bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Free Cortisol Index for Laboratory Assessment of Pituitary-Adrenal Function
Authors: Bonte Harry A. , van den Hoven Ron J. , van der Sluijs Veer Gertjan , Vermes István
Published: October 2004

We developed a time-resolved-fluoro-immunoassay to measure cortisol binding globulin (CBG) in serum. It is a microtitre plate, solid phase, reagent excess, sandwich assay in which the same polyclonal antiserum is used as a source of capture and labeled antibodies. The results of this assay were shown to be reliable and were fully comparable with those obtained by a commercially available kit. As a reflection of the free cortisol concentration we measured cortisol and CBG concentrations in serum and calculated the Free Cortisol Index (FCI) = [cortisol]serum/[CBG]serum · 100. The clinical use of this parameter, as a screening test for disturbances of the pituitary-adrenal axis, was investigated in different groups of subjects: healthy men and women, women using oral contraceptives, pregnant women at term, patients with thyroidal illnesses, patients using anti-epileptic drugs and patients suffering from adrenal diseases. In a number of groups we compared the FCI results with measurements of cortisol in saliva, another parameter used as an estimate of the concentration of free cortisol in blood. Our conclusion is that the FCI, in contrast to a total cortisol measurement alone, can prevent unnecessary further testing.
Isoenzmyes of Class I and II Alcohol Dehydrogenase in Chronic Hepatitis
Authors: Chrostek Lech , Szmitkowski Maciej
Published: October 2004

Using class-specific fluorogenic substrates, the activities of class I and II alcohol dehydrogenase (ADH) isoenzymes were determined in the sera of patients with chronic hepatitis. The activity of the total alcohol dehydrogenase and indicator enzymes of liver damage were also investigated. We found a statistically significant increase of class I alcohol dehydrogenase isoenzymes in the total tested group which included those with the viral hepatitis. The (2-fold) increase in the activity of class I isoenzymes was similar to the increase of aminotransferases. The serum activity of class II isoenzymes was unchanged. Here an increase in total enzyme activity was not statistically significant. Class I isoenzymes and total enzyme activity correlated well with aminotransferases. These results demonstrate that serum activity of class I ADH measured with fluorogenic substrates confirms liver cell damage and may be useful in the diagnosis of chronic hepatitis.
Mechanisms of Antigen Presentation
Authors: Jensen Peter E.
Published: October 2004

T-lymphocytes recognize short peptide antigens bound stably to polymorphic major histocompatibility complex (MHC)-encoded glycoproteins expressed on the surface of antigen-presenting cells (APC). Two general pathways have evolved to generate peptide-MHC complexes. The MHC class II antigen processing pathway provides a mechanism for sampling proteins present in endosomal compartments. CD4+ regulatory T-cells recognize peptides bound to MHC class II molecules, which are selectively expressed in specialized APC that have efficient mechanisms for uptake of microbial antigens, and express costimulatory molecules required for activating naive T-cells. CD8+ T-cells recognize peptides bound to MHC class I molecules. Class I molecules are widely expressed and bind peptides derived from the normal turnover of cellular proteins, providing a mechanism to display a sampling of cellular components to be monitored for abnormalities by cytotoxic T-cells. Specialized accessory proteins influence the efficiency of antigen presentation and the specificity of immune responses through their roles in generating peptides, targeting antigen and MHC glycoproteins to selected intracellular compartments, and by direct participation in the peptide-loading mechanism. It has recently been discovered that some viruses have evolved ways to inhibit or subvert discrete steps in antigen processing, providing a mechanism to evade immune recognition.
Immunostimulatory CpG Motifs Trigger a T Helper-1 Immune Response to Human Immunodeficiency Virus Type-1 (HIV-1) gp160 Envelope Proteins
Authors: Deml Ludwig , Schirmbeck Reinhold , Reimann Jörg , Wolf Hans , Wagner Ralf
Published: October 2004

