bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclodextrin-induced Color Changes in Polymerized Diacetylene Langmuir-Schaefer Films
Authors: Cho Jae-Taek , Woo Sung-Min , Ahn Dong June , Ahn Kwang-Duk , Lee Haiwon , Kim Jong-Man
Published: February 2003

We have observed the first example of a cyclodextrin-induced color change of polymerized diacetylene film sensor. The PDA film, prepared from a diacetylene monomer containing a terminal anilide moiety was found to preferentially interact with α-cyclodextrin causing a color transition which is both time and concentration dependent.
A Combinational Auction Improves School Meals in Chile
Authors: Epstein Rafael , Henríquez Lysette , Catalán Jaime , Weintraub Gabriel Y. , Martínez Cristián
Published: February 2003

Chileȧs school system is using mathematical modeling to assign catering contracts in a singleround sealed-bid combinational auction. The Chilean state spends around US$180 million a year to feed 1,300,000 students from low income families, making this one of the largest state auctions. To improve the quality of the assignment in the auction process, we constructed an integer linear programming model to decide contract awards optimally among different concession holders. The model completely changed the nature of the process in three crucial aspects. First, it gave transparency and objectivity to the complete process, generating competition among firms. Second, it allowed the companies to build flexible territorial bids to include their scale economies, leading to efficient resource allocation. Finally, the model indeed found an optimal solution, which is not easy because the assignment problem was NP-complete with more than 10,000 binary variables. This new methodology improved the price-quality ratio of the meals with yearly savings of around US$40 million—equivalent to the cost of feeding 300,000 children during one year.
SchedulExpert: Scheduling Courses in the Cornell University School of Hotel Administration
Authors: Hinkin Timothy R. , Thompson Gary M.
Published: February 2003

A major curriculum review in the School of Hotel Administration at Cornell University revealed that course scheduling was a major problem for the school. We devised a methodology to improve the system and developed a computer program, SchedulExpert, to automate the scheduling process. By using the program, we have eliminated conflicts among core required courses by year and among electives within areas and minimized conflicts among elective sets specified by faculty members. We used to spend weeks on scheduling, but now we achieve better results in only a few hours.
Optimization of an industrial afterburner
Authors: Öberg Tomas
Published: February 2003

An industrial afterburner was optimized using statistical experimental design. A computer‐generated optimal design was adapted to domain constraints and previous knowledge about the experimental variables. Carbon monoxide was used as a general indicator for the operating conditions, and a reduced response surface model was fitted to the experimental data. In a second phase the initial results were verified and investigated in more detail with regard to chlorinated aromatics. The empirical models obtained were further interpreted using results from laboratory investigations and more fundamental knowledge from combustion theory. Copyright © 2003 John Wiley & Sons, Ltd.
Centering and scaling in component analysis
Authors: Bro Rasmus , Smilde Age K.
Published: February 2003

In this paper the purpose and use of centering and scaling are discussed in depth. The main focus is on two‐way bilinear data analysis, but the results can easily be generalized to multiway data analysis. In fact, one of the scopes of this paper is to show that if two‐way centering and scaling are understood, then multiway centering and scaling is quite straightforward. In the literature it is often stated that preprocessing of multiway arrays is difficult, but here it is shown that most of the difficulties do not pertain to three‐ and higher‐way modeling in particular. It is shown that centering is most conveniently seen as a projection step, where the data are projected onto certain well‐defined spaces within a given mode. This view of centering helps to explain why, for example, centering data with missing elements is likely to be suboptimal if there are many missing elements. Building a model for data consists of two parts: postulating a structural model and using a method to estimate the parameters. Centering has to do with the first part: when centering, a model including offsets is postulated. Scaling has to do with the second part: when scaling, another way of fitting the model is employed. It is shown that centering is simply a convenient technique to estimate model parameters for models with certain offsets, but this does not work for all types of offsets. It is also shown that scaling is a way to fit models with a weighted least squares loss function and that sometimes this change in objective function cannot be performed by a simple scaling step. Further practical aspects of and alternatives to centering and scaling are discussed, and examples are used throughout to show that the conclusions in the paper are not only of theoretical interest but can have an impact on practical data analysis. Copyright © 2003 John Wiley & Sons, Ltd.
Multivariate data analysis: quo vadis?
Authors: Esbensen Kim H. , Höskuldsson Agnar
Published: February 2003

Industry and academe are characterized by steadily increasing huge amounts of data with very different data structures. Both static and dynamic data contexts need to be addressed. A new generic, flexible and comprehensive general data‐modelling concept is needed to cope with these demands. During the past 20 years, object‐oriented programming (OOP) has become a de facto industry standard of how programming tasks should be defined and carried out in the context of deterministic data modelling. We present here a first framework of analogous ideas for multivariate data analysis. A new strategy, object‐oriented data modelling (OODM), is proposed which is invariant with respect to the specific data structures and the practical data context. We present a first delineation of meta‐principles, ideas and stimulants for tomorrow's possible development paths of modelling, in which the fundamental data analysis unit is the generalized ‘PLS object’ in the OOP sense. The key novel aspect concerns inter‐object information transfer, facilitated by ‘root‐sum‐of‐squares averaging’ (RSSA), which uses w loading weights as between‐object transfer agents. These features allow a powerful generalization beyond multiblock as well as hierarchical bilinear modelling to be laid out. The present part I outlines a first framework for the new data‐modelling approach, while part II forms a complementing catalogue of specific options and possibilities when implementing the new principles. Copyright © 2003 John Wiley & Sons, Ltd.
O2‐PLS, a two‐block (X–Y) latent variable regression (LVR) method with an integral OSC filter
Authors: Trygg Johan , Wold Svante
Published: February 2003

