bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct claudins and associated PDZ proteins form different autotypic tight junctions in myelinating Schwann cells
Authors: Poliak Sebastian , Matlis Sean , Ullmer Christoph , Scherer Steven S. , Peles Elior
Published: October 2002

The apposed membranes of myelinating Schwann cells are joined by several types of junctional specializations known as autotypic or reflexive junctions. These include tight, gap, and adherens junctions, all of which are found in regions of noncompact myelin: the paranodal loops, incisures of Schmidt-Lanterman, and mesaxons. The molecular components of autotypic tight junctions have not been established. Here we report that two homologues of Discs Lost–multi PDZ domain protein (MUPP)1, and Pals-associated tight junction protein (PATJ), are differentially localized in myelinating Schwann cells and associated with different claudins. PATJ is mainly found at the paranodal loops, where it colocalized with claudin-1. MUPP1 and claudin-5 colocalized in the incisures, and the COOH-terminal region of claudin-5 interacts with MUPP1 in a PSD-95/Disc Large/zona occludens (ZO)-1 (PDZ)-dependent manner. In developing nerves, claudin-5 and MUPP1 appear together in incisures during the first postnatal week, suggesting that they coassemble during myelination. Finally, we show that the incisures also contain four other PDZ proteins that are found in epithelial tight junctions, including three membrane-associated guanylate-kinase proteins (membrane-associated guanylate-kinase inverted-2, ZO-1, and ZO-2) and the adaptor protein Par-3. The presence of these different tight junction proteins in regions of noncompact myelin may be required to maintain the intricate cytoarchitecture of myelinating Schwann cells.
Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1
Authors: Tsai Billy , Rapoport Tom A.
Published: October 2002

The toxic effect of cholera toxin (CT) on target cells is caused by its A1 chain. This polypeptide is released from the holotoxin and unfolded in the lumen of the ER by the action of protein disulfide isomerase (PDI), before being retrotranslocated into the cytosol. The polypeptide is initially unfolded by binding to the reduced form of PDI. We show that upon oxidation of the COOH-terminal disulfide bond in PDI by the enzyme Ero1, the A1 chain is released. Both yeast Ero1 and the mammalian Ero1α isoform are active in this reaction. Ero1 has a preference for the PDI–toxin complex. We further show that the complex is transferred to a protein at the lumenal side of the ER membrane, where the unfolded toxin is released from PDI by the action of Ero1. Taken together, our results identify Ero1 as the enzyme mediating the release of unfolded CT from PDI and characterize an additional step in retrotranslocation of the toxin.
The face of TSR revealed
Authors: Silverstein Roy L.
Published: October 2002

In this issue, Tan et al. (2002) report the first high resolution (1.9 Å) structural data for thrombospondin (TSP)-1, a large multifunctional protein that regulates cell adhesion, angiogenesis, cell proliferation and survival, TGFβ activation, and protease function (for review see Chen et al., 2000). Because TSP-1 has multiple binding partners and many functions, precise structural information is crucial to understanding its biology. The structure now reported, derived from crystals of the second and third type I repeats of TSP-1 is of particular interest because of the specific functions attributed to these repeats and because domains homologous to the repeats appear in many other proteins in nature. The novel layered fold motif described brings great insight into how the complicated functions of TSP-1 and related molecules are affected.
Collection evaluation through citation analysis techniques: a case study of the Ministry of Education, Singapore
Authors: Tan Yeok Ching Joanna , Chennupati K.R.
Published: October 2002

Knowing how the library’s collection is being used and how patrons are feeling about its collection are important for the evaluation of the library collection. The former can be measured by conducting library collection use studies and the latter through a user survey method. Another method is to check library holdings against standard bibliographies. The citation analysis technique was chosen to evaluate the collection of the Ministry of Education library, Singapore. Results were counter checked with ILL data analysis results. Books were the most cited (96 per cent) resources followed by journal articles (1.5 per cent) and 69 per cent of the citations were published between 1980‐1994. The library had only 20 per cent of the citations and the rest were supplied through ILL. Results show a need for a change in acquisition policy with more focus on books, reduction in non‐used journals, and development of an efficient ILL.
Circulating libraries
Authors: Glasgow Eric
Published: October 2002

The nature of the 18th century circulating library is briefly described and its role in forming initial readings habits for women leading to the great 19th century women novelists, and so in the development of women’s cultural liberation, is discussed. The changing nature of reading habits and the influence of Mudie and W.H. Smith in the 19th century are described. The evolving nature of reading and reading matter is discussed in a comparison with contemporary reading habits.
Franchising in global markets: towards a conceptual framework
Authors: Sashi C.M. , Prasad Karuppur Devi
Published: October 2002

When is franchising the appropriate organizational form for implementing marketing strategy in global markets? In this paper we identify conditions under which franchising facilitates efficient transactions globally with the help of constructs from transaction cost analysis, agency theory, and franchising research in domestic contexts. Some bases for setting initial fees and royalty payments as well as the rationale for establishing master franchises are also explored. The advantages and limitations of adopting franchising as the mode of operation in global markets are briefly discussed. A conceptual framework that provides an integrated multidisciplinary approach for studies of franchising from a global marketing perspective is developed.
School/university partnerships: a viable model
Authors: Peel Henry A. , Peel Betty B. , Baker Marty E.
Published: October 2002

