bluuebunny/crossref_metadata_2025 huggingface dataset:
The Life Cycle of a Complex Product System
Authors: Davies Andrew
Published: October 2003

This paper examines the evolution of the cellular mobile communications system which is treated as an example of a Complex Product System (CoPS). It distinguishes between architectural, component and systemic innovations in order to isolate different phases of innovation in the birth, growth and transformation of the cellular systems and other CoPS. An architectural phase in the birth and early development of a CoPS is powerfully influenced by regulators, system suppliers, standard-making bodies and large users. In this phase, emphasis is placed on developing and testing new system architectures prior to commercialisation. In a new product generation phase, the rate of component and systemic innovation increases and successive new product generations are introduced without fundamentally changing the established architectural design. Industries supplying CoPS are often relatively stable because suppliers have developed core capabilities to accommodate the periodic introduction of new product generations.
Technological Discontinuities: A Multi-Disciplinary Model of Organisational Responses
Authors: McGrath Robert N. , Bennett Nathan
Published: October 2003

There is a dearth of management research addressing the proactive management of technological discontinuities. Drawing on diverse literatures, we develop a multi-disciplinary model of organisational responses to technological discontinuities and develop exemplary propositions to guide future research. Specifically, we suggest industry incumbents use the media to praise or attack the legitimacy of technological innovations that potentially enhance or destroy prevailing competencies.
The Context and Process of Effective NPD: A Typology
Authors: Jin Zhong-Qi , Birks David F. , Targett David
Published: October 2003

Instead of attempting to find a generic solution to improve new product development (NPD) performance, this paper explores contingent approaches to effective NPD. A modified repertory grid analysis technique is used to analyse 30 new product cases, of which all the development processes are identified as effective. The result yields six different approaches which adhere to different contexts. It therefore suggests that there is no unique way to achieve effective NPD. Managers should react differently according to the contexts the NPD is engaged in. Though not comprehensive, the results may serve as a guide to effective NPD in relevant contexts.
Benchmarking the Internationalisation and Co-Ordination of R&D of Western European and Japanese Multi-National Corporations
Authors: Reger Guido
Published: October 2003

There are few publications that provide benchmarking of suitable forms and mechanisms for the co-ordination of international R&D and innovation processes in multi-national corporations. This paper aims to help close this gap on the basis of interviews conducted in 18 Western European and Japanese enterprises. In this respect, the analysis of the differences between European and Japanese corporations is highly important because the co-ordination in Japanese firms is often regarded as a model of "best practice". The empirical results reveal that the major strengths of Japanese companies are their effective co-ordination of the value chain and integration of R&D into their business strategies. Both advantages are achieved through intensive use of personal contacts, informal communication and socialisation. However, European enterprises obviously underestimate these instruments and rely more on internal quasi-markets in R&D. These advantages in Japanese R&D management are also accompanied by drawbacks: while co-ordination is successfully supported within the company in Japan, the integration of international R&D is rendered more difficult.
Team Approaches to Developing Innovative Products and Processes
Authors: Caird Sally , Roy Robin , Wield David
Published: October 2003

International competitiveness, accelerated by the impact of new technologies, has pressurised industry to meet the challenges for higher productivity, faster product cycles, higher levels of quality and lower costs in increasingly internationalised markets. Multi-functional teams have been heralded as a management solution and an innovative organisational approach to address these challenges. This paper summarises the findings from a research programme which aimed to identify the most appropriate team approaches for co-ordinating innovative product/process developments and for enhancing their success. It is based on case studies of environmental technology projects in 25 companies in the United Kingdom. Team approaches were broadly classified as "single-disciplinary", "multi-disciplinary" or "multi-functional" according to members' expertise and innovation function, which could be more or less integrated. The research findings emphasised the diversity of organisational teams which varied according to different projects, organisational, inter-organisational and market conditions, and were more complex when several departments, teams or companies were involved. The findings revealed that multi-functional teams were important in achieving success in open markets, because of their control over appropriate expertise, even though they did not guarantee commercial success. Integrated team approaches were not sufficient for achieving susscess, although most companies regarded their teams as necessary.
Key National Factors in the Emergence of Computational Chemistry Firms
Authors: Mahdi Surya , Pavitt Keith
Published: October 2003

Using information compiled from the Internet, we find that the number of computational chemistry firms in each of the 10 OECD countries (The United States, the United Kingdom, Germany, Japan, France, the Netherlands, Canada, Switzerland, Sweden and Australia) is: (i) strongly correlated with the country's strength in computational chemistry science and with the extent of the national scientific networks; (ii) is weakly correlated with the size of the domestic markets; and (iii) not correlated with the extent of the infrastructure as measured by the number of supercomputers installed. These results show that the emergence of firms based on new science depends heavily on the strength of universities and public research institutes in the underlying sciences. This is particularly true for the leading country — the United States.
Conflict and Co-Operation in Technology-Based Alliances
Authors: Bower D. Jane , Keogh William
Published: October 2003

This paper focuses on conflicts of interest faced by technology-based firms which are embedded in an industry network. In the industry situation analysed here, issues have arisen as to how they can innovate effectively when judged from the perspective of their network partners while achieving their own internal objectives of growth and enhancement of innovative capability. The conceptual conclusions derived from the study are assessed for their generalisability to the global context of the oil industry, and to other industries in the United Kingdom (UK) and elsewhere. It is concluded that where a perceived conflict of interest arises in sharing leading edge technology, firms act in ways which are detrmental to the industrial network as a whole and, ultimately, to the technology leader firm itself. In order to maximise the returns to the technology-based firm, it must (i) select the group of clients/suppliers and portfolio of projects which offer the best spectrum of complementary resources in the light of its growth strategy; and (ii) structure its set of relationships to minimise the perceived risk to its competitive position. Thus, it must identify how to select, win and manage a portfolio of appropriately worded contracts, which collectively minimise its own and its multiple partners' conflicts of interest while ensuring that the required complementary resources will be forthcoming for current and future projects.
Improving New Technology Commercialisation
Authors: Neale Michael R. , Corkindale David R.
Published: October 2003