The O2‐PLS method is derived from the basic partial least squares projections to latent structures (PLS) prediction approach. The importance of the covariation matrix (Y
TX) is pointed out in relation to both the prediction model and the structured noise in both X and Y. Structured noise in X (or Y) is defined as the systematic variation of X (or Y) not linearly correlated with Y (or X). Examples in spectroscopy include baseline, drift and scatter effects. If structured noise is present in X, the existing latent variable regression (LVR) methods, e.g. PLS, will have weakened score–loading correspondence beyond the first component. This negatively affects the interpretation of model parameters such as scores and loadings. The O2‐PLS method models and predicts both X and Y and has an integral orthogonal signal correction (OSC) filter that separates the structured noise in X and Y from their joint X–Y covariation used in the prediction model. This leads to a minimal number of predictive components with full score–loading correspondence and also an opportunity to interpret the structured noise. In both a real and a simulated example, O2‐PLS and PLS gave very similar predictions of Y. However, the interpretation of the prediction models was clearly improved with O2‐PLS, because structured noise was present. In the NIR example, O2‐PLS revealed a strong water peak and baseline offset in the structured noise components. In the simulated example the O2‐PLS plot of observed versus predicted Y‐scores (u vs u
hat) showed good predictions. The corresponding loading vectors provided good interpretation of the covarying analytes in X and Y. Copyright © 2003 John Wiley & Sons, Ltd.
Multivariate analysis of G protein‐coupled receptors
Authors: Gunnarsson Ingrid , Andersson Per , Wikberg Jarl , Lundstedt Torbjörn
Published: February 2003

With the rapidly increasing amount of data of a bioinformatic nature, it is of great interest to find different methods to help overview, classify, identify outliers and in other ways extract information from the large amounts of data. In this paper, chemometric methods often applied in statistical process control are utilized to analyse a large number of G protein‐coupled receptors. They have been investigated with respect to groupings among the sequences based on their physicochemical properties using multivariate methods. The transmembrane (TM) regions of 897 receptors were examined. The sequences were multivariately characterized using principal properties for amino acids. The methods used include principal component analysis (PCA), hierarchical principal component analysis (HPCA) and partial least squares projections to latent structures (PLS). The results show that groups of receptors belonging to the same functional class can be identified using this approach, and that the rhodopsin class of G protein‐coupled receptors is very different from other classes present in the study with regard to their physicochemical properties. Copyright © 2003 John Wiley & Sons, Ltd.
Multivariate data analysis: quo vadis?
Authors: Höskuldsson Agnar , Esbensen Kim H.
Published: February 2003

In part I we presented an analysis of the situation facing multivariate data analysis at the turn of the
millenium. As a direct analogy to object‐oriented programming we presented similar
ideas for multivariate data analysis, resulting in a proposal for a new paradigm for
object‐oriented data modelling (OODM), which is invariant w.r.t. data
structures and practical data contexts. In this part II we give a first overview of tomorrow's
meta‐principles, ideas and stimulants for the implementation of multivariate OODM. This is
exemplified by analysing the typical objectives behind data modelling, and we give numerous
suggestions for what may be important development areas for the near future. We have
arranged the many disparate data analysis objectives in a series of ‘levels of modelling’
in an attempt to make a systematic categorization. Copyright © 2003 John Wiley & Sons,
Ltd.
Socially responsible investment in the UK—criteria that are used to evaluate suitability
Authors: Jayne Michael Ross , Skerratt Glynn
Published: February 2003

Ethical and environmental investment criteria, collectively grouped under the title socially responsible investment (SRI), are becoming increasingly important factors in today's markets. Nowadays, banks, pension funds and other investment institutions frequently undertake some form of environmental risk analysis of an organization's relevant operational practices before committing themselves to direct investment. Factors such as a company's past pollution record, its future potential to contaminate and its overall social policy are often cited as important influences in this respect.

Many funding institutions now have their own ethical investment arms, even if these are not part of their mainstream activity. Understanding the role of ‘ethical’ investors and their ‘ethical’ considerations is becoming increasing important to fund managers and businesses alike.

The activities of fund managers who are specifically marketing themselves and their products as ‘ethical’ have been explored using an in‐depth questionnaire, in order to determine the nature of the environmental and sustainability criteria that are used as a basis for directing investments, and the ways in which these factors are compared and balanced during the evaluation process. Copyright © 2003 John Wiley & Sons, Ltd. and ERP Environment.
Should we measure corporate social responsibility?
Authors: Korhonen Jouni
Published: February 2003

This paper is critical towards efforts that try and measure corporate social responsibility (CSR). A critical approach can be important for the development of the theory of the emerging field of corporate social responsibility. A critical and provocative approach can generate discussion and debate. Three main points of critique are presented toward the current efforts in the literature to measure corporate contributions to economic, social and ecological sustainability. First, the use of the concepts of eco‐efficiency and eco‐efficacy in measuring corporate contributions to sustainability are criticized from the viewpoint of the complementarity relation of human‐manufactured capital, natural capital and social sustaining functions. Second, the use of measures that focus on an individual process or an individual company are reconsidered with an approach to industrial and firm networks. Third, the use of the monetary value is reconsidered, e.g. by suggesting an approach based on physical material and energy flows and on a new paradigmatic foundation for social responsibility. The social and ecological indicators illustrating the social and environmental impacts of economic activity and of firms can be combined with economic indicators, but not expressed in monetary terms. Copyright © 2003 John Wiley & Sons, Ltd. and ERP Environment.
Gene expression profiling in islet biology and diabetes research
Authors: Bernal‐Mizrachi Ernesto , Cras‐Méneur Corentin , Ohsugi Mitsuru , Permutt M. Alan
Published: February 2003

