bluuebunny/crossref_metadata_2025 huggingface dataset:
No evidence for a putative involvement of platelet‐activating factor in systemic lupus erythematosus without active nephritis
Authors: Denizot Yves , Liozon Eric , Guglielmi Laurence , Ly Kim , Soria Pascale , Loustaud Véronique , Vidal Elisabeth , Jauberteau Marie Odile
Published: May 2004

Background: Platelet‐activating factor (PAF) seems to be implicated in systemic lupus erythematosus (SLE) patients with associated renal diseases.Aims: In this study, we ensured the role of PAF in SLE patients without renal complications.

Methods: Blood PAF and acetylhydrolase activity, plasma soluble phospholipase A2, and the presence of antibodies against PAF were investigated in 17 SLE patients without active nephritis and in 17 healthy controls.

Results: Blood PAF levels were not different (P = 0.45) between SLE patients (6.7±2.8 pg/ml) and healthy subjects (9.6±3.1 pg/ml). Plasma acetylhydrolase activity (the PAF‐degrading enzyme) was significantly (P = 0.03) elevated in SLE patients (57.8±6.4 nmol/min/ml) as compared with controls (37.9±2.6 nmol/min/ml). Plasma soluble phospholipase A2 (the key enzyme for PAF formation) was not different (P = 0.6) between SLE patients (59.1±5.1 U/ml) and controls (54.7±2.4 U/ml). Antibodies against PAF were detected only in 3/17 SLE patients. Flow cytometry analysis did not highlight PAF receptors on circulating leukocytes of SLE patients.

Conclusion: This clinical study highlights no evidence for a putative important role of PAF in SLE patients without active nephritis.
Natural killer cytolytic activity is associated with the expression of killer cell immunoglobulin‐like receptors on peripheral lymphocytes in human
Authors: Kogure Toshiaki , Mantani Naoki , Sakai Shinya , Shimada Yutaka , Tamura Jun′ichi , Terasawa Katsutoshi
Published: May 2004

Although it has been shown that killer cell immunoglobulin‐like receptors (KIRs) on peripheral lymphocytes are upregulated by interleukin‐2 (IL‐2), which activates natural killer (NK) activity, it has not been demonstrated whether the expression of KIRs is related to NK activity. Therefore, we investigated the association between the KIR expression on lymphocytes and NK activity. CD158a/b expression on lymphocytes obtained from 37 subjects was analyzed using flow cytometry. Simultaneously, NK activity was measured each sample using a 51Cr‐release assay. Additionally, lymphocytes were cultured in RPMI 1640 medium with or without IL‐2 for 48 h, and then their CD158a/b expression and NK activity was analyzed. CD158a/b expression was significantly correlated with NK activity. Especially, the percentage of CD16+CD158a+ and CD8+CD158a/b+ cells in lymphocytes showed a highly significant correlation with NK activity. However, analysis of CD8+ and CD16+ cells revealed that there was only a significant correlation between the percentage of CD8+CD158a+ cells among only CD8+ cells and NK activity. The upregulation of CD16+CD158a+/b+ cells in response to IL‐2 tended to be related to the increase of NK activity, but the relationship was not significant. In conclusion, the level of KIR expression was correlated with NK activity, and IL‐2 treatment resulted in an increase of NK activity as well as KIR expression, suggesting that upregulation of KIRs enhances the ability to sort target cells, such as virus‐infected cells from uninfected cells, according to major histocompatibility complex class I expression.
Serum levels of soluble CD30 in adult patients affected by atopic dermatitis and its relation to age, duration of disease and Scoring Atopic Dermatitis index
Authors: Di Lorenzo Gabriele , Gangemi Sebastiano , Merendino Rosaria Alba , Minciullo Paola Lucia , Cannavò Serafina Paola , Martinelli Nicola , Mansueto Pasquale , Rini Giovanni Battista , Corrocher Roberto , Pacor Maria Luisa
Published: May 2004

The value of CD30 and the soluble circulating fragment of CD30 (sCD30) for atopic dermatitis (AD) remains unclear. In particular, little is known about the effects of age, duration of disease and Scoring Atopic Dermatitis index (SCORAD) on the levels of serum sCD30 in patients affected by AD. In the present study, we have analysed serum sCD30 levels of adult patients affected by AD. The study′s population includes 18 non‐smoking outpatients, with a diagnosis of AD. As a control group we studied 18 non‐atopic subjects from laboratory staff, matched for sex and age. These subjects had no history of AD, urticaria or seasonal or perennial rhinitis or asthma, and had negative skin prick test to a panel of allergens.

The sCD30 serum levels were clearly higher in patients affected by AD (14.2±9.0 IU/ml) than in healthy subjects (1.2±0.8 IU/ml) (P < 0.001). No differences were observed between males and females affected by atopic dermatitis, regarding age, duration of disease and SCORAD. Significant correlations were found between serum levels of sCD30 levels and age (r = −0.55; 95% confidence interval (CI) for r (Fisher′s z transformed)=−0.81 to −0.12;P = 0.01), duration of the disease (months) (r = −0.64; 95% CI for r (Fisher′s z transformed)=−0.85 to −0.24; P = 0.004) and SCORAD r = −0.74; 95% CI for r (Fisher′s z transformed)=−0.89 to −0.42; P = 0.004).