Educational partnerships between universities and public schools have existed for over 100 years. During this time, especially the last decade, many educational partnerships were formed, only to fizzle shortly thereafter. When educational partnerships have been formed to provide only temporary band‐aid solutions to very complex and multifaceted problems, they, like other trends, have faded away. Yet, some educational partnerships have continued to shine and to become viable coalitions. Successful partnerships focused on complex issues related to staff development, teacher training and school leadership require extensive collaboration, reflection, and continued revision. The purpose of this article is to explore some of the tenets that lead to the success and demise of school/university partnerships. In addition, this article describes a collaborative process employed by a university department of educational leadership, a regional consortium, and three school systems to design and offer a principal preparation program, delivered entirely in the field.
The school leader’s imperative: leading change
Authors: Calabrese Raymond L.
Published: October 2002

School leadership in contemporary society is immersed in the chaotic nature of change. The rapid rate of change, driven by technology and fueled by growing economic and global concerns, impacts the small rural school district as well as the large urban school district. Effective school leaders understand the magnitude of what it means to lead change. The consequences of reacting to change are immense to school organizations and the population the organizations serve. A starting point for the school leader in learning to lead change is in understanding the nature of change.
Discrimination areas in higher education institutions in Turkey and a scale development study
Authors: Kasimoğlu Murat , Halici Ali
Published: October 2002

Despite legal and administrative arrangements and increase in the sensitiveness for human rights, discriminative applications are important problems in organizations, because different applications and unfair behaviors for workers lead to negative consequences for the workers and the organization. The main discrimination areas that are stated in the literature are race, language, religion, sex, ideology and physical insufficiency etc., but these subjects would differ according to the region and sector. The aim of this study is to determine the discrimination areas in higher education Institutions in Turkey and develop a scale for measuring the level of discrimination in those areas. Discrimination areas are determined by an ethnographic study in the research. Within this context, factor analysis was applied to the related questions by Varimax approach and a reliable and valid scale was obtained.
An analysis of co‐operative agreements from a knowledge‐based perspective: an integrative conceptual framework
Authors: Escribá‐Esteve Alejandro , Anastasio Urra‐Urbieta José
Published: October 2002

The last decade has been witness to an unprecedented growth in the number of alliances between companies. This growing importance of interfirm co‐operation, together with its inherent complexity, have generated a progressive interest in the study of this phenomenon, which has materialised in a vast but fragmented literature concerning it. As a response to the demands which these conditions pose, we have endeavoured to develop a conceptual framework which, from a knowledge‐based and learning perspective, integrates an extensive series of contributions and concepts for the study of the processes of co‐operation between companies. As distinctive features, our conceptual framework proposal sets up a bridge between formulation and implementation in alliance processes and goes into the alliance micro‐level processes, both in the framework of the co‐operative agreement and in the setting of the partners’ organisations. Additionally, our proposal also considers the different ontological levels where knowledge develops and the links existing between them.
Basque Country: the knowledge cluster
Authors: Luis Arboníes Angel , Moso Mónica
Published: October 2002

Clusters have basically been conceptualised as a concentration of firms that prosper on the basis of their interaction. However, the classical cluster concept is developing in a more cultural perspective. The so‐called Knowledge Society and the development of information and telecommunications technologies have opened the playing field. New countries and regions can thus meaningfully reduce their distance with respect to other leading regions, provided they create a structure to acquire and disseminate knowledge. This emerging concept also offers more possibilities to be used by all the types of regions in different circumstances, including developing countries. The basic tool for beginning this learning capability will be the creation of a co‐operation structure such as a cluster, including all actors of the innovation system in a country or region. They can be called knowledge clusters: the knowledge cluster in the Basque Country is one of these experiences.
Capital systems: implications for a global knowledge agenda
Authors: Carrillo Francisco J.
Published: October 2002

This paper explores ways in which knowledge management (KM) can enrich and be enriched by practices associated with social‐level knowledge‐based development (KBD), thus bridging both fields. It begins by establishing a continuity between personal‐, organizational‐ and social‐level KM. Social‐level KBD is referred to economic growth theory in search of a complete, consistent, systematic and inclusive framework for global development. Enter capital systems, a KM framework aiming to satisfy those criteria at the organizational level. The capital systems approach, originally developed as a solution to some methodological concerns in intellectual capital valuation, is described as the operationalization of a generic value structure. Such a structure is applied to the analysis of production or value‐enhancing dynamics underlying major economic eras throughout human history until the present day. Structural constraints in current financing for development practices are identified. New knowledge‐based development strategies are explored and, finally, examples of current KBD policies are examined in the light of this analysis and alternative strategies to systematically identify and develop individual, organizational and capital systems are suggested.
Evolving knowledge for development: the role of knowledge management in a changing world
Authors: Castro Laszlo Kathia , Laszlo Alexander
Published: October 2002

In today’s changing world, knowledge, and the processes to generate it and manage it, have become key factors in creating competitive business advantage. However, the challenges facing contemporary global societies, from human conflicts to environmental degradation, call for an expanded research agenda in the field of knowledge management. Issues such as improvement of the role of corporate citizenship to promote socially and ecologically responsible operations and development of human and social capital should become part of a purposeful strategy for creating a better future. “Knowledge is power” – and it is up to those with access to knowledge to decide if that power will continue to be used over others to increase the gap between rich and poor or if it will be a power to empower visions and realities based on an inclusive planetary ethic. From an evolutionary systems perspective, this paper explores some of the implications and key contributions that knowledge management can make for the transition toward sustainable forms of social organization. The heuristic of evolutionary learning community (ELC) is presented as a participatory strategy for promoting learning and knowledge creation for evolutionary development.
New product development team improvisation and speed‐to‐market: an extended model
Authors: Akgün Ali E. , Lynn Gary S.
Published: October 2002

