bluuebunny/crossref_metadata_2025 huggingface dataset:
From doctoral dissertation to publication
Authors: Anwar Mumtaz A.
Published: February 2005

This article examines the publishing activity of 54 individuals who received their doctoral degrees from American universities in 1995 and the publications that were derived from their dissertations. Publication data covered two five-year periods, 1991-1995 research-in-progress and 1996-2000 postdoctoral period. One third of the graduates did not publish anything during these 10 years. The mean number of publications for all graduates came to 0.54 per year. Only one half of these graduates produced publications out of their dissertations. The mean number of publications derived from their dissertations came to 0.85 for all graduates. Only one of these publications was the result of student/advisor collaboration indicating a very low level of such activity.
Reader development and ICT
Authors: Bird Angela , Tedd Lucy A.
Published: February 2005

The role of the public library in encouraging reading and using ICT in the reading development process has been included in a number of Government reports during the 1990s and 2000s in the UK. Following the successful implementation of the People’s Network many public libraries are developing ways of using ICT in reader development. In Wales, as part of an initiative called Estyn Allan (Branching Out) all 22 public library authorities have staff responsible for reader-development issues covering, in many cases, both the Welsh and English languages. This article reports on the results of a questionnaire, sent to all reader-development librarians in Wales, and provides examples of some of the work being undertaken.
Pierce Butler’s An Introduction to Library Science: a tract for our times?
Authors: Cronin Blaise
Published: February 2005

Considers the historic and contemporary import of Pierce Butler’s An Introduction to Library Science. Characterizes the content of each chapter and critically analyses the central theses. Relates Butler’s positivistic premises, assumptions and conclusions to the congeries of competing epistemological and ideological standpoints that defines current thinking in library and information science research.
The Sublime Object of Entrepreneurship
Authors: Jones Campbell , Spicer André
Published: February 2005

This paper engages with debates on enterprise culture and one of its key subjects—the entrepreneur. Enlisting the work of Jacques Lacan and Slavoj Žižek, we attempt to explain the continuing failure of entrepreneurship discourse to assign the character of the entrepreneur a positive identity. Shifting away from stable categories such as ‘the entrepreneur’, we describe entrepreneurship in terms of Lacan’s concept of the Real and Žižek’s concept of the sublime object. This allows us to critically scrutinize the operation of the phantasmic category of the entrepreneur. In addition to indicating some prospects for the future of psychoanalytic cultural criticism in organization studies, we make a case for a continual questioning of the subject, a questioning that is today being foreclosed by those critics who were first to call the subject into question.
The Merger Storm Recognizes No Borders: An Analysis of Media Rhetoric on a Business Manoeuvre
Authors: Kuronen Marja-Liisa , Tienari Janne , Vaara Eero
Published: February 2005

Despite the central role of the media in contemporary society, studies examining the rhetorical practices of journalists are rare in organization and management research. We know little of the textual micro strategies and techniques through which journalists convey specific messages to their readers. Partially to fill the gap, this paper outlines a methodological framework that combines three perspectives of text analysis and interpretation: critical discourse analysis, systemic functional grammar and rhetorical structure theory. Using this framework, we engage in a close reading of a single media text (a press article) on a recent case of industrial restructuring in the financial services. In our empirical analysis, we focus on key arguments put forward by the journalists’ rhetorical constructions. We maintain that these arguments—which are not frame-breaking but rather tend to confirm existing presuppositions held by the audience—are an essential part of the legitimization and naturalization of specific management ideas and ideologies.
Formal Theory and Case-Study Methods in EU Studies
Authors: Pahre Robert
Published: February 2005

EU studies have long been dominated by case studies, although formal theories have made substantial inroads into the field over the past decade. This article examines the advantages and challenges of combining these two methods, with an analysis grounded in both the philosophy of science and research design. Looking at the philosophy of science highlights several practices and principles shared by formal theorists and case-study researchers. The logic of discovery in both methodologies prizes studies of puzzles that can be found in a single case. Both are inclined to retain a research program even in the face of acknowledged anomalies. In the area of research design, many formal hypotheses take functional forms that cannot be reduced to linear, additive models. Most of these hypotheses lend themselves easily to case-study methods. Thus, although research design has provided an avenue for applying the logic of statistical inference to qualitative research, case studies retain independent value.
Choice, circumstance, and the value of equality
Authors: Scheffler Samuel
Published: February 2005

Many recent political philosophers have attempted to demonstrate that choice and responsibility can be incorporated into the framework of an egalitarian theory of distributive justice. This article argues, however, that the project of developing a responsibility-based conception of egalitarian justice is misconceived. The project represents an attempt to defuse conservative criticism of the welfare state and of egalitarian liberalism more generally. But by mimicking the conservative’s emphasis on choice and responsibility, advocates of responsibility-based egalitarianism unwittingly inherit the conservative’s unsustainable justificatory ambitions, unattractive moralism, and questionable metaphysical commitments. More importantly, they misrepresent the nature of our concern with equality as a value.
Liberty and Leviathan
Authors: Pettit Philip
Published: February 2005

