anti- T. gondii IgM antibodies were detected in seven (6.5 %) patients and in one (0.9 %) control. A high percentage of positivity for Toxoplasma antibodies in patients with neoplasia was detected. Therefore, parasitological surveys of this patient group should be periodically performed.
Chlamydophila pneumoniae induces p44/p42 mitogen-activated protein kinase activation in human fibroblasts through Toll-like receptor 4
Authors: Haralambieva Iana H , Iankov Ianko D , Ivanova Petya V , Mitev Vanio , Mitov Ivan G
Published: November 2004

Chlamydophila pneumoniae, an obligately intracellular Gram-negative bacterium and a common causative agent of respiratory tract infections, has been implicated in the induction and progression of atherosclerosis and coronary artery disease. In this study, the signalling mechanism of C. pneumoniae in human fibroblasts, a prominent cell population in chronic inflammation and persistent infection, contributing to plaque formation, was investigated. C. pneumoniae elementary bodies were demonstrated to up-regulate the phosphorylation of p44/p42 mitogen-activated protein kinase (MAPK) in human fibroblasts. The effect was independent of the chlamydial lipopolysaccharide and was likely to be mediated by a heat-labile chlamydial protein. Furthermore, an anti-Toll-like receptor 4 (TLR4) antibody was shown to abolish C. pneumoniae-induced cell activation, whereas an anti-TLR2 antibody had no effect, indicating the role of TLR4 in p44/p42 MAPK activation. Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 and phosphodiesterase 4 (PDE 4) inhibitor Rolipram enhanced C. pneumoniae-induced MAPK phosphorylation and attenuated C. pneumoniae infectivity in vitro. Together the results indicate that C. pneumoniae triggers rapid TLR4-mediated p44/p42 MAPK activation in human fibroblasts and chemical enhancement of MAPK phosphorylation modulates in vitro infection at the molecular level.
Antimicrobial resistance of invasive Streptococcus pneumoniae isolates in a British district general hospital: the international connection
Authors: Birtles Andrew , Virgincar Nilangi , Sheppard Carmen L , Walker Rachel A , Johnson Alan P , Warner Marina , Edwards-Jones Valerie , George Robert C
Published: November 2004

Between January 2000 and March 2001,Streptococcus pneumoniaewere isolated from the blood of 56 patients admitted to a single district general hospital in the South-East of England. The serotype and antibiotic susceptibility were determined for all isolates and, for those resistant to erythromycin, the presence or absence of themef(A) anderm(B) genes was determined by PCR. Multi-locus sequence typing, along with PFGE, was undertaken on all isolates resistant to penicillin or erythromycin and a group of antibiotic-susceptible isolates, to identify whether globally distributed pneumococcal clones, as described by the Pneumococcal Molecular Epidemiology Network (PMEN), were present in the study population. Three serotype 9V penicillin-resistant isolates were identified as belonging to the Spain9V-3 clone, while 14 erythromycin-resistant isolates of serotype 14 belonged to the England14-9 clone. A single multi-resistant isolate of serotype 6B, was found to be a single-locus variant of the Spain6B-2 clone. All 14 erythromycin-resistant serotype 14 isolates possessed themef(A) gene, while the single multi-resistant isolate possessed theerm(B) gene. These findings confirm the wide distribution and clinical impact of PMEN clones, which accounted for all of the penicillin and erythromycin resistance observed amongst invasive isolates in a district general hospital over a 15-month period.
The Great Non‐Communicator? The Mass Communication Deficit of the European Parliament and its Press Directorate*
Authors: ANDERSON PETER J. , McLEOD AILEEN
Published: November 2004

This article was prompted by the poor turnout for the 1999 European Parliament elections and the failure of MEPs since to address effectively key causes of electoral apathy. It focuses on the extent to which the Parliament's press and information directorate, DG‐III, and to a lesser extent, MEPs, are successful in handling their relationships with the mass media, given that the latter is a crucial means of communicating images of the Parliament to the electorate. Having unearthed serious inadequacies in the communication performance of the Parliament, the article investigates the causes of these and the likelihood of their being addressed. The article largely reflects the situation with regard to press and information policy as far as it could be discerned up and until March 2002 (with the exception of the website and external office updates which were undertaken during 2003). Among other things, it paves the way for further studies of the relationship between the European Parliament and the media which will focus on the recent 2004 elections.
Legitimately Diverse, yet Comparable: On Synthesizing Social Inclusion Performance in the EU*
Authors: CHERCHYE LAURENS , MOESEN WIM , VAN PUYENBROECK TOM
Published: November 2004