Speed‐to‐market is cited as being vital in today’s competitive, uncertain and turbulent environments. To help companies in their quest for speed in new product development, many tools and techniques have been developed. One of the these techniques – team improvisation – is receiving a great deal of attention in both practice as well as theory. However, we know surprisingly little about improvisation in a new product development context. In this paper, we extend previous team improvisation models and test them in a new product development context. By studying 354 new product projects, we found that team improvisation has a positive impact on speed‐to‐market under turbulent markets and technology conditions, and there are some mechanisms that can facilitate a team’s ability to improvise, such as team stability and teamwork. We also found that having a clear project goal will detract from a team’s ability to improvise.
Emerging e‐commerce business models: an analysis of case studies from West Lothian, Scotland
Authors: Kinder Tony
Published: October 2002

The paper surveys existing theory of e‐commerce business models and associated conceptual instruments. It employs three original case studies of SMEs using e‐commerce to demonstrate the dynamic nature of e‐commerce business models for networked SMEs. The idea of evolutionary business planning based upon Molina’s sociotechnical constituency approach and the diamond of alignment is introduced.
Innovation networks in economics: from the incentive‐based to the knowledge‐based approaches
Authors: Pyka Andreas
Published: October 2002

Innovation networks have become a persistent organisational phenomenon in industrial innovation processes. However, in economics they were considered in the first place only as a temporary hybrid phenomenon between markets and a hierarchical organisation within a single firm. The main focus of traditional neo‐classical analysis simply was on cost reduction of R&D within a network. Only with the coming up of evolutionary economics with its prevailing knowledge orientation, learning and synergistic partnering also move to the centre of interest. Without a consideration of the roles strong uncertainty, heterogeneity as well as the historical character of time play in innovation, networks cannot be explained as a self‐organisational persistent phenomenon. The present paper brings together different strands of the new theory of innovation and develops an evolutionary theory of innovation networks.
DUALITY OF HOPF C*-ALGEBRAS
Authors: NG CHI-KEUNG
Published: October 2002

In this paper, we study the duality theory of Hopf C*-algebras in a general "Hilbert-space-free" framework. Our particular interests are the "full duality" and the "reduced duality". In order to study the reduced duality, we define the interesting notion of Fourier algebra of a general Hopf C*-algebra. This study of reduced duality and Fourier algebra is found to be useful in the study of other aspects of Hopf C*-algebras (see e.g. [12–14]).
ANALOG OF WILCZYNSKI'S PROJECTIVE FRAME IN LIE SPHERE GEOMETRY: LIE-APPLICABLE SURFACES AND COMMUTING SCHRÖDINGER OPERATORS WITH MAGNETIC FIELDS
Authors: FERAPONTOV E. V.
Published: October 2002

We propose a construction of surfaces in Lie sphere geometry based on the linear system which copies equations of Wilczynski's projective frame. In the particular case of Lie-applicable surfaces this linear system describes joint eigenfunctions of a pair of commuting Schrödinger operators with magnetic terms.
PARABOLIC VECTOR BUNDLES AND EQUIVARIANT VECTOR BUNDLES
Authors: MUNDET I RIERA IGNASI
Published: October 2002

Given a complex manifold X, a normal crossing divisor D ⊂ X whose irreducible components D1, …, Ds are smooth, and a choice of natural numbers [Formula: see text], we construct a manifold [Formula: see text] with an action of a torus Γ and we prove that some full subcategory of the category of Γ-equivariant vector bundles on [Formula: see text] is equivalent to the category of parabolic vector bundles on (X, D) in which the lengths of the filtrations over each irreducible component of D are given by [Formula: see text]. When X is Kaehler, we study the Kaehler cone of [Formula: see text] and the relation between the corresponding notions of slope-stability.
THE INTEGRATION OF TASK AND DATA PARALLEL SKELETONS
Authors: KUCHEN HERBERT , COLE MURRAY
Published: October 2002

We describe a skeletal parallel programming library which integrates task and data parallel constructs within an API for C++. Traditional skeletal requirements for higher orderness and polymorphism are achieved through exploitation of operator overloading and templates, while the underlying parallelism is provided by MPI. We present a case study describing two algorithms for the travelling salesman problem.
GENERIC PROGRAMMING OF PARALLEL APPLICATIONS WITH JANUS
Authors: GERLACH JENS
Published: October 2002

Janus is a conceptual framework and C++ template library that provides a flexible and extensible collection of efficient data structures and algorithms for a broad class of data-parallel applications. In particular, finite difference methods, (adaptive) finite element methods, and data-parallel graph algorithms are supported. An outstanding advantage of providing a generic C++ framework is that it provides application-oriented abstractions that achieve high performance without relying on language extension or non-standard compiler technology. The C++ template mechanism allows to plug user-defined types into the Janus data structures and algorithms. Moreover, Janus components can easily be combined with standard software packages of this field.
COSTING NESTED ARRAY CODES
Authors: LECHTCHINSKY ROMAN , CHAKRAVARTY MANUEL M. T. , KELLER GABRIELE
Published: October 2002