Following the sequencing of most of the human and mouse genomes, the next task for physicians and scientists will be to assess the relative levels of expression of these genes during development, following exposure to various nutritional and pharmacological conditions, and in disease states such as diabetes and related metabolic disorders. This review provides an overview of the various methodologies available for monitoring global gene expression. Use of cDNA libraries, Expressed Sequence Tag (EST)equencing projects and databases, differential display (DD), serial analysis of gene expression (SAGE), subtractive cloning, and both cDNA and oligo microarrays are discussed, along with their merits and limitations. The Endocrine Pancreas Consortium http://www.cbil.upenn.edu/EPConDB/ has constructed mouse and human cDNA libraries from adult and various stages of embryonic development of endocrine pancreas. Over 100 000 ESTs have been deposited in public databases, and each clone is available through the IMAGE Consortium. A guide to Internet access is provided for future investigation. Copyright © 2002 John Wiley & Sons, Ltd.
The prevalence of coeliac disease in Libyan children with type 1 diabetes mellitus
Authors: Ashabani Abdelhakim , Abushofa Umaima , Abusrewill Suliman , Abdelazez Mahmoud , Tučková Ludmila , Tlaskalová‐Hogenová Helena
Published: February 2003

Background

Diagnosis of atypical and silent forms of coeliac disease (CD) is important because of its serious complications. Increased prevalence of coeliac disease worldwide in individuals with type 1 diabetes mellitus (DM) was described. There are no data on the prevalence of CD in the Libyan population and Libyan DM patients. The aim of this study was to test the occurrence of CD‐related markers in a group of Libyan children with DM.

Methods

A cohort of 234 Libyan children with DM (121 males and 113 females) aged between 2 and 25 years and 50 healthy school children were screened for CD using the enzyme‐linked immunosorbent assay (ELISA) for IgA and IgG antigliadin (AGA), anti‐tissue transglutaminase (tTG), and anticalreticulin antibodies. An IgA antiendomysial antibody (EmA) was determined by immunofluorescence.

Results

Fifty patients (21.3%) were positive for IgA‐ and/or IgG‐AGA, tTG, and anticalreticulin antibodies. Nineteen of these patients were EmA positive and seven were EmA negative. From the EmA negative patients we found that five sera with IgA deficiency had high IgG class in antigliadin, anti‐tissue transglutaminase, and anticalreticulin antibodies. All these patients underwent intestinal biopsy. Twenty‐four had clear histological (atrophy) evidence of CD including the EmA negative patients with IgA deficiency; prevalence of CD in this study was thus 10.3%.

Conclusion

The prevalence of CD in diabetic children in Libya was found to be higher than in several European countries. Serological markers are useful for identifying DM patients who should undergo a small intestinal biopsy. Copyright © 2002 John Wiley & Sons, Ltd.
Ascorbic acid supplementation restores defective leukocyte‐endothelial interaction in alloxan‐diabetic rats
Authors: Onishi Zanardo Renata Cristina , Cruz José Walber Miranda Costa , de Oliveira Maria Aparecida , Fortes Zuleica Bruno
Published: February 2003

Background

Defective leukocyte‐endothelial interactions are observed in experimental diabetes and may reduce the capacity to mount an adequate inflammatory response. The present study investigated the effect of ascorbic acid, an inhibitor of free radical and glycated protein formation as well as an aldose reductase inhibitor, on leukocyte‐endothelial interaction in alloxan‐diabetic rats.

Methods

Rats were rendered diabetic by alloxan injection (40 mg/kg; iv). After 30 days, diabetic and nondiabetic controls were supplemented for 12 days with ascorbic acid (50 or 200 mg/kg/day) or received saline by gavage. The number of rollers, stickers after zymosan‐activated plasma (10%) or leukotriene B4 (1 µM) applied topically, and migrated cells after local injection of carrageenan (100 µg) were determined in the venules of the internal spermatic fascia by intravital microscopy. Erythrocyte velocity and wall shear rate were determined as well. Reactive oxygen species formation by endothelial cells was measured in vivo by the same technique. Immunocytochemistry for ICAM‐1 detection on the endothelium of the venules of the internal spermatic fascia was carried out in cross sections of the whole testis of the animals.

Results

The reduced number of rollers, stickers and migrated cells, as well as the higher production of reactive oxygen species by endothelial cells in diabetic rats was corrected by ascorbic acid supplementation. The low immunoreactivity for ICAM‐1 in the venules of diabetic rats was improved by ascorbic acid supplementation. Ascorbic acid supplementation did not interfere with erythrocyte velocity or wall shear stress. Ascorbic acid administered to control rats did not alter the parameters studied above.