As demonstrated by the close correlation with age, duration of disease and SCORAD, serum levels of sCD30 appear to be an additional marker for the follow‐up of AD.
Malondialdehyde in benign prostate hypertrophy: a useful marker?
Authors: Merendino Rosaria Alba , Salvo Francesco , Saija Antonella , Di Pasquale Giuseppe , Tomaino Antonio , Minciullo Paola Lucia , Fraccica Giuseppe , Gangemi Sebastiano
Published: May 2004

Benign prostate hypertrophy (BPH) is the most common benign tumor in men due to obstruction of the urethra and, finally, uremia. Malondialdehyde (MDA) is a product derived from peroxidation of polyunsaturated fatty acids and related esters. Evaluation of MDA in serum represents a non‐invasive biomarker of oxidative stress. Prostate‐specific antigen (PSA) is a sensitive marker for prostatic hypertrophy and cancer. We analyzed MDA serum levels to evaluate the oxidative stress in BPH. To this end, 22 BPH patients and 22 healthy donors were enrolled. Data show an increase of MDA level in BPH patients and a positive correlation between PSA and MDA levels. In conclusion, we describe a previously unknown relationship between PSA and MDA as an index of inflammation and oxidative stress in BPH.
Anti‐inflammatory actions of acupuncture
Authors: Zijlstra Freek J. , van den Berg-de Lange Ineke , Huygen Frank J. P. M. , Klein Jan
Published: May 2004

Acupuncture has a beneficial effect when treating many diseases and painful conditions, and therefore is thought to be useful as a complementary therapy or to replace generally accepted pharmacological intervention. The attributive effect of acupuncture has been investigated in inflammatory diseases, including asthma, rhinitis, inflammatory bowel disease, rheumatoid arthritis, epicondylitis, complex regional pain syndrome type 1 and vasculitis. Large randomised trials demonstrating the immediate and sustained effect of acupuncture are missing. Mechanisms underlying the ascribed immunosuppressive actions of acupuncture are reviewed in this communication. The acupuncture‐controlled release of neuropeptides from nerve endings and subsequent vasodilative and anti‐inflammatory effects through calcitonine gene‐related peptide is hypothesised. The complex interactions with substance P, the analgesic contribution of β‐endorphin and the balance between cell‐specific pro‐inflammatory and anti‐inflammatory cytokines tumour necrosis factor‐α and interleukin‐10 are discussed.
Workshop on Targets and Moderators for Spallation Sources
Authors: Mezei F. , Gutberlet T.
Published: May 2004

The fast neutrons produced by the spallation process are slowed down to velocities adequate for neutron scattering experiments by a complex target-reflector-moderator system. The neutron performance of a spallation source depends decisively on the design and efficiency of this system. In spite of decades of accumulated experience, target-moderator systems still present major challenges in terms of understanding the basic principles and relationships, numerical and optimisation approaches and engineering solutions. A particularly important aspect is the interplay between moderator performance and instrument design. This is a two way street: the desires of instrument builders provide important input for the target people. At the same time, it is in the best interest of instrument builders to have an understanding of what happens in the target and moderators, to appreciate potentials and difficulties. This interaction between the two sides will help us get the most out of future spallation sources. In order to promote this process, Hahn-Meitner-Institut, as the lead laboratory for the ESS instrumentation task, organised an international workshop on 12–14 March 2001, in order to review the current state of moderator development and requirement by neutron instrumentation. The workshop was generously supported by a grant from the EU Neutron Round Table. About 40 participants attended, with strong contributions by the American and Japanese communities as well as from Europe. Constructive and lively discussions on the various aspects of the workshop topic demonstrated the importance of moderator design, target-moderator set-up and requirements by neutron instrumentation for future spallation sources. Although most presentations given during the workshop are published in the present volume, due to the very preliminary status of results, some work as recent calculations by Filges et al. on the neutronic performance of moderators for ESS appears elsewhere. The presented results and discussions will have an important influence on the ESS moderator and instrumentation R and D as well as other spallation source projects.
Development of Hydrogen Cold Moderator Systems for a Spallation Neutron Source
Authors: Kiyanagi Y. , Ooi M. , Ogawa H. , Furusaka M.
Published: May 2004

Hydrogen is at present the most realistic cold moderator material for a high-intensity spallation neutron source, although the neutronic characteristics are not as good as those of methane. Therefore, methods to improve the neutronic characteristic of the hydrogen moderator are required. Some methods to increase the neutron intensity and the pulse characteristics were tried for coupled and decoupled liquid hydrogen moderators. It was indicated for the coupled moderator that composite reflector and para-rich hydrogen were useful and for the decoupled moderator, a premoderator of water and also para-rich hydrogen were useful.
Optimization of Coupled and Decoupled Hydrogen Moderators for a Short-pulse Spallation Source
Authors: Watanabe Noboru , Harada Masahide , Kai Tetsuya , Teshigawara Makoto , Ikeda Yujiro
Published: May 2004