We discuss a language-based cost model for array programs built on the notions of work complexity and parallel depth. The programs operate over data structures comprising nested arrays and recursive product-sum types. In a purely functional setting, such programs can be implemented by way of the flattening transformation that converts codes over nested arrays into vectorised code over flat arrays. Flat arrays lend themselves to a particularly efficient implementation on standard hardware, but the overall efficiency of the approach depends on the flattening transformation preserving the asymptotic complexity of the nested array codes. Blelloch has characterised a class of first-order array programs, called contained programs, for which flattening preserves the asymptotic depth complexity. However, his result is restricted to programs processing only arrays and tuples. In the present paper, we extend Blelloch's result to array programs processing data structures containing arrays as well as arbitrary recursive product-sum types. Moreover, we replace the notion of containment by the more general concept of fold programs.
ASTROPHYSICAL NEUTRINOS: 20TH CENTURY AND BEYOND
Authors: BAHCALL J. N.
Published: October 2002

I summarize the first four decades of solar neutrino research and suggest what may be possible to learn with extragalactic neutrinos and with solar neutrinos in the next decade.
A CENTURY OF GRAVITY: 1901–2000 (PLUS SOME 2001)
Authors: DESER S.
Published: October 2002

This lecture consists of two parts. The first is a (totally unsystematic) survey of some of the high points in the evolution of gravity and its successors, primarily in the course of the past century. The second summarizes some new work on surprising properties of higher (> 1) spin fields in cosmological backgrounds: the presence of Λ gives rise to discrete sets of massive models endowed with gauge invariances, that divide the (m2, Λ) plane into unitary and non-unitary phases. The unitary region common to fermions and bosons shrinks to flat space (Λ → 0) as their spins increase.
SPONTANEOUS CP VIOLATION: ALTERNATIVE TO THE STANDARD MODEL
Authors: Frampton Paul H.
Published: October 2002

We propose a model of soft CP violation that evades the strong CP problem and can describe observed CP violation in the neutral kaon sector, both direct and indirect. Our model requires two "duark" mesons carrying quark number two that have complex (CP-violating) bare masses and are coupled to quark pairs. Aside from the existence of these potentially observable new particles with masses of several hundred GeV, we predict a flat unitarily triangle (i.e., no observable direct CP violation in the B-meson sector) and a possibly anomalous branching ratio for the decay mode [Formula: see text].
THE MEASURE OF COSMOLOGICAL PARAMETERS
Authors: FREEDMAN W. L.
Published: October 2002

New, large, ground and space telescopes are contributing to an exciting and rapid period of growth in observational cosmology. The subject is now far from its earlier days of being data-starved and unconstrained, and new data are fueling a healthy interplay between observations and experiment and theory. I report here on the status of measurements of a number of quantities of interest in cosmology: the expansion rate or Hubble constant, the total mass-energy density, the matter density, the cosmological constant or dark energy component, and the total optical background light.
PROGRESS IN WEAKLY COUPLED STRING PHENOMENOLOGY
Authors: GAILLARD MARY K.
Published: October 2002

The weakly coupled vacuum of E8 ⊗ E8 heterotic string theory remains an attractive scenario for particle physics. The particle spectrum and the issue of dilaton stabilization are reviewed. A specific model for hidden sector condensation and supersymmetry breaking, that respects known constraints from string theory, is described, and its phenomenological and cosmological implications are discussed.
THE SYMMETRY, OR LACK OF IT, BETWEEN MATTER AND ANTIMATTER
Authors: QUINN HELEN R.
Published: October 2002

This talk reviews the history of ideas on antimatter, the symmetry of physical laws for matter and antimatter, and the breaking of that symmetry, in these laws and in the evolution of the Universe.
ANOMALY CANCELLATION: A RETROSPECTIVE FROM A MODERN PERSPECTIVE
Authors: SCHWARZ JOHN H.
Published: October 2002

The mechanism by which gauge and gravitational anomalies cancel in certain string theories is reviewed. The presentation is aimed at theorists who do not necessarily specialize in string theory.
THE DARK SIDE OF THE UNIVERSE
Authors: SILK JOSEPH
Published: October 2002

Most of the matter in the universe is invisible. I review the status of dark matter and describe how both the theory of galaxy formation and novel types of experimental searches are revitalizing attempts to find non-baryonic dark matter.
NONABELIAN GAUGE THEORIES ON NONCOMMUTATIVE SPACES
Authors: BRACE D. , CERCHIAI B. L. , ZUMINO B.
Published: October 2002

In this paper, we describe a method for obtaining the nonabelian Seiberg-Witten map for any gauge group and to any order in θ. The equations defining the Seiberg-Witten map are expressed using a coboundary operator, so that they can be solved by constructing a corresponding homotopy operator. The ambiguities, of both the gauge and covariant type, which arise in this map are manifest in our formalism.
Effects of Selective Inhibitors of Nitric Oxide Synthase-2 Dimerization on Acute Cardiac Allograft Rejection
Authors: Szabolcs Matthias J. , Sun Ji , Ma Ningsheng , Albala Arline , Sciacca Robert R. , Philips Gary B. , Parkinson John , Edwards Niloo , Cannon Paul J.
Published: October 2002

Background—

Nitric oxide synthase-2 (NOS2) is expressed during acute cardiac allograft rejection in association with myocardial inflammation, contractile dysfunction, and death of cardiomyocytes by necrosis and apoptosis. Recently, allosteric inhibitors of NOS2 monomer dimerization that block NOS2 activity have been developed.