The open method of co‐ordination (OMC) intends to enhance EU Member States’performance on social inclusion. In this context a set of commonly agreed performance indicators plays an important role. While the communicative power of a synthetic indicator has been recognized, several objections have been raised against such a construction. In this article, we argue that a set of separate indicators can in principle be combined into a meaningful synthetic performance index without giving up on the notion of subsidiarity, and without fundamentally impairing the peer pressure incentives that constitute an important rationale for OMC. We complement the presentation of the conceptual framework with a number of empirical applications, thereby indicating how the basic method may be instrumental for policy benchmarking practice.
The Power of the Presidency: Brokerage, Efficiency and Distribution in EU Negotiations*
Authors: TALLBERG JONAS
Published: November 2004

Decision‐making in the European Union is subject to the risk of negotiation failure, because of governments’incentives to conceal their true preferences. This article argues that the EU Presidency possesses a set of informational and procedural resources that can help unlock incompatible negotiating positions and secure efficient agreements, while simultaneously allowing the government in office to shape distributional outcomes. Drawing on general bargaining theory and rational choice institutionalism, it presents a theory of the demand for, and supply of, brokerage by the chair. The explanatory power of this theory is demonstrated through two case studies: Germany's chairing of the Agenda 2000 negotiations, and France's chairing of the IGC 2000 negotiations.
‘She's always the person with a very global vision’: The Gender Dynamics of Migration, Narrative Interpretation and the Case of Jamaican Transnational Families
Authors: Bauer Elaine , Thompson Paul
Published: November 2004

Migration and gender are two areas in which oral history and life story evidence has been recognised as having a special potential. The article begins with a review of social and historical research on migration, indicating that there has been a surprising lack of in‐depth research published on gender in migration. It then looks at the contribution of oral historians to this literature, and suggests that the focus on narrative styles may not always help us to understand the gender dynamics of migration. Next it presents a case study of Jamaican families who migrated to Britain and North America, showing how women were as often autonomous migrants as men, and that some women, unlike men, were activators of multiple family migration. In conclusion, it argues for more comparative research, using a broader methodological approach.
Mary Malone's Lessons: A Narrative of Citizenship in Federation Australia
Authors: Hearn Mark
Published: November 2004

Between 1886 and 1896 Mary Malone, a young Australian woman of Irish Catholic background, selected eighty‐two articles and fifty‐nine poems to preserve in an old school exercise book. This article argues that the clippings Mary assembled in her exercise book formed a narrative designed to secure a sense of social identity as the Australian colonies moved towards Federation in 1901. The exercise book reflects Mary's meditation on the stories of the colonial public sphere, a meditation that in turn faciliated her participation in community, work and as a citizen. Mary's exercise book reveals the mutual dependence of public and private realms of knowledge and experience, and the subjective assimilation of public discourse required to take a place in the social world.
Female Patriots: Women, War and the Nation in the Period of the Prussian‐German Anti‐Napoleonic Wars
Authors: Hagemann Karen
Published: November 2004

The period of the wars against Napoleon between 1806 and 1815 represents a central phase in German history for the formation of a national political culture organised along gender lines. Acting as a sort of catalyst, these wars accelerated and intensified the nationalisation of the gender order and the ‘gendering’ of the nation, and also permanently influenced the fundamental structures of the relationship between women, the state and the nation. The article analyses the contents and forms of patriotic national women's activities during this period, as well as the ways in which they were perceived and judged in public discourse. In so doing, it explores the relationship between women, war and the nation.
Genetic polymorphisms predicting the outcome of bone marrow transplants
Authors: Dickinson Anne M. , Middleton Peter G. , Rocha Vanderson , Gluckman Eliane , Holler Ernst ,   Eurobank members
Published: November 2004

Analysis of non‐histocompatibility leucocyte antigen (HLA) functional genomics, together with conventional risk factors in haematopoietic stem cell transplantation (HSCT) can lead to predicting outcome in HLA‐matched sibling transplant recipients. Polymorphisms of cytokine genes including tumour necrosis factor α, interleukin‐10, interferon γ and interleukin (IL)‐6, associate with more severe acute graft‐versus‐host disease (aGvHD). Donor genotype for IL‐1 receptor antagonist (IL‐1Ra) has been associated with reduced aGvHD severity. Other genotypes (patient IL‐1Ra, IL‐6 and donor IL‐1α) have been associated with chronic GvHD, or overall survival (Vitamin D receptor and oestrogen receptor). Polymorphisms within genes associated with host defence/inflammatory responses (mannose binding lectin genes, myeloperoxidase genes and the FCγ receptors) have been associated with infections. Polymorphisms of pharmacogenes, such as methylenetetrahydrofolate‐reductase, have been associated with aGvHD and other post‐transplant complications. The NOD2 gene polymorphism, associated with Crohn's disease, has been shown to be associated with risk of gut GvHD. The majority of the studies have been carried out in single centre HLA‐matched sibling cohorts and in relatively few matched unrelated donor transplants. This review gives an overall perspective of the current field of non‐HLA genetics with regard to HSCT outcome, clinical relevance and potential application of the results to clinical management of HSCT.
The role of granulocyte transfusions in neutropenic patients
Authors: Bishton M. , Chopra R.
Published: November 2004

