bluuebunny/crossref_metadata_2025 huggingface dataset:
EFD: A Hybrid Knowledge/Statistical‐Based System for the Detection of Fraud
Authors: Major John A. , Riedinger Dan R.
Published: March 2003

Electronic Fraud Detection (EFD) assists Investigative Consultants in the Managed Care & Employee Benefits Security Unit of The Travelers Insurance Companies in the detection and preinvestigative analysis of health care provider fraud. The task EFD performs, scanning a large population of health insurance claims in search of likely fraud, has never been done manually. Furthermore, the available database has few positive examples. Thus, neither existing knowledge engineering techniques nor statistical methods are sufficient for designing the identification process. To overcome these problems, EFD uses knowledge discovery techniques on two levels. First, EFD integrates expert knowledge with statistical information assessment to identify cases of unusual provider behavior. The heart of EFD is 27 behavioral heuristics, knowledge‐based ways of viewing and measuring provider behavior. Rules operate on them to identify providers whose behavior merits a closer look by the investigative consultants. Second, machine learning is used to develop new rules and improve the identification process. Pilot operations involved analysis of nearly 22,000 providers in six metropolitan areas. The pilot is implemented in SAS Institute's SAS System, AICorp's Knowledge Base Management System, and Borland International's Turbo Prolog.
Trust in Government: Personal Ties that Bind?
Authors: Brewer Paul R. , Sigelman Lee
Published: March 2003

Objective. This research note compares the views of the federal government held by federal government workers, their family members, their close friends, and state and local government workers to the views held by other U.S. citizens. Methods. We analyze data from a 2000 survey of Washington, D.C. metropolitan‐area residents. Results. Respondents employed at any level of government—not only federal but also state and local—trust the federal government more than respondents with no ties to government. Being the family member or friend of a federal government employee has no impact on trust in government. Conclusions. A confidence gap divides government employees from the rest of the public.
Targeting Democracies: Regime Type and America’s “Aggressively Unilateral” Trade Policy
Authors: Sherman Richard
Published: March 2003

Objectives. The American trade policy instrument Section 301 authorizes the president to demand changes in foreign states’ trade policies and to fortify these demands with threats of sanctions. I examine the economic and political factors that influence the selection of states as targets for Section 301 proceedings. Methods. I develop an argument connecting a state’s regime type to the likelihood that it will be targeted under Section 301. Controlling for other relevant factors, democratic states are predicted to have a higher probability of being targeted. I test the hypothesis in a set of regression models on cross–sectional time series data with both targeting incidence and targeting frequency as dependent variables. Results. States with more open and competitive political systems are more likely to be targeted under Section 301. Of the included variables, only a state’s regime type and the size of its trade relationship with the United States have consistently significant effects across alternative model specifications. Conclusions. Section 301 plays on the rivalry between protectionist and export–oriented interests by demanding reductions in trade barriers and backing them up with threats directed against export industries. Industries currently favored by protectionist policies have a higher chance of losing such a political contest in a political system more open to interest–group competition. The institutional form of political competition within a state affects the state’s response to international pressure on trade policy.
In Silico Pattern-Based Analysis of the Human Cytomegalovirus Genome
Authors: Rigoutsos Isidore , Novotny Jiri , Huynh Tien , Chin-Bow Stephen T. , Parida Laxmi , Platt Daniel , Coleman David , Shenk Thomas
Published: March 2003

More than 200 open reading frames (ORFs) from the human cytomegalovirus genome have been reported as potentially coding for proteins. We have used two pattern-based in silico approaches to analyze this set of putative viral genes. With the help of an objective annotation method that is based on the Bio-Dictionary, a comprehensive collection of amino acid patterns that describes the currently known natural sequence space of proteins, we have reannotated all of the previously reported putative genes of the human cytomegalovirus. Also, with the help of MUSCA, a pattern-based multiple sequence alignment algorithm, we have reexamined the original human cytomegalovirus gene family definitions. Our analysis of the genome shows that many of the coded proteins comprise amino acid combinations that are unique to either the human cytomegalovirus or the larger group of herpesviruses. We have confirmed that a surprisingly large portion of the analyzed ORFs encode membrane proteins, and we have discovered a significant number of previously uncharacterized proteins that are predicted to be G-protein-coupled receptor homologues. The analysis also indicates that many of the encoded proteins undergo posttranslational modifications such as hydroxylation, phosphorylation, and glycosylation. ORFs encoding proteins with similar functional behavior appear in neighboring regions of the human cytomegalovirus genome. All of the results of the present study can be found and interactively explored online (
http://cbcsrv.watson.ibm.com/virus/
).
GROUP-THEORETIC BIFURCATION MECHANISM OF PATTERN FORMATION IN THREE-DIMENSIONAL UNIFORM MATERIALS
Authors: TANAKA REIKO , SAIKI ISAO , IKEDA KIYOHIRO
Published: March 2003

An underlying mathematical mechanism for formation of periodic geometric patterns in uniform materials is investigated. Symmetry of a rectangular parallelepiped domain with periodic boundaries is modeled as an equivariance to a group O (2) × O (2) × O (2). The standard group-theoretic approach is used to investigate possible patterns of this domain that emerge through direct and some secondary bifurcations. This investigation clarifies the mechanism of successive symmetry-breaking bifurcation, which entails a variety of geometrical patterns in three-dimensional uniform materials. In particular, a few characteristic geometric patterns, such as oblique layer, column and diamond patterns, are identified and classified. Pattern simulations are conducted on geometrical patterns of joints in a calcite and folds in a stratum to reinforce pertinence of the pattern formation mechanism. Images of three-dimensional patterns of joints and folds are expanded into the triple Fourier series, and transient processes of bifurcation are reconstructed to arrive at possible courses of successive bifurcation. Qualitative information from this approach can offer insight into transient courses of deformation, which have been overlooked up to now.
THE NATURAL MEASURE OF NONATTRACTING CHAOTIC SETS AND ITS REPRESENTATION BY UNSTABLE PERIODIC ORBITS
Authors: DHAMALA MUKESHWAR , LAI YING-CHENG
Published: March 2003