Methods and Results—

To investigate effects of selective NOS2 blockade, 15 mg/kg of BBS-1 or BBS-2 was administered twice daily subcutaneously to rats starting the day of heterotopic heart transplantation. Cardiac allograft survival was increased significantly, from 6.8 days in controls to 13.3 and to 14.2 days in NOS2-inhibited allografts. At day 5 after heart transplantation, synthesis of NOx was reduced by 53%. There were significantly fewer T lymphocytes and macrophages in the inflammatory infiltrate, as well as less edema and cardiomyocyte damage, and the International Society of Heart and Lung Transplantation score fell from 5 to 4 and 3.5. NOS2 and nitrotyrosine immunostaining and the mean numbers of apoptotic cells and of apoptotic cardiomyocytes were significantly diminished in the treated allografts.

Conclusions—

The data indicate that selective inhibition of NOS2 dimerization prolongs survival and reduces myocardial inflammation and cardiomyocyte damage in acute cardiac allograft rejection.
Cardiac Troponin I Predicts Short-Term Mortality in Vascular Surgery Patients
Authors: Kim Lauren J. , Martinez Elizabeth A. , Faraday Nauder , Dorman Todd , Fleisher Lee A. , Perler Bruce A. , Williams G. Melville , Chan Daniel , Pronovost Peter J.
Published: October 2002

Background—

Cardiac troponin I (cTnI) is a highly sensitive and specific marker for myocardial injury that predicts outcomes in patients with acute coronary syndromes. Cardiovascular complications are the leading cause of morbidity and mortality in patients who have undergone vascular surgery. However, postoperative surveillance with cardiac enzymes is not routinely performed in these patients. We evaluated the association between postoperative cTnI levels and 6-month mortality and perioperative myocardial infarction (MI) after vascular surgery.

Methods and Results—

Two hundred twenty-nine patients having aortic or infrainguinal vascular surgery or lower extremity amputation were included in this study. Blood samples were analyzed for cTnI immediately after surgery and the mornings of postoperative days 1, 2, and 3. An elevated cTnI was defined as serum concentrations >1.5 ng/mL in any of the 4 samples. Twenty-eight patients (12%) had postoperative cTnI >1.5ng/mL, which was associated with a 6-fold increased risk of 6-month mortality (adjusted OR, 5.9; 95% CI, 1.6 to 22.4) and a 27-fold increased risk of MI (OR, 27.1; 95% CI, 5.2 to 142.7). Furthermore, we observed a dose-response relation between cTnI concentration and mortality. Patients with cTnI >3.0 ng/mL had a significantly greater risk of death compared with patients with levels ≤0.35 ng/mL (OR, 4.9; 95% CI, 1.3 to 19.0).

Conclusions—

Routine postoperative surveillance for cTnI is useful for identifying patients who have undergone vascular surgery who have an increased risk for short-term mortality and perioperative MI. Further research is needed to determine whether intervention in these patients can improve outcome.
Long-Term Outcome of Patients Treated With Repeat Percutaneous Coronary Intervention After Failure of γ-Brachytherapy for the Treatment of In-Stent Restenosis
Authors: Prpic Ross , Teirstein Paul S. , Reilly John P. , Moses Jeffrey W. , Tripuraneni Prabhakar , Lansky Alexandra J. , Giorgianni Joseph-Anthony , Jani Shirish , Wong S. Chiu , Fish R. David , Ellis Stephen , Holmes David R. , Kereiakas Dean , Kuntz Richard E. , Leon Martin B.
Published: October 2002

Background—

Although
192
Ir intracoronary brachytherapy has been demonstrated to dramatically reduce the recurrence of in-stent restenosis, up to 24% of these patients will still require repeat target-vessel revascularization. The short- and long-term outcomes of repeat percutaneous intervention in this population have not been characterized.

Methods and Results—

Analysis was performed of all patients enrolled in the GAMMA-I and GAMMA-II brachytherapy trials who underwent repeat percutaneous target lesion revascularization (TLR) because of restenosis. Subjects were divided into 2 cohorts: those who had received
192
Ir brachytherapy and those randomized to placebo. Forty-five (17.6%) of a total of 256 patients whose index treatment was intracoronary radiation therapy and 36 (29.8%) of 121 patients whose index treatment was placebo required repeat percutaneous TLR. The mean time to this first TLR was 295±206 days in the irradiated group and 202±167 days in the placebo group (
P
=0.03). Acute procedural success occurred in 100% of irradiated patients and 94% of placebo controls (
P
=0.19). After the first TLR, a subsequent TLR was required in 15 (33.3%) of 45 brachytherapy patients versus 17 (47.2%) of 36 placebo failure patients (
P
=0.26). There was no significant difference in time to second TLR between the 2 groups. Other long-term major adverse event rates in both groups were comparable to those of other contemporary angioplasty/stenting series.