Neutronic performance of coupled and decoupled hydrogen moderators for a short pulse spallation source was extensively studied by calculations to seek the optimal parameters, especially the para/ortho hydrogen ratio. A decoupled 100% para-hydrogen moderator gives excellent pulse characteristics at lower energies. Gadolinium (Gd) poisoning is useful to obtain narrower pulses up to about 70 meV at a reasonable intensity penalty. At higher energies, where the pulse tail decay characteristics become most important, the choice of the reflector material and the decoupling energy (Ed) play an important role. One important technical issue is the radiation damage of a Gd-poison and a boron carbide decoupler. We discuss the possibility of using a composite decoupler material such as Cd + In (indium) + Eu (europium). In a coupled moderator a 100% para-hydrogen moderator of a larger volume gives an additional intensity gain over a normal one but the gain is not as large as in a decoupled one.
Improved Thermal Neutron Scattering Kernels for Liquid Hydrogen and Deuterium
Authors: Granada J.R. , Gillette V.H. , Pepe M.E. , Sbaffoni M.M.
Published: May 2004

Recent experimental information about the dynamics and structure of liquid hydrogen and deuterium has been used to produce new descriptions of the interaction of slow neutrons with these cryogenic moderators. These models were employed as input data to generate new scattering cross-section libraries using the NJOY code. The molecular translational motion, for both diffusive and collective degrees of freedom, has been reanalysed and represented by different spectral frequency distributions compared to those originally built into the code. Recent structural studies of liquid deuterium are considered in the present work, to use a realistic structure factor for the calculation of the scattering law at different temperatures within the ranges corresponding to the liquid phase of H2 and D2. The preliminary validation tests performed so far using the new libraries indicate that they are able to produce results in better agreement with the experiments than the existing ones.
Prospects for Solid Ammonia as a Cold Moderator
Authors: Carpenter J.M. , Iverson E.B. , Littrell K.C.
Published: May 2004

We explore what is known about solid ammonia as a moderator, suggest and demonstrate a method for deriving from measurements on normal ammonia results that apply to the separated isotopic form, and survey the needs for further research.
Decoupled Moderators—Do We Always Need Them? or: A New Approach for Pulse Shaping
Authors: Parizzi A.A. , Lee W.-T. , Felcher G.P. , Klose F.
Published: May 2004

At a spallation neutron source, the wavelength of a neutron is generally determined by its time-of-flight (TOF) from the source to the detector. The achievable precision is ultimately limited by the non-zero emission time-width of the source/moderator system. Particularly, coupled moderators that are used to produce high-intensity cold neutron beams show long “tails” in the intensity/time distribution for all wavelengths. For this reason, much less intense decoupled moderators are often used for instruments that require high resolution. We present here a novel technique for dynamic energy filtering of thermal and cold polarized neutron beams. The device consists of a polarizer/analyzer system and an energy-selective spin-resonance flipper. By drifting its resonance condition in synchronization with the TOF, the filter controls the energy resolution of a broad bandwidth TOF neutron pulse. Calculations show that substantial resolution gains are obtainable by applying this technique to a TOF neutron reflectometer.
Performance of Reflectometers on Different Moderators and Target Stations of the ESS Project
Authors: Fritzsche H. , Lieutenant K.
Published: May 2004

We have investigated the performance of a reflectometer on an ambient water and liquid hydrogen moderator with different characteristics (coupled, decoupled poisoned, decoupled unpoisoned) on different target stations, which are currently under discussion for the planned European Spallation Source (ESS): 5 MW short pulse at 50 Hz, 1 MW short pulse at 10 Hz and 5 MW long pulse at 16.67 Hz. The Monte-Carlo simulations performed using the software package VITESS show that the performance of a reflectometer is roughly proportional to the power of the source. Therefore, the coupled cold moderator together with the most powerful target station (5 MW short pulse or 5 MW long pulse) is the best choice for reflectometry. The repetition rate and pulse length are of minor importance.
Experiments on Neutron Leakage Currents and Moderator Storage Times of Various Spallation Target–Moderator–Reflector Assemblies
Authors: Conrad Harald
Published: May 2004

Results from spallation neutron source mock-up experiments on neutron leakage currents and storage times of ambient temperature as well as cryogenic moderators are presented. The experiments were carried out in support of high power sources like the German SNQ and the European ESS. The vast amount of work performed elsewhere will not be treated in this review. Lead, tungsten and depleted uranium targets were bombarded with protons and deuterons with energies between 400 MeV and 1.1 GeV. Beryllium, graphite, lead and D2O reflectors, as well as polyethylene and H2O pre-moderators around the liquid hydrogen moderators, were employed. The results for the time average leakage currents from both ambient and cold moderators are compared to those from the high flux reactor at the ILL in Grenoble. From the results on moderator storage times, the peak neutron leakage currents for pulsed operation of various target/moderator/reflector assemblies as a function of the proton pulse duration have been deduced.
The Spallation Neutron Source High Power Target Station Moderator Performance: Calculations and Studies
Authors: Iverson E.B. , Ferguson P.D. , Gallmeier F.X. , Murphy B.D.
Published: May 2004

We address recent progress in the continued neutronic design of the Spallation Neutron Source Target Station as regards moderator performance. The Spallation Neutron Source Target Station will receive 2 MW of 1 GeV protons at 60 Hz. This level of proton power offers unprecedented neutronic performance for pulsed neutron production for time-of-flight neutron scattering, as well as unprecedented challenges in providing such a performance. We report on the results of recent design optimization studies and the importance of carefully matching moderator performance characteristics to the needs of the neutron scattering instruments.
ISIS Target Station II: Preliminary Target and Moderator Simulations
Authors: Bennington S.M. , Campbell S.I. , Broome T.A. , Picton D.J. , Beynon T.D.
Published: May 2004