Bacterial DNA sequences containing unmethylated CpG motifs have recently been proposed to exhibit immunostimulatory effects on B-, T- and NK cells, leading to the induction of humoral and cell-mediated immune responses. In the present study we investigated the immunomodulatory effects of a CpG-containing oligodeoxynucleotide (CpG ODN) to the HIV-1 gp160 envelope (Env) protein in the BALB/c mouse model. Priming and boosting of mice with gp160 adsorbed to aluminium hydroxide (Alum) induced a typical T helper-2 (Th2)-dominated immune response with high titers of gp160-specific immunoglobulin (Ig)G1 isotypes but a weak IgG2a response. Specifically re-stimulated splenocytes from these mice predominantly secreted interleukin (IL)-5 but only minute amounts of interferon-γ (IFN-γ) upon specific re-stimulation. In contrast, a boost immunisation of gp160/Alum primed mice with a gp160/Alum/CpG combination resulted in a seven times higher production of IgG2a antibodies, without affecting the titers of IgG1 isotypes. Furthermore, approximately 10-fold increased levels of IFN-γ, but significantly reduced amounts of IL-5, were secreted from gp160-restimulated splenic cells. A further greater than 30-fold increase in the levels of specific IgG2a responses and a substantially elevated secretion of IFN-γ were observed when the mice received gp160/Alum/CpG combinations for priming and boost injections. Thus, CpG ODNs are useful as an adjuvant to induce a typical Th0/Th1 response to HIV gp160 proteins. However, despite the induction of a more Th1-like immune response, gp160/Alum/CpG combinations were not sufficient to prime an Env-specific cytotoxic T-cell (CTL) response.
Activation and Regulation of NFκB during Acute Inflammation
Authors: Lentsch Alex B. , Ward Peter A.
Published: October 2004

During the acute inflammatory response, there is induction of a mediator cascade which functions to activate residential macrophages and recruit blood leukocytes to the site of the inflammatory insult. Dysregulation of this process can cause an exaggerated inflammatory response and lead to tissue injury. Recent studies have focused on the transcription factor NFκB, which controls the gene expression of many pro-inflammatory mediators. Under normal conditions, NFκB is retained in the cytosol by inhibitory proteins of the IκB family. In response to an inflammatory insult, IκB proteins are degraded and the free NFκB complex translocates to the nucleus where it initiates gene transcription. An understanding of thein vivomechanisms leading to the activation of NFκB, and the regulatory mechanisms that exist to limit this activation, may lead to the development of novel new therapeutic options for inflammatory injury. In this review we will discuss the current knowledge of the role of NFκB in the development of acute inflammation, as well as the regulatory mechanisms that exist to prevent the activation of NFκB and resolve inflammatory tissue injury.
CD 14++Monocytes, CD14+/CD16+Subset and Soluble CD14 as Biological Markers of Inflammatory Systemic Diseases and Monitoring Immuno-suppressive Therapy
Authors: Scherberich Juergen E. , Nockher Wolfgang A.
Published: October 2004

The majority of peripheral blood monocytes strongly positive for the lipopolysaccharides (LPS)-receptor CD14 are negative for Fcγ receptor type III (CD16). However, a subset of monocytes coexpressing CD14 and CD16 accounts for about 8% of all monocytes. This population exhibits features of tissue macrophages, and is largely expanded (> 20 %) during acute and chronic inflammatory diseases including cases with pararheumatic systemic vasculitis. In addition, compared to normal controls, soluble CD14 (sCD14) is elevated (> 3 μg/ml) in serum specimens of these patients. CD14+/CD16+monocytes show a higher phagocytosis rate than CD14+/CD16 negative cells, and express higher levels of interleukin-1 and major histocompatibility complex, such as histocompatibility antigens HLA-DR, -DP and -DQ antigens. Glucocorticoids downregulate expression of CD14 and rapidly deplete CD14+/CD16+monocytes from peripheral blood. Patients under chronic immunosuppressive therapy exhibit low CD14/+/CD16+ rates, which may rise during infectious and non-infectious inflammatory complications, however. Thus, serial analyses for sCD14 and the proinflammatory CD14+/CD16+subset of monocytes suggest a valuable tool monitoring patients under immunosuppressive and/or antiinflammatory therapy.
Effects of Oxidized Low Density Lipoprotein, Lipid Mediators and Statins on Vascular Cell Interactions
Authors: Weber Christian , Erl Wolfgang , Weber Kim S. C. , Weber Peter C.
Published: October 2004