Conclusion

We conclude that ascorbic acid improves leukocyte‐endothelial interaction in diabetic rats at least in part by restoring the expression of ICAM‐1 in the venules of diabetic rats. Copyright © 2002 John Wiley & Sons, Ltd.
The ability of murine dendritic cell subsets to direct T helper cell differentiation is dependent on microbial signals
Authors: Manickasingham Shivanthi P. , Edwards Alexander D. , Schulz Oliver , Sousa Caetano Reis e
Published: February 2003

Dendritic cells (DC) initiate T cell responses and direct the class of T cell immunity through the production of Th‐polarizing cytokines. In the mouse, immunization with CD8α+ DC has led to Th1 priming whereas immunization with CD8α– DC has been associated with Th2 induction. Here, we use a direct T cell priming assay in vitro to re‐examine the Th‐directing potential of total DC or purified CD4+ DC, CD8α+ DC or CD4– CD8α– (double‐negative; DN) DC subsets from mouse spleen. We show that the default Th effector phenotype induced by priming with DC depends on the protocol used for T cell purification, the T cell:antigen‐presenting cell ratio and the antigen dose but is only marginally affected by DC subtype. All DC subsets can direct increased Th1 development in response to microbial stimuli known to elicit IL‐12 production. Similarly, all subsets can suppress Th1 development and allow Th2 cellsto expand upon exposure to IL‐10‐inducing microbial agents. The flexibility of DC in directing Th development in function of microbial signals argues against the notion of pre‐determined "DC1" and "DC2" subsets and suggests that multiple DC subtypes can direct an appropriate Th response to different classes of infectious agents.
β‐Catenin expression in thymocytes accelerates thymic involution
Authors: Xu Youyuan , Sen Jyoti
Published: February 2003

Age‐related thymic involution in mammals is accompanied by decreased generation of naïve T cells without significant reduction in the number of peripheral T cells. This leads to inefficient immune responses and inadequate combating of infections and other challenges to the immune system in older mammals. The molecular mechanisms that underlie this phenomenon are not known. In this report we show that expression of β‐catenin in thymocytes enhances thymic involution. The effect of β‐catenin expression is seen in all the thymic sub‐populations, suggesting that an age‐related developmental process is accelerated. We also show that, as in normal mice, thymic involution does not lead to a drastic reduction in splenic T cells in β‐catenin‐transgenic mice. This study identifies β‐catenin expression in thymocytes as a molecular target of age‐related thymic involution.
Severe Mycobacterium bovis BCG infections in a large series of novel IL–12 receptor β1 deficient patients and evidence for the existence of partial IL–12 receptor β1 deficiency
Authors: Lichtenauer‐Kaligis Elgin G. R. , de Boer Tjitske , Verreck Frank A. W. , van Voorden Sjaak , Hoeve Marieke A. , Vosse Esther van de , Ersoy Fugen , Tezcan Ilhan , van Dissel Jaap T. , Sanal Ozden , Ottenhoff Tom H. M.
Published: February 2003

Cell mediated immunity plays a critical role in human host defence against intracellular bacteria. In patients with unusual, severe infections caused by poorly pathogenic species of mycobacteria and salmonellae, genetic deficiencies have been identified in key genes in the type‐1 cytokine pathway, especially in IFNGR1 and IL12RB1. Here, we analyzed 11 patients originating from Turkey and suffering from unusual Mycobacterium bovis Bacille Calmette‐Guerin infections following vaccination, and found that most patients (n=8) are deficient in IL‐12Rβ1 expression and function. No defects were found in patients' IFN‐γR or IL‐18R. In addition, a first patient suffering from partial IL‐12Rβ1 deficiency is described. This patient presented with an intermediate cellular and immunological phenotype: a consistent, low response to IL‐12 was found, which could be further augmented by IL‐18. Despite a lack of cell surface IL‐12Rβ1 expression, normal levels of intracellular IL‐12Rβ1 protein were detectable, which was not seen in the other, completely IL‐12Rβ1 deficient patients examined. Moreover, this patient had a relatively mild clinical phenotype and was the only individual with a single homozygous amino acid substitution in IL‐12Rβ1 (C198R). Collectively, our findings indicate that idiopathic, unusually severe infections due to M. bovis BCG can be caused by complete as well as partial IL‐12Rβ1 deficiency.
Clonally expanded CD4+CD28null T cells in rheumatoid arthritis use distinct combinations of T cell receptor BV and BJ elements
Authors: Wagner Ulf , Pierer Matthias , Kaltenhäuser Sylke , Wilke Bernd , Seidel Wolfram , Arnold Sybille , Häntzschel Holm
Published: February 2003

Clonally expanded, autoreactive CD4+CD28null cells can be found in the peripheral blood of patients with rheumatoid arthritis and have been shown to be associated with severeextra‐articular disease manifestations. We investigated the size of the CD4+CD28null compartment and the TCR β chain repertoire of expanded CD4+ clonotypes in 94 rheumatoid arthritis patients by complementarity‐determining region 3 (CDR3) length analysis (spectratyping) in the BV6 and BV14 TCR families, with primers specific for three arbitrarily chosen β chain joining elements (BJ1S2, BJ2S3 and BJ2S7). The spectratyping results showed a strong correlation of the size of the CD4+CD28null compartment with the detected number of BV14 clonotypes, whereas no association with BV6 oligoclonality was found. Only clones using the BV14–BJ1S2 and BV14–BJ2S3 combinations contributed to this correlation, however, whereas BV14–BJ2S7 clones did not. This preferential correlation implies a role for the TCR β chain in stimulating clonal outgrowth and argues against the previously suggested superantigenic stimulation of in‐vivo‐expanded clones. Instead, since no evidence for shared antigen specificity could be detected, clonal expansion of T cells in rheumatoid arthritis might be influenced by the BJ elements because of changes in the flexibility of the protein backbone of the β‐chain.
Dok protein family members are involved in signaling mediated by the type 1 Fcϵ receptor
Authors: Abramson Jakub , Rozenblum Guido , Pecht Israel
Published: February 2003