The precise role for donor granulocyte infusions remains to be delineated, partly because of the lack of defined clinical trials. The aim of this article is to summarize the studies undertaken so far and highlight the logistical problems associated with undertaking future studies. We also aim to provide a practical guide to the application of this therapeutic approach.
Pathology of bone marrow in human herpes virus‐8 (HHV8)‐associated multicentric Castleman disease
Authors: Bacon Chris M. , Miller Robert F. , Noursadeghi Mahdad , McNamara Christopher , Du Ming‐Qing , Dogan Ahmet
Published: November 2004

Human herpes virus‐8 (HHV8)‐associated multicentric Castleman disease (MCD) is an unusual systemic lymphoid hyperplasia induced by HHV8‐infected B cells. Most cases develop in the background of human immunodeficiency virus (HIV) infection. Despite the haematological problems at presentation and the difficulties in the initial diagnosis, the bone marrow appearances of MCD have not been described. In this study we examined the pathology of bone marrow in MCD with a view to identify the features that may be helpful in early diagnosis. Bone marrow aspirates and biopsies from 13 cases of MCD (11 of which were HIV+) and 66 control bone marrow biopsies from HIV‐infected cases were studied. The specimens were routinely processed and stained. Immunohistochemistry for HHV8, immunoglobulin light chains, B‐cell and plasma‐cell markers was performed. The most important features were the presence of characteristic MCD lymphoid follicles containing HHV8+ plasmablasts in three of 13 cases of MCD and scattered interstitial HHV8+ plasmablasts in 11 of 13 cases. In control cases, no such follicles were seen and interstitial HHV8+ plasmablasts were rarely detected (four of 66 cases). Our results suggest that the presence of HHV8+ plasmablasts within lymphoid follicles and/or interstitium of the bone marrow are helpful features for the early diagnosis of MCD.
Somatic deletion of the normal β‐globin gene leading to thalassaemia intermedia in heterozygous β‐thalassaemic patients
Authors: Galanello Renzo , Perseu Lucia , Perra Chiara , Maccioni Liliana , Barella Susanna , Longinotti Maurizio , Cao Antonio , Cazzola Mario
Published: November 2004

Two β‐thalassaemia patients, whose constitutive genotype was β39C/β39C→T, had the clinical phenotype β‐thalassaemia intermedia. Analysis of leucocyte DNA showed the presence of the mutated β39C→T‐gene exclusively, while the normal β39C‐gene was also present in reticulocyte RNA. Deletional analysis of chromosome 11p15.5 on leucocyte DNA showed large deletions including the β‐globin gene. Two populations of erythroid progenitors, one heterozygous and the other hemizygous for the β39C→T mutation, were demonstrated in one case. This confirms that, in heterozygous individuals, β‐thalassaemia intermedia may be caused by inactivation of the β‐locus in trans as a result of chromosome 11p15.5 deletions in a subpopulation of haematopoietic cells.
Ferroportin gene silencing induces iron retention and enhances ferritin synthesis in human macrophages
Authors: Gallí Anna , Bergamaschi Gaetano , Recalde Helios , Biasiotto Giorgio , Santambrogio Paolo , Boggi Sabrina , Levi Sonia , Arosio Paolo , Cazzola Mario
Published: November 2004

Missense mutations in the ferroportin gene (SLC11A3) result in haemochromatosis type 4 [HFE4, Online Mendelian Inheritance in Man (OMIM) reference 606069] or ferroportin disease, an autosomal dominant disorder characterized by predominantly reticuloendothelial iron accumulation. To verify whether HFE4 is caused by defective iron recycling because of loss of functionality of ferroportin, we down‐regulated SLC11A gene expression in human macrophages by using small interfering RNAs (siRNAs). Transfection experiments with ferroportin siRNAs resulted in a marked reduction (about two‐thirds on average) in ferroportin mRNA levels as detected by quantitative real time polymerase chain reaction. When macrophages were grown in medium supplemented with iron, cells transfected with siRNAs displayed three‐ to eightfold increases in staining intensities following Perls reaction. These macrophages also showed significant increases in H‐ferritin content. The observation that ferroportin mRNA down‐regulation to levels compatible with haplo‐insufficiency causes increased iron retention and H‐ferritin synthesis in cultured macrophages has important implications. First, this indicates that ferroportin levels must be finely regulated in order to maintain cellular iron homeostasis, and that both copies of SLC11A3 must function efficiently to prevent iron accumulation. Second, this observation supports the hypothesis that reticuloendothelial iron overload in patients with ferroportin disease is caused by loss‐of‐function mutations in the SLC11A3 gene that mainly impair macrophage iron recycling.
Pro‐apoptotic therapy with the oligonucleotide GenasenseTM (oblimersen sodium) targeting Bcl‐2 protein expression enhances the biological anti‐tumour activity of rituximab
Authors: Ramanarayanan Jeyanthi , Hernandez‐Ilizaliturri Francisco J. , Chanan‐Khan Asher , Czuczman Myron S.
Published: November 2004