The natural measure of a chaotic set in a phase-space region can be related to the dynamical properties of all unstable periodic orbits embedded in the chaotic set contained in that region. This result has been shown to be valid for hyperbolic chaotic invariant sets. The aim of this paper is to examine whether this result applies to nonhyperbolic, nonattracting chaotic saddles which lead to transient chaos in physical systems. In particular, we examine, quantitatively, the closeness of the natural measure obtained from a long trajectory on the chaotic saddle to that evaluated from unstable periodic orbits embedded in the set. We also analyze the difference between the long-time average values of physical quantities evaluated with respect to a dense trajectory and those computed from unstable periodic orbits. Results with both the Hénon map and the Ikeda–Hammel–Jones–Moloney map for which periodic orbits can be enumerated lend credence to the conjecture that the unstable periodic-orbit theory of the natural measure is applicable to nonhyperbolic chaotic saddles.
The combinatorial structure of trigonometry
Authors: Antippa Adel F.
Published: February 2003

The native mathematical language of trigonometry is
combinatorial. Two interrelated combinatorial symmetric functions
underlie trigonometry. We use their characteristics to derive
identities for the trigonometric functions of multiple distinct
angles. When applied to the sum of an infinite number of
infinitesimal angles, these identities lead to the power series
expansions of the trigonometric functions. When applied to the
interior angles of a polygon, they lead to two general constraints
satisfied by the corresponding tangents. In the case of multiple
equal angles, they reduce to the Bernoulli identities. For the
case of two distinct angles, they reduce to the Ptolemy identity.
They can also be used to derive the De Moivre‐Cotes identity. The
above results combined provide an appropriate mathematical
combinatorial language and formalism for trigonometry and more
generally polygonometry. This latter is the structural language
of molecular organization, and is omnipresent in the natural
phenomena of molecular physics, chemistry, and biology.
Polygonometry is as important in the study of moderately complex
structures, as trigonometry has historically been in the study of
simple structures.
Selberg′s trace formula on the k‐regular tree and applications
Authors: Terras Audrey , Wallace Dorothy
Published: February 2003

We survey graph theoretic analogues of the Selberg trace and
pretrace formulas along with some applications. This paper
includes a review of the basic geometry of a k‐regular tree
Ξ (symmetry group, geodesics, horocycles, and the analogue of
the Laplace operator). A detailed discussion of the spherical
functions is given. The spherical and horocycle transforms are
considered (along with three basic examples, which may be viewed
as a short table of these transforms). Two versions of the
pretrace formula for a finite connected k‐regular graph
X≅Γ\Ξ are given along with two applications. The first application is to obtain an asymptotic formula for the number of closed paths of length r in X (without backtracking but possibly with tails). The second
application is to deduce the chaotic properties of the induced
geodesic flow on X (which is analogous to a result of Wallace
for a compact quotient of the Poincaré upper half plane).
Finally, the Selberg trace formula is deduced and applied to the
Ihara zeta function of X, leading to a graph theoretic analogue
of the prime number theorem.
The fixed‐point property in Banach spaces containing a copy of c0
Authors: Pineda Maria A. Japón
Published: February 2003

We prove that every Banach space containing an isomorphic copy of
c0 fails to have the fixed‐point property for asymptotically
nonexpansive mappings with respect to some locally convex topology
which is coarser than the weak topology. If the copy of c0 is asymptotically isometric, this result can be improved, because
we can prove the failure of the fixed‐point property for
nonexpansive mappings.
Local properties of maps of the ball
Authors: Kannai Yakar
Published: February 2003

Let f be an essential map of Sn−1 into itself (i.e., f is not homotopic to a constant mapping) admitting an extension
mapping the closed unit ball into ℝn. Then, for every interior point y of Bn, there exists a point x in f−1(y) such that the image of no neighborhood of x is contained in a coordinate half space with y on its boundary.
Under additional conditions, the image of a neighborhood of x covers a neighborhood of y. Differential versions are valid
for quasianalytic functions. These results are motivated by
game‐theoretic considerations.
Connectivity properties for subspaces of function spacesdetermined by fixed points
Authors: Gonçalves Daciberg L. , Kelly Michael R.
Published: February 2003

We study the topology of a subspace of the function space of
continuous self‐mappings of a given manifold: the subspace
determined by maps having the least number of fixed points in its
homotopy class. In the case that the manifold is a closed disk of
finite dimension, we prove that this subspace is both globally
and locally path connected. We also prove this result when the
manifold is a sphere of dimension 1, 3, or 7.
On the modulus of u‐convexity of Ji Gao
Authors: Mazcuñán-Navarro Eva María
Published: February 2003

We consider the modulus of u‐convexity of a Banach space introduced by Ji Gao (1996) and we improve a sufficient condition for the fixed‐point property (FPP) given by this author. We also
give a sufficient condition for normal structure in terms of the modulus of u‐convexity.
Measure of nonhyperconvexity and fixed‐point theorems
Authors: Bugajewski Dariusz , Espínola Rafael
Published: February 2003