Aggregation of type 1 Fcϵ receptors (FcϵRI) on mast cells activates a biochemical cascade that culminates in secretion of inflammatory mediators, as well as in changes of cell morphology and adhesion properties. Some of the intracellular components involved in the early coupling events are still unidentified. Here we show that two adaptor proteins, downstream of tyrosine kinases (Dok)‐1 and Dok‐2, are involved in the FcϵRI coupling cascade in the rat mucosal‐type mast cells of the RBL‐2H3 line. Dok‐1 is found to be constitutively associated with the FcϵRI, even in untreated cells, and this interaction is not affected by this receptor's aggregation. Both Dok forms undergo a fast and relatively long‐term tyrosyl‐phosphorylation. This modification of Dok‐1 increases its association with RasGAP, suggesting that it is modulating Ras activity. Indeed, we further found that FcϵRI‐mediated Ras/Raf1/Erk signaling as well as the de novo synthesis of TNF‐α are markedly reduced in cells overexpressing Dok‐1. Moreover, FcϵRI clustering causes both Dok‐1 and Dok‐2 to become docking sites for other signaling molecules including Nck, CrkL and Cas. The latter proteins have been implicated particularly in regulation of the actin‐cytoskeletal reorganization. Hence Dok‐1/Dok‐2 may also be involved in the FcϵRI‐stimulated processes of cytoskeleton rearrangement required for cell adhesion, membrane ruffling and exocytosis.
Natural killer cell‐mediated lysis of dorsal root ganglia neurons via RAE1/NKG2D interactions
Authors: Backström Eva , Chambers Benedict J. , Ho Emily L. , Naidenko Olga V. , Mariotti Raffaella , Fremont Daved H. , Yokoyama Wayne M. , Kristensson Krister , Ljunggren Hans‐Gustaf
Published: February 2003

Natural killer cells have been reported to be able to kill various transformed and virus‐infected target cells. It was recently observed that NK cells also could kill syngeneic dorsal root ganglia (DRG) neurons by a perforin‐dependent mechanism. We demonstrate here that this phenomenon does not reflect a general ability of NK cells to kill neurons in culture. While DRG neurons of the peripheral nervous system were readily killed, ventral spinal cord neurons and hippocampal neurons of the central nervous system (CNS) were resistant to lysis. The resistance to NK cell‐mediated lysis of the latter neurons was not related to protection by MHC class I molecules, since similar β2‐microglobulin–/– neurons were equally resistant to lysis. While exploring other possible molecular mechanisms for the selective triggering of lysis of DRG neurons, we observed that the retinoic acid early inducible gene‐1 (RAE‐1), the product of which is a ligand for the NK cell‐activating receptor NKG2D, was expressed at high levels in the DRG neurons. In contrast, RAE‐1 was expressed only at very low levels in the resistant CNS‐derived neurons. Blocking NK cells withanti‐NKG2D antibodies inhibited NK cell‐mediated killing of the DRG neurons. Thus, we demonstrate that NK cell‐mediated lysis of DRG neurons correlates with the expression of RAE‐1 and that this lysis is dependent on activation of NK cells via NKG2D. This observation demonstrates that NK cells can kill non‐pathogen‐infected or non‐transformed syngeneic cells through activation of the NKG2D receptor.
Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer
Authors: Bauernhofer Thomas , Kuss Iris , Henderson Brent , Baum Andrew S. , Whiteside Theresa L.
Published: February 2003

Natural killer (NK) cells (CD56+/CD3–) in the circulation of cancer patients were reported to have low NK activity and undergo spontaneous apoptosis. A possible relationship between apoptosis and impaired NK activity was studied by Annexin V‐binding and NK‐cell assays performed with peripheral blood mononuclear cells of patients with head and neck cancer (HNC), breast cancer (BC) and normal controls (NC). Cells stained with Annexin V (Anx) and antibodies to CD56, CD3, CD95, CD25, CD122 or CD132 were examined by flow cytometry. NK activity was tested against K562 targets in 4‐h 51Cr‐release assays. The ratio of CD56dim/CD56bright NK cells was significantly different in patients vs. controls (10 vs. 16; p<0.01). A significantly greater percentage of CD56dim NK cells bound Anx in HNC patients (27±17%, median ± SD) or BC (46±18%) than in NC (15±18%, p<0.04and p<0.0002, respectively). CD56dim NK cells were preferentially targeted for apoptosis. NK activity was significantly lower in patients with HNC and BC than in NC (p<0.009). An inverse correlation between NK activity and the percent of Anx+CD56dim NK cells was observed in cancer patients (p =0.002) but not in NC. In patients, circulating CD56dim NK cells were targeted for apoptosis, leading to low levels of NK activity.
Increased expression of DC‐SIGN+IL‐12+IL‐18+ and CD83+IL‐12–IL‐18– dendritic cell populations in the colonic mucosa of patients with Crohn's disease
Authors: Velde Anje A. te , van Kooyk Yvette , Braat Henri , Hommes Daan W. , Dellemijn Trees A. M. , Slors J. Frederik M. , van Deventer Sander J. H. , Vyth‐Dreese Florry A.
Published: February 2003