When ISIS was first constructed the target and moderators were optimised to exploit the large epithermal fluxes of neutrons that are inherent to pulsed neutron sources. Since then, experience has shown that pulsed sources can effectively compete with reactors for certain applications even in the thermal and cold neutron regions. The plan to build a second target station at ISIS, that is specifically designed to use these low energy neutrons, has prompted this design study. The second target station will use one pulse in five from an upgraded 300 μA synchrotron giving a total power of 48 kW. This low power makes it possible to use highly efficient target designs such that, for some instruments, there will be substantial gains in flux compared to similar instruments on the existing ISIS target. In this preliminary report we present our current thoughts on the design of the second target station and the results of Monte-Carlo calculations of flux and pulse shape.
The JESSICA Moderator System: A Cryogenic Moderator System
Authors: Stelzer H. , Barnert-Wiemer H. , Bayer N.
Published: May 2004

Jülich Experimental Spallation Target Set-up In COSYArea (JESSICA) is a full-scale model of the target-reflector-moderator system for the European Spallation Source (ESS), which has been built up at the COSY accelerator in the research centre Juelich. JESSICA has been designed for prototyping experiments for the ESS and to validate simulation methods concerning the transport and interaction of particles as well as to optimize the technical layout of the target-reflector-moderator system and to compare the results by using different moderator materials. This year JESSICA will become operational with one cryogenic moderator and one ambient below the target, and two ambient moderators above it. For the cryogenic moderator, different moderator materials will be used. (a) Liquid hydrogen (b) Solid methane as a block (c) Solid methane pellets surrounded by liquid hydrogen. The engineering design of JESSICA, including the cryogenic moderator system and safety aspects, will be discussed.
Status of Pelletised Moderator Neutronics Research for the Spallation Neutron Source Long Wavelength Target Station
Authors: Iverson E.B. , Forsythe D.C. , Heuser B.J. , Carpenter J.M.
Published: May 2004

We explore methods for making detailed calculations on the neutronic performance of a pelletised moderator, wherein a significant fraction of the moderating medium is heterogeneously distributed. This pellet approach appears to be necessary to provide cooling capabilities to a solid moderator material under heavy heat loads, and furthermore appears to offer the only realistic mechanism for permitting solid moderators in situations where the moderator material stores energy from radiation damage at a significant rate. Current use of solid moderators (e.g. methane at the Intense Pulsed Neutron Source facility) is significantly limited by the need to avoid catastrophic release of this stored energy.
Rheological Properties of Living Materials. From Cells to Tissues
Authors: Verdier C.
Published: May 2004

In this paper, we review the role of the rheological properties at the cellular and macroscopic scale. At the cellular scale, the different components of the cell are described, and comparisons with other similar systems are made in order to state what kind of rheological properties and what constitutive equations can be expected. This is based on expertise collected over many years, dealing with components such as polymers, suspensions, colloids and gels. Various references are considered. Then we review the various methods available in the literature, which can allow one to go from the microscopic to the macroscopic properties of an ensemble of cells, in other words a tissue. One of the questions raised is: can we find different properties at the macroscopic level than the ones that we start with at the cellular level? Finally, we consider different biological materials which have been used and characterized, in order to classify them. Constitutive laws are also proposed and criticized. The most difficult part of modeling is taking into account the active part of cells, which are not just plain materials, but are living objects.
Modeling the Cytokine Network In Vitro and In Vivo
Authors: Müller Johannes , Tjardes Thorsten
Published: May 2004

The present paper consist of two parts: in the first part an experiment investigating the endothelial cell/interleukin 1 system is analyzed by means of a model. The most interesting outcome is a bistability of the system: a small challenge will not lead to a reaction, while a challenge slightly above a certain threshold leads to a complete activation of the endothelial cells. This finding is used in the second part of the paper, where a caricature model of the innate immune response (the part of the immune system that is not based on acquired immunity) is described and analyzed. In this analysis, especially, the possible patterns of the dynamics in the absence of a challenge have been targeted. We find a variety of
behaviors possible for the resulting planar system. For certain parameter values, a small challenge is ignored, while a challenge above a certain threshold leads to a massive strike of the immune system that comes eventually to rest again. Also bistability, periodic behavior or an unstable resting state can be found. It is heuristically possible to link most of these dynamical patterns with natural or pathological situations that can be found in clinical pictures.
Multiscale Modeling and Mathematical Problems Related to Tumor Evolution and Medical Therapy
Authors: Bellomo Nicola , De Angelis Elena , Preziosi Luigi
Published: May 2004

This paper provides a survey of mathematical models and methods dealing with the analysis and simulation of tumor dynamics in competition with the immune system. The characteristic scales of the phenomena are identified and the mathematical literature on models and problems developed on each scale is reviewed and critically analyzed. Moreover, this paper deals with the modeling and optimization of therapeutical actions. The aim of the critical analysis and review consists in providing the background framework towards the development of research perspectives in this promising new field of applied mathematics.
Lymphangiogenesis
Authors: Tait Catherine R. , Jones Pamela F.
Published: May 2004

While much effort is given to the modelling of tumour angiogenesis, little attention is paid to lymphangiogenesis and its potential role in tumour progression and metastasis. This is due at least in part to the controversy that surrounds tumour lymphangiogenesis—opinion is divided as to whether tumours actively promote the development of lymph channels in the same way that they promote the development of vasculature. Given that it was decades before Folkman′s theory of tumour angiogenesis became widely accepted, it is possible that the concept of tumour lymphangiogenesis will in time also become generally accepted and hence may itself become the subject of mechanistic studies and mathematical modelling. This review summarises the process of lymphangiogenesis and the potential mechanism of its induction in tumours.
The “Technology of Happiness” and the Tradition of Economic Science
Authors: Bruni Luigino
Published: May 2004