New strategies have evolved in the treatment of patients with non‐Hodgkin's lymphoma (NHL). Anti‐sense oligonucleotides (ASO) and monoclonal antibody (mAb) therapy, though proven to be safe and effective, have not demonstrated to be curative when used as single agents. We tested an innovative combination strategy involving various mAbs and ASO against Bcl‐2 (G3139) in aggressive preclinical models. G3139, under optimal transfection conditions, decreased the proliferation rate of lymphoma cells by 60–75% when compared with controls. In addition, apoptosis was demonstrated in Raji (25%) and DHL‐4 cells (30%) treated with Genasense following downregulation of Bcl‐2 protein. Downregulation of Bcl‐2 by G3139 was associated with a higher degree of rituximab‐associated, complement‐mediated cytotoxicity and antibody dependent cellular cytotoxicity when compared with rituximab alone‐treated controls. In vivo studies in severe combined immunodeficiency (SCID) mice clearly demonstrated synergistic activity between G3139 and rituximab. Treatment of lymphoma‐bearing SCID mice with G3139 for two consecutive days prior to each rituximab dose resulted in better disease control and survival than treatment with either agent alone or controls. Our findings suggest that Bcl‐2 downregulation by G3139, followed by the administration of rituximab is an efficient anti‐tumour strategy associated with improved survival in lymphoma‐bearing SCID mice.
Characterization of the imprinted polycomb gene L3MBTL, a candidate 20q tumour suppressor gene, in patients with myeloid malignancies
Authors: Bench Anthony J. , Li Juan , Huntly Brian J. P. , Delabesse Eric , Fourouclas Nasios , Hunt Adrienne R. , Deloukas Panos , Green Anthony R.
Published: November 2004

Chromosome 20q deletion is a recurrent chromosomal abnormality associated with myeloid malignancies. L3MBTL represents a strong candidate tumour suppressor gene since it lies within the common deleted region, is a member of the Polycomb‐like family, encodes the human homologue of a Drosophila tumour suppressor and is expressed within haematopoietic progenitor cells. We describe the structure of L3MBTL, identify two putative promoters each associated with two CpG islands and characterize a complex pattern of alternative splicing events. Mutation analysis of the gene in patients with and without a 20q deletion identified several polymorphisms but no acquired mutations. The two CpG islands spanning promoter 2 undergo monoallelic methylation in normal haematopoietic cells consistent with imprinting of L3MBTL. Samples from patients with a 20q deletion retained either the methylated or unmethylated allele but retention of the methylated allele did not correlate with reduction in L3MBTL mRNA levels. The absence of a correlation between L3MBTL methylation and transcription could be shown to reflect loss of imprinting in one patient. In addition, our results demonstrate that inactivation of L3MBTL is not a common occurrence in patients with a 20q deletion or in cytogenetically normal patients with polycythaemia vera.
Antibody levels in adult patients with coeliac disease during gluten‐free diet: a rapid initial decrease of clinical importance
Authors: Midhagen G. , Åberg A.‐K. , Olcén P. , Järnerot G. , Valdimarsson T. , Dahlbom I. , Hansson T. , Ström M.
Published: November 2004

Objective. Analysis of antibodies against tissue transglutaminase (tTG) has been shown valuable in the diagnosis of coeliac disease (CD) but how quickly serum titres decrease after introduction of a gluten‐free diet (GFD) is not known in adults. CD is a well‐recognized disorder amongst the general population and many persons try a GFD for fairly vague symptoms before they seek medical advice. Therefore, it is important to determine the time that the serologic tests remain predictive of the disease after the introduction of a GFD.

Methods. Sera were taken from 22 consecutively biopsy‐proven adult patients with CD in connection with the diagnostic biopsy. The patients were followed for 1 year and sera were taken after 1, 3, 6 and 12 months after start of a GFD. Sera were stored at −20 °C and analysed for IgA antibodies against gliadin, endomysium and two different commercial tTG assays based on recombinant human tTG (tTGrh) and guinea‐pig liver (tTGgp).

Results. Twenty patients could be followed during GFD and all antibody titres fell sharply within 1 month after introduction of a GFD and continued to decline during the survey interval. Thirty days after beginning the diet only 58, 84, 74 and 53% of all patients had positive antibody levels of tTGrh, tTGgp, EmA and AGA respectively.