Dentritic cells (DC) as antigen‐presenting cells are most likely responsible for regulation of abnormal T cell activation in Crohn's disease (CD), a chronic inflammatory bowel disease. Wehave analyzed the expression of activation and maturation markers on DC in the colon mucosa from patients with CD compared with normal colon, using immunohistochemical techniques. We found two distinct populations of DC present in CD patients: a DC‐specific ICAM‐3 grabbing non‐integrin (DC‐SIGN)+ population that was present scattered throughout the mucosa, and a CD83+ population that was present in aggregated lymphoid nodules and as single cells in the lamina propria. In normal colon the number of DC‐SIGN+ DC was lower and CD83+ DC were detected only in very few solitary lymphoid nodules. Co‐expression of activation markers and cytokine synthesis was analyzed with three‐color confocal laser scanning microscopy analysis. CD80 expression was enhanced on the majority of DC‐SIGN+ DC in CD patients, whereas only a proportion of the CD83+ DC co‐expressed CD80 in CD as well as in normal tissue. Surprisingly, IL‐12 and IL‐18were only detected in DC‐SIGN+ DC and not in CD83+ DC. A similar pattern of cytokine production was observed in normal colon albeit to a much lesser extent. The characteristics ofthese in‐situ‐differentiated DC markedly differ from the in‐vitro‐generated DC that simultaneously express DC‐SIGN, CD83 and cytokines.
The kidney as a second site of human C‐reactive protein formation in vivo
Authors: Jabs Wolfram J. , Lögering Birgit A. , Gerke Peter , Kreft Burkhard , Wolber Eva‐Maria , Klinger Matthias Heinrich Friedrich , Fricke Lutz , Steinhoff Jürgen
Published: February 2003

C‐reactive protein (CRP) is the main acute phase reactant in humans. Its production is presumably restricted to the liver but extrahepatic expression by inflamed tissue has not been studied indetail. By real‐time PCR and immunohistochemistry we here show that renal cortical tubular epithelial cells (TEC) express CRP mRNA and protein within 6 h after stimulation with conditioned medium (CM) or IL‐6, but not IL‐1α or TNF‐α. Western blot analysis with monoclonal anti‐CRP antibody that recognizes native CRP revealed protein secretion into supernatants of CM‐stimulated TEC cultures. While hepatoma‐derived Hep3B cells could be induced similarly, peripheral blood mononuclear cells could not. CRP mRNA transcripts were observed in nephrectomized renal allografts with severe acute rejection but not with chronic allograft nephropathy (CAN). Of 19 needle biopsies of acutely rejecting kidney transplants, 15 demonstrated CRP mRNA production with the relative expression levels increasing with the severity of rejection. On the other hand, none of 7 graft biopsies with acute tubular necrosis (ATN) or CAN showed CRP mRNA expression. By using monoclonal anti‐CRP antibody, cortical tubules as well as glomerular cells were shown to locally express CRP in rejecting, but not in ATN kidneys. We conclude that inflamed kidneys represent a so far unknown site of CRP formation in vivo. These data shed new light on the acute phase reaction not merely representing a systemic inflammatory pathway but probably being part of the local immune response.
Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal model for autoimmune disease studies
Authors: Chen Dan , Ueda Roanna , Harding Fiona , Patil Namrata , Mao Yifan , Kurahara Carole , Platenburg Gerard , Huang Manley
Published: February 2003

Linkage studies indicate close associations of certain HLA alleles with autoimmune diseases. To better understand how specific HLA alleles are related to disease pathogenesis, we have generated an HLA DR3/DQ2 transgenic mouse utilizing a 550‐kb yeast artificial chromosome (YAC) construct containing the complete DRα, DRβ1, DRβ3, DQα, and DQβ regions. The transgenic mouse (4D1/C2D) in an I‐Aβo background appears healthy with no signs of autoimmune diseases. Lymphoid tissues as well as CD4+ T cells develop normally. Characterization of the transgene expression demonstrates that ∼90% of B cells express high levels of DR3 and 50–70% of B cells express DQ2. CD11c+ dendritic cells express high levels of DR and DQ. Approximately12–18% of resting T cells are positive for DR expression, and further up‐regulation to 40–50% expression is seen upon activation with anti‐CD3/anti‐CD28 mAb. These results suggest that the transgenic construct confers a high fidelity to the normal human temporal and spatial expression profile. Analysis of T cell receptor repertoire in transgenic mice confirms that DR3/DQ2 are able to mediate thymic selection. Furthermore, transgenic mice respond to a DR3‐restricted antigen, demonstrating antigen processing and presentation by antigen‐presenting cells (APC). Purified T cells from ovalbumin (OVA)‐immunized 4D1 mice respond to human APC co‐cultured with OVA, suggesting appropriate antigen/DR3 or DQ2 recognition by murine T cells. Immunoglobulin isotype switching is also observed, indicating functional T‐B cognate interactions. Thus, the DR3/DQ2 transgenic mouse has normal lymphoid development and functionality that are mediated by HLA transgenes and can be used to investigate HLA‐associated immunological questions.
Mechanisms of H4/ICOS costimulation: effects on proximal TCR signals and MAP kinase pathways
Authors: Feito Maria Jose , Vaschetto Rosanna , Criado Gabriel , Sánchez Alejandra , Chiocchetti Annalisa , Jiménez‐Periáñez Arturo , Dianzani Umberto , Portoles Pilar , Rojo Jose M.
Published: February 2003