Conclusions—

In those patients who “fail”
192
Ir intracoronary brachytherapy for in-stent restenosis, treatment with
192
Ir delays the time to first TLR. Additionally, repeat percutaneous intervention in these patients is safe and efficacious in the short term, with acceptable long-term results.
Delivered Dose and Vascular Response After β-Radiation for In-Stent Restenosis
Authors: Morino Yoshihiro , Kaneda Hideaki , Fox Tim , Takagi Atsushi , Hassan Ali H.M. , Bonan Raoul , Crocker Ian , Lansky Alexandra J. , Laskey Warren K. , Suntharalingam Mohan , Bonneau Heidi N. , Yock Paul G. , Honda Yasuhiro , Fitzgerald Peter J.
Published: October 2002

Background—

Observations from previous intracoronary radiation therapy trials noted a considerable discrepancy between the prescribed radiation dose and the dose actually delivered. The aims of this study were to investigate the effect of actual delivered dose on vascular changes and to test the appropriateness of the current dose prescription.

Methods and Results—

Serial volumetric intravascular ultrasound (IVUS) analysis was performed in 30 in-stent restenosis cases treated with a 40-mm
90
Sr/Y source train. The fixed dose was prescribed at 2 mm from the centerline of the source train (18.4 Gy at 2 mm for reference diameter ≤3.35 mm and 23 Gy for diameter ≥3.36 mm). Only stent segments with full radiation coverage and device injury were enrolled and divided into 2-mm-long subsegments (n=202). D
S90
EEM (the minimum dose absorbed by 90% of the external elastic membrane surface) was calculated as the delivered dose corresponding to each segment, assuming that the radiation catheter occupied the same position in the vessel as the IVUS catheter. Mean D
S90
EEM of 23.5±5.82 Gy (range 12.3 to 41.7 Gy) was delivered to these subsegments. Overall, intimal hyperplasia volume remained constant from postintervention to follow-up (2.23±1.10 to 2.32±1.09 mm
3
/m;
P
=NS). Regression analysis revealed there was no correlation between delivered dose intensity and changes in intimal hyperplasia volume. No particular dose-dependent complications were appreciated in this delivered dose range.

Conclusions—

The current dose-prescription protocol of
90
Sr/Y radiation to native in-stent restenosis lesions may provide substantial inhibition of neointimal reproliferation regardless of the actual delivered dose intensity.
Emergency Coronary Artery Bypass Surgery in the Contemporary Percutaneous Coronary Intervention Era
Authors: Seshadri Niranjan , Whitlow Patrick L. , Acharya Naveen , Houghtaling Penny , Blackstone Eugene H. , Ellis Stephen G.
Published: October 2002

Background—

Since the advent of percutaneous coronary interventions (PCIs), technological advances, adjunctive pharmacotherapy, and increasing operator experience have contributed to lowering the occurrence of major complications. However, emergency coronary artery bypass surgery (CABG) for failed PCI is still associated with important morbidity and mortality, even in the era of coronary stenting. We sought to determine the prevalence, indications, predictors, and complications of emergency CABG after PCI in the past decade.

Methods and Results—

We reviewed 18 593 PCIs performed from 1992 through 2000. There was a need for emergency CABG in 113 (0.61%) cases. The major indications were extensive dissection (n=61, 54%), perforation/tamponade (n=23, 20%), and recurrent acute closure (n=23, 20%). Prevalence of emergency CABG decreased from 1.5% of PCIs in 1992 to 0.14% in 2000 (
P
<0.001). Independent predictors of the need for emergency CABG included the worst ACC/AHA scoring of the intervened lesion (
P
<0.001) and female sex (
P
= 0.028), whereas history of prior bypass surgery and use of stents resulted in a decreased need for emergency CABG (
P
<0.001 for both). In patients undergoing emergency CABG, there were 17 (15%) in-hospital deaths, 14 (12%) perioperative Q-wave myocardial infarctions, and 6 (5%) cerebrovascular accidents.

Conclusions—

The need for emergency CABG has considerably decreased over time. Risk factors include female sex and a higher ACC/AHA score of the intervened lesion. However, morbidity and mortality of emergency CABG remain high even in the new millennium.
Dietary Fat Intake Determines the Effect of a Common Polymorphism in the Hepatic Lipase Gene Promoter on High-Density Lipoprotein Metabolism
Authors: Ordovas Jose M. , Corella Dolores , Demissie Serkalem , Cupples L. Adrienne , Couture Patrick , Coltell Oscar , Wilson Peter W.F. , Schaefer Ernst J. , Tucker Katherine L.
Published: October 2002

Background—

Gene-nutrient interactions affecting high-density lipoprotein cholesterol (HDL-C) concentrations may contribute to the interindividual variability of the cardiovascular disease risk associated with dietary fat intake. Hepatic lipase (HL) is a key determinant of HDL metabolism. Four polymorphisms in linkage disequilibrium have been identified in the HL gene (LIPC), defining what is known as the −514T allele. This allele has been associated with decreased HL activity and increased HDL-C concentrations. However, the effect is variable among populations.