The integrin heterodimer CD11b/CD18 (αMβ2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2α (8-epi-PGF2α) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear-resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet αllbβ3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endotheliumex vivowas increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac-1-mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDLin vitro, indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs.
Mycophenolic Acid Influences T Helper 2 (Th2) Cytokine Induced Expression of Intercellular Cell Adhesion Molecule -1 (ICAM-1) on Human Endothelial Cells
Authors: Weigel Guenter , Bertalanffy Peter , Dubsky Peter , Griesmacher Andrea , Wolner Ernst
Published: October 2004

A possible synergistic effect of mycophenolic acid (MPA) and the immunosuppressive cytokines IL-4, IL-10 and IL-13 was investigated in human umbilical vein endothelial cells (HUVEC). These cytokines, which are produced by Th2-lymphocytes, were shown to induce the expression of vascular cell adhesion molecule-1 (VCAM-1) and production of IL-6 in endothelial cells. In this study we found IL-4 to induce both intercellular cell adhesion molecule-1 (ICAM-1) and VCAM-1 expression, whereas IL-13 induced VCAM-1 only. The surface expression of E-selectin was not influenced by any of the cytokines tested. MPA on its own led to statistically significant ICAM-1 expression on HUVEC. The combination of MPA with IL-4 led to a significant ICAM-1 expression in an additive manner compared to the cytokine alone. In contrast, MPA neither induced VCAM-1 nor did it influence the effects of IL-4 and IL-13 on VCAM-1 expression. A clinically relevant concentration of mycophenolic acid (10 μmol/l) decreased intracellular guanosine-5′-triphosphate (GTP) levels significantly. Since intracellular nucleotides are responsible for the glycosylation of proteins, a disturbance of the endothelial nucleotide balance could be responsible for the effects of MPA on ICAM-1. Guanine and guanosine prevented and partially reversed the actions of MPA, on both intracellular GTP and ICAM-1 expression, which strongly implies that MPA by interfering with nucleotide metabolism, affects the adhesive properties of endothelial cells, and by acting synergistically with IL-4 probably influences Th2 cytokine effects.
C-Reactive Protein: Structural Biology and Host Defense Function
Authors: Szalai Alexander J. , Agrawal Alok , Greenhough Trevor J. , Volanakis John E.
Published: October 2004

Human C-reactive protein is a Ca2+-binding acute phase-protein with binding specificity for phosphocholine. Recent crystallographic and mutagenesis studies have provided a solid understanding of the structural biology of the protein, while experiments using transgenic mice have confirmed its host-defense function. The protein consists of five identical protomers in cyclic symmetry. On one face of each protomer there is a binding site for phosphocholine consisting of two Ca2+ions that ligate the phosphate group and a hydrophobic pocket that accommodates the methyl groups of phosphocholine. On the opposite face is a deep cleft formed by parts of the N and C termini and bordered by an α-helix. Mutational studies indicate that the C1q-binding site of the molecule is located at the open end of this cleft with Asp112and Tyr175representing contact residues. Using human C-reactive protein transgenic mice, we investigated the host defense functions of the protein. Transgenic mice infected withStreptococcus pneumoniaehad increased lifespan and lowered mortality compared to wild-type mice. This was attributable to an up to 400-fold reduction in bacteremia mediated mainly by the interaction of C-reactive protein with complement. A complement-independent host protective effect was also demonstrated.
Annexin V and Phospholipid Metabolism
Authors: Russo-Marie Françoise
Published: October 2004