H4/ICOS is a costimulatory molecule related to CD28. Its effects on early TCR signals have been analyzed in mouse CD4+ Th2 cells, expressing H4/ICOS at higher levels than Th1 clones. Anti‐H4/ICOS antibodies strongly enhanced CD3‐mediated tyrosine phosphorylation of ZAP‐70, ζ, or Vav, as well as extracellular signal‐regulated kinase (ERK), Jun N‐terminal kinase (JNK) and p38 MAP kinase activation in these cells. The association of phosphoinositide 3‐kinase (PI‐3K) to H4/ICOS was enhanced by H4/ICOS cross‐linking, and PI‐3K inhibitors inhibited ERK and JNK activation andIL‐4/IL‐10 secretion, but not p38 MAP kinase or ZAP‐70 activation. H4/ICOS‐mediated activation of JNK, but not ERK or p38, is partially dependent on the expression of CD4 by the cells, whereas H4/ICOS costimulation is partially independent on CD28 expression. Cytochalasin D, an inhibitor of actin polymerization, inhibited ZAP‐70, MAP kinase activation, or IL‐4/IL‐10 secretion. Neither cyclosporin A nor inhibitors of PKC produced detectable inhibition of ZAP‐70 phosphorylation or MAP kinase activation in these Th2 cells. Cyclosporin A strongly inhibited IL‐4, but not IL‐10 secretion. ERK or JNKinhibitors partially inhibited IL‐4 and IL‐10 secretion, while PKC or p38 inhibitors had no significant effects on IL‐4 or IL‐10 secretion. Taken together, our data show clear similarities of costimulation mechanisms between H4/ICOS and CD28 during the early steps of TCR activation.
Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis
Authors: Cao Duojia , Malmström Vivianne , Baecher‐Allan Clare , Hafler David , Klareskog Lars , Trollmo Christina
Published: February 2003

In the homeostasis of the immune system regulatory cells play a major role. Removal of one group of regulatory cells, the CD25+CD4+ T cells, leads to autoimmune manifestations in experimental animal models, and reintroduction of this population prevents disease. This study addresses the role of such regulatory T cells in humans with an autoimmune disease, where we demonstrate the presence of CD25brightCD4+ T cells in the target organ of patients with active rheumatoid arthritis. The patients displayed an enrichment of CD25brightCD4+ T cells in synovial fluid as compared to peripheral blood. These cells are functional regulatory cells, as they were able to suppress in vitro proliferation of autologous T cells, bothfrom synovial and peripheral blood origin. Although the frequency of CD25brightCD4+ T cells varied between patients, it was found to be constant over time in any one joint during each relapse. Numbers were also comparable in two inflamed knee joints of one and the same patient, emphasizing the symmetry of the disease. In summary, it is striking that in addition to all activated, potentially pathological T cells the synovial fluid from RA patients also contains CD25‐expressing CD4+ T cells with a regulatory capacity.
Prevention of mucosally induced uveitis with a HSP60‐derived peptide linked to cholera toxin B subunit
Authors: Phipps Paula A. , Stanford Miles R. , Sun Jia‐Bin , Xiao Bao‐Guo , Holmgren Jan , Shinnick Thomas , Hasan Adam , Mizushima Yutaka , Lehner Thomas
Published: February 2003

Oral administration of the uveitogenic peptide (aa 336‐351) derived from human HSP60 induced clinical and histological manifestations of uveitis in 65.8% (48/73) of Lewis rats. Uveitis was significantly decreased to 16.7% (11/66) in parallel experiments with the peptide linked to recombinant cholera toxin B subunit (rCTB), also given by mouth (χ2=34.2, p<0.0001). The protective efficacy between tolerized and immunized animals was 74.7%. Adoptive transfer of mesenteric lymph node cells from tolerized rats prevented the development of uveitis. A significantly higher proportion of regulatory CD4+CD45RClowRT6+ subset of Th2 memory cells were found in the mesenteric lymph nodes (p<0.005) and spleens (p⩽0.05) of tolerized rats without uveitis, as compared with immunized rats and uveitis. In situ hybridization studies of mesenteric lymph nodes and/or the uveal tract showed significant increases in IL‐10 and TGF‐β mRNA but decreases in IFN‐γ and IL‐12 mRNA in tolerized, as compared with immunized animals. Thus, the mechanism of tolerance, preventing the development of uveitis may involve a regulatory subset of memory cells and a shift from Th1 to Th2 and Th3 cytokines. We suggest that mucosally induced uveitis can be prevented by oral administration of the peptide‐rCTB conjugate.
Precautionary motives and portfolio decisions
Authors: Hochguertel Stefan
Published: February 2003

This paper studies the empirical relevance of precautionary and other motives for household portfolio behaviour using recent panel data from the Netherlands. Dutch households' portfolios exhibit low degrees of risk taking and diversification. It is possible that this is the outcome of a rational, precautionary response to unavoidable exposure to background risk (stemming from the labour market or health conditions, etc.). We consider as alternative explanations liquidity needs and habits. The endogenous variable is the fraction of clearly safe in total financial assets at the household level. Parametric and semi‐parametric censored regression models for pooled cross‐sections and random and fixed effects models for panel data show that both heteroscedasticity and unobserved heterogeneity are of major importance in the data. With subjective indicators of income uncertainty we find a limited role for precautionary motives. Copyright © 2002 John Wiley & Sons, Ltd.
Second trimester diagnosis of Neu Laxova syndrome
Authors: Shivarajan M. A. , Suresh S. , Jagadeesh Sujatha , Lata S. , Bhat Lathaa
Published: February 2003