Hobbes made a distinctive contribution to the discussion of freedom on two fronts. He persuaded later, if not immediate, successors that it is only the exercise of a power of interference that reduces people’s freedom, not its (unexercised) existence - not even its existence in an arbitrary, unchecked form. Equally, he persuaded them that the exercise of a power of interference always reduces freedom in the same way, whether it occurs in a republican democracy, purportedly on a ‘non-arbitrary’ basis, or under a dictatorial, arbitrary regime. But the basis on which Hobbes maintained those two propositions was very different from any that successors would have found plausible. This article explores the idiosyncratic principles that led Hobbes to develop his influential point of view.
Proteins with two SUMO-like domains in chromatin-associated complexes: The RENi (Rad60-Esc2-NIP45) family
Authors: Novatchkova Maria , Bachmair Andreas , Eisenhaber Birgit , Eisenhaber Frank
Published: February 2005

Background

Post-translational modification by Small Ubiquitin-like Modifiers (SUMO) has been implicated in protein targeting, in the maintenance of genomic integrity and in transcriptional control. But the specific molecular effects of SUMO modification on many target proteins remain to be elucidated. Recent findings point at the importance of SUMO-mediated histone NAD-dependent deacetylase (HDAC) recruitment in transcriptional regulation.

Results

We describe the RENi family of SUMO-like domain proteins (SDP) with the unique feature of typically containing two carboxy-terminal SUMO-like domains. Using sequence analytic evidence, we collect family members from animals, fungi and plants, most prominent being yeast R ad60, E sc2 and mouse NI P45 http://mendel.imp.univie.ac.at/SEQUENCES/reni/. Different proteins of the novel family are known to interact directly with histone NAD-dependent deacetylases (HDACs), structural maintenance of chromosomes (SMC) proteins, and transcription factors. In particular, the highly non-trivial designation of the first of the two successive SUMO-domains in non-plant RENi provides a rationale for previously published functionally impaired mutant variants.

Conclusions

Till now, SUMO-like proteins have been studied exclusively in the context of their covalent conjugation to target proteins. Here, we present the exciting possibility that SUMO domain proteins, similarly to ubiquitin modifiers, have also evolved in a second line – namely as multi-domain proteins that are non-covalently attached to their target proteins. We suggest that the SUMO stable fusion proteins of the RENi family, which we introduce in this work, might mimic SUMO and share its interaction motifs (in analogy to the way that ubiquitin-like domains mimic ubiquitin). This presumption is supported by parallels in the spectrum of modified or bound proteins e.g. transcription factors and chromatin-associated proteins and in the recruitment of HDAC-activity.
Troglitazone, a PPAR-γ activator prevents endothelial cell adhesion molecule expression and lymphocyte adhesion mediated by TNF-α
Authors: Sasaki Makoto , Jordan Paul , Welbourne Tomas , Minagar Alireza , Joh Takashi , Itoh Makoto , Elrod John W , Alexander J Steven
Published: February 2005

Background

Cytokine mediated induction of the mucosal addressin cell adhesion molecule-1(MAdCAM-1) expression is associated with the onset and progression of inflammatory bowel disease (IBD).

Results

Using western blotting and cell-based ELISA, we show in this study that troglitazone, an activator of the peroxisome proliferator-activated receptor-γ (PPAR-γ), widely used in the treatment of diabetes, has as well recently been highlighted as protective in models of inflammation and cancer. We found that troglitazone (10–40 μM), significantly reduced the TNF-α (1 ng/ml) mediated induction of endothelial MAdCAM-1 in a dose-dependent manner, achieving a 34.7% to 98.4% reduction in induced MAdCAM-1. Trogliazone (20μM) reduced TNF-α induced VCAM-1, ICAM-1 and E-selectin expression. Moreover, troglitazone significantly reduced α4β7-integrin dependent lymphocyte adhesion to TNF-α cultured endothelial cells.

Conclusions

These results suggest that PPAR-γ agonists like troglitazone may be useful in the clinical treatment of IBD.
Systemic effects and skin injury after experimental dermal exposure to monochloroacetic acid
Authors: Dote Tomotaro , Kono Koichi , Usuda Kan , Shimizu Hiroyasu , Tanimoto Yoshimi , Dote Emi , Hayashi Satsuki
Published: February 2005

There have been many fatal occupational accidents of skin exposure to monochloroacetic acid (MCA). However, there have been no reports of dermatological findings and the lethal consequences have not yet been demonstrated. Therefore, harmful local and systemic effects were investigated after dermal exposure to MCA. A 0.5 mL aliquot of MCA solution (40% w/w) was applied to the abdominal skin of ten 10-week-old male SD rats under anesthesia. The exposure area (25 × 25 mm2) was 1.6% of the total surface area. The dose of MCA per area was 34.1 mg/cm2. Saline was similarly administered to 10 control rats. Histopathological findings after 10 min were observed by light microscopy. Blood samples were collected by exsanguinations from the carotid arteries after 4 h. Skin samples were collected 10 min after the initial exposure. Histological findings showed severe degeneration of collagen bundles in the epidermis and subcutaneous tissues. PCO2, HCO3−, TCO2, BE and glucose levels were decreased in the MCA group. AST, m-AST, ALT, BUN, Cr, NH3, lactic acid, pyruvic acid, RBC, Hb, Hct, total protein and albumin were increased in the MCA group. The burn was determined to be a third-degree burn on the basis of the histopathological findings. The severe toxicity was probably a consequence of the rapid permeability. Biochemical parameters were a consequence of hepatocellular injuries, renal dysfunction, dysglyconeogenesis and dysfunction of ammonia metabolism. MCA reportedly enters the TCA cycle and inhibits aconitase. MCA metabolites also inhibit pyruvate carboxylase in the gluconeogenesis pathway. Therefore, the important serum biochemical abnormalities such as hypoglycemia and lactic acidosis should be monitored to find the acute systemic disorders.
The multistage model of cancer development: some implications
Authors: Ritter Gordon , Wilson Richard , Pompei Francesco , Burmistrov Dimitriy
Published: February 2005