Conclusions.As the antibodies used to confirm the diagnosis of CD fall rapidly and continue to decline following the introduction of a GFD, it is important that health care providers carefully inquire about the possibility of self‐prescribed diets before patients sought medical attention.
The association between total energy intake and early mortality: data from the Malmö Diet and Cancer Study
Authors: Leosdottir M. , Nilsson P. , Nilsson J.‐Å. , Månsson H. , Berglund G.
Published: November 2004

Objectives.  In animal studies, low energy intake (EI) has been associated with a longer lifespan. We examine whether EI is an independent risk factor for prospective all‐cause mortality, cardiovascular and cancer mortality in humans.

Design.  Population‐based, prospective cohort study.

Setting and subjects.  The Malmö Diet and Cancer Study is a population‐based prospective cohort study. A total of 28 098 individuals, mean age 58.2 years, completed questionnaires on diet and life‐style and attended a physical examination during 1991–96.

Main outcome measures.  Information on mortality was acquired from national registries during a mean follow‐up time of 6.6 years. Subjects were categorized by quartiles of total EI. The first quartile was used as a reference point in estimating multivariate relative risks (RR; 95% CI, Cox's regression model). Adjustments were made for confounding by age and various life‐style factors.

Results.  The lowest total mortality was observed for women in the third quartile (RR: 0.74; CI: 0.57–0.96) and for men in the second and third quartiles (RR: 0.85; CI: 0.69–1.04 and RR: 0.85; CI: 0.69–1.04 respectively). Similar U‐shaped patterns were observed for cardiovascular mortality amongst women and cancer mortality amongst men. A statistically significant trend (P = 0.029) towards lower cardiovascular mortality from the first to the fourth quartile was observed for men.

Conclusions.  Low caloric consumers did, on average, not have lower mortality than average or high caloric consumers. Generally, individuals approximately meeting national recommendations for total EI had the lowest mortality. For men, high caloric intake was associated with lower cardiovascular mortality.
A Pseudomonas aeruginosa quorum‐sensing molecule influences Candida albicans morphology
Authors: Hogan Deborah A. , Vik Åshild , Kolter Roberto
Published: November 2004

Candida albicans is an opportunistic pathogen that is commonly found as a member of the human microflora. The ability of C. albicans to alter its cellular morphology has been associated with its virulence; yeast cells are more prevalent in commensal interactions whereas filamentous cells appear important in opportunistic infections. C. albicans encounters a multitude of other microbial species in the host environment and it is likely that they impact the C. albicans transition between virulent and non‐virulent states. Here, we report that C. albicans morphology is significantly affected by the presence of Pseudomonas aeruginosa, another opportunistic pathogen. In a screen using a C. albicans HWP1–lacZ strain to indicate regions of filamentous growth, we identified P. aeruginosa mutants incapable of inhibiting C. albicans filamentation. Through these studies, we found that 3‐oxo‐C12 homoserine lactone, a cell–cell signalling molecule produced by P. aeruginosa, was sufficient to inhibit C. albicans filamentation without affecting fungal growth rates. Both microscopic analysis and real‐time reverse transcription polymerase chain reaction analysis of morphology‐specific markers confirmed that filamentation was suppressed by 200 µM 3‐oxo‐C12 homoserine lactone. Structurally related compounds with a 12‐carbon chain length, e.g. C12‐acyl homoserine lactone and dodecanol also affected C. albicans filamentation at similar concentrations. In contrast, other acylated homoserine lactones of different chain lengths did not affect fungal morphology. The activity of 3OC12HSL is compared with that of farnesol, a C. albicans‐produced molecule also with a C12‐backbone. The effects that bacteria have on the morphology of C. albicans represents one of the ways by which bacteria can influence the behaviour of fungal cells.
The ATP‐dependent ClpXP and Lon proteases regulate expression of the Yersinia pestis type III secretion system via regulated proteolysis of YmoA, a small histone‐like protein
Authors: Jackson Michael W. , Silva‐Herzog Eugenia , Plano Gregory V.
Published: November 2004

The Yersinia pestis plasmid pCD1‐encoded type III secretion system (T3SS) is essential for the pathogenicity of Y. pestis in mammalian hosts. T3SS‐associated genes are maximally expressed at 37°C in the absence of extracellular calcium. Expression of T3SS genes requires LcrF, an AraC‐like transcriptional activator, and is repressed by YmoA, a small histone‐like protein. The mechanism by which temperature regulates T3SS gene expression has not been determined; however, changes in DNA topology have been implicated in this process. We report here that a Y. pestis strain deficient in production of the ClpXP and Lon proteases does not express a functional T3SS partly because of high cytosolic levels of YmoA. YmoA is rapidly degraded at 37°C in wild‐type Y. pestis, but remains stable in a clpXPlon deletion mutant. The stability of YmoA in wild‐type Y. pestis increased as the growth temperature of the culture decreased; in contrast, YmoA was stable at all temperatures examined in the clpXPlon deletion mutant. These results indicate that the ClpXP and Lon proteases contribute to the environmental regulation of the Y. pestis T3SS system through regulated proteolysis of YmoA.
A potential role for ICP, a leishmanial inhibitor of cysteine peptidases, in the interaction between host and parasite
Authors: Besteiro Sébastien , Coombs Graham H. , Mottram Jeremy C.
Published: November 2004