It is a matter of fact that happiness is once again one of the foci of interest for economists, the “professors of the dismal science” (Carlyle 1850, p. 43). This is also the conviction of the editor of the “Controversy” onEconomics and HappinessinThe Economic Journalin 1997: “Economists from different backgrounds … all believe that happiness must play a more central role in economic science once again” (Dixon 1997, p. 1812). Dixon's thesis is twofold: (a) “Once again”: the reference is to the Neapolitanpubblica felicita(public happiness), developedby Genovesi andothers in the mid-1700s. In fact, Dixon sees a link between the new interest on happiness by contemporary economists andthe XVIII century debate on “public happiness” in the Latin countries, and in Italy in particular, as he explicitly says in a footnote; (b) “More central role” according to Dixon, is that happiness nowadays does not play a central role in economics.
British Economists and Philosophers on Marx's Value Theory, 1920–1925
Authors: Steedman Ian
Published: May 2004

In the aftermath of the Great War and the Bolshevik revolution, the years 1920–1925 witnessed a great upsurge of academic writing in Britain on Karl Marx's theory of value. We shall not seek to explain this phenomenon but it may nevertheless be of interest first to sketch, as a contrasting background, the limited interest shown in this topic in the pages of the Economic Journal, 1891–1920. For that journal did indeed, in that period, devote considerable space to matters socialist—taken in a broad sense (see Steedman 1990).
Jeremiah Jenks: A Pioneer of Industrial Organization?
Authors: Brown John Howard
Published: May 2004

Jeremiah Whittle Jenks currently ranks as one of the more obscure academic economists of the Gilded Age and Progressive Era. While other prominent economists of the era such as Richard T. Ely and John Bates Clark have been the subject of many books and articles (Everett 1946, Rader 1966, and Henry 1996, for example) Jenks remains almost unknown and unheralded. For instance, he is scarcely mentioned in the relevant volume of Joseph Dorfman's The Economic Mind in American Civilization (Dorfman 1948, III), despite his very substantial scholarly and public roles in the economics of the day. He was likewise below the radar of Joseph A. Schumpeter's (1954) magisterial, History of Economic Analysis, and Mark Blaug's (1985) Economic Theory in Retrospect. Where Jenks's career has attracted scholarly notice, the aspects examined have focused less on his economic scholarship and more on his public policy roles. (Green 1956, Weinstein 1968, Furner 1975, Parrini and Sklar 1983) The reasons for Jenks's relative neglect are unclear, although several hypotheses will be entertained below.
James Buchanan's Economic Theory of Morals: The Case of the Work Ethic
Authors: Smith James F.
Published: May 2004

James M. Buchanan is a unique figure in modern economics. A Nobel Prize winner and a pioneer of public choice theory, he is in some ways a respected pillar of the profession. Yet at the same time, he is an outspoken critic of certain fundamental practices of mainstream economics who refuses to confine his work within the conventional boundaries of the discipline. Whether seen as an innovator or an iconoclast, he has consistently been among the most methodologically and philosophically self-aware of the profession's elite.
A Note on Francesco Ferrara's Cost of Reproduction
Authors: Minelli Enrico , Guidi Marco E. L. , Guccione Antonio
Published: May 2004

For those readers who are not familiar with the history of Italian economic thought, the Cost of Reproduction Doctrine (CRD) is an interpretation ofthe theory of value developed by the distinguished scholar Francesco Ferrara (1810–1900) around the middle of the nineteenth century. This was a time when many of the flaws of the classical system had been identified but the analytical tools needed for their elimination were not yet available.
Both Maturation and Survival of Human Dendritic Cells are Impaired in the Presence of Anergic/Suppressor T Cells
Authors: Frasca L. , Scottà C. , Lombardi G. , Piccolella E.
Published: May 2004

T cell suppression is a well established phenomenon, but the mechanisms involved are still a matter of debate. Mouse anergic T cells were shown to suppress responder T cell activation by inhibiting the antigen presenting function of DC. In the present work we studied the effects of co‐culturing human anergic CD4+ T cells with autologous dendritic cells (DC) at different stages of maturation. Either DC maturation or survival, depending on whether immature or mature DC where used as APC, was impaired in the presence of anergic cells. Indeed, MHC and costimulatory molecule up‐regulation was inhibited in immature DC, whereas apoptotic phenomena were favored in mature DC and consequently in responder T cells. Defective ligation of CD40 by CD40L (CD154) was responsible for CD95‐mediated and spontaneous apoptosis of DC as well as for a failure of their maturation process. These findings indicate that lack of activation of CD40 on DC by CD40L‐defective anergic cells might be the primary event involved in T cell suppression and support the role of CD40 signaling in regulating both activation and survival of DC.
Essential Microenvironment for Thymopoiesis is Preserved in Human Adult and Aged Thymus
Authors: Shiraishi J. , Utsuyama M. , Seki S. , Akamatsu H. , Sunamori M. , Kasai M. , Hirokawa K.
Published: May 2004