Annexins, protein kinases C and cytosolic phospholipase
A2 belong to three families of ubiquitous cytoplasmic
proteins involved in signal transduction. All
annexins share the property of binding to phospholipids
in the presence of calcium. Most annexins are substrates
for protein kinases C except annexin V, the
most ubiquitous and abundant annexin. Protein kinases
C (PKC) belong to three distinct groups of kinases,
conventional PKCs (cPKCs) that depend on
calcium, diacylglycerol and negatively charged phospholipids
for their activity, novel PKCs (nPKCs) and
atypical PKCs (aPKCs), that do not require calcium for
their activity, although they both require negatively
charged phospholipids. Cytosolic phospholipase A2
(cPLA2) depends on calcium for its catalytic activity as
well as on serine phosphorylation by MAP kinases. We
report that annexin V modulates the activity of cPKCs
as well as of cPLA2 by interfering with their ability to
bind to negatively charged phospholipids and calcium.
We propose that annexin V could interfere with the
calcium and phospholipid signalling pathway.
Regulation of Leukocyte Trafficking by Lipoxins
Authors: Diamond Pauline , McGinty Ann , Sugrue Declan , Brady Hugh R. , Godson Catherine
Published: October 2004

Lipoxins arelipoxygenaseinteraction products formed by transcellular metabolism during host defence and inflammation. In model systems, lipoxins modulate polymorphonuclear leukocytes (PMN) chemotaxis, adhesion molecule expression, inhibit PMN-endothelial cell adhesion, and attenuate cytokine release from epithelial cells. These observations raise the possibility that lipoxins are ‘stop signals’ for PMN-mediated tissue injury and promote the resolution of acute inflammation.
Lipoxin and Aspirin-Triggered 15-epi-Lipoxin Cellular Interactions Anti-Inflammatory Lipid Mediators
Authors: Serhan Charles N. , Takano Tomoko , Gronert Karsten , Chiang Nan , Clish Clary B.
Published: October 2004

Eicosanoids are known to play important roles in inflammation. Recent findings have given rise to several new concepts regulating the generation of eicosanoids, illustrated in Figure 1. Lipoxins (LX) are trihydroxytetraene-containing eicosanoids that are generated within vascular lumen by platelet-leukocyte interactions and at mucosal surfaces by leukocyte-epithelial cell interactions. During these cell-cell interactions, transcellular biosynthetic pathways are used as major routes, and thus, in humans, LX are formedin vivoduring multicellular responses such as inflammation, atherosclerosis, and thrombosis. This branch of the eicosanoid cascade generates specific tetraene-containing products that appear to function as stop signals, since they inhibit key steps in leukocyte-mediated inflammation. Of special interest, it appears that aspirin also functions in part via production of novel epimers of lipoxins or 15-epi-lipoxins (Figure 1). Here, we review recent developments on the cellular interactions of these novel anti-inflammatory mediators.
Polymorphonuclear Granulocyte Stimulation by Cellulose-Based Hemodialysis Membranes
Authors: Körmöczi Günther F. , Rosenkranz Alexander R. , Zlabinger Gerhard J.
Published: October 2004

Hemodialyis with cellulose-based membranes is associated with an array of adverse reactions, including leukopenia, pulmonary sequestration and dysfunction of leukocytes. Activation of the alternative pathway of complement due to direct contact of plasma with dialysis membrane is considered to be responsible for the induction of these side effects. In recent years, evidence has accumulated that other neutrophil effector functions such as reactive oxygen intermediate production play an important role as well. Here the importance of burst formation in cooperation with other inflammatory effector functions in the mechanisms of hemodialysis-related adverse effects will be discussed.
Reduction of Circulating Cholesterol and Apolipoprotein Levels during Sepsis
Authors: Fraunberger Peter , Schaefer Steffen , Werdan Karl , Walli Autar K. , Seidel Dietrich
Published: October 2004