The aim of this paper is to work with the measure of
nonhyperconvexity in a similar way as J. Cano (1990) does with the
index of nonconvexity. We apply this measure to obtain different
extensions of the famous Schauder fixed‐point theorem in
hyperconvex spaces.
Relaxed submonotone mappings
Authors: Donchev Tzanko , Georgiev Pando
Published: February 2003

The notions of relaxed submonotone and relaxed
monotone mappings in Banach spaces are introduced and many of their properties are investigated. For example, the Clarke subdifferential of a locally Lipschitz function in a separable Banach space is relaxed submonotone on a residual subset. For
example, it is shown that this property need not be valid on the whole space. We prove, under certain hypotheses, the surjectivity of the relaxed monotone mappings.
A weak ergodic theorem for infinite products of Lipschitzianmappings
Authors: Reich Simeon , Zaslavski Alexander J.
Published: February 2003

Let K be a bounded, closed, and convex subset of a Banach
space. For a Lipschitzian self‐mapping A of K, we denote by Lip(A) its Lipschitz constant. In this paper, we establish a
convergence property of infinite products of Lipschitzian
self‐mappings of K. We consider the set of all sequences
of such self‐mappings with the property
limsupt→∞Lip(At ) ≤ 1. Endowing it with an appropriate topology, we establish a weak ergodic
theorem for the infinite products corresponding to generic sequences in this space.
Fixed‐point and coincidence theorems for set‐valued maps with nonconvex or noncompact domains in topological vector spaces
Authors: Włodarczyk Kazimierz , Klim Dorota
Published: February 2003

A technique, based on the investigations of the images of maps,
for obtaining fixed‐point and coincidence results in a new class of maps and domains is described. In particular, we show that the problem concerning the existence of fixed points of expansive set‐valued maps and inner set‐valued maps on not necessarily convex or compact sets in Hausdorff topological vector spaces has a solution. As a consequence, we prove a new intersection theorem concerning not necessarily convex or compact sets and its applications. We also give new coincidence and section theorems for maps defined on not necessarily convex sets in Hausdorff topological vector spaces. Examples and counterexamples show a fundamental difference between our results and the well‐known ones.
A remark on the approximate fixed‐point property
Authors: Kuczumow Tadeusz
Published: February 2003

We give an example of an unbounded, convex, and closed set C in the Hilbert space l2 with the following two properties: (i) C has the approximate fixed‐point property for nonexpansive
mappings, (ii) C is not contained in a block for every orthogonal basis in l2.
On oscillation of a food‐limited population model with time delay
Authors: Berezansky Leonid , Braverman Elena
Published: February 2003

For a scalar nonlinear delay differential equation Ṅ(t) = r(t)N(t)(K − N(h(t)))/(K + s(t)N(g(t))),r(t) ≥ 0, h(t) ≤ t, g(t) ≤ t and some generalizations of this equation, we establish explicit oscillation and nonoscillation conditions. Coefficient r(t) and delays are not assumed to be continuous.
On representations of Lie algebras of a generalized Tavis‐Cummings model
Authors: Hanna L. A. M.
Published: February 2003

Consider the Lie algebras , [K3, K1] = rK1, [K3, K2] = −rK2, [K3, K4] = 0, [K4, K1] = −tK1, and [K4, K2] = tK2, subject to the physical conditions, K3 and K4 are real diagonal operators representing energy, , and the Hamiltonian H = ω1K3 + (ω1 + ω2)K4 + λ(t)(K1eiΦ + K2eiΦ) is a Hermitian operator. Matrix representations are discussed and faithful representations of least degree for satisfying the physical requirements are given for appropriate values of r, s, t ∈ ℝ.
Consistency and Akrasia in Plato's Protagoras
Authors: Woolf Raphael
Published: February 2003

Relatively little attention has been paid to Socrates' argument against akrasia in Plato's Protagoras as an example of Socratic method. Yet seen from this perspective the argument has some rather unusual features: in particular, the presence of an impersonal interlocutor ("the many") and the absence of the crisp and explicit argumentation that is typical of Socratic elenchus. I want to suggest that these features are problematic, considerably more so than has sometimes been supposed, and to offer a reading of the argument that accounts for them. My reading revolves around the connections between Socratic method, consistency and akrasia. I argue that Socrates' discussion of akrasia aims at exposing the interlocutor's inconsistency, and to this extent is typical of Socratic inquiry; but it is also untypical, insofar as Socrates' chief concern here is with the inconsistency between an interlocutor's statements and his actions (what I call "word-deed inconsistency") rather than, as more usually, inconsistency among an interlocutor's various statements ("word-word inconsistency"). I use this reading to show how the akrasia argument, despite its untypical features, is not just a variant, but in an important way a paradigm, of Socratic method.
A Platonic Cento in Cicero
Authors: Glucker John
Published: February 2003

De Divinatione 1.115 has been ascribed in the past to Posidonius, to 'a Pythagoreanizing Posidonius', or to 'the Stoics'. Its emphasis on the soul's eternity and knowledge of 'all things in Hades and on earth' precludes such sources. I point out that the passage contains clear reminiscences of the myth of transmigration and αναμνησις in Meno and of a passage in the myth of Er, probably combining them with Republic 571-2. No philosopher or school known to us could be Cicero's source for such a combination, taking, as it does, such details of the Platonic myths as literal truths. I suggest that Cicero's source for this passage was some contemporary or slightly earlier 'Pythagoreanizing Platonist', whose identity can no longer be established.
Enantio- and Diastereoselectivity in 1,3-Dipolar Cycloaddition Reactions of Nitrones with 3-Crotonoyl-2-oxazolidinone Catalyzed by Ni(II)- Binaphthyldiimine Complexes
Authors: Suga Hiroyuki , Kakehi Akikazu , Ito Suketaka , Sugimoto Hiroaki
Published: February 2003