The multistage model, introduced by Armitage and Doll, was very successful at describing many features of cancer development. Doll and Peto noted a significant departure below the prediction of the model and suggested that this could be due to undercounting of cases at older ages, or to the ‘biology of extreme old age.’ Moolgavkar pointed out that it could also be due to the approximation used. The recent observation that cancer incidence falls rapidly above age 80 has stimulated new modelling investigations, such as the Pompei-Wilson beta model (which does reproduce the rapid fall). In the present paper, we argue that Moolgavkar’s criticisms, while mathematically correct, do not affect the conclusions, particularly the constancy of the number of stages across different cancer registries (Cook, Doll and Fellingham. 1969: A mathematical model for the age distribution of cancer in man. International Journal of Cancer 4, 93-112). We discuss several exact solutions, compare them with the most recent data, and prove rigorously that the standard Armitage-Doll multistage model can never reproduce the sharp turnaround in cancer incidence at old age seen in the data. We discuss in detail multistage processes which have a property observed in many laboratory studies, namely that some stages progress much faster than the others. We verify mathematically the intuition that sufficiently fast stages do not appreciably affect the incidence rate of cancer, and discuss implications of this fact for cancer treatment strategies. We also show that the simplest possible modification of the Armitage-Doll model to incorporate cellular senescence just leads to the Pompei-Wilson beta model.
Genetics of lupus nephritis
Authors: Lauwerys B R , Wakeland E K
Published: February 2005

Susceptibility to lupus nephritis is the end-result of complex interactions between polymorphic genetic factors involved in the regulation of immune responses. In humans, genome-wide screens and candidate-gene analyses led to the identification of several loci containing potential targets (FcgRIIa, PTPN22, PD-1, IL-10) for physiopathological research and therapeutic interventions. In mice, the generation of congenic mice, bearing in a normal genetic background one single disease-associated locus, greatly improved our understanding of the mechanisms mediating the genetic contribution to the disease. In the future, the identification of disease-associated genes will open new perspectives for the development of more targeted therapies of lupus nephritis.
Pathogenic autoantibodies in lupus nephritis
Authors: Waldman M , Madaio M P
Published: February 2005

Lupus nephritis is a major complication of systemic lupus erythematosus (SLE) and is associated with a high rate of morbidity and mortality. While many different immunologic and nonimmunologic factors contribute to disease expression in lupus nephritis, a large body of evidence suggests that the production of anti-DNA antibodies and the formation of glomerular immune deposits are important initial events in the pathogenesis of the disease. This review will summarize our current understanding of the differences between pathogenic and nonpathogenic autoantibodies, the mechanisms by which these autoantibodies induce renal injury and the effector mechanisms which are subsequently activated by the deposited autoantibodies that ultimately lead to the expression of the different lupus lesions.
Mycophenolate mofetil in lupus nephritis
Authors: Ginzler E M , Aranow C
Published: February 2005

There is an increasing body of literature suggesting the efficacy and tolerability of mycophenolate mofetil (MMF) for the treatment of lupus nephritis. The rationale for its use is based upon its successful profile as an immunosuppressive agent for prevention of allograft rejection, as well as studies in murine models of lupus which have reported improved renal function and animal survival compared to placebo. This report reviews the data regarding MMF therapy in murine lupus models, and describes the initial anecdotal experience with MMF in human lupus, especially in patients with glomerulonephritis who were unresponsive to corticosteroids and cyclophosphamide, or who had unacceptable toxicity on this standard of care regimen. The results of several nonblinded, controlled clinical trials are also described, in which MMF was compared to intravenous or oral cyclophosphamide in patients with lupus nephritis. MMF was found to be well tolerated, with most studies showing fewer infections than that associated with cyclophosphamide. Efficacy of MMF was at least equivalent to cyclophosphamide, and therefore appears to provide an alternative as a standard of care for induction and maintenance treatment of lupus nephritis.
Pregnancy after lupus nephritis
Authors: Moroni G , Ponticelli C
Published: February 2005

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects primarily women, commonly in their reproductive years but does not influence fertility. For these reasons, the clinician has often to face the many problems of pregnancy in patients with SLE including the influence of SLE on fetal outcome and that of pregnancy on SLE. As there is increasing evidence of an important role of sex hormones in immunity, the influence of pregnancy on SLE is probably due to the changes in sex hormone levels during pregnancy that are more important than in any other period of life.