The marketing literature clearly indicates that one activity which is highly associated with the successful commercial development of new technology is the involvement of potential customers in the process as intimately and as early as possible. This paper summarises the literature on the value of customer involvement and concludes that the process of "co-development" has extra merit. This is not, however, universally employed by new technology originator firms. This paper also explores the apparent barriers to the involvement of customers and found that, among other things, trust seems to be an essential element in allowing technology originators to enter into necessary relationships with potential customers. It is likely that participants in such joint developments had experienced a number of similar, trusting business relationships. Those who rated themselves as being unwilling to divulge confidential information with potential customers, which is essential to the process, seemed to have few other trusting business relationships. The methodology that was used to explore the question empirically is described together with the fieldwork that was conducted. A single industry, the electronics industry, was examined in one state of Australia. The industry comprises small and medium-sized enterprises who trade with customers locally, nationally and internationally. A sample of 15 companies in the industry, as well as some of their customers, were subjected to purposive, in-depth interviews. The findings are drawn from this relatively small pool of qualitative data and the limitations of the study, as well as the areas for further research, are indicated at the end of the paper.
Innovation and Networks: Linking Diffusion and Implementation
Authors: Hislop Donald , Newell Sue , Scarbrough Harry , Swan Jacky
Published: October 2003

This paper examines the appropriation of IT-based innovations within firms. It argues that such innovations represent a challenge to the tendency in the existing literature towards the analytical separation of diffusion and implementation as distinct theoretical domains. In contrast, this paper develops a more transcendent analysis of such innovations by focusing on the cognitive translations and appropriations which link idea generation, diffusion and implementation. This analysis identifies the processes linking wider inter-organisational diffusion networks and intra-firm distributions of expertise as playing a crucial role in the appropriation of innovation. We refer to these as processes of articulation: a formulation which leads to a reappraisal of the networking activities of boundary-spanning individuals.
Mechanism of Stabilizer Acceleration in Electroless Nickel at Wirebond Substrates
Authors: Xu Hongwu , Brito Juan , Sadik Omowunmi A.
Published: October 2003

This paper examines the mechanism of stabilizer concentration at electroless nickel wirebond electrodes. A one-step activation protocol was first achieved on copper substrates using acetic acid and dimethylamineborane. Thereafter nickel multilayers were grown onto the substrates using nickel sulfate heptahydrate as the source of nickel, sodium hypophosphite as the reducing agent, acetic acid as the complexing agent, and thiourea/lead acetate as the stabilizing agent. The morphology of the nickel layers and the effective concentration of the stabilizer were determined using quartz crystal microbalance, gravimetric techniques, and energy-dispersive X-ray analysis (EDX). The plating rate was obtained by measuring the thickness of the Ni-plated using X-ray fluorescence spectroscopy. It was found that lead acetate completely inhibited the plating, and a bimodal distribution was observed as the concentration of the thiourea was varied. We proposed a mechanism for the effect of stabilizer in electroless Ni baths. This mechanism was confirmed using Fourier Transform Infrared and EDX measurements. © 2003 The Electrochemical Society. All rights reserved.
Surge motion on a floating cylinder in water offinite depth
Authors: Bhatta Dambaru D.
Published: October 2003

We derived added mass and damping coefficients of a vertical
floating circular cylinder due to surge motion in calm water of
finite depth. This is done by deriving the velocity potential for
the cylinder by considering two regions, namely, interior region
and exterior region. The velocity potentials for these two regions
are obtained by the method of separation of variables. The
continuity of the solutions has been maintained at the imaginary
interface of these regions by matching the functions and gradients
of each solution. The complex matrix equation is numerically
solved to determine the unknown coefficients. Some
computational results are presented for different depth‐to‐radius
and draft‐to‐radius ratios.
The Hermite polynomials and the Bessel functions from a general point of view
Authors: Dattoli G. , Srivastava H. M. , Sacchetti D.
Published: October 2003

We introduce new families of Hermite polynomials and of Bessel
functions from a point of view involving the use of
nonexponential generating functions. We study their relevant
recurrence relations and show that they satisfy
differential‐difference equations which are isospectral to those
of the ordinary case. We also indicate the usefulness of some of
these new families.
Integral equations of the first kind of Sonine type
Authors: Samko Stefan G. , Cardoso Rogério P.
Published: October 2003

A Volterra integral equation of the first kind with a locally
integrable kernel is called
Sonine equation if there exists another locally integrable
kernel ℓ(x) such that (locally integrable divisors of the unit, with respect to the
operation of convolution). The formal inversion
is well known, but
it does not work, for example, on solutions in the spaces
X = Lp(ℝ1) and is not defined on the whole range
K(X). We develop many properties of Sonine kernels which allow
us—in a very general case—to construct the real inverse
operator, within the framework of the spaces Lp(ℝ1),
in Marchaud form: with the interpretation of the
convergence of this hypersingular integral in Lp‐norm. The
description of the range K(X) is given; it already requires the
language of Orlicz spaces even in the case when X is the
Lebesgue space Lp(ℝ1).
On k‐nearly uniform convex property in generalized Cesàro sequence spaces
Authors: Sanhan Winate , Suantai Suthep
Published: October 2003