The biological role of a natural inhibitor of cysteine peptidases (designated ICP) of Leishmania has been investigated by genetic manipulation of the parasite. Null mutants grew normally in vitro, were as infective to macrophages in vitro as wild‐type parasites, but had reduced infectivity to mice. Mutants re‐expressing ICP from a single gene gave partial restoration of virulence in vivo, whereas mutants overexpressing ICP secreted the inhibitor and showed markedly reduced virulence in mice. Promastigotes of the null mutants had similar cysteine peptidase activities as the wild‐type parasites, suggesting that ICP is not required for the expression or processing of the enzymes. The only proteins found to bind to ICP in promastigote cell lysates were fully processed forms of CPA and CPB, showing that ICP does not bind in abundance either to zymogens of the cysteine peptidases or other leishmanial proteins. However, only a small proportion of ICP colocalized with CPA and CPB in the promastigote (in the endoplasmic reticulum and Golgi) and the majority of ICP resided in vesicles that are apparently distinct from endosomes and the multivesicular tubule (MVT)‐lysosome. These data suggest that ICP has a role other than modulation of the activity of the parasite’s own cysteine peptidases and their normal trafficking to the MVT‐lysosome via the flagellar pocket. The finding that ICP partially colocalized with an endocytosed cysteine peptidase leads us to postulate that ICP has a role in protection of the parasite against the hydrolytic environment of the sandfly gut and/or the parasitophorous vacuole of host macrophages.
The RNase E of Escherichia coli has at least two binding sites for DEAD‐box RNA helicases: functional replacement of RhlB by RhlE
Authors: Khemici Vanessa , Toesca Isabelle , Poljak Leonora , Vanzo Nathalie F. , Carpousis Agamemnon J.
Published: November 2004

The non‐catalytic region of Escherichia coli RNase E contains a protein scaffold that binds to the other components of the RNA degradosome. Alanine scanning yielded a mutation, R730A, that disrupts the interaction between RNase E and the DEAD‐box RNA helicase, RhlB. We show that three other DEAD‐box helicases, SrmB, RhlE and CsdA also bind to RNase E in vitro. Their binding differs from that of RhlB because it is not affected by the R730A mutation. Furthermore, the deletion of residues 791–843, which does not affect RhlB binding, disrupts the binding of SrmB, RhlE and CsdA. Therefore, RNase E has at least two RNA helicase binding sites. Reconstitution of a complex containing the protein scaffold of RNase E, PNPase and RhlE shows that RhlE can furnish an ATP‐dependent activity that facilitates the degradation of structured RNA by PNPase. Thus, RhlE can replace the function of RhlB in vitro. The results in the accompanying article show that CsdA can also replace RhlB in vitro. Thus, RhlB, RhlE and CsdA are interchangeable in in vitro RNA degradation assays.
Identification of a polar targeting determinant for Bacillus subtilis DivIVA
Authors: Perry S. E. , Edwards D. H.
Published: November 2004

The Bacillus subtilis protein DivIVA controls both the positioning of the vegetative cell division site and the polar attachment of the chromosome during sporulation. In vegetative growth DivIVA attracts the bipartite cell division inhibitor MinCD away from the cell centre and towards the cell pole. This process ensures the inactivation of old polar division sites and leaves the cell centre free for the assembly of a new cell division complex. During sporulation MinCD and DivIVA levels fall, but DivIVA remains at the cell poles and becomes involved in the migration of the chromosomes to the pole. In order to investigate polar targeting of DivIVA, we undertook a mutational analysis of the 164‐amino‐acid protein. These studies identified one mutant (divIVAR18C) that could not localize to the cell pole but which retained the ability to support both vegetative growth and 50% sporulation efficiency. Further analysis revealed that, in the absence of polar targeting, DivIVAR18C localized to the nucleoid during vegetative growth in a Spo0J/Soj‐dependent manner and required Spo0J/Soj and MinD to orientate the chromosomes correctly during sporulation. We demonstrate that polar targeting of DivIVAR18C is not essential during vegetative growth because the mutant can recognize the cell division site and influences the localization of MinD. Similarly we show that DivIVAR18C can function during sporulation because it can support the Spo0J/Soj orientation of the chromosome. In addition, we establish that both residues 18 and 19 constitute a DivIVA polar targeting determinant.
Clp ATPases are required for stress tolerance, intracellular replication and biofilm formation in Staphylococcus aureus
Authors: Frees Dorte , Chastanet Arnaud , Qazi Saara , Sørensen Karen , Hill Philip , Msadek Tarek , Ingmer Hanne
Published: November 2004