Early reports emphasized a high fetal and maternal risk in particular in patients with lupus nephritis. However in the same period the prognosis of lupus nephritis was poor, so it was difficult to know whether pregnancy actually influenced the prognosis of the disease. More recent prospective studies indicate that pregnancy is safe for the majority of mothers if it is planned when SLE is quiescent. Instead, although fetal risk has been progressively reduced in the last 40 years, it continues to be higher than that occurring in pregnancies of healthy women. In particular the presence of antiphospholipid antibodies considerably worsen the fetal outcome.
Renal transplantation in lupus nephritis
Authors: Ponticelli C , Moroni G
Published: February 2005

Most patients with systemic lupus erythematosus (SLE) are suitable candidates for renal transplantation. However, a number of them may present some disease-related problems. As cardiovascular disease is a leading cause of morbidity and mortality in SLE patients, a careful pretransplant cardiovascular screening is recommended. A search for antiphospholipid antibodies is also useful as the presence of these antibodies can cause an early graft thrombosis. The risk of recurrence of SLE nephritis after transplantation may range between 2 and 30%. In most cases recurrence is characterized by mild histologic lesions. Only rarely does it lead to graft failure. Postransplant immunosuppression does not differ from that used routinely. Whenever possible, a steroid-free immunosuppression should be scheduled to prevent iatrogenic toxicity in patients who have already received long-term steroid treatment. The results of kidney transplantation largely depend on the clinical conditions at transplantation. In patients with poor clinical status or receiving an aggressive immunosuppression it is advisable to postpone the transplant. When some selection criteria are respected, the results of renal trasplantation in SLE patients are at least as good as in other transplant recipients.
Preproinsulin‐Specific CD8+ T Cells Secrete IFNγ in Human Type 1 Diabetes
Authors: RATHMANN SILVIA , RAJASALU TARVO , ROSINGER SILKE , SCHLOSSER MICHAEL , EIERMANN THOMAS , BOEHM BERNHARD O. , DURINOVIC‐BELLÓ IVANA
Published: February 2005

Abstract: In animal models autoreactive CD8+ T cells are crucial in the development of type 1 diabetes (T1D); however, their role in human T1D is still not known. To address the role of CD81 T cells we performed a pilot study by investigating CD8+ T cell‐mediated cytokine secretion after in vitro stimulation with 94 preproinsulin (PPI) peptides. We were able to show that CD8+ T cells contribute to a strong IFNγ reactivity against PPI in human T1D. Further investigations defining epitope specificity, cytokine secretion, and cytotoxic capacity are important to clarify their role in T1D development.
An Insulin‐like Growth Factor 2‐Derived Self‐Antigen Inducing a Regulatory Cytokine Profile after Presentation to Peripheral Blood Mononuclear Cells from DQ8+ Type 1 Diabetic Adolescents: Preliminary Design of a Thymus‐Based Tolerogenic Self‐Vaccination
Authors: GEENEN V , LOUIS C , MARTENS H ,   THE BELGIAN DIABETES REGISTRY
Published: February 2005

Abstract: This work aims to evaluate the potential use of insulin‐like growth factor 2 (IGF‐2) as the dominant thymic self‐antigen precursor of the insulin family in designing a tolerogenic approach to type 1 diabetes (T1D) prevention. This evaluation was primarily based on cytokine profile driven by MHC presentation of insulin and IGF‐2‐derived antigens to PBMC cultures derived from 16 T1D DQ8+ adolescents. Insulin B9‐23, one dominant β‐cell autoantigen, and the homologous sequence B11‐25 of IGF‐2 display the same affinity and fully compete for binding to DQ8, a MHC‐II allele conferring major genetic susceptibility to type 1 diabetes (T1D). However, compared to insulin B9‐23, presentation of IGF‐2 B11‐25 elicits a suppressive/regulatory cytokine profile with a higher number of IL‐10‐secreting cells (P < 0.05), a much higher ratio of IL‐10/IFN‐γ (P < 0.01), as well as a lower number of IL‐4‐secreting cells (P < 0.05). Thus, with regard to T1D prevention, administration of IGF‐2‐derived self‐antigen(s) seems to be an efficient approach that combines both antagonism for binding to a major susceptibility MHC‐II allele, as well as downstream promotion of an antigen‐driven tolerogenic response.
Closer Association of IA‐2 Humoral Autoreactivity with HLA DR3/4 than DQB1*0201/*0302 in Korean T1D Patients
Authors: PARK YONGSOO , TAIT BRIAN D. , KAWASAKI EIJI , ROWLEY MERRILL , MACKAY IAN R.
Published: February 2005

Abstract: The HLA DQB1*0302 allele on DR4 haplotypes is a well‐known marker for T1D susceptibility. The contribution of this DQ molecule to overall disease susceptibility may be genotype dependent. On Asian DR4 haplotypes, not only DQB1*0302, but also DQB1*0401 confer susceptibility to T1D, which is mediated by DRB1*0405 on the same haplotype. To analyze further the association of DQB1*0302 and DQB1*0401 haplotypes in Asian patients with T1D, we investigated HLA DR and DQ alleles with the presence or the persistence of GAD, ICA, and IA‐2 autoantibodies in 121 Korean T1D patients. In Korean patients, there was an association of IA‐2 autoantibodies with DR4 as well as DR3, but not with DQA1*0301‐DQB1*0302. GAD autoantibodies were not associated with the DR3‐DQB1*0201, DQA1*0301‐DQB1*0302, or DR4. In this low‐risk population, autoantibodies to islet‐cell antigens were associated with different HLA molecules. In different populations, the immune response to different β cell autoantigens is mediated via varying HLA class II molecules from different loci. Design of the antigen‐specific immunointervention trials should take into account such HLA DR and DQ association.
Prevalence of Autoantibodies to Carbonic Anhydrase II and Lactoferrin in Patients with Type 1 Diabetes
Authors: DI CESARE ENRICO , PREVITI MARCELLO , LOMBARDO FORTUNATO , MAZZÙ NICOLA , DI BENEDETTO ANTONINO , CUCINOTTA DOMENICO
Published: February 2005