Chiral Ni(II)-1,1′-binaphthyl-2,2′-diimine complexes were found to be effective Lewis-acid catalysts for an asymmetric 1,3-dipolar cycloaddition reaction of N-benzylideneaniline N-oxide with 3-crotonoyl-2-oxazolidinone. In the presence of molecular sieves (4 Å), when the chiral N,N′-bis(2,6-dichlorobenzylidene)-1,1′-binaphthyl-2,2′-diamine (BINIM-DC) and Ni(ClO4)2·6H2O were used to prepare the catalyst, up to 81% ee of the corresponding endo-cycloadduct was obtained with endo-selectivity (87 : 13, and up to 96 : 4). The use of N,N′-bis(3-chloro-substituted 2-hydroxybenzylidene) derivatives as ligands under similar conditions showed high exo-selectivity (up to 95 : 5) with moderate enantioselectivity. Although almost no diastereoselectivity was observed, endo- and exo-cycloadducts were obtained with promising levels of enantioselectivity (up to > 98%) in the presence of catalysts, which were prepared from chiral BINIM-DC, NiBr2, and AgBF4, AgSbF6, or AgPF6.
Influence of the Polarity of the Medium on the Catalysis of Formation, Rate of Hydrolysis and Stability of the Schiff Bases Formed by Pyridoxal 5′-Phosphate with l-Tryptophan
Authors: Gorostidi Gerardo R Echevarría , Santos José G , Basagoitia Andrea , Castillo Marta , Blanco Francisco García
Published: February 2003

The apparent rate constants of formation (k1) and hydrolysis (k2), and the equilibrium constant (KpH), of the Schiff bases formed by pyridoxal 5′-phosphate with l-tryptophan in water and different aqueous ethanol mixtures at a variable pH, 25 °C and an ionic strength of 0.1 M (1 M = 1 mol dm−3) were determined. The individual rate constants of formation and hydrolysis of the Schiff bases of the systems corresponding to the different chemical species present in the medium, as a function of its acidity, were also determined, as were the pK values for the Schiff bases. The influence of the solvent medium on the formation and hydrolysis rate constants of the Schiff bases is discussed.
Kinetic Resolution of Racemic Ferrocenylphosphine Compounds by Enantioselective Oxidation Using Cyclic Selenoxides Having a Chiral Ligand
Authors: Miyake Yoshihiro , Yamauchi Akiyoshi , Nishibayashi Yoshiaki , Uemura Sakae
Published: February 2003

Cyclic selenoxides having an optically active binaphthyl skeleton work as the reagents for enantioselective oxidation of phosphines to the corresponding phosphine oxides. Treatment of a racemic 2-oxazolin-2-ylferrocenylphosphine with one of the selenoxides in carbon tetrachloride in the presence of phenol affords the corresponding phosphine oxide together with the unreacted starting phosphine, both with moderate enantioselectivities (the phosphine oxide, up to 13% ee; the phosphine, up to 29% ee).
Electrochemical Oxidation of Substituted Amide Oximes and 4,5-Dihydro-1,2,4-Oxadiazoles
Authors: Okimoto Mitsuhiro , Takahashi Yukio
Published: February 2003

The electrooxidation of several substituted amide oximes to yield the corresponding nitriles, alcohols, and imidate was successfully carried out. The reaction products were dependent on the substituents. Additionally, 4,5-dihydro-1,2,4-oxadiazoles derived from amide oximes were electrooxidized to afford 1,2,4-oxadiazoles in good yields.
Comparing cancer risks between radiation and dioxin exposure based on two‐stage model
Authors: Nakamura Tsuyoshi , Hoel David G.
Published: March 2003

This study investigates the use of the Moolgavkar two‐stage model to compare the biological and statistical nature of cancer risks from dioxin exposure and from radiation exposure. The two‐stage model is a biologically based stochastic model for carrying out statistical inferences of cancer risks using biologically motivated hypothesis. This article briefly describes the conditional likelihood for the model recently developed by the authors and then presents results obtained from applying it to dioxin dietary data in rats (Kociba et al., 1978) and radiation exposure data in mice. Comparing the results following the two different types of exposures based on the two‐stage model confirms that the radiation exposure increases the initiation rates while the dioxin exposure increases the net‐proliferation rate. The results indicate that the effect of TCDD at 100 ng/kg/day is an approximately 40 per cent increase in the net‐proliferation rate in the intermediate cells. Portier et al. (1996b) and Moolgavkar et al. (1996) used the two‐stage in‐vivo initiation‐promotion model in the rat liver. Measuring liver foci after administration of DEN followed by TCDD as a promoter, they observed an increase in proliferation rate in their initiated cells by 25–35 per cent. This closely agrees with our estimated increase of 40 per cent in the whole animal cancer incidence study of (Kociba et al., 1978). Another statistically important aspect obtained from the study is that the proportional hazards model is appropriate to apply to cancer incidence data following radiation exposure but is not appropriate for cancer risks following dioxin exposure. Copyright © 2003 John Wiley & Sons, Ltd.
Challenges posed by the precautionary principle and accountability in ecological risk assessment
Authors: Matsuda Hiroyuki
Published: March 2003