The Hsp100/Clp ATPases constitute a family of closely related proteins of which some members function solely as chaperones whereas others additionally can associate with the unrelated ClpP peptidase forming a Clp proteolytic complex. We have investigated the role of four Clp ATPases in the versatile pathogen, Staphylococcus aureus. Previously, we showed that ClpX is required for expression of major virulence factors and for virulence of S. aureus, but not for survival during heat shock. In the present study, we have inactivated clpC, clpB and clpL and, while none of these mutations affected toxin production, both ClpC and ClpB and to a minor extent ClpL were required for intracellular multiplication within bovine mammary epithelial cells. These defects were paralleled by an inability of the clpC mutant to grow at high temperature and of the clpB mutant to induce thermotolerance indicating that the protective functions of these proteins are required both at high temperature and during infection. By primer extension analysis and footprint studies, we show that expression of clpC and clpB is controlled by the negative heat‐shock regulator, CtsR, and that ClpC is required for its repressor activity. Thus, ClpC is a likely sensor of stress encountered during both environmental stress and infection. In addition to virulence factor production the ability to form biofilms is of importance to S. aureus as a nosocomial pathogen. Interestingly, biofilm formation was reduced in the absence of ClpX or ClpC whereas it was enhanced in the absence of ClpP. Thus, our data show that Clp proteolytic complexes and the Clp ATPases control several key processes of importance to the success of S. aureus as a pathogen.
Regulation of phospholipid biosynthesis by phosphatidylinositol transfer protein Sec14p and its homologues
Authors: Holič Roman , Zágoršek Miloš , Griač Peter
Published: November 2004

Transcription of yeast phospholipid biosynthesis structural genes, which contain an inositol‐sensitive upstream activating sequence in their promoters, responds to the availability of the soluble precursors inositol and choline and to changes in phospholipid metabolism. The INO1 gene is deregulated (derepressed when inositol is present) under the conditions of increased phosphatidylcholine (PtdCho) turnover, as occurs in the sec14Δ cki1Δ strain (SEC14 encodes the major yeast phosphatidylinositol transfer protein; CKI1 encodes choline kinase of the cytidine diphosphate choline pathway of PtdCho biosynthesis). Five proteins (Sfhp) share sequence homology with phosphatidylinositol transfer protein Sec14p. Two (Sfh2p and Sfh4p), when overexpressed largely complement the otherwise essential Sec14p requirement concerning growth and secretion. In this study, we analysed the ability of Sec14 homologues to correct the defect in regulation of phospholipid biosynthesis resulting from defective or missing Sec14p. We also analysed how PtdCho turnover relates to the transcriptional regulation of phospholipid biosynthesis. The results show that (a) none of the Sec14 homologues was able to substitute for Sec14p in its regulatory aspects of phospholipid biosynthesis, (b) removal of phospholipase D activity corrected the aberrant INO1 gene regulation in yeast strains with otherwise high PtdCho turnover, and (c) increased steady‐state phosphatidic acid levels correlated with derepressed levels of the INO1 gene. Overall, the results support the model in which high phosphatidic acid levels lead to derepression of the genes of phospholipid biosynthesis [Henry, S.A. & Patton‐Vogt, J.L. (1998) Prog. Nucleic Acid Res. Mol. Biol.61, 133–179].
Structural determination of the polar glycoglycerolipids from thermophilic bacteria Meiothermus taiwanensis
Authors: Yang Feng‐Ling , Lu Chun‐Ping , Chen Chien‐Sheng , Chen Mao‐Yen , Hsiao Hung‐Liang , Su Yeu , Tsay San‐San , Zou Wei , Wu Shih‐Hsiung
Published: November 2004