Abstract: Recently, the high prevalence of autoantibodies against antigens expressed in exocrine pancreatic cells such as carbonic anhydrase II (ACA) and lactoferrin (ALF) was found in sera from adult Japanese patients with type 1 diabetes. Hence, we determined by ELISA the presence of ACA and ALF both in children (n= 27) and adult (n= 15) Caucasian patients with type 1 diabetes at diagnosis. Among children, ACA were found in one patient (3.7%) and ALF in three (11.1%). Among adults, CAA and ALF were detected in three patients (20%) and in one patient (6.7%), respectively. The prevalence of ACA and ALF observed in our Caucasian patients with type 1 diabetes at diagnosis did not reach the high value previously reported in adult Japanese patients.
No Evidence of Pancreatic Autoimmunity among Patients with Multiple Sclerosis
Authors: BILBAO J. RAMÓN , VILLOSLADA PABLO , MARTIN‐PAGOLA AINHOA , CASTAÑO LUIS
Published: February 2005

Abstract: Although multiple sclerosis (MS) usually appears isolated from other autoimmune disorders, an overlap with type 1 diabetes mellitus (T1DM) has been described in Sardinia, where T1DM‐associated haplotype HLA‐B18‐DR3‐DQ2 contributes to MS risk. To determine whether in our population MS patients show signs of pancreatic autoimmunity and share this haplotype, sera from 49 MS patients were tested for GAD, IA2, and CPH autoantibodies, and MICA exon 5 polymorphism was genotyped in 30 patients. Pancreatic autoimmune markers were not present among MS patients, nor was any MICA allele associated with MS. Overall, there is no evidence supporting a T1DM/MS overlap in our population.
IDDM17: Polymorphisms in the AMACO Gene Are Associated with Dominant Protection against Type 1A Diabetes in a Bedouin Arab Family
Authors: ELLER ELISE , VARDI PNINA , DALY MARK J. , BABU SUNANDA , ROBERTS CHRISTINE , YANG FAN , EISENBARTH GEORGE S. , FAIN PAMELA R.
Published: February 2005

Abstract: Haplotype blocks characterized from 78 single‐nucleotide polymorphisms (SNPs) in a 1‐ to 2‐centiMorgan region in the human diabetes susceptibility gene IDDM17 were tested for association with type 1 diabetes mellitus (T1DM). Two haplotypes in two adjacent blocks in AMACO, a von Willebrand factor homologue, appear to be associated with the absence of T1DM; transmission tests support this hypothesis. Interestingly, in both haplotype blocks, a single SNP distinguishes the protective haplotype from the other haplotypes. One SNP is noncoding, whereas the other SNP causes a change from glutamic acid to glycine. Future work in identifying the protective allele includes association tests of block haplotypes in other populations.
Killer Cell Immunoglobulin‐like Receptor Genes in Latvian Patients with Type 1 Diabetes Mellitus and Healthy Controls
Authors: NIKITINA‐ZAKE LIENE , RAJALINGHAM RAJA , RUMBA INGRIDA , SANJEEVI CARANI B.
Published: February 2005

Abstract: T1DM is very common in Sweden and is positively associated with HLA class II genes. Approximately 89% of the newly diagnosed patients carry the high‐risk HLA DR4‐DQ8 and DR3‐DQ2. The remaining 11% develop T1DM without them. This can be due to involvement of other genes and environmental factors. Natural killer (NK) cells of the innate immune system are important in antiviral and antitumor immunity. They are implicated in the etiology of autoimmune T1DM. Human NK cells express killer cell immunoglobulin‐like receptors (KIR) that belong to the polymorphic multigene family in chromosome 19q3.4. They modulate NK cell response by interacting with HLA class I. In addition, polymorphic MICA in HLA class I interacts with non‐polymorphic NKG2D receptor on NK cells. We have studied, in addition to HLA‐DR and ‐DQ, genes of the innate immune system MICA and KIR in Latvian patients (n= 98) with T1DM and controls (n= 100). They were genotyped using standard PCR‐based typing methods. MICA allele 5 is positively associated with T1DM. KIR2DL2 and KIR2DS2 were both positively associated. Combined association of MICA4 and KIR2DL2 gave an odds ration (OR) of 26.7. However, the combined risk of KIR2DL2 and HLA class II genes, HLADR3 (OR = 73.4), DR4 (OR = 66.8), and DR3 and DR4 (OR = 88.3), was higher. The maximum risk was when KIR2DL2, MICA5, and DR3/DR4 were in combination. In conclusion, our results suggest that a balance between innate and acquired immunity is important, and an imbalance coud lead to T1DM.
1,25‐Dihydroxyvitamin D3 Alters the Profile of Bone Marrow‐Derived Dendritic Cells of NOD Mice
Authors: VAN ETTEN EVELYNE , DARDENNE OLIVIER , GYSEMANS CONNY , OVERBERGH LUT , MATHIEU CHANTAL
Published: February 2005