In order to protect the environment, type II errors, e.g. a species is not listed as endangered (H0) when it is in fact endangered (H1), are avoided at the risk of making a type I error. However, it is almost impossible to determine if management efforts have been efficient or if many type II errors have occurred. Applying the precautionary principle to environmental protection without full scientific certainty requires a new academic code for scientists. If we manage ecosystems or bioresources under uncertainty, we need to incorporate new knowledge (accountability) and to change actions with ecosystem states (adaptability). This is called adaptive management. The extinction risk of exploited species under adaptive management is much lower than that under constant exploitation. The revised management procedure (RMP) in whaling and the deer management program in Hokkaido, Japan, share the merit of adaptive management. Under the RMP, the period allowed in considering the extinction risk of the southern hemisphere minke whale is far too long. Population management of over‐abundant deer threatened endangered eagles, because of lead contamination from bullets. Although the effect of lead contamination on the extinction risk of eagles was uncertain, the Hokkaido Government prohibited the use of lead bullets in deer hunting. When designing management programs, it is also important to consider cost–benefit measures in the ecological risks. The value of biodiversity is often much higher than the economic benefit from exploiting the bioresource by agriculture, forestry or fisheries. Copyright © 2003 John Wiley & Sons, Ltd.
BCL‐2/JH translocation in peripheral blood lymphocytes of unexposed individuals: Lack of seasonal variations in frequency and molecular features
Authors: Roulland Sandrine , Lebailly Pierre , Roussel Gilbert , Briand Mélanie , Cappellen David , Pottier Didier , Hardouin Agnès , Troussard Xavier , Bastard Christian , Henry‐Amar Michel , Gauduchon Pascal
Published: March 2003

BCL‐2/JH rearrangement has been proposed as a biomarker for evaluating the genotoxicity of occupational and environmental exposures. Available data on time‐related modification of this rearrangement in peripheral blood lymphocytes in unexposed healthy individuals is scarce. We investigated the characteristics of BCL‐2/JH rearrangements in 33 adults unexposed to genotoxins at 2 seasonal time points: winter and spring. BCL‐2/JH rearrangement was detected in 79% of individuals (detection limit = 8.48 × 10−8). Its frequency ranged from <1 to 40 translocations per million lymphocytes with a significant (p = 0.04) positive correlation with age. No significant modifications of BCL‐2/JH rearrangement frequency or in the number of clones harboring this rearrangement were observed according the 2 time points. No obvious influence of season‐related environmental factors on frequency or molecular features of BCL‐2/JH rearrangements was found in this population suggesting that this would not be a confounding factor. © 2003 Wiley‐Liss, Inc.
Differential effects between amphoterin and advanced glycation end products on colon cancer cells
Authors: Kuniyasu Hiroki , Chihara Yoshitomo , Kondo Hideaki
Published: March 2003

Amphoterin is 1 ligand of the receptor for advanced glycation end products (RAGE). We studied expression of amphoterin and RAGE mRNA and proteins in colorectal carcinoma cells and investigated their associations with the invasive activities of cells exposed to advanced glycation end products (AGE). Expression of RAGE and amphoterin was examined in 4 colorectal carcinoma cell lines. All cell lines expressed both RAGE and amphoterin. The effects of RAGE and amphoterin on cell growth (MTT assay), migration (wound healing assay) and invasion (in vitro invasion assay) were tested by treatment of cells with RAGE and amphoterin antisense S‐oligodeoxynucleotides (ODNs). Cell growth, migration and invasion were inhibited significantly in Colo320 and WiDr carcinoma cells treated with RAGE and amphoterin antisense S‐ODNs compared with sense‐treated cells. Differences in ligand activity between amphoterin and AGE were examined with AGE‐bovine serum albumin (BSA). AGE‐BSA decreased cell growth, migration and invasion of amphoterin antisense S‐ODN‐treated Colo320 and WiDr cells compared with those of cells treated with Colo320 conditioned medium. Phosphorylation of extracellular signal‐regulated kinase‐1/2, Rac1 and AKT and production of matrix metalloproteinase 9 were increased to a greater degree by amphoterin than by AGE‐BSA. In contrast, production of inducible nitric oxide synthase and nuclear factor‐κBp65 were increased to a greater degree by AGE‐BSA than by amphoterin. © 2003 Wiley‐Liss, Inc.
Policy management of strategy (hoshin kanri)
Authors: Witcher Barry J.
Published: March 2003

This paper reports on an Economic and Social Research Council investigation of Policy Management (Hoshin Kanri) practice in UK‐based companies. It covers:

The background to the emerging literature.

The research applied a tracer approach where strategic objectives were followed by researchers in real time to see how these were developed, deployed and managed.

The findings are presented under categories using each of the FAIR (focus, alignment, integration, review) framework areas for good practice strategic management.

The characterizing features of Policy Management are summarized.

Policy Management is compared to the Balanced Scorecard.

Management by Objectives.

The conclusion is that Policy Management is a good approach for building strategy into daily management on an organization‐wide basis.

Copyright © 2003 John Wiley & Sons, Ltd.
Distribution of HLA gene and haplotype frequencies in Taiwan: a comparative study among Min‐nan, Hakka, Aborigines and Mainland Chinese
Authors: Shaw C.‐K. , Chen L.‐L. , Lee A. , Lee T.D.
Published: March 2003