We define a generalized Cesàro sequence space ces(p),
where p = (pk) is a bounded sequence of positive real
numbers, and consider it equipped with the Luxemburg norm. The
main purpose of this paper is to show that ces(p) is
k‐nearly uniform convex (k‐NUC) for k ≥ 2 when limn→∞infpn > 1. Moreover, we also obtain
that the Cesàro sequence space cesp(where 1 < p < ∞) is k‐NUC, kR, NUC, and has a drop property.
Sich die Realität vorstellen: Die Bedeutung von Spiel und positiven Erfahrungen für geistiges Wachstum1,2
Authors: Alvarez Anne
Published: October 2003

Die Autorin widmet sich dem Problem der Symbolisierungsfähigkeit. Dem Kontinuum von der symbolischen Gleichsetzung im Sinne von H. Segal über die Übergangsobjekte von Winnicott bis zur echten Symbolisierungsfähigkeit fügt sie noch eine «vierte Position» hinzu, die vor oder jenseits der symbolischen Gleichsetzung liegen kann. Am Beispiel des planlosen, inhaltslosen und bedeutungslosen Spielens mancher schwer gestörter Kinder legt sie dar, dass das Problem die unerträgliche Ferne des Objekts ist, nicht seine übermässige Nähe. Sie vertritt die Meinung, dass gute Erfahrungen nicht nur einen positiven Effekt auf die emotionale Entwicklung von Kindern haben, sondern auch auf die geistige Entwicklung. Die Autorin illustriert ihre theoretischen Überlegungen mit einigen klinischen Beispielen.
Das Geisslein im Uhrenkasten und die Frau im Kleiderschrank The Young Kid in the Clock-Case and the Woman in the Wardrobe
Authors: Schnell Monika
Published: October 2003

Betrachtet wird die Entwicklung der Imaginationsfähigkeit und der Symbolisierungsfähigkeit in Beziehung zur Entwicklung des «inneren Raumes». Ausgangspunkt ist die Überlegung, dass es auch Imaginationen, Phantasien und Träume gibt, die nicht zu Symbolen werden können, sowie die Frage, was ein Symbol zu einem Symbol werden lässt. Die Bedeutung des «symbolischen Raumes» als «potentieller Raum», als Schutzraum oder «Ort des seelischen Rückzugs» wird in Zusammenhang mit der Entwicklung der symbolischen Einstellung betrachtet. Unter symbolischer Einstellung wird die Fähigkeit verstanden, sich mit sich selbst in Verbindung zu setzen und in einen Dialog mit den eigenen Bildern, Träumen und Imaginationen eintreten zu können. Diese Fähigkeit zu einem Dialog mit sich selbst ist ein kreativer Prozess, der Niederschlag internalisierter Beziehungserfahrungen ist. Die Funktionen des inneren Raumes für die Entwicklung der Symbolisierungsfähigkeit werden dargestellt. Anhand von zwei Bildern, dem «Geisslein im Uhrenkasten» und der «Frau im Kleiderschrank» und zwei Fallvignetten werden die Gedanken über Symbole und Symbolbildungsprozesse erläutert.
Postjungianische Analyse in der Kindheit – Ein entwicklungs- psychologischer Ansatz1
Authors: Feldman Brian
Published: October 2003

Diese Arbeit legt eine postjungianische Sicht der Kinderanalyse dar. Methode und Bedeutung der Säuglingsbeobachtung werden untersucht, um deren Relevanz für die Hypothesenbildung bezüglich der Säuglingsentwicklung und für die Praxis der Kinderanalyse zu verstehen. Säuglingsbeobachtung und klinisches Material aus der Analyse eines psychotischen Kindes werden herangezogen, um die theoretischen Konzepte zu veranschaulichen.
Zwischen Sorgen und Banalem
Authors: Paira Götz
Published: October 2003

Leider besteht für diesen Artikel keine Zusammenfassung. Als Einstieg stellen wir den Textanfang zur Verfügung. Die Kontroverse ereignet sich im Zusammenhang mit Tragischem im Allgemeinen wie Tragischem im Persönlichen. Darauf weist der Ort nochmals eindrücklich hin, an dem die Aufforderung zur Beteiligung an der Kontroverse in dieser Zeitschrift steht, der Ort neben dem Nachruf für Arvid Erlenmeyer. Zeitgleich erinnern die Medien an 60 Jahre Grauen nach Stalingrad, während in Israel die Katastrophe ihren Fortgang nimmt, die in Nürnberg verhandelt wurde. Diese Konstellation legt Schweigen nahe wie Flucht in das Schweigen. Zu Hitler falle ihm nichts ein, sagt Karl Kraus. Zu Jung und Hitler fällt mir auch nichts ein. Jedes Wort scheint richtig, und jedes falsche Wort übergewichtig. Die Kluft tut sich auf zwischen dem, was wir wissen, und dem, was wir oft sagen. Zwischen wirksamen psychologischen Einsichten, die wir haben, und Psychojargon, der zur Banalität verkommen kann und dabei böse wird. Die Furcht ergreift, in der zweiten Nazigeneration die Balance zu verlieren bei der teilnehmenden Betrachtung und abzurutschen in die banale Betrachtung oder die schädigende Teilnahme. Dann tauchen die Figuren von Gut und Böse auf, die Tragödie wandelt sich zum Drama und verführt zu Verfolgungen. Schliesslich schreckt das Grauen vor dem Bösen, um das es in der Kontroverse geht. Es schwächt die Fähigkeit zur Distanz, und der Nazischatten droht, bei seiner Behandlung die Oberhand zu gewinnen, zu überschwemmen und zu verschlingen.
The Roles of Soluble Osteopontin Using Osteopontin-Transgenic Mice in vivo: Proliferation of CD4+ T Lymphocytes and the Enhancement of Cell-Mediated Immune Responses
Authors: Higuchi Yasunori , Tamura Yoichi , Uchida Tomohisa , Matsuura Keiko , Hijiya Naoki , Yamamoto Shunsuke
Published: October 2003