Abstract: 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] prevents autoimmune diabetes in nonobese diabetic (NOD) mice. A major target for 1,25(OH)2D3 in the immune system is the dendritic cell (DC). Since important DC abnormalities have been described in NOD mice, we investigated the effects of 1,25(OH)2D3 on the yield and phenotype of DCs generated from bone marrow of NOD mice compared to control congenic nonobese diabetes‐resistant (NOR) mice. In both mouse strains, exposure of the bone marrow‐derived cells to 1,25(OH)2D3 increased the proportion of CD11c+ DCs after culture. Surface expression of MHC II, CD86, and CD54 on NOR‐derived DCs was decreased after 1,25(OH)2D3 treatment, while CD40 remained unchanged. On NOD‐derived DCs, 1,25(OH)2D3 only inhibited the expression of MHC II and CD86. 1,25(OH)2D3 inhibited IL‐12 and IL‐10 secretion after IFNγ and LPS stimulation. In vitro treatment with 1,25(OH)2D3 alters DC yield from bone marrow cultures and alters the phenotype of the cells in NOD as well as in NOR mice. NOD‐derived DCs were more resistant to the 1,25(OH)2D3 effects than were NOR‐derived DCs.
Identification of Key β Cell Gene Signaling Pathways Involved in Type 1 Diabetes
Authors: SILVA DIEGO , PETROVSKY NIKOLAI
Published: February 2005

Abstract: In type 1 diabetes, β cells die through a process of immune‐mediated apoptosis. To better understand this process, it has been accepted practice to study β cell or islet apoptosis in vitro in response to a range of immune stimuli, such as interferon gamma, interleukin‐1, nitric oxide or free radicals. In particular, much use has been made of immortalized β cell lines for such studies, although it is not clear to what extent the behavior of these cell lines might mimic the behavior of normal β cells in vivo, or freshly isolated β cells ex vivo. To address this question we compared the gene expression of freshly isolated NOD islets in the presence or absence of insulitis, with previously published data examining either islet or β cell gene or protein expression in a range of different species and contexts. There was a high correlation between β cell genes found be to be expressed by mouse and rat islets, by either gene expression or proteomic analysis. There was also a surprisingly high correlation between β cell genes found be to be expressed by islets exposed to insulitis in vivo and islets stimulated with IFN‐γ and IL‐1βin vitro, suggesting that these two cytokines as produced by the islet infiltrate are important for priming β cells in vivo. There was a much lower correlation when gene expression was compared between fresh β cells and β cell lines, consistent with the view that β cell lines are very poorly representative of real β cells. Hence, any results obtained using β cell lines should be interpreted with great caution when extrapolating to the behavior of real β cells.
Experimental Autoimmune Diabetes: A New Tool to Study Mechanisms and Consequences of Insulin‐Specific Autoimmunity
Authors: RAJASALU TARVO , BARTH CHRISTOPH , SPYRANTIS ANDREAS , DURINOVIC‐BELLÓ IVANA , UIBO RAIVO , SCHIRMBECK REINHOLD , BOEHM BERNHARD O. , KARGES WOLFRAM
Published: February 2005

Abstract: (Prepro)insulin is considered a central antigenic determinant in diabetic autoimmunity. Insulin has been used to modify diabetes development in NOD mice and prediabetic individuals. We have recently shown that (prepro)insulin can adversely promote diabetes development in murine type 1 diabetes. Based on these findings we have developed experimental autoimmune diabetes (EAD), a new mouse model characterized by (1) CD4+/CD8+ insulitis, induced by (2) (prepro)insulin DNA vaccination, leading to (3) beta cell damage and insulin deficiency in (4) RIP‐B7.1 transgenic mice (H‐2b). EAD develops rapidly in 60‐95% of mice after intramuscular, but not intradermal (“gene gun”), vaccination; and DNA plasmids expressing insulin or the insulin analogues glargine, aspart, and lispro are equally potent to induce EAD. Similar to NOD mice, diabetes is adoptively transferred into syngeneic recipients by spleen cell transplantation in a dose‐dependent fashion. We have devised a two‐stage concept of EAD in which T cell activation and expansion is driven by in vivo autoantigen expression, followed by islet damage that requires beta cell expression of costimulatory B7.1 for disease manifestation. Taken together, EAD is a novel, genetically defined animal model of type 1 diabetes suitable to analyze mechanisms and consequences of insulin‐specific T cell autoimmunity.
Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors
Authors: Kortmansky Jeremy , Shah Manish A. , Kaubisch Andreas , Weyerbacher Amanda , Yi Sandy , Tong William , Sowers Rebecca , Gonen Mithat , O'Reilly Eileen , Kemeny Nancy , Ilson David I. , Saltz Leonard B. , Maki Robert G. , Kelsen David P. , Schwartz Gary K.
Published: February 2005

Purpose

Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01.

Patients and Methods

FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m2 over 72 hours in cycle 1 and 67.5 mg/m2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction.

Results

We escalated the weekly FU dose to 2,600 mg/m2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines.

Conclusion

The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m2.
P2Y12 Receptors Play a Significant Role in the Development of Platelet Microaggregation in Patients with Diabetes
Authors: Matsuno Hiroyuki , Tokuda Haruhiko , Ishisaki Akira , Zhou Yuan , Kitajima Yasuo , Kozawa Osamu
Published: February 2005