Sepsis with multiple organ failure is frequently associated
with a substantial decrease of cholesterol levels.
This decrease of cholesterol is strongly associated
with mortality suggesting a direct relation between inflammatory
conditions and altered cholesterol homeostasis.
The host response during sepsis is mediated by
cytokines and growth factors, which are capable of influencing
lipid metabolism. Conversely lipoproteins
are also capable of modulating cytokine production
during the inflammatory response. Therefore the decrease
in circulating cholesterol levels seems to play a
crucial role in the pathophysiology of sepsis. In this review
the interaction between cytokines and lipid metabolism
and its clinical consequences will be discussed.
Outcome Prediction by Traditional and New Markers of Inflammation in Patients with Sepsis
Authors: Oberhoffer Mathias , Vogelsang Heinz , Rußwurm Stefan , Hartung Thomas , Reinhart Konrad
Published: October 2004

Patients (n = 242) admitted to intensive care unit for
longer than 48 hours were categorised for sepsis according
to American College of Chest Physicians/Society
of Critical Care Medicine (ACCP/SCCM) Consensus
Conference criteria. Body temperature, leukocyte
count, C-reactive protein (CRP) and procalcitonin (PCT)
as well as tumor necrosis factor-α (TNF-α), interleukin
(IL)-6, IL-8, IL-10 and HLA-DR expression on monocytes
were determined. Data of one randomly choosen day
per patient entered analysis. Immunologic mediators
contributing significantly to outcome were determined
by logistic regression analysis. Area under the
curves (AUC) of receiver operating characteristic
curves of clinical markers of inflammation predicting
prognosis were compared with AUC of relevant immunologic
mediators. TNF-α, IL-6 and HLA-DR expression
on monocytes were significantly associated with outcome;
the AUC's were 0.835, 0.844 and 0.761 respectively.
AUC's for clinical markers were 0.878, 0.811,
0.620 and 0.614 for PCT, CRP, leukocyte count and body
temperature respectively. PCT had the highest AUC
compared to other clinical markers. These data indicate
that PCT might be a better marker than the classic
criteria of inflammation, CRP, leukocyte count, and
body temperature to identify patients endangered by
severe infection or sepsis.
The Lady's Rhetorick (1707): The Tip of the Iceberg of Women's Rhetorical Education in Enlightenment France and Britain
Authors: Smith Tania Sona
Published: October 2004

Abstract The Lady's Rhetorick is a well-developed rhetorical handbook for women that appears in print at a surprising time and place in British rhetorical history, when there were few precedents for rhetorical treatises addressed to women. This rare and relatively unknown handbook includes a feminist argument for the inclusion of women within the realm of rhetoric, through addressing its instruction to women, defining rhetoric in gender-inclusive ways, and including examples of women's rhetorical practice. It adapts Classical and French rhetorical traditions through strategies that are potentially effective with its female, English audience. Thus its publication was a bold and strategic contribution to women's and men's rhetorical culture within the context of contemporary gender ideology and educational change. The handbook's uniqueness and rarity should be viewed by scholars as the tip of an iceberg, signaling that a significant amount of women's informal rhetorical practice and education could have been acknowledged in its own time as “rhetorical.”
Measuring bubble, drop and particle sizes in multiphase systems with ultrasound
Authors: Cents A. H. G. , Brilman D. W. F. , Versteeg G. F. , Wijnstra P. J. , Regtien P. P. L.
Published: October 2004

A technique is developed for measurement of bubble, droplet and particle‐size distributions in multiphase systems, based on the propagation speed and attenuation of ultrasound. The measurement of the size distribution of the dispersed phase in multiphase systems was desired to analyze the mass‐transfer mechanism in gas‐liquid‐liquid and gas‐liquid‐solid systems. To obtain this information, both the ultrasonic velocity and the attenuation coefficient of tone‐burst signals are determined for a large frequency range (typically 100 kHz – 100 MHz). From these parameters, the size distributions and the volume fraction of the different dispersed phases can be determined using a scattering model. It was shown that the interfacial area can be determined very accurately, however, for the exact size distribution of the gas bubbles in the used size range (1–3 mm) an independent gas holdup determination is required. Experiments were performed in gas‐liquid, solid‐liquid, and gas‐liquid‐solid systems. The results showed good agreement of the particle‐size distribution compared to a commercial laser‐scattering analyzer, both with and without gas bubbles present. Furthermore, a good agreement between the scattering model and the experiments was found in the systems that contained gas bubbles, but these results should be validated using for instance, a digital camera technique. © 2004 American Institute of Chemical Engineers AIChE J, 50: 2750–2762, 2004
Transient permeation of butanes through ZSM‐5 and ZSM‐11 zeolite membranes
Authors: Gardner Tracy Q. , Falconer John L. , Noble Richard D.
Published: October 2004