A total of 8,497 blood samples were typed for HLA‐A, B, DR and DQ. Of these, 7,137 Min‐nan, 714 Hakka, 535 Mainland Chinese (152 from North China, 211 from Middle China, and 172 from South China) and 111 Aborigines were randomly selected from Tzu Chi Taiwan Marrow Donor Registry (TCTMDR). Differences in HLA gene and antigen frequencies have been observed between various ethnic groups of the Chinese population in Taiwan. The phylogenic tree shows Taiwan Aborigines and Javanese cluster together; Min‐nan shares a common cluster with Hakka, Southern Hans and Thai; and Northern Hans shares a cluster with Middle Hans. The separation between Northern/Middle and Southern Chinese Hans support the idea that Northern and Southern Chinese have different genetic background. Aborigines appeared to be quite distinct in the distribution of a majority of the class I and class II antigens. High frequency of HLA‐A24 (60.4%) and relatively restricted HLA polymorphisms are noted in Aborigines. The HLA haplotypes with high frequency in Aborigines included A24‐B60‐DRB1*04, A24‐B60‐DRB1*14, A24‐B48‐DRB1*04, and A24‐B48‐DRB1*14, which are different from the other ethnic groups. Although the phylogenic tree separates Aborigines and Han Chinese populations, 4 out of 20 most common HLA‐A, ‐B, and ‐DR haplotypes presented in both Aborigines and Han Chinese may reflect an ancient common origin or intermixture between early settlers of Han Chinese and Taiwan Aborigines. The results in this study are essentially a summary of the observed gene/haplotype frequencies and differences among various ethnic groups in Taiwan.
HLA haplotypes and microsatellite polymorphisms in and around the major histocompatibility complex region in a Native American population with a high prevalence of scleroderma (systemic sclerosis)
Authors: Tan F.K. , Stivers D.N. , Arnett F.C. , Chakraborty R. , Howard R. , Reveille J.D.
Published: March 2003

Choctaw Native Americans in southeastern Oklahoma have the highest prevalence of scleroderma or systemic sclerosis yet found (469/100,000). An Amerindian HLA DR2 haplotype (DRB1*1602) was significantly associated with scleroderma in this population in a previous study. It is not known, however, if other disease genes are linked to this HLA haplotype. The regions flanking the HLA loci were studied with polymorphic microsatellite markers. An extended HLA DR2 (DRB1*1602, DQA1*0501, DQB1*0301, DPB1*1301) haplotype that includes the class I and III regions was identified which was significantly associated with scleroderma in the Oklahoma Choctaw. No other significant associations with microsatellite marker alleles immediately flanking the HLA region were found.
Aberrant splicing of intron 1 creates a novel null HLA‐B*1501 allele
Authors: Curran M.D. , Williams F. , Little A.‐M. , Rima B.K. , Madrigal J.A. , Middleton D.
Published: March 2003

A comparison of serological and DNA HLA class I typing data identified a serological “blank” HLA‐B15 antigen in a volunteer donor on the bone marrow registry. Isoelectric focusing and Western blot analysis of a cell line established from this individual confirmed that the HLA‐B15 antigen is not expressed at the cell surface. Nucleotide sequence analysis of the HLA‐B*15 null allele revealed a 10‐bp deletion near the 3′ end of intron 1, when compared to the normal HLA‐B*1501 sequence. All of the HLA‐B*15 specific cDNA clones examined retained the intron 1 sequence. Reverse transcription‐polymerase chain reaction (RT‐PCR) and Southern blot analysis demonstrated that the HLA‐B*15 mRNA molecule contained the intron 1 sequence, indicating an inability to efficiently splice out intron 1 from the mRNA transcript. The retention of the mutated intron 1 sequence in the mRNA causes a frameshift and premature termination of translation at the start of exon 2, explaining the HLA‐B*1501 null phenotype. Our data predicts that the HLA‐B*1501 null allele would express a small truncated protein containing the signal sequence fused to an ORF within intron 1 and terminating (out of frame) just within exon 2.
HLA‐A33 and ‐B44 and susceptibility to postherpetic neuralgia (PHN)
Authors: Ozawa A. , Sasao Y. , Iwashita K. , Miyahara M. , Sugai J. , Iizuka M. , Kawakubo Y. , Ohkido M. , Naruse T. , Anzai T. , Takashige N. , Ando A. , Inoko H.
Published: March 2003

HLA class I and class II alleles of 32 Japanese patients with postherpetic neuralgia (PHN) and 136 healthy controls were analyzed by serological (class I) and DNA (class II) typing for any significance in the susceptibility to varicella‐zoster virus (VZV). We recognized positive associations of the development of PHN with the HLA class I antigens HLA‐A33 and ‐B44, and the HLA‐A33‐B44 haplotype. This haplotype is tightly linked to DRB1*1302 in a Japanese healthy population. However, no significant association between PHN and HLA class II alleles was observed with no linkage of the HLA haplotype HLA‐A33‐B44 to HLA‐DRB1*1302 in the patients with PHN. These findings suggest that HLA class I gene may genetically control the immune response against VZV in the pathogenesis of PHN.
HLA‐B locus sequence‐based typing
Authors: Pozzi S. , Longo A. , Ferrara G.B.
Published: March 2003

We describe an approach for HLA‐B high‐resolution typing. A single locus‐specific amplification generates a 1‐kb fragment useful for direct sequencing. Four internal primers are necessary for exon 2 and 3 cycle‐sequencing in both directions. Fluorescent dye‐labelled nucleotides are incorporated during cycle‐sequencing and reaction products are analyzed in an automated DNA sequencer. At present, software programs allow automatic assignment of exon 2 only; analysis of exon 3 is not automatic. In the future, the development of more sophisticated software will improve allele assignment. The approach described in this work offers a precise and efficient identification of known allele sequences and at the same time can differentiate new alleles. Furthermore, it may be applied as a model for the development of similar molecular typing approaches for other polymorphic HLA loci.
CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family‐based association study
Authors: Holopainen P. , Arvas M. , Sistonen P. , Mustalahti K. , Collin P. , Mäki M. , Partanen J.
Published: March 2003