Methods and Results—

We have examined interaction effects between the −514(C/T) LIPC polymorphism, dietary fat, and HDL-related measures in 1020 men and 1110 women participating in the Framingham Study. We found a consistent and highly significant gene-nutrient interaction showing a strong dose-response effect. Thus, the T allele was associated with significantly greater HDL-C concentrations only in subjects consuming <30% of energy from fat (
P
<0.001). When total fat intake was ≥30% of energy, mean HDL-C concentrations were lowest among those with the TT genotype, and no differences were observed between CC and CT individuals. We found similar gene-nutrient interactions when the outcome variables were HDL
2
-C (
P
<0.001), large HDL subfraction (
P
<0.001), or HDL size (
P
=0.001). These interactions were seen for saturated and monounsaturated fat intakes (highly correlated with animal fat in this population), but not for polyunsaturated fat.

Conclusions—

Dietary fat intake modifies the effect of the −514(C/T) polymorphism on HDL-C concentrations and subclasses. Specifically, in the Framingham Study, TT subjects may have an impaired adaptation to higher animal fat diets that could result in higher cardiovascular risk.
First Model of Spontaneous Vagal Hyperreactivity and Its Mode of Genetic Transmission
Authors: Livolsi Angelo , Feldman Josiane , Feingold Josué , Weiss Laurence , Alembik Yves , Sharifah-Anion Ismail M. , Fischbach Michel , Messer Jean , Bousquet Pascal
Published: October 2002

Background—

The main purpose of our study was to define an animal model of vagal hyperreactivity and its genetic transmission.

Methods and Results—

We first investigated the vagal reactivity with phenylephrine in conscious rabbits. Barosensitivity and the maximal bradycardic response were measured at the upper mean blood pressure plateau. Hyperreactive (H) animals were selected and crossbred with normal (N) ones. Results showed no significant difference between calculated barosensitivity values after the different doses of phenylephrine. In contrast, an increase of the values and a great dispersion appeared 1 to 5 beats after the end of the ramp. Marked pauses (6000 to 20 000 ms) were obtained with some rabbits, which were blocked by atropine. A significant excess of hyperreactive offspring was observed in H×H crossings compared with N×N ones (39.4% male and 42.3% female offspring versus 14.4% and 4.4%, respectively). Few female offspring were hyperreactive compared with males in N×H and N×N crossings (4.1% versus 23.4% and 4.4% versus 14.4%, respectively).

Conclusions—

This study describes the first model of spontaneous vagal pauses. The inheritance could be polygenic with a partial sex-limited character.
Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties
Authors: Proost Paul , Schutyser Evemie , Menten Patricia , Struyf Sofie , Wuyts Anja , Opdenakker Ghislain , Detheux Michel , Parmentier Marc , Durinx Christine , Lambeir Anne-Marie , Neyts Johan , Liekens Sandra , Maudgal Prabhat C. , Billiau Alfons , Van Damme Jo
Published: October 2002

The interferon (IFN)–inducible chemokines, specifically, IFN-γ–inducible protein-10 (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T-cell α-chemoattractant (I-TAC), share a unique CXC chemokine receptor (CXCR3). Recently, the highly specific membrane-bound protease and lymphocyte surface marker CD26/dipeptidyl peptidase IV (DPP IV) was found to be responsible for posttranslational processing of chemokines. Removal of NH2-terminal dipeptides by CD26/DPP IV alters chemokine receptor binding and signaling, and hence inflammatory and anti–human immunodeficiency virus (HIV) activities. CD26/DPP IV and CXCR3 are both markers for Th1 lymphocytes and, moreover, CD26/DPP IV is present in a soluble, active form in human plasma. This study reports that at physiologic enzyme concentrations CD26/DPP IV cleaved 50% of I-TAC within 2 minutes, whereas for IP-10 and Mig the kinetics were 3- and 10-fold slower, respectively. Processing of IP-10 and I-TAC by CD26/DPP IV resulted in reduced CXCR3-binding properties, loss of calcium-signaling capacity through CXCR3, and more than 10-fold reduced chemotactic potency. Moreover, IP-10 and I-TAC cleaved by CD26/DPP IV acted as chemotaxis antagonists and CD26/DPP IV–truncated IP-10 and Mig retained their ability to inhibit the angiogenic activity of interleukin-8 in the rabbit cornea micropocket model. These data demonstrate a negative feedback regulation by CD26/DPP IV in CXCR3-mediated chemotaxis without affecting the angiostatic potential of the CXCR3 ligands IP-10 and Mig.
Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates
Authors: Roth David A. , Kessler Craig M. , Pasi K. John , Rup Bonita , Courter Suzanne G. , Tubridy Karen L.
Published: October 2002

Human plasma–derived factor IX (pdFIX) concentrates are routinely used to treat patients with hemophilia B, an X-linked bleeding disorder that affects 1 in 30 000 males, but concerns remain regarding transmission of blood-borne pathogens. Therefore, the safety and efficacy of recombinant human factor IX (rFIX) were evaluated. A 20-center international trial was conducted in previously treated patients with severe or moderate (< 5 IU/dL factor IX activity) hemophilia B. Participants received rFIX for pharmacokinetic studies, treatment of or prophylaxis against hemorrhage, or surgical hemostasis, and were assessed at 3-month intervals for 2 years. Fifty-six subjects were treated. Mean incremental rFIX recovery was 0.75 IU/dL per IU/kg, 30% lower than expected for pdFIX, although the mean half-life was similar. Pharmacokinetic parameters were stable over time. Somewhat lower recoveries were seen in subjects younger than 15 years of age and in those with no detectable factor IX antigen. A total of 7362 infusions of rFIX were administered. All 1796 hemorrhages were controlled, 80.9% of which required only one rFIX infusion. Effective hemostasis was also achieved in prophylactic and surgical settings. One individual developed a low titer (1.2 Bethesda unit) transient inhibitor that spontaneously resolved. rFIX was not associated with serious adverse events, thrombogenicity, or virus transmission. rFIX is safe and effective for the treatment of hemophilia B. Despite a lower recovery compared with pdFIX, rFIX controlled hemorrhage in a wide variety of settings and may provide a safety advantage in terms of risk from blood-borne pathogens.
Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin
Authors: Skibeli Venke , Nissen-Lie Gro , Torjesen Peter
Published: October 2002