The polar glycolipids were isolated from the thermophilic bacteria Meiothermus taiwanensis ATCC BAA‐400 by ethanol extraction and purified by Sephadex LH‐20 and silica gel column chromatography. The fatty acid composition of O‐acyl groups in the glycolipids was obtained by gas chromatography mass spectroscopy analysis on their methyl esters derived from methanolysis and was made mainly of C15:0 (34.0%) and C17:0 (42.3%) fatty acids, with the majority as branched fatty acids (over 80%). Removal of O‐acyl groups under mild basic conditions provided two glycolipids, which differ only in N‐acyl substitution on a hexosamine. Electrospray mass spectroscopy analysis revealed that one has a C17:0 N‐acyl group and the other hydroxy C17:0 in a ratio of about 1 : 3.5. Furthermore, complete de‐lipidation with strong base followed by selective N‐acetylation resulted in a homogeneous tetraglycosyl glycerol. The linkages and configurations of the carbohydrate moiety were then elucidated by MS and various NMR analyses. Thus, the major glycolipid from M. taiwanensis ATCC BAA‐400 was determined with the following structure: α‐Galp(1‐6)‐β‐Galp(1‐6)‐β‐GalNAcyl(1,2)‐α‐Glc(1,1)‐Gro diester, where N‐acyl is C17:0 or hydroxy C17:0 fatty acid and the glycerol esters were mainly iso‐ and anteisobranched C15:0 and C17:0.
Suppression of heat‐ and polyglutamine‐induced cytotoxicity by nonsteroidal anti‐inflammatory drugs
Authors: Ishihara Keiichi , Yamagishi Nobuyuki , Hatayama Takumi
Published: November 2004

We have shown that sodium salicylate activates the heat shock promoter and induces the expression of heat shock proteins (hsps), with a concomitant increase in the thermotolerance of cells. To determine whether these effects are generally displayed by nonsteroidal anti‐inflammatory drugs (NSAIDs), we examined the effects of a cyclooxygenase inhibitor, indomethacin, and a lipoxygenase inhibitor, nordihydroguaiaretic acid. Both inhibitors up‐regulated the hsp promoter at 37 °C through the activation of heat shock factors, and increased cellular levels of hsps in mammalian cells, although the degree of the expression of hsps and thermotolerance of cells differed depending on the drugs. Furthermore, NSAIDs such as sodium salicylate and indomethacin suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. These findings suggest that NSAIDs generally induce the expression of hsps in mammalian cells and may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.
Age‐related impairment of mitochondrial matrix aconitase and ATP‐stimulated protease in rat liver and heart
Authors: Delaval Evelyne , Perichon Martine , Friguet Bertrand
Published: November 2004

Mitochondrial matrix proteins are sensitive to oxidative inactivation, and oxidized proteins are known to accumulate during ageing. The Lon protease is believed to play an important role in the degradation of oxidized matrix proteins such as oxidized aconitase. We reported previously that an age‐related accumulation of altered proteins occurs in the liver matrix of rats and that the ATP‐stimulated proteolytic activity, referred as to Lon‐like protease activity, decreases considerably in 27 month‐old rats, whereas no concomitant changes in the levels of Lon protein expression occur in the liver. Here, we report that this decline is associated with a decrease in the activity of aconitase, an essential Krebs' cycle enzyme. Contrary to what we observed in the liver, the ATP‐stimulated protease activity was found to remain constant in the heart mitochondrial matrix during ageing, and the levels of expression of the Lon protease increased in the older animals in comparison with the younger ones. Although the ATP‐stimulated protease activity remained practically the same in older animals as in younger ones, a decrease in the level of aconitase activity was still observed. Altogether, these results indicate that matrix proteins, such as the critical enzymes aconitase and Lon protease, are inactivated with ageing and that the effects of ageing vary from one organ to another.
Negative chronotropic response to adenosine receptor stimulation in rat right atria after run training
Authors: Priviero Fernanda , De Nucci Gilberto , Antunes Edson , Zanesco Angelina
Published: November 2004

1. The aim of the present study was to evaluate the potency and maximal responses (Emax) to the adenosine receptor agonists N6‐cyclopentyladenosine (CPA), N‐ethylcarboxamidoadenosine (NECA) and N6‐(3‐iodobenzyl)‐5′‐N‐methylcarbaxamidoadenosine (IB‐MECA) in right atria from trained rats. We also investigated the interaction between the training bradycardia and the sensitivity of the chronotropic response mediated by adenosine receptor stimulation.

2. Animals were submitted to run training for 60 min, 5 days a week, over a period of 8 weeks. Mean blood pressure and heart rate were measured in conscious animals. Right atria were isolated and concentration–response curves to CPA, NECA and IB‐MECA were obtained.

3. A reduction in heart rate was found in trained rats, indicating that the training programme was successful in inducing physical conditioning. The three adenosine receptor agonists induced a concentration‐dependent negative chronotropic response. The rank order of potency and Emax for the three adenosine receptor agonists was CPA > NECA > IB‐MECA.

4. Dynamic exercise for 8 weeks did not alter the Emax for CPA, NECA and IB‐MECA. Similarly, the potencies of CPA and NECA were not affected by run training, whereas the potency of IB‐MECA was reduced (6.10 ± 0.09 vs 5.66 ± 0.10 for sedentary and trained groups, respectively).

5. In conclusion, run training for 8 weeks induced a desensitization of the chronotropic response to IB‐MECA without changing the potency of CPA and NECA. These findings exclude the participation of adenosine receptors in the training bradycardia.