Butane isomer adsorption isotherms and diffusivities in the transport pathways through Al‐ZSM‐11 (MEL), Al‐ZSM‐5 (MFI), and B‐ZSM‐5 zeolite membranes were measured by a transient permeation technique. The permeate responses to feed step changes were measured between 383 and 473 K, and the diffusion was modeled as Maxwell–Stefan surface diffusion with dual‐site Langmuir adsorption. The effects of adsorption and diffusion on the n‐C4/i‐C4 ideal selectivities were quantified, and the selectivity differences between the membranes were explained based on the adsorption properties and the diffusivities. The resistance of the porous tubular supports affected the coverage in the zeolite at the permeate boundary, and the ratio of the n‐C4/i‐C4 diffusion driving forces consequently increased with increasing temperature. The n‐C4 diffusivities were almost the same in the three membranes, but the i‐C4 diffusivities in the MEL membrane were an order of magnitude higher than those in the MFI membranes. The bulkier i‐C4 molecules are apparently significantly less constrained in the straight, circular pores and slightly larger intersections of MEL zeolite, although the structural differences do not affect the mobility of n‐C4. Higher i‐C4 coverages in the Al‐ZSM‐11 and B‐ZSM‐5 membranes compared to the Al‐ZSM‐5 membrane were attributed to a smaller change in entropy upon adsorption in the channels of Al‐ZSM‐11 and to a higher heat of adsorption in the intersections of the more substituted B‐ZSM‐5. Initial transient flux overshoots and undershoots after i‐C4 feed concentration changes were apparently caused by a small amount of pressure‐driven flow (<10% of the total i‐C4 flux and <0.1% of the total n‐C4 flux) through parallel pathways. The effective membrane thicknesses were also estimated from the transient measurements. © 2004 American Institute of Chemical Engineers AIChE J, 50: 2816–2834, 2004
Intraparticle diffusion of phosphates in OH‐type strongly basic ion exchanger
Authors: Galinada Wilmer A. , Yoshida Hiroyuki
Published: October 2004

The intraparticle diffusions of H3PO4, H2PO, HPO, and PO ions in an OH‐type strongly basic ion exchanger, DIAION SA10A, were investigated by measuring the uptake curves for adsorption of phosphates by using the shallow‐bed method. The experimental uptake data were correlated by applying the homogeneous Fickian diffusion model and the parallel diffusion model for surface and pore diffusions. In all phosphate systems, the values of intraparticle effective diffusivity (Deff) obtained from the homogeneous model increased with the increase in the bulk‐phase concentration, and suggested the existence of a parallel transport of phosphates in the particle by the surface and pore diffusions. The surface diffusivities (DS) for the parallel diffusion model were determined from the intercepts of the plots of Deff[1 + (εPC0/q0)] vs. εPC0/q0. The accurate pore diffusivities (DP) were obtained by matching the theoretical uptake curves for the parallel diffusion model with the experimental uptake data. The parallel diffusion model agrees reasonably well with the experimental uptake data. © 2004 American Institute of Chemical Engineers AIChE J, 50: 2806–2815, 2004
High‐gradient magnetic separation of coated magnetic nanoparticles
Authors: Moeser Geoffrey D. , Roach Kaitlin A. , Green William H. , Alan Hatton T. , Laibinis Paul E.
Published: October 2004