We generated transgenic mice expressing osteopontin (OPN) under the control of the α1-antitrypsin promoter. These mice (OPN-T mice) expressed OPN mRNA in liver and kidney, and released a large amount of plasma OPN, which increased after stimulation with turpentine oil. Before sensitization, the number of CD4+ T cells in lymph nodes was significantly higher in OPN-T than nontransgenic mice, and that in spleen was slightly higher, whereas that of CD8+ T cells was no different between OPN-T and nontransgenic mice. After sensitization, the CD4+ T cell numbers in spleen increased significantly, while there were almost no changes in the CD8+ T cells in lymph nodes and spleen. The intensity of contact hypersensitivity responses to 2,4-dinitrofluorobenzene (DNFB) was obviously enhanced in OPN-T mice. In the delayed-type hypersensitivity (DTH) model elicited by DNFB, the number of CD8+ T cells among DNFB-2,4,6-trinitrobenzenesulfonic acid (TNBS)-peritoneal exudate cells was significantly higher in OPN-T than nontransgenic mice, while there was almost no difference in that of CD4+ T cells. Adoptive transfer experiments revealed that the enhanced reactivity is carried by CD4+ and CD8+ T cells, respectively, although the ability of transferring DTH was significantly lower in CD8+ than in CD4+ T cells. The enhancement of CD8+ T cell migration was observed in OPN-T mice. These results suggest that OPN induces a proliferation of effector CD4+ and CD8+ cells in cell-mediated reactions and plays a role in the migration of CD8+ T cells.
Expression of Uridine Diphosphate N-Acetyl-α-D-Galactosamine: Polypeptide N-Acetylgalactosaminyl Transferase 3 in Adenocarcinoma of the Pancreas
Authors: Yamamoto Shinji , Nakamori Shoji , Tsujie Masanori , Takahashi Yuji , Nagano Hiroaki , Dono Keizo , Umeshita Koji , Sakon Masato , Tomita Yasuhiko , Hoshida Yoshihiko , Aozasa Katsuyuki , Kohno Kimitoshi , Monden Morito
Published: October 2003

Uridine diphosphate (UDP) N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase 3 (GalNAc-T3), one of the enzymes that catalyze the initial glycosylation of mucin type O-linked proteins, was shown to associate with the differentiation of cancer cell lines and the prognosis of some kinds of cancers. In the present study, the association of GalNAc-T3 expression with clinicopathologic features of pancreatic adenocarcinoma and patients’ survival was examined. The level of expression of GalNAc-T3 was analyzed immunohistochemically in paraffin-embedded tumor samples from surgically resected specimens of 59 patients with pancreatic ductal adenocarcinoma. The correlations of GalNAc-T3 expression with clinicopathologic features and prognosis were studied. Thirty-five tumors showed high- intensity GalNAc-T3 staining, whereas 24 showed low-intensity staining. A close association was observed between GalNAc-T3 staining intensity and histologic differentiation and the stage of the tumors. The low-intensity group showed a high rate of the poorly differentiated subtype (p < 0.001) and T4 of the pTNM staging system (p < 0.05). These findings indicate that the expression of GalNAc-T3 is associated with the differentiation and aggressiveness of ductal adenocarcinoma of the pancreas.
Expression of RhoC Is Associated with Metastasis of Gastric Carcinomas
Authors: Kondo Tomohiro , Sentani Kazuhiro , Oue Naohide , Yoshida Kazuhiro , Nakayama Hirofumi , Yasui Wataru
Published: October 2003

Objectives:RhoC, a member of the ras-related small GTPase protein family, regulates cytoskeletal structures and has the potential to transform cultured cells. It has recently been reported that RhoC contributes to the metastatic phenotype of melanoma cells. The purpose of this study was to clarify its biological relevance to gastric carcinogenesis and metastasis. Methods: We examined the expression of RhoC by quantitative RT-PCR in 51 cases of gastric carcinoma tissues from prior surgical cases (intestinal type: 24 cases, diffuse type: 27 cases) and in 8 gastric carcinoma cell lines. Results:RhoC expression levels in primary tumors were significantly higher in cases with metastasis than in those without metastasis (p = 0.0202; Mann-Whitney U test). RhoC expression levels in primary tumor and their metastatic tumors were significantly higher than their corresponding nonneoplastic mucosa (p = 0.0357, and 0.0173, respectively; Wilcoxon signed rank test). RhoC mRNA expression was confirmed in the gastric carcinoma cell lines. Conclusion: Our findings suggest that elevated expression of the RhoC gene may be involved in the metastasis of gastric carcinomas and may be a good genetic marker for the prediction of a metastatic potential.
Association between Expression Levels of CA 19-9 and N-Acetylglucosamine-β1,3-Galactosyltransferase 5 Gene in Human Pancreatic Cancer Tissue
Authors: Hayashi Nobuyasu , Nakamori Shoji , Okami Jiro , Nagano Hiroaki , Dono Keizo , Umeshita Koji , Sakon Masato , Narimatsu Hisashi , Monden Morito
Published: October 2003

Objective: CA 19-9, equivalent to Sialyl Lewisa antigen, is a well-known tumor marker in pancreatic cancer. At the initial step of the biosynthesis of CA 19-9, N-acetylglucosamine-β1,3-galactosyltransferase (β3Gal-T) transfers galactose to N-acetylglucosamine (GlcNAc). Recently, β3Gal-T5 has been presumed to be related to the formation of the type 1 chain in an in vitro experiment in terms of kinetic enzyme characterization. The purpose of this study was to investigate which β3Gal-T is related to the synthesis of CA 19-9 in human pancreatic cancer tissues. Methods: We examined β3Gal-T1, T2, T3, T4, and β3Gal-T5 mRNA expressions in 13 noncancerous and cancerous tissues of the human pancreas using real-time polymerase chain reaction, and compared those gene expression levels with the immunoreactivity of CA 19-9 and its precursor DUPAN-2 in cancerous tissues. Results:β3Gal-T5 gene expression significantly augmented in cancerous tissues, when compared with the adjacent noncancerous tissues. Additionally, there was a good correlation between β3Gal-T5 gene transcription levels and immunohistochemical grades of CA 19-9 or its precursor DUPAN-2 in cancerous tissues. However, no correlation was observed between β3Gal-T1, T2, T3, and β3Gal-T4 gene expression levels and CA 19-9 or DUPAN-2 immunoreactive grades in cancerous tissue. Conclusion: β3Gal-T5 is presumed to be responsible for the synthesis of CA 19-9 in pancreatic cancer tissue.
Inflammatory Cytokines, Pleuropneumonia Infection and the Effect of Dexamethasone
Authors: Myers Michael J. , Farrell Dorothy E. , Snider 3rd T.G. Ron , Post Lynn O.
Published: October 2003

Objectives:Actinobacillus pleuropneumoniae causes an often fatal infection of swine due to pleuropneumonia. To determine if inflammatory cytokines are associated with A. pleuropneumoniae-induced pneumonia, infected and noninfected animals were concomitantly administered saline or dexamethasone. Methods: Twenty-four swine were treated with saline, A. pleuropneumoniae, dexamethasone, or A. pleuropneumoniae and dexamethasone (n = 6). The plasma levels of TNF-α, IL-1β, IL-6, IL-8, and IL-10 were examined through time of necropsy (72 h). Gross pathology and histopathology was performed on all animals. Results: Dexamethasone had no effect on A. pleuropneumoniae-induced increases in lung/body weight ratios. Gross pathology of the infected pigs included fibrinous pleuropneumonia with necrosis and hemorrhage in a focal to a multifocal pattern. Histopathology of infected pig lungs revealed necrotizing extensive, fibrinopurulent pneumonia with edema and fibrinopurulent pleuritis. Plasma IL-6 levels were elevated in A. pleuropneumoniae-infected animals beginning 6 h after infection. Dexamethasone treatment did not alter A. pleuropneumoniae-induced plasma IL-6 levels. A. pleuropneumoniae infection did not elicit plasma levels of TNF-α, IL-1β, IL-8, or IL-10. Conclusion: These results suggest that the pneumonia caused by A. pleuropneumoniae infection is not due to the release of systemic inflammatory cytokines.
Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy
Authors: Nakada Chisato , Tsukamoto Yoshiyuki , Oka Akira , Nonaka Ikuya , Sato Kenzo , Mori Shigeo , Ito Hisao , Moriyama Masatsugu
Published: October 2003

Objectives: Ankyrin-repeated protein with PEST and a proline-rich region (ARPP) is a recently identified protein with 4 ankyrin-repeated motifs in its central portion. Type 1 myofibers of skeletal muscle express high levels of ARPP. Recently, we have found that ARPP expression was induced in mouse denervated skeletal muscle. This led us to hypothesize that ARPP expression might be induced in skeletal muscle under some pathological conditions. Methods: In this study, we performed immunohistochemical analysis of ARPP expression in biopsy specimens of muscle tissue from 15 patients with muscular dystrophies (MDs), 13 with congenital myopathies and 11 with spinal muscular atrophies (SMAs). Results: The ARPP expression levels of all the specimens from MD patients appeared to be lower than control muscle levels. In contrast, the specimens from the 13 patients with congenital myopathies were all ARPP positive. We also found increased numbers of ARPP-positive myofibers in patients with congenital myopathies, and these myofibers co-expressed the slow myosin heavy chain. Indeed, it has been reported that type 1 myofibers are predominant in patients with congenital myopathies, suggesting that increased numbers of ARPP-positive myofibers in such patients may be associated with increased numbers of type 1 fibers. In patients with SMAs, we found that ARPP-positive myofibers tended to be distributed in groups. As grouped myofibers have been reported to result from the process of denervation, innervation and subsequent denervation of re-innervated myofibers, the grouped ARPP-positive myofibers in SMA patients may result from denervation of the motor units. Conclusions: These findings suggest that evaluation of ARPP may be helpful for the histological diagnosis of muscle diseases.
Differential Expression of Protease-Activated Receptors 1, 2, and 4 on Human Endothelial Cells from Different Vascular Sites
Authors: Fujiwara Masakazu , Jin Enjing , Ghazizadeh Mohammad , Kawanami Oichi
Published: October 2003

Objective: Protease-activated receptors (PARs) mediate DNA synthesis in endothelial cells when activated by serine proteases. However, despite the existence of heterogeneity among endothelial cells from each tissue, the responses to PAR-1, PAR-2, and PAR-4 activation are poorly defined and compared between endothelial cells from different sites. The aim of this study was to investigate whether PAR-mediated DNA synthesis differed in various endothelial cell types. Methods: We examined the incorporation of BrdU by human pulmonary artery endothelial cells (HPAECs), human aortic endothelial cells (HAECs), and human umbilical vein endothelial cells (HUVECs). Results: When the endothelial cells were treated with the selective PAR-1-activating peptide, SFLLRN, HAECs showed the highest BrdU incorporation rate (182 ± 28%). In contrast, treatment with the PAR-2-activating peptide, SLIGKV, resulted in the highest BrdU incorporation rate (173 ± 37%) in HPAECs, when pretreated with TNF-α. The PAR-4-activating peptide, GYPGQV, induced DNA synthesis in HPAECs and HAECs, but not in HUVECs. Conclusion: These findings suggest that each PAR preferentially targets an endothelial cell type, and thus plays a distinct role in diverse physiological or pathological conditions.
Human Herpesvirus-6: A Short Review of Its Biological Behavior
Authors: Krueger Gerhard R.F. , Ablashi Dharam V.
Published: October 2003

HHV-6 shows a widespread distribution with life-long persistence. The virus is frequently reactivated, yet remains clinically inapparent unless the patient is immunodeficient in some way. Even then, HHV-6 reactivation may simply enhance the pathogenicity of other viruses or existing autoimmune disorders rather than becoming a pathogen itself. Future clinical studies need to focus on such indirect viral influences mediated through molecular mimicry and interference with cell receptor expression, and cytokine and chemokine network regulation. Nevertheless, such disturbances may afford therapeutic intervention to disrupt herpesvirus interference and improve certain disease processes. There are only a few diseases for which an immediate causal relationship to HHV-6 infection has been suggested.
Safety Evaluation of GX-12, a New HIV Therapeutic Vaccine: Investigation of Integration into the Host Genome and Expression in the Reproductive Organs
Authors: Kang Kyung Koo , Choi Seul Min , Choi Jae Hoon , Lee Dong Sup , Kim Chae Young , Ahn Byung Ok , Kim Byung Moon , Kim Won Bae
Published: October 2003

AIDS is one of the greatest infectious disease threats to human health despite the extensive efforts made since the discovery of HIV in 1983. The use of plasmid DNA vaccination to elicit humoral and cell-mediated immune responses against HIV infection has produced promising results in animal and in human trials. However, there are several safety concerns about the use of a DNA vaccine, which include the possibility of integration into the host genome, adverse immunopathology, and anti-DNA autoantibody induction. In this study, we examined the potential integration and distribution of GX-12, a new therapeutic vaccine for HIV infection, at various times in muscles and reproductive organs of rats. Animals of both sexes were injected with GX-12 at the dose of 400 µg/animal i.m. once a week for 4 weeks, and host genome integration and tissue distribution were examined on day 1, 5, 15, 30 and 45 days after the final injection. A PCR-based assay revealed that GX-12 was not integrated into the host genome, nor expressed in reproductive organs at any time. These findings suggest that the risk of mutation or germline transmission due to GX-12 injection is negligible.
Analysis of T Cell Receptor Variable Regions and Complementarity Determining Region 3 of Infiltrating T Lymphocytes in the Liver of Patients with Chronic Type B Hepatitis
Authors: Maru Yasushi , Yokosuka Osamu , Imazeki Fumio , Saisho Hiromitsu , Omata Masao
Published: October 2003

Objectives: T cell receptor (TCR) variable regions and complementarity determining regions 3 (CDR3) of infiltrating T cells in the livers of patients with chronic hepatitis B were examined in detail. Methods: TCR usage was examined by the inverse polymerase chain reaction in 2 hepatitis B e antigen-positive patients, one at an early stage and the other at an advanced stage. Results: In 61 productively rearranged clones bearing TCRα genes in the liver of the patient with early stage chronic hepatitis B, the Vα 7.2 gene segment was most frequently used (16.4%), while the other Vα gene segments were used less frequently. All but one of the clones with the Vα7.2 gene were joined with the Jα33 gene, and the CDR3 regions of these clones were the same length and similar in amino acid sequence. In contrast, in 68 productively rearranged clones from the liver of the patient with advanced stage disease, all Vα gene segments were used less frequently, and combinations of the Vα and Jα gene segments varied. Conclusions: Our data suggest a relatively restricted usage of TCR in the liver in early stage chronic hepatitis B.
E/NS1 Modifications of Dengue 2 Virus after Serial Passages in Mammalian and/or Mosquito Cells
Authors: Chen Wei-June , Wu Hsin-Rong , Chiou Shyang-Song
Published: October 2003

Objective: Dengue viruses are routinely maintained in nature by transmission cycles involving the passage of virus between humans and Aedes mosquitoes. The number of dengue virus lineages has been increasing over time. The aim of this study was to identify the genetic diversity of dengue 2 virus serially transferred in mammalian and/or mosquito cells. Methods: The E/NS1 gene of dengue 2 virus variants derived from serial passages in Vero or C6/36 cells, or alternately in both cell systems, was amplified and sequenced in order to observe gene modification after serial passages. Results: Three nucleotides (two in E and one in NS1) or two amino acids (one each in E and NS1) changed in the virus that was continuously cultured in Vero cells for 20 passages, whereas four nucleotides (two each in E and NS1) or three amino acids (one in E and two in NS1) changed in the virus cultured for 30 passages. The genome of dengue 2 virus remained stable even when the virus was serially transferred in C6/36 cells for 30 generations. However, there was one amino acid substitution (E46 I→V) resulting from a single nucleotide change in the E region of dengue 2 virus alternately transferred in C6/36 and Vero cells for either 20 or 30 passages. In addition, dengue 2 virus obtained from serially cultured Vero cells usually replicated better when it reinfected Vero cells, reflecting its high adaptation fitness to the host cell. Conclusions: It is concluded that genetic changes of dengue 2 virus are constrained in Vero (mammalian) cells, resulting in a variety of genome-related quasispecies populations. Some populations of the virus are subsequently selected by and genetically (at least in the E/NS1 portion of the viral genome) maintained in C6/36 (mosquito) cells during replicative competition.
Long-Term Outcome, with Monitoring of Platelet Counts, in Patients with Chronic Hepatitis C and Liver Cirrhosis after Interferon Therapy
Authors: Moriyama Mitsuhiko , Matsumura Hiroshi , Aoki Hiroshi , Shimizu Toshihiro , Nakai Kazuhiko , Saito Takahide , Yamagami Hiroaki , Shioda Atsuo , Kaneko Miki , Goto Iori , Tanaka Naohide , Arakawa Yasuyuki
Published: October 2003

Objective: Because the determination of the stage of fibrosis depends on rather subjective judgment, more objective parameters are needed. In this study, we followed the long-term outcome, with monitoring of platelet counts, in patients with chronic hepatitis C or liver cirrhosis (LC) who had undergone interferon (IFN) therapy. Methods: 596 patients who were diagnosed at our institute from 1987 to 1998 with chronic hepatitis C and LC were treated with IFNs. A further 58 patients were not treated (NT). The annual rate of changes in platelet counts were calculated and compared for IFN-treated and NT patients. Results: The relationship between the efficacy of IFN therapy and the incidence of hepatocellular carcinoma (HCC) showed that the patients who were virologic sustained responders (VSR) had a significantly lower incidence of HCC than the nonresponders (NR) and NT patients. The change in platelet counts was +4,350/µl/year in the VSR, +1,010/µl/year in the biochemical sustained responders (BSR), –4,540/µl/year in the NR and –6,180/µl/year in the NT patients, indicating a significant platelet increase in the VSR, a decrease of the same magnitude in the NR and NT patients, and no change in the BSR. The cumulative probability of developing HCC and liver failure was significantly higher in groups with decreased platelet counts than in groups with increased platelet counts among patients who had undergone IFN therapy. Multivariate analyses revealed that a decrease in platelet counts was the cardinal risk factor for development of HCC and liver failure in chronic hepatitis C or LC patients. Conclusion: Investigation of platelet counts was useful for determining the long-term outcome of patients who had undergone IFN therapy and for predicting the development of HCC.
Full-Length Sequences of Six Hepatitis E Virus Isolates of Genotypes III and IV from Patients with Sporadic Acute or Fulminant Hepatitis in Japan
Authors: Takahashi Kazuaki , Kang Jong-Hon , Ohnishi Sachiyo , Hino Kunihiko , Miyakawa Hiroshi , Miyakawa Yuzo , Maekubo Hiroshi , Mishiro Shunji
Published: October 2003

Objective: Ranges of variation and conservation in sequence need to be defined for detecting and genotyping hepatitis E virus (HEV). Methods: Six HEV isolates from Japanese patients were sequenced over the entire genome and compared phylogenetically along with 16 reported HEV isolates, including two from pigs. Results: Three of the six HEV isolates were of genotype III, and the remaining three were of genotype IV. Local clusterings of Japanese HEV isolates were observed in the phylogenetic analyses, including a swine HEV isolate reported previously (swJ570). All six HEV isolates possessed three open reading frames (ORFs). The ORF3 in the three isolates of genotype III were in a different reading frame, while that in the three isolates of genotype IV were in the same reading frame as ORF1. A stretch of 46–96 nucleotides was identified, point mutations and deletions in which were specific for the four genotypes (I–IV). A polymerase chain reaction method was developed with 9 nested universal primers, deduced from conserved regions in the 5′-terminal sequences of the 22 HEV genomes. Conclusions: Conserved and genotype-specific variation in HEV sequences, identified in the comparison of 22 full-length genomes, would be useful in designing primers for sensitive detection and specific genotyping of HEV RNA.
Characterization of HeLa Cells Persistently Infected with Influenza Virus B/Lee/40 with Respect to Telomerase Activity and Apoptosis
Authors: Hayase Yukiharu , Tobita Kiyotake
Published: October 2003

Objective: The purpose of this study was to examine telomerase activity and apoptotic changes in HeLa cells persistently infected with influenza viruses B/Lee/40 (He/Le cells). Methods: He/Le cells were established as described previously [Intervirology 2002;45:67–70], and passaged twice a week. The existence of influenza virus genes was monitored by the reverse transcription polymerase chain reaction (RT-PCR). Telomerase activities in He/Le cells were assayed by Telochaser (stretch PCR method). Apoptotic changes in He/Le cells were examined using the Apoptotic DNA Ladder Kit and the In situ Cell Death Detection Kit, Fluorescence. Results: In He/Le cells, (1) all eight influenza virus genes were detected by RT-PCR until 62 days post infection (p.i.); (2) only nucleoprotein gene remained detectable until 120 days p.i.; (3) telomerase activity of He/Le cells normalized to those of uninfected HeLa cells was remarkably decreased (16–55% of control) during the persistence of influenza and recovered up to 80% of control on day 168 p.i. when no influenza virus gene was detected by RT-PCR, and (4) no apoptotic changes were detected despite the continuous existence of influenza virus genes. Conclusion: In He/Le cells, telomerase activity was suppressed exclusively during the persistence of influenza, and no apoptotic changes were detected.
Genetic Analysis of Short Stature
Authors: Kant S.G. , Wit J.M. , Breuning M.H.
Published: October 2003

Short stature is a major concern for patients and their parents, and represents a diagnostic challenge to the clinician. A correct diagnosis is of particular importance in view of the availability of effective, but costly, therapy in a small subset of cases. Many different genetic etiologies of short stature are known. Therefore, chromosome as well as molecular analysis are requisite diagnostic investigations in children with short stature. Particularly in the group of children with idiopathic short stature, possibilities of molecular analysis are often underestimated. Important options are UPD7 and the FGFR3, SHOX, GH1 and GHR genes. Furthermore, analysis of the IGF and IGF1R genes should be considered. We propose a flow chart for molecular analysis in short stature.
Acarbose and Idiopathic Reactive Hypoglycemia
Authors: Peter Sebastian
Published: October 2003

Background/Aim: Therapy for idiopathic reactive hypoglycemia is ineffective and impractical. Acarbose, an α-glucosidase inhibitor, decreases the absorbed glucose load. This study was done to determine the efficacy of acarbose in this syndrome. Methods: Six patients with symptoms suggestive of postprandial hypoglycemia were chosen consecutively. Three-hour oral glucose tolerance tests using 75 g of glucose were done on each patient. The patients were then treated with acarbose with each meal. Results: All patients had symptomatic hypoglycemia during testing. After 4 weeks of acarbose therapy, all patients were asymptomatic on a regular diet. Conclusion: Acarbose is efficacious in the management of idiopathic reactive hypoglycemia.
Long-Term Follow-Up of Childhood-Onset Hypopituitarism in Patients with the PROP-1 Gene Mutation
Authors: Pavel Marianne E. , Hensen Johannes , Pfäffle Roland , Hahn Eckhart G. , Dörr Helmuth G.
Published: October 2003

Objective: The PROP-1 gene mutation is a rare disorder leading to combined pituitary hormone deficiencies over time. The aim was to analyze the clinical picture of 40 years of an almost untreated PROP-1 gene mutation. Methods: We describe the clinical and hormonal data of 2 brothers from childhood to adulthood as well as imaging procedures (MRI of the pituitary gland, bone mineral density by QCT and DPX). The PROP-1 gene mutation (301–302delAG) was confirmed by DNA sequencing. Results: Although long-standing untreated hypopituitarism was present, there was normal physical and professional activity. Bone mineral density was low only in 1 patient. Adrenocortical deficiency occurred late at 45 and 39 years. Conclusions: The biological evolution of the PROP-1 gene mutation illustrates the importance of continuous care for these patients. Hormonal deficiencies do not necessarily lead to the same phenotype as is obvious in differences of bone age and bone mineral density.
Pilot Study of Elevated Levels of Insulin-Like Growth Factor-Binding Protein-2 as Indicators of Hepatocellular Carcinoma
Authors: Ranke Michael B. , Maier Klaus-Peter , Schweizer Roland , Stadler Bernd , Schleicher Sabine , Elmlinger Martin W. , Flehmig Bertram
Published: October 2003

Background/Aims: Insulin-like growth factor-binding protein-2 (IGFBP-2) is expressed in many malignant tissues, and elevated serum levels can be indicators of tumour activity in addition to conventional tumour markers. Our aim was to evaluate the role of IGFBP-2 levels together with insulin-like growth factor (IGF)-I, IGF-II and IGFBP-3 in the diagnostic work-up of patients with hepatocellular carcinoma (HCC). Methods: In 50 (39 males, 11 females) histologically confirmed and TNM-graded patients with HCC who had not received adjuvant chemotherapy, the basal serum levels of IGF-I, IGF-II, IGFBP-3, IGFBP-2 and α-fetoprotein (AFP) were measured. The median age of the patients was 66 (37–84) years, body mass index was normal (25 (35–16) kg/m2). Results: The levels of IGF-I, IGF-II and IGFBP-3 were diminished, as is the case when nutrition, hepatic function and growth hormone (GH) secretion are decreased. The levels of AFP and IGFBP-2 were markedly high. In 37 cases, IGFBP-2 levels were above the age-related norm, and in 40 cases AFP levels were also elevated. In 3 cases, both AFP and IGFBP-3 were normal, and in 4 cases AFP was high but IGFBP-2 normal, whereas in 10 cases AFP was normal but IGFBP-2 was high. Conclusions: In addition to AFP, IGFBP-2 appears to be a suitable marker for the evaluation of the serological status of HCC patients. A longitudinal study during disease management is required to assess the full potential of IGFBP-2 measurements as a marker.
Growth Velocity: A Presentation of Reference Values in Dutch Children
Authors: Gerver W.J.M. , de Bruin R.
Published: October 2003

Normal values are given for height velocity in a Dutch population. A construction of velocity curves is given and a comparison is made with other studies.
Leptin in Relation to Hepatocellular Carcinoma in Patients with Liver Cirrhosis
Authors: Wang Ya-Yu , Lin Shih-Yi
Published: October 2003

Objectives: This study was conducted to investigate whether leptin is involved in the etiogenesis of hepatocellular carcinoma (HCC) in cirrhotic patients. Methods: Thirty-one male cirrhotic patients with HCC, 26 male cirrhotic patients without HCC, and 25 control subjects were included in this study. Body fat mass (FM) was determined by bioelectrical impedance analysis, and serum leptin and hormone concentrations were measured by immunoassay. Results: A significant correlation of serum leptin levels to FM was observed in both patient groups and control subjects (r = 0.760, p < 0.001; r = 0.520, p < 0.01; r = 0.460, p < 0.05, respectively). The serum leptin levels in cirrhotic patients with or without HCC were significantly higher than those in control subjects (6.0 ± 1.1 vs. 6.1 ± 0.6 vs. 3.8 ± 0.3 ng/ml, p < 0.05), though their body FM was lower. Using a multiple logistic regression analysis, it was found that the odds ratio of serum leptin for HCC was 1.04 (95% CI 0.79–1.33) after adjustment of several known risk factors. Conclusions: Our study demonstrated that cirrhotic patients with or without HCC had increased serum leptin concentrations. However, leptin did not appear to be associated with the development of HCC in cirrhotic patients.