Ninety-eight diabetic patients (type 2) were studied together with 24 healthy normotensive controls. Microaggregates (particle scale, <25 μm) of platelets were detected by a laser scattering system. Microaggregates in the control group showed a time-dependent reversible change; however, they existed continuously in 82 of 98 diabetic patients. When platelets of diabetics were stimulated by a shear stress alone without ADP, 74 also showed spontaneous and irreversible microaggregates even though they were not observed in all control subjects. In control subjects, microaggregates were inhibited by MRS2279 (a P2Y1 antagonist), but not AR-C69931MX (a P2Y12 antagonist). However, AR-C69931MX prevented irreversible microaggregates in diabetic patients. When either aspirin or ticlopidine was administered to diabetic patients with irreversible microaggregates, both drugs significantly decreased microaggregates induced by a low dose of ADP. Ticlopidine additionally reduced the microaggregates induced by shear stress alone. In conclusion, microaggregates of platelets via P2Y12 receptors could play a key role in the hypersensitivity of platelets in diabetic patients, and the measurement of microaggregation could be a useful marker to estimate of thrombogenesis. These findings present a possible new means for patients with diabetes to prevent ischemic events.
Association of the Intestinal Fatty Acid-Binding Protein Ala54Thr Polymorphism and Abdominal Adipose Tissue in African-American and Caucasian Women
Authors: Lara-Castro Cristina , Hunter Gary R. , Lovejoy Jennifer C. , Gower Barbara A. , Fernández José R.
Published: February 2005

Genetic variants in the intestinal fatty acid-binding protein-2 (FABP2) gene have been associated with body composition phenotypes. We examined the association between the Ala54Thr variant in the FABP2 gene and levels of visceral (VAT) and sc (SAAT) abdominal fat in a group of 223 premenopausal African-American (n = 103) and Caucasian (n = 120) women. Subjects were genotyped for the marker. In addition, body composition was assessed by dual energy x-ray absorptiometry, and VAT was determined from a single computed tomography scan. The frequency of the Thr mutant allele did not differ significantly by ethnic group. After adjusting for total body fat, total abdominal adipose tissue (TAT) and SAAT were significantly lower in carriers of either one or two copies of the mutant Thr allele (P < 0.01). There was no association between total fat mass or VAT and the FABP2 polymorphism. Separate analyses by ethnic group showed that the association between the polymorphism and TAT and SAAT was observed in Caucasian (P < 0.01), but not in African-American (not significant), women. We conclude that women carriers of the FABP2 Thr allele have lower TAT and SAAT than noncarriers of the mutation. This association is present in Caucasian, but not in African-American, women.
Genetic Variation at the Locus Encompassing 11-β Hydroxylase and Aldosterone Synthase Accounts for Heritability in Cortisol Precursor (11-Deoxycortisol) Urinary Metabolite Excretion
Authors: Keavney Bernard , Mayosi Bongani , Gaukrodger Nicole , Imrie Helen , Baker Michelle , Fraser Robert , Ingram Mary , Watkins Hugh , Farrall Martin , Davies Eleanor , Connell John
Published: February 2005

Genetic variation in the gene encoding aldosterone synthase (CYP11B2) has previously been shown to be associated with hypertension and left ventricular hypertrophy. The intermediate phenotype most consistently associated with variation at this locus is that of elevated plasma 11-deoxycortisol (S). However, in normal subjects, aldosterone synthase does not metabolize S, which is converted to cortisol (F) by the enzyme 11β hydroxylase, encoded by the gene CYP11B1, which lies adjacent to CYP11B2 on chromosome 8. It is possible that the quantitative trait locus for the phenotype is within CYP11B1 and that linkage disequilibrium across the extended locus could account for these observations. However, variation across the whole CYP11B1/B2 locus had not been extensively characterized with respect to these phenotypes. We genotyped six polymorphisms in the CYP11B2 gene and three polymorphisms in the CYP11B1 gene in 248 Caucasian nuclear families comprising 1428 individuals. We measured plasma levels of S and F in 460 individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 individuals from 105 families. We examined heritability of the phenotypes and their association with genotypes and haplotypes at this locus.

All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P < 0.00001). There was strong linkage disequilibrium across the CYP11B1/B2 locus. There was modest evidence for association between polymorphisms of CYP11B2 and plasma levels of S (P = 0.02 for T4986C polymorphism) and the plasma S to F ratio, reflecting the activity of 11-β hydroxylase (P = 0.01 for T4986C polymorphism). There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for the CYP11B1 exon 1 polymorphism (P = 0.00002). Addition of other marker data to CYP11B1 exon 1 did not improve the fit of a log-linear model. Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population. Thus, it is likely that linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms account for the previous observations. Further fine-mapping studies across the CYP11B1 locus are required to localize the causative variant(s) for the biochemical phenotype; this may also identify susceptibility alleles for hypertension and left ventricular hypertrophy.
Gene Expression Analysis Reveals Evidence for Increased Expression of Cell Cycle-Associated Genes and Gq-Protein-Protein Kinase C Signaling in Cold Thyroid Nodules
Authors: Eszlinger Markus , Krohn Knut , Berger Kerstin , Läuter Jürgen , Kropf Siegfried , Beck Martin , Führer Dagmar , Paschke Ralf , Führer-Sakel Dagmar
Published: February 2005

In contrast to the molecular etiology of autonomously functioning thyroid nodules, the molecular cause of cold thyroid nodules (CTNs), their benign, functional inactive counterparts, are so far largely unknown. Because of the partially dedifferentiated phenotype of CTNs, alterations in signaling cascades that favor proliferation, but not differentiation, are likely candidates for tumor induction and progression. The importance of RAS mutations for the development of benign nodules with follicular histology is still in question. However, differentially expressed genes in the context of their signaling cascades could define aberrant signaling in CTNs. Therefore, we investigated gene expression in 22 CTNs and their normal surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed an increased expression of cell cycle-associated genes and a special relevance of protein kinase C signaling, whereas no evidence of RAS-MAPK signaling in CTNs was found. Moreover, we determined 31 differentially regulated genes in CTNs, including several histone mRNAs. Taken together, these results explain recent findings showing an increased proliferation in CTNs and draw attention to protein kinase C signaling, but away from RAS-MAPK signaling, as being involved in the etiology of CTNs.
Lack of Effect of Calcium Intake on the 25-Hydroxyvitamin D Response to Oral Vitamin D3
Authors: Goussous Rula , Song Lingyi , Dallal Gerard E. , Dawson-Hughes Bess
Published: February 2005