Normal human thymuses at various ages were immunohistologically examined in order to determine whether adult or aged thymus maintained the microenvironment for the T cell development and thymopoiesis was really ongoing. To analyze the thymic microenvironment, two monoclonal antibodies (MoAb) were employed. One is MoAb to IL‐1 receptor (IL‐1R) recognizing medullary and subcapsular cortical epithelial cells of normal infant human thymus. The other is UH‐1 MoAb recognizing thymic epithelial cells within the cortex, which are negative with IL‐1R‐MoAb. Thymus of subjects over 20 years of age was split into many fragments and dispersed in the fatty tissue. However, the microenvironment of each fragment was composed of both IL‐1R positive and UH‐1 positive epithelial cells, and the UH‐1 positive portion was populated with lymphocytes showing a follicle‐like appearance. Lymphocytes in these follicle‐like portions were mostly CD4+CD8+ double positive cells and contained many proliferating cells as well as apoptotic cells. Thus these follicle‐like portions in adult and aged thymus were considered to be functioning as cortex as in infant thymus. Proliferative activity of thymocytes in the thymic cortex and the follicle‐like portions definitely declined with advance of age, while incidence of apoptotic thymocytes increased with aging.
The Primary Responses of Murine Neonatal Lymph Node CD4+ Cells are Th2‐skewed and are Sufficient for the Development of Th2‐biased Memory
Authors: Adkins Becky , Bu Yurong , Vincek Vladimir , Guevara Patricia
Published: May 2004

Exposure of neonatal mice to antigen often results in Th2‐biased responses in later life. Examples of this Th2 tendency are (a) secondary antibody responses dominated by the Th2‐associated IgG1 isotype and (b) Th2‐mediated tolerance to alloantigens. We previously reported that neonates develop primary Th1 and Th2 function in the lymph nodes but exclusive Th2 primary splenic responses. Here, we have tested whether the Th2 bias of adults initially immunized as neonates is due to the early, primary Th2 polarization in the spleen. Surprisingly, removal of the spleen at birth had no affect on either IgG1‐dominant secondary responses or the development of tolerance to alloantigens. Thus, neonatal lymph nodes are sufficient to generate Th2‐biased function following neonatal antigen exposure. To understand how this could arise, we examined the primary Th1/Th2 responses of CD4+ lymph node cells. Unlike the balanced Th1/Th2 responses seen with total lymph node cells, the primary responses of isolated CD4+ cells were skewed to IL‐4 producing function. These results suggest that the early development of Th2‐dominant responses by lymph node CD4+ cells contributes substantially to the subsequent development of Th2‐dominant memory in neonates.
Second‐Hand Smoke Increases Bronchial Hyperreactivity and Eosinophilia in a Murine Model of Allergic Aspergillosis
Authors: Seymour Brian W. P. , Schelegle Edward S. , Pinkerton Kent E. , Friebertshauser Kathleen E. , Peake Janice L. , Kurup Viswanath P. , Coffman Robert L. , Gershwin Laurel J.
Published: May 2004

Involuntary inhalation of tobacco smoke has been shown to aggravate the allergic response. Antibodies to fungal antigens such as Aspergillus fumigatus (Af) cause an allergic lung disease in humans. This study was carried out to determine the effect of environmental tobacco smoke (ETS) on a murine model of allergic bronchopulmonary aspergillosis (ABPA). BALB/c mice were exposed to aged and diluted sidestream cigarette smoke to simulate ′second‐hand smoke′. The concentration was consistent with that achieved in enclosed public areas or households where multiple people smoke. During exposure, mice were sensitized to Af antigen intranasally. Mice that were sensitized to Af antigen and exposed to ETS developed significantly greater airway hyperreactivity than did mice similarly sensitized to Af but housed in ambient air. The effective concentration of aerosolized acetylcholine needed to double pulmonary flow resistance was significantly lower in Af + ETS mice compared to the Af + AIR mice. Immunological data that supports this exacerbation of airway hyperresponsiveness being mediated by an enhanced type 1 hypersensitivity response include: eosinophilia in peripheral blood and lung sections. All Af sensitized mice produced elevated levels of IL4, IL5 and IL10 but no IFN‐γ indicating a polarized Th2 response. Thus, ETS can cause exacerbation of asthma in ABPA as demonstrated by functional airway hyperresponsiveness and elevated levels of blood eosinophilia.
Characterization of Vascular Adhesion Molecules that may Facilitate Progenitor Homing in the Post‐natal Mouse Thymus
Authors: Lepique Ana Paula , Palencia Sharina , Irjala Heikki , Petrie Howard T.
Published: May 2004

T cell progenitors derive from the bone marrow but must migrate via bloodstream to the thymus in order to differentiate. The mechanism by which the thymus recruits progenitors from the blood is unknown. It is known, however, that there are receptive and refractory periods for progenitor recruitment and that when cells are imported, they enter the thymus through post‐capillary venules. Therefore, recruitment is an active process temporally and spatially regulated. In order to characterize the mechanism of recruitment, we evaluated vascular signals known to regulate leukocyte extravasation, with respect to their intrathymic location and temporal fluctuations. We find that CD34, MECA79, VCAM‐1, ICAM‐1 and VAP‐1 are all expressed in thymic blood vessels. MECA79 and VAP‐1 appear to be specific for post‐capillary venules, while ICAM‐1 and VCAM‐1 are also found on intrathymic stromal cells. MAdCAM is also expressed in the thymus, but is not associated with vascular tissues. Only MECA79 is upregulated during recruitment peaks, suggesting a role for this molecule in the periodicity of recruitment. Together, these studies reveal potential roles for l‐selectin ligands, VCAM‐1, ICAM‐1 and VAP‐1 in progenitor recruitment to the thymus, and implicate the presence of other periodic signals, such as chemokines and cytokines, that cooperate to execute this essential function.
The Effect of Dosage, Gestational Age and Splenectomy on Anti‐IgM Interception of Prenatal B‐cell Development in Sheep
Authors: McCullagh P. , Press C. McL. , McClure S. J. , Larsen H. J. , Landsverk T.
Published: May 2004