Erythropoietin (EPO) from sera obtained from anemic patients was successfully isolated using magnetic beads coated with a human EPO (hEPO)–specific antibody. Human serum EPO emerged as a broad band after sodium dodecyl sulfate–polyacrylamide gel electrophoresis, with an apparent molecular weight slightly smaller than that of recombinant hEPO (rhEPO). The bandwidth corresponded with microheterogeneity because of extensive glycosylation. Two-dimensional gel electrophoresis revealing several different glycoforms confirmed the heterogeneity of circulating hEPO. The immobilized anti-hEPO antibody was capable of binding a representative selection of rhEPO glycoforms. This was shown by comparing normal-phase high-performance liquid chromatography profiles of oligosaccharides released from rhEPO with oligosaccharides released from rhEPO after isolation with hEPO-specific magnetic beads. Charge analysis demonstrated that human serum EPO contained only mono-, di-, and tri-acidic oligosaccharides and lacked the tetra-acidic structures present in the glycans from rhEPO. Determination of charge state after treatment of human serum EPO with Arthrobacter ureafaciens sialidase showed that the acidity of the oligosaccharide structures was caused by sialic acids. The sugar profiles of human serum EPO, describing both neutral and charged sugar, appeared significantly different from the profiles of rhEPO. The detection of glycan structural discrepancies between human serum EPO and rhEPO by sugar profiling may be significant for diagnosing pathologic conditions, maintaining pharmaceutical quality control, and establishing a direct method to detect the misuse of rhEPO in sports.
The leucine zipper region of Myb oncoprotein regulates the commitment of hematopoietic progenitors
Authors: Karafiát Vı́t , Dvořáková Marta , Pajer Petr , Králová Jarmila , Hořejšı́ Zuzana , Čermák Vladimı́r , Bartůněk Petr , Zenke Martin , Dvořák Michal
Published: October 2002

The development of blood cells proceeds from pluripotent stem cells through multipotent progenitors into mature elements belonging to at least 8 different lineages. The lineage choice process during which stem cells and progenitors commit to a particular lineage is regulated by a coordinated action of extracellular signals and transcription factors. Molecular mechanisms controlling commitment are largely unknown. Here, the transcription factor v-Myb and its leucine zipper region (LZR) are identified as regulators of the commitment of a common myeloid progenitor and progenitors restricted to the myeloid lineage. It is demonstrated that wild-type v-Myb with the intact LZR directs development of progenitors into the macrophage lineage. Mutations in this region compromise commitment toward myeloid cells and cause v-Myb to also support the development of erythroid cells, thrombocytes, and granulocytes, similar to the c-Myb protein. In agreement with that, the wild-type v-Myb induces high expression of myeloid factors C/EBPβ, PU.1, and Egr-1 in its target cells, whereas SCL, GATA-1, and c-Myb are more abundant in cells expressing the v-Myb LZR mutant. It is proposed that Myb LZR can function as a molecular switch, affecting expression of lineage-specifying transcription factors and directing the development of hematopoietic progenitors into either myeloid or erythroid lineages.
Regulatory role of tetraspanin CD9 in tumor–endothelial cell interaction during transendothelial invasion of melanoma cells
Authors: Longo Natividad , Yáñez-Mó Marı́a , Mittelbrunn Marı́a , de la Rosa Gonzalo , Muñoz Marı́a-Luisa , Sánchez-Madrid Francisco , Sánchez-Mateos Paloma
Published: October 2002

Heterotypic interaction among tumor cells (TCs) and endothelial cells (ECs) may play a critical role during the vascular dissemination of neoplastic cells and during pathologic angiogenesis in tumors. To identify molecules involved in these processes, the distribution of vascular junctional proteins was first studied by immunofluorescence at sites of heterologous intercellular contact using TC-EC mosaic monolayers grown on 2-dimensional collagen. Several members of the tetraspanin superfamily, including CD9, CD81, and CD151, were found to localize at the TC-EC contact area. The localization of tetraspanins to the TC-EC heterologous contact area was also observed during the active transmigration of TCs across EC monolayers grown onto 3-dimensional collagen matrices. Dynamic studies by time-lapse immunofluorescence confocal microscopy showed an active redistribution of endothelial CD9 to points of melanoma insertion. Anti-CD9 monoclonal antibodies were found to specifically inhibit the transendothelial migration of melanoma cells; the inhibitory effect was likely caused by a strengthening of CD9-mediated heterotypic interactions of TCs to the EC monolayer. These data support a novel mechanism of tetraspanin-mediated regulation of TC transcellular migration independent of TC motility and growth during metastasis and a role for these molecules in the formation of TC-EC mosaic monolayers during tumor angiogenesis.