This study was conducted to examine the effect of calcium intake on the rise in serum 25-hydroxyvitamin D [25(OH)D] levels in response to supplemental vitamin D3. Fifty-two healthy older men and women were randomly assigned to take calcium (500 mg twice daily with meals) or placebo tablets for 90 d between October 1 and the end of March. All participants were placed on 800 IU/d (20 μg/d) vitamin D3. Serum 25(OH)D measurements were made at baseline and on d 30, 60, and 90. The mean baseline 25(OH)D values were 19.2 ± 6.4 ng/ml (47.9 ± 15.9 nmol/liter) in the calcium group and 19.6 ± 6.7 ng/ml (49.1 ± 16.7 nmol/liter) in the control group (P = 0.808). The difference in pattern of change in 25(OH)D was not statistically significant (group by time interaction, P = 0.651); the calcium group increased 6.5 ± 5.9 ng/ml (16.2 ± 14.8 nmol/liter; P < 0.001), and the control group increased 6.6 ± 7.0 ng/ml (16.6 ± 17.4 nmol/liter; P < 0.001). The 95% confidence interval for difference in mean increase, calcium vs. control, was −3.8 ± 3.5 ng/ml (−9.6, 8.7) nmol/liter. In older men and women, the level of calcium intake, within the range of 500-1500 mg/d, does not have an important effect on the rise in serum 25(OH)D that occurs in response to 800 IU (20 μg)/d vitamin D3.
Beneficial Postprandial Effect of a Small Amount of Alcohol on Diabetes and Cardiovascular Risk Factors: Modification by Insulin Resistance
Authors: Greenfield Jerry R. , Samaras Katherine , Hayward Chris S. , Chisholm Donald J. , Campbell Lesley V.
Published: February 2005

Moderate alcohol consumption protects against type 2 diabetes and cardiovascular disease. Because humans spend most of their time in the postprandial state, we examined the effect of 15 g alcohol on postprandial metabolic factors in 20 postmenopausal women over 6 h. We measured 1) glucose, insulin, lipids, C-reactive protein, and adiponectin levels; 2) augmentation index by applanation tonometry; and 3) energy expenditure and substrate oxidation by indirect calorimetry. Subjects received low carbohydrate (LC; visits 1 and 2) and high carbohydrate (HC; visits 3 and 4) high fat meals with and without alcohol. Alcohol augmented the postprandial increment in insulin (P = 0.07) and reduced the postprandial increment in glucose (P = 0.04) after the LC meal only. Triglycerides were increased by alcohol after the LC (P = 0.002) and HC (P = 0.008) meals. Total and high-density lipoprotein cholesterol, fatty acids, and total adiponectin responses were unaffected. C-reactive protein levels decreased postprandially; reductions were enhanced by alcohol after the HC meal, but were attenuated after the LC meal. Postprandial reductions in the augmentation index were increased by alcohol after the LC meal only (P = 0.007). Alcohol enhanced the postprandial increase in energy expenditure 30–60 min after the LC meal (increase, 373 ± 49 vs. 236 ± 32 kcal/d; P = 0.02) and HC meal (increase, 362 ± 36 vs. 205 ± 34 kcal/d; P = 0.0009), but suppressed fat and carbohydrate oxidation. Some of our findings may be mechanisms for lower diabetes and cardiovascular risks in moderate drinkers.
Aurora B Overexpression Associates with the Thyroid Carcinoma Undifferentiated Phenotype and Is Required for Thyroid Carcinoma Cell Proliferation
Authors: Sorrentino Rosanna , Libertini Silvana , Pallante Pier Lorenzo , Troncone Giancarlo , Palombini Lucio , Bavetsias Vassilios , Spalletti-Cernia Daniela , Laccetti Paolo , Linardopoulos Spiros , Chieffi Paolo , Fusco Alfredo , Portella Giuseppe
Published: February 2005

Alterations in chromosome number (aneuploidy) are common in human neoplasias. Loss of mitotic regulation is believed to induce aneuploidy in cancer cells and act as a driving force during the malignant progression. The serine/theronine protein kinases of aurora family genes play a critical role in the regulation of key cell cycle processes. Aurora B mediates chromosome segregation by ensuring orientation of sister chromatids and overexpression of Aurora B in diploid human cells NHDF (normal human diploid fibroblast) induces multinuclearity.

We analyzed Aurora B expression in human thyroid carcinomas. Cell lines originating from different histotypes showed an increase in Aurora B expression. Immunohistochemical analysis of archive samples showed a high expression of Aurora B in anaplastic thyroid carcinomas; conversely, Aurora B expression was not detectable in normal thyroid tissue. Real-time PCR analysis confirmed a strong expression of Aurora B in anaplastic thyroid carcinomas.

The block of Aurora B expression induced by RNA interference or by using an inhibitor of Aurora kinase activity significantly reduced the growth of thyroid anaplastic carcinoma cells.