The administration of a single bolus of anti‐IgM antibody to foetal lambs early in pregnancy produces prolonged B‐cell depletion. The present study investigated this depletion by examining the effect, on B‐cell development in the ileal Peyer′s patches, of varying the timing and dosage of antibody administration and by supplementing anti‐IgM with surgical splenectomy. The capacity of a 1 mg bolus of anti‐IgM to deplete Peyer′s patches of B cells was lost if its administration was deferred until two thirds of the way through pregnancy, but persisted beyond this time if weight‐adjusted doses were used. Splenectomy of the foetus performed at an earlier age failed to extend the age at which a 1 mg dose of antibody remained effective. As the concentration of murine immunoglobulin in foetal serum was greatly reduced after 21 days, it is inferred that ongoing suppression of B‐cell development is not dependent on the continued presence of murine immunoglobulin. The enduring nature of suppression could be attributable to a limited period during which differentiation of B cells from stem cells normally occurs, although further studies will be needed to investigate this and other possible explanations for the effect of anti‐IgM treatment on prenatal B‐cell development in sheep.
CTLA‐4 Engagement Inhibits Th2 but not Th1 Cell Polarisation
Authors: Ubaldi Vanessa , Gatta Lucia , Pace Luigia , Doria Gino , Pioli Claudio
Published: May 2004

CTLA‐4 deficient mice show severe lymphoproliferative disorders with T helper sub‐population skewed toward the Th2 phenotype. In the present work, we investigated the role of CTLA‐4 in T helper cell subset differentiation. Naïve CD4+ cells were stimulated with anti‐CD3 and anti‐CD28 mAbs in the presence of either IL‐12 or IL‐4 to induce polarisation to Th1 or Th2 cells, respectively. Under these two polarising conditions cells express comparable levels of CTLA‐4. CTLA‐4 was stimulated by plastic‐bound mAb. The frequency of IFN‐γ‐ and IL‐4‐producing cells were estimated by FACS analysis. In parallel cultures, polarised Th1 and Th2 cells were re‐stimulated with anti‐CD3 and anti‐CD28 mAbs for 48 h and their culture supernatants analysed by ELISA. Results show that CTLA‐4 engagement during differentiation inhibits polarisation of naïve CD4+ cells to the Th2 but not the Th1 cell subset. At variance, once cells are polarised, CTLA‐4 engagement inhibits cytokine production in both effector Th2 and Th1 cells. Altogether these data indicate that CTLA‐4 may interfere not only in the signalling involved in acute transcriptional activation of both Th1 and Th2 cells but also in the development of one of the Th cell subsets.
Pathomechanisms of Paraneoplastic Myasthenia Gravis
Authors: Ströbel Philipp , Preisshofen Tobias , Helmreich Markus , Müller-Hermelink Hans Konrad , Marx Alexander
Published: May 2004

Thymic T cell development is characterized by sequential selection processes to ensure generation of a self‐tolerant, immuncompetent mature T cell repertoire. Malfunction of any of these selection processes may potentially result in either immunodeficiency or autoimmunity. Myasthenia gravis (MG) is a typical autoimmune manifestation of thymic epithelial tumors (thymomas) and is related to the capacity of these tumors to generate and export mature T cells. Analysis of the factors that lead to autoimmunization in thymomas will help to understand the mechanisms that prevent MG under physiological conditions in humans. In a comparison of MG(+) and MG(‐) thymomas, we could show that only thymomas capable of generating mature CD45RA+CD4+ T cells are associated with MG (p< 0.0001), while terminal thymopoiesis was abrogated in MG(‐) thymomas. In particular, acquisition of the CD27+CD45RA+ phenotype appears to be a critical checkpoint of late T cell development in the human thymus and may play an important role in the prevention of autoimmunity. Moreover, MG(‐) thymomas were virtually depleted of regulatory (CD4+CD25+) T cells (regT), while regT were readily detectable in MG(+) thymomas, albeit at significantly reduced numbers compared to control thymuses. Thus, in MG(+) thymoma patients, thymectomy apparently also results in removal of a regulatory T cell pool and may explain the frequent temporary postoperative deterioration of MG in these patients.
Rapid Development of Th2 Activity During T Cell Priming
Authors: Cunningham Adam F. , Toellner Kai-Michael
Published: May 2004