The feasibility is examined of using high‐gradient magnetic separation (HGMS) to recover about 8‐nm magnetite nanoparticles that are tailored specifically to extract target solutes (polymer‐coated nanoparticles for the extraction of soluble organic contaminants from water and phospholipid‐coated particles for the selective extraction of proteins). A general model for nanoparticle capture based on calculating the limit of static nanoparticle buildup around the wires in an HGMS column is presented. Model predictions are compared successfully with experimental results from a bench‐scale HGMS column for both the polymer‐ and phospholipid‐coated particles. A minimum diameter for successful particle capture is derived for both individually dispersed nanoparticles and aggregates of nanoparticles. The individually dispersed polymer‐coated nanoparticles are less easily captured in the HGMS column than are the phospholipid‐coated particles, which exist as submicron aggregates. © 2004 American Institute of Chemical Engineers AIChE J, 50: 2835–2848, 2004
Synthesis and Evaluation of some Novel Quinazolinone Derivatives as Diuretic Agents
Authors: Maarouf Azza R. , El‐Bendary Eman R. , Goda Fatma E.
Published: October 2004

A new series of quinazolin‐4(3H)‐one derivatives containing either a thiazole or a 1, 3, 4‐thiadiazole moiety were prepared in order to study the effect of such a heterocyclic combination on the expected diuretic activity. Synthesis of the target compounds (2, 4, and 6) has been achieved through an interaction of the starting 7‐chloro‐2‐methyl‐4H‐3, 1‐benzoxazin‐4‐one 1 with different heterocyclic amines. Alkylation of 3‐(2‐mercapto‐1, 3, 4‐thiadiazol‐5‐yl)quinazolin‐4(3H)‐one derivative 4 with different alkyl halides or chloroacetic acid afforded the corresponding thioethers 5 while interaction of 2‐methyl‐3‐(1, 3, 4‐thiadiazol‐5‐yl or thiazol‐5‐yl)quinazolin‐4(3H)‐ones (2 and 6) with various aromatic aldehydes resulted in the formation of the arylvinyl analogs 3 and 7, respectively. On the other hand, 2‐morpholinomethyl‐3‐(2‐sulfamoyl or mercapto‐1, 3, 4—thiadiazol‐5‐yl)quinazolin‐4(3H)‐one derivatives 10 have also been synthesized through an interaction of the sulfonamide or thiol analog 9 with the appropriate amine. Biological evaluation of some of the target compounds as diuretic agents was carried out. The results showed that 2‐[2‐(4‐chlorophenyl)vinyl]‐7‐chloro‐3‐(2‐sulfamoyl‐1, 3, 4‐thiadiazol‐5‐yl)quinazolin‐4(3H)‐one 7b exhibited significant diuretic activity. The detailed synthesis, spectroscopic and biological data are reported.
Synthesis and Potent Antimicrobial Activity of Some Novel 4‐(5, 6‐Dichloro‐1H‐benzimidazol‐2‐yl)‐N‐substituted Benzamides
Authors: Özden Seçkin , Karataş Hacer , Yıldız Sulhiye , Göker Hakan
Published: October 2004

A series of 4‐(5, 6‐dichloro‐1H‐benzimidazol‐2‐yl)‐N‐substituted benzamides were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin‐resistant S. aureus (MRSA), methicillin‐resistant S. epidermis (MRSE), Enterococcus faecalis, Escherichia coli and Candida albicans. Certain compounds inhibit bacterial growth with low MIC values (μg/mL). Among them, compounds 10 and 11 exhibited the greatest antibacterial activity with MIC values of 3.12 μg/mL against S. aureus, MRSA and MRSE.
Practical Synthesis of Fenbufen Ethanolamide
Authors: Zohrabi‐Kalantari Vida , Link Andreas
Published: October 2004

The ongoing interest in ethanolamide derivatives of anti‐inflammatory drugs as potential synthetic cannabinoids and mechanistic tools for the study of cannabinoid and vanilloid receptors prompted us to develop a practical gram scale synthesis for the hitherto unknown ethanolamide of fenbufen. Dehydration of fenbufen leads to intramolecular