This is the first report of a prenatally diagnosed case of Neu Laxova syndrome (NLS) from India. This also includes a case of NLS in monochorionic diamniotic twins and two more cases in which we were able to detect most of the features of NLS as early as 19 to 20 weeks by routine antenatal ultrasonography. Severe intrauterine growth retardation (IUGR), microcephaly, central nervous system (CNS) abnormality, joint contractures, and abnormal facies are the major diagnostic features observed in prenatal ultrasonography. Risk factors such as consanguinity and history of intrauterine death or stillbirth in siblings have been noted in all the cases, but none of the three families that were reported had previously had an affected fetus. The spectrum of skin manifestations and frequency of occurrence of major clinical features of the syndrome have been discussed. Review of the literature on NLS and possibility of detecting the syndrome in the second trimester is discussed. Copyright © 2002 John Wiley & Sons, Ltd.
Fetal liver hyperechogenicity on sonography may be a serendipitous sign of a transient myeloproliferating disorder
Authors: Vimercati Antonella , Greco Pantaleo , Gentile Antonia , Ingravallo Giuseppe , Loverro Giuseppe , Selvaggi Luigi
Published: February 2003

Objective

To demonstrate that thorough antenatal and postnatal investigations are helpful in any genetic syndrome.

Case Report

A woman without a specific risk had a finding of hyperechogenic foci at ultrasound. Karyotype on fetal blood was 47, XY+21 and extensive biochemical investigation revealed abnormal liver function. Given the suspicion of a coincidental hepatic compromise, targeted postmortem examination was performed, which showed hepatic fibrosis, megakaryocytes proliferation and invasion of sinusoid capillaries, all suggestive of a transient myeloproliferative disorder.

Conclusion

When compared with chorionic villous and amniotic fluid sampling, fetal blood allows the collection of additional data, which may help in understanding the pathological process behind an apparently serendipitous association. Copyright © 2002 John Wiley & Sons, Ltd.
Congenital erythropoietic porphyria (Günther's disease): two cases with very early prenatal manifestation and cystic hygroma
Authors: Pannier E. , Viot G. , Aubry M. C. , Grange G. , Tantau J. , Fallet‐Bianco C. , Muller F. , Cabrol D.
Published: February 2003

Congenital erythropoietic porphyria (CEP) or Günther's disease is the rarest form of the porphyrias. The disease is usually diagnosed at birth or during early infancy, but rarely in utero. We describe here the first two cases of very early prenatal expression of CEP with cystic hygroma diagnosed at 14 weeks in the first fetus and at 19 weeks in the second. Both fetuses presented with severe nonimmune hydrops fetalis as early as 19 and 22 weeks, associated with intrauterine growth retardation, hyperechogenic kidneys and bones. Amniotic fluid was dark brown and uro‐ and coproporphyrin I was dramatically increased. Molecular screening of the CEP gene detected heterozygous C73R mutation in both fetuses, the other parental mutation being as yet unknown. Copyright © 2002 John Wiley & Sons, Ltd.
Prenatal diagnosis of molybdenum cofactor deficiency and isolated sulfite oxidase deficiency
Authors: Johnson Jean L.
Published: February 2003

Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are autosomal recessive inborn errors of metabolism with severe neurological symptoms resulting from a lack of sulfite oxidase activity. The deficiencies can be diagnosed prenatally by monitoring sulfite oxidase activity in chorionic villus sampling (CVS) tissue. In those families in which the specific defects have been identified, diagnosis can be achieved by mutation analysis or linkage studies directed at affected genes. These include MOCS1, MOCS2 or GEPH, in cases of molybdenum cofactor deficiency, or SUOX in patients with isolated sulfite oxidase deficiency. Copyright © 2002 John Wiley & Sons, Ltd.
Triploidy in a twin pregnancy: small placenta volume as an early sonographical marker
Authors: Gassner Rainer , Metzenbauer Martin , Hafner Erich , Vallazza Ursula , Philipp Karl
Published: February 2003

Introduction

We report a case of a twin pregnancy with triploidy of maternal phenotype of one foetus and no chromosomal anomaly of the other twin and the role of sonographical placental volumetry.

Case

At 12 weeks of gestation, a dichorionic twin pregnancy discordant in growth is diagnosed. 3D ultrasound reveals a distinctly small placental volume of foetus II. Amniocentesis at 16 weeks discloses triploidy of this foetus. Sonography reveals asymmetrical foetal growth retardation, a severe heart defect and bilateral cleft lip and palate, typical findings in triploidy. Selective feticide at week 20+3 is followed by pre‐term birth of foetus I at 27 weeks.

Conclusion

Small placental volume in addition to growth restriction of one foetus early in the course of a twin pregnancy could be an important early marker influencing the decision for chorionic villous sampling at 12 weeks instead of amniocentesis at 16 weeks and it could lead to an earlier selective pregnancy termination of a triploid twin. This would lower the risk of pre‐term birth and enable a better outcome for the remaining healthy foetus. Copyright © 2002 John Wiley & Sons, Ltd.