The paradigm of T helper‐1 (Th‐1) and Th‐2 cells developing from non‐committed naïve precursors is firmly established. Th1 cells are characterized by IFN production and, in mice, the selective switching to IgG2a. Conversely IL‐4 production and selective switching to IgG1 and IgE characterize Th2 cells. Analysis of Th2 induction in vitro indicates that this polarization develops gradually in T cells activated by anti‐CD3 in the presence of IL‐4; conversely anti‐CD3 and IFN induce Th1 cells. In this report, we explore evidence that indicates that the T helper cell polarization in vivo cannot solely be explained by the cytokine environment. This is provided by studying the early acquisition of Th1 and Th2 activities during responses to a mixture of Th1 and Th2‐inducing antigens. It is shown that these divergent forms of T cell help can rapidly develop in cells within a single lymph node. It is argued that early polarization to show Th‐1 or Th‐2 behavior can be induced by signals delivered during cognate interaction between virgin T cells and dendritic cells, in the absence of type 1 or type 2 cytokines. This contrasts with the critical role of the cytokines in reinforcing the Th‐phenotype and selectively expanding T helper clones.
Effects of HIV Triple Therapy on Methadone Levels
Authors: Akerele Evaristo O. , Levin Frances , Nunes Edward , Brady Ronald , Kleber Herbert
Published: May 2004

There is a belief among methadone patients that triple therapy for HIV reduces methadone potency. This cross‐sectional study compared the rate of methadone metabolism (peak‐trough blood levels) in two groups of methadone‐maintained patients, AIDS patients receiving triple therapy (N = 17), and HIV patients without triple therapy (N = 19). These preliminary findings suggest that triple therapy may increase the rate of methadone metabolism, though further studies are warranted.
A Brief History of Immunotoxicology and a Review of the Pharmaceutical Guidelines
Authors: Dean Jack H.
Published: May 2004

This article provides a brief history of the development of the field of immunotoxicology from one individual perspective and separates the discussion into five phases: the methods development and validation phase; the compound testing phase; the many meetings and organization of the specialty section phase; the mechanistic studies phase; and the guidelines phase. During the discussion of each phase, major highlights, accomplishments, contributors and key references are provided. The immunotoxicology guidelines for the testing of pharmaceutical chemical entities across the three major geographic axes are also presented and compared, along with some of the concerns raised by industry with these guidelines. The mandatory requirement of functional tests represents the major concern and difference between the Committee of Proprietary Medicinal Products (CPMP) and the new Food and Drug Administration (FDA) guidance. The scientific basis for the recommendation of the functional tests proposed in the guidance documents based on National Institute of Environmental Health and Safety/National Toxicology Program (NIEHS/NTP)-sponsored studies is described. Experience at Sanofi-Synthelabo, with the testing of 29 new chemical drug entities developed across a broad range of therapeutic classes using this testing paradigm and functional tests to define their immunotoxic potential, yielded a low number of compounds (6.8%) that produced any abnormal reaction. The two positive compounds might have been anticipated based on their pharmacology.
Effects of Chlordane and Lindane on Testosterone and Vitellogenin Levels in Green Neon Shrimp (Neocaridina denticulata)
Authors: Huang Da-Ji , Chen Hon-Cheng
Published: May 2004

The purpose of this study was to investigate the acute toxicity of chlordane and lindane as well as their endocrine disruption effect on green neon shrimp ( Neocaridina denticulata), a common habitant in freshwater system of eastern Asia and Hawaii. First, the organisms were exposed to chlordane and lindane to estimate the 96-h LC50(96-h median lethal concentration). Then, levels of testosterone and vitellogenin in hemolymph of N. denticulata after exposure to sublethal concentrations of chlordane (1 ng/L and 10 ng/L) and lindane (0.1 μg/L and 1 μg/L) were also examined. The 96-h LC50 values obtained from the results of acute exposure were 127.03 (130.11–122.35) ng/L and 9.36 (8.00–10.96) μg/L for chlordane and lindane, respectively. Furthermore, reductions of testosterone concentration were observed in both chlordane- and lindane-treated shrimps, whereas induction of vitellogenin-like protein was only apparent in chlordane-treated shrimps. Thus, it is concluded that chlordane and lindane may probably show some disruption endocrine functions on N. denticulata.
Meeting Requirements of the California Cholinesterase Monitoring Program
Authors: Wilson Barry W. , Henderson John D. , Arrieta Daniel E. , O’Malley Michael A.
Published: May 2004

California (CA) has a long-standing formal blood cholinesterase (ChE) monitoring program for mixers, loaders, and applicators of pesticides. When the authors found commercial clinical kits were not optimal for assaying blood ChEs, CA regulations were revised to specify use of the Ellman ChE assay or to demonstrate a conversion factor with a correlation ( r2) of 0.9 or better. The authors were enlisted to work with the clinical laboratories. Only two of seven participating laboratories generated an acceptable correlation for red blood cells (RBCs), whereas four of five laboratories had an acceptable correlation for plasma ChE. Subsequently, the CA Department of Pesticide Regulation (DPR) restated the need to meet this requirement and the authors worked with several of the clinical laboratories using a bovine ghost RBC ChE as a reference. Unfortunately, only 3 of 10 laboratories had acceptable correlations. Next, the authors provided all interested laboratories with human blood and plasma samples to perform the comparison study outlined in the regulation (Section 6728f). Fourteen laboratories participated; 9 met the ChE criteria for whole blood, 14 for plasma, and 6 for RBCs. Based on such data, on July 8, 2003, DPR notified the CA Agricultural Commissioners that nine of the participating laboratories were approved for ChE testing. Later work resulted in acceptable RBC values for two of the laboratories and their approval. The authors continue to work with laboratories interested in being on the approved list. The current list may be seen at www.cdpr.ca.gov/docs/whs/lablist.htm .