Celiac disease (CD) is a common small intestinal injury caused by sensitivity to gliadin in genetically‐predisposed individuals. The only susceptibility locus established is the HLA‐DQ. We tested whether the chromosomal region of the CD28/CTLA4 genes on 2q33 is linked to CD. These genes encode receptors regulating the T‐lymphocyte activation. Recently, this gene region was reported to be linked to the susceptibility to many autoimmune diseases, including insulin‐dependent diabetes (IDDM12locus). It is thus an obvious candidate locus also for CD, since the intestinal injury is mediated by the immune system. Genetic linkage between seven marker loci in this gene region and CD was studied in 69 Finnish families. In the multipoint linkage analysis, the highest non‐pararametric linkage score (NPL) was 1.75 (P=0.04) for D2S116, suggesting weak linkage for this candidate locus. To evaluate this finding, an additional 31 families were typed for all markers. In the combined set of 100 families the NPL score for marker D2S116 was 2.55 (P=0.006) and for other markers 1.90–2.47 (P=0.029–0.007), supporting genuine linkage at this region. Significantly, locus D2S116 also showed a clear allelic association in these 100 families (P=0.0001). The transmission/disequilibrium test (TDT) for locus D2S116 gave preliminary evidence for preferential maternal non‐transmission of allele *136 to patients (TDTmax=8.3; P<0.05). No paternal deviation was found suggesting that the effect of the locus might be mediated by a sex‐dependent factor protective against CD. Our results indicate that the CD28/CTLA4 gene region can contain a novel susceptibility locus for CD and support the hypothesis that CD has an immune system‐mediated component. Like the HLA, the CD28/CTLA4 genes appear to be associated with genetic susceptibility to various autoimmune diseases.
Sequencing of HLA class II genes based on the conserved diversity of the non‐coding regions: sequencing based typing of HLA‐DRB genes
Authors: Kotsch K. , Wehling J. , Blasczyk R.
Published: March 2003

In this paper, we present a novel sequencing based typing strategy for the HLA‐DRB1, 3, 4 and 5 loci. The new approach is based on a group‐specific amplification from intron 1 to intron 2 according to the serologically‐defined antigens. For this purpose, we have determined the 3′ 500 bp‐fragment of intron 1 and the 5′ 340 bp‐fragment of intron 2 of all serological antigens and their most frequent subtypes. We discovered a remarkably conserved diversity characterized by lineage‐specific sequence motifs. This lineage‐specificity of non‐coding motifs in the 1st and 2nd intron offered the possibility to establish a clear serology‐related amplification strategy. The method allows the complete analysis of the 2nd exon and the definition of the cis/trans linkage of sequence motifs by intron‐mediated polymerase chain reaction (PCR)‐based separation of the haplotypes in nearly all serologically heterozygous samples. In particular, the non‐coding variabilities between the DR52‐associated DRB1 groups made their independent amplification possible. Thus, compared to the standard procedures using exon‐based amplification primers, the groups DR3, DR12, some DR13 alleles (1301, 1302) and the DR14 group could be amplified by specific primer mixes. The DR8 could be amplified with an individual primer mix not co‐amplifying the DR12. The DR11 and DR13 did not show any individual motif in intron 1 or intron 2. In order to achieve a separate amplification, they had to be amplified by multispecific primer mixes (DR3/11/13/14; DR3/11/13 or DR11/13/14) excluding the other haplotype. Thus, exclusively the alleles in rare DR11,13 heterozygosities without a DRB1*1301 or 1302 could not be amplified separately. Fourteen primer mixes are used to amplify the specificities DR1‐14, and 6 primer mixes for the specificities DR51‐53. The sequence homology of the 3′ end of intron 1 facilitated the application of only three different sequencing primers for all DRB alleles.
HLA‐DR polymorphism influences T‐cell precursor frequencies to Epstein‐Barr virus (EBV) gp110: implications for the association of HLA‐DR antigens with rheumatoid arthritis
Authors: Toussirot E. , Auger I. , Roudier C. , Luka J. , Wendling D. , Tiberghien P. , Roudier J.
Published: March 2003

To study whether HLA‐DR haplotypes associated with susceptibility to develop rheumatoid arthritis (RA) may influence T‐cell responses to the Epstein‐Barr virus (EBV) gp110 (a protein of the late replicative cycle of EBV), we evaluated the frequency in peripheral blood of T cells capable to proliferate to EBV gp110 by direct limiting dilution analysis in 50 HLA‐DR‐typed healthy subjects. We found that HLA‐DRB1*07, an allele associated with reduced risk to develop RA, is associated with the highest frequencies of T cells specific for gp110 in peripheral blood. In contrast, HLA‐DRB1*0404, one of the susceptibility alleles is associated with the lowest frequencies of gp110 specific T cells. Finally, people expressing both HLA‐DRB1*07 and HLA‐DRB1*0404 display low precursor frequencies to EBV gp110.
Behçet’s disease, the Silk Road and HLA‐B51: historical and geographical perspectives
Authors: Verity D.H. , Marr J.E. , Ohno S. , Wallace G.R. , Stanford M.R.
Published: March 2003

Behçet’s disease (BD), also known as the Silk Road disease, is a blinding inflammatory disorder of young adults found predominantly between the Mediterranean basin and the Orient, and is strongly associated with the major histocompatibility complex (MHC) antigen HLA‐B51. In this article we review the history of Behçet’s disease since its first description by Hippocrates, the development of the trading routes collectively known as the Silk Road and the effect of population movement on the distribution of HLA‐B51. The global distribution of this antigen among healthy control populations bears a striking similarity both to the ancient trading routes and the distribution of Behçet’s disease, suggesting a genetic risk that migrated in parallel with population movement between the Mediterranean and Asia. However, certain indigenous Amerindian peoples have a high prevalence of HLA‐B51 but no reported cases of BD. Furthermore, a clear genealogical relationship exists between eastern, but not central, Siberian populations with the Amerindians. Since a high level of recombination within the MHC is known to have occurred in these eastern populations before their migration into Beringia, we suggest that disruption of genetic loci in linkage disequilibria with HLA‐B51 may be one reason for the absence of disease in these high HLA‐B51‐bearing populations. However, a contributory influence of environmental factors is not excluded by this data, and the wide variation that exists in relative risk of HLA‐B51 even within Europe would support other non‐genetic risk factors on the Silk Road which may be absent, or non‐contributory to disease, in the Americas.
DNA typing of HLA class II genes (HLA‐DR, ‐DQ and ‐DP) in Japanese patients with histiocytic necrotizing lymphadenitis (Kikuchi’s disease)
Authors: Tanaka T. , Ohmori M. , Yasunaga S. , Ohshima K. , Kikuchi M. , Sasazuki T.
Published: March 2003

The pathogenesis of histiocytic necrotizing lymphadenitis (HNL), which was reported first by Kikuchi et al. and Fujimoto et al. in 1972, is as yet unknown. HNL is frequently reported in Asian countries including Japan, however it is rare in Europe and North America. To elucidate whether the human leukocyte antigen (HLA) alleles and haplotypes are associated with HNL, we performed DNA typing of HLA class II genes (HLA‐DR, ‐DQ, and ‐DP) in 86 patients with HNL and 525 unrelated healthy Japanese controls with polymerase chain reaction using sequence‐specific oligonucleotide probes (PCR‐SSOP). In this study, we found DPA1*01 and DPB1*0202 allele frequencies in HLA class II genes are significantly higher in HNL patients than in normal controls. It is known that the frequency of DPB1*0202 alleles is extremely low or absent in Caucasians (e.g., French 0.4%, Italian 0.8%) and Negroid (e.g., South African 0%, Hottentot 0%), but relatively frequent in Asians (e.g., Korean 9.9%, Japanese 4.5%). Previous reports have said the incidence of HNL is frequent in Asians but rare in other races. In light of this background, HLA class II genes of HNL and the incidence of HNL in Asian countries, including Japan, might have a positive relationship to DPA1*01 and DPB1*0202 allele.
Polymorphic analysis of the high‐affinity tumor necrosis factor receptor 2
Authors: Pantelidis P. , Lympany P.A. , Foley P.J. , Fanning G.c , Welsh K.I. , du Bois R.M.
Published: March 2003

The tumor necrosis factor receptor 2 (TNF‐RII, CD120b, TNF‐R p75/80) gene has recently been characterised. It is located on chromosome 1p36.2 and consists of 10 exons and 9 introns. A number of biallelic polymorphisms have been found in exons 4, 6, 9 and 10 based on differences between published sequences. In this study we have used polymerase chain reaction methodology in association with sequence‐specific primers (PCR‐SSP) incorporating mismatches at the 3′ end to identify these polymorphisms. We were able to confirm the presence of a single biallelic polymorphism in exon 6 corresponding to a (T/G) at nucleotide 676 of TNF‐RII mRNA (gb:M32315) which results in an amino acid change and three biallelic polymorphisms in exon 10 (in the3′UTR) corresponding to (A/G) at nucleotide 1663, (T/G) at nucleotide 1668 and a (C/T) at nucleotide 1690 of gb:M32315, whereas no polymorphisms were observed in exons 4 and 9. Here we report that in 192 unrelated UK Caucasian individuals the allele frequencies determined by direct counting were: 676‐T (0.77), 1663‐G (0.51), 1668‐T (0.95), and 1690‐T (0.64) and the calculated gene frequencies were: 676‐T (0.52), 676‐G (0.12); 1663‐G (0.30), 1663‐A (0.28); 1668‐T (0.77), 1668‐G (0.025); and 1690‐T (0.40), 1690‐C (0.20). Furthermore, the presence of an A allele at nucleotide position 1663 was found to be strongly associated with the presence of a C allele at nucleotide position 1690 and a G allele at nucleotide position 1668 whereas the presence of a G allele at position 1663 was associated with the absence of a C allele at nucleotide position 1690.
Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease
Authors: Fogdell‐Hahn A. , Ligers A. , Grønning M. , Hillert J. , Olerup O.
Published: March 2003

Acknowledgments:

This study was supported by grants from the Swedish Medical Research Council, the Childrens’ Cancer Foundation, the Tobias Foundation and the Swedish association of the Neurologically Disabled.

Multiple sclerosis (MS) is a presumed autoimmune disease of the central nervous system, shown to be associated with the HLA class II haplotype DRB1*15,DQB1*06. Carrying the HLA class II haplotype DRB1*15,DQB1*06 increases the risk of MS by 3.6. By adopting a polymerase chain reaction (PCR)‐based typing technique for HLA class I and class II genes, 200 Swedish MS patients and 210 Swedish healthy controls were analysed for their HLA alleles. Additional HLA class I alleles that increase and decrease the genetic susceptibility to MS were identified. The HLA‐A*0301 allele increases the risk of MS (odds ratio=2.1) independently of DRB1*15,DQB1*06. HLA‐A*0201 decreases the overall risk (odds ratio=0.52) and the presence of A*0201 reduces the risk of MS for DRB1*15,DQB1*06 carriers from 3.6 to 1.5. Our findings are the first to identify a major modulating effect of HLA class I alleles on the susceptibility to a human autoimmune disease; a phenomenon that has previously only been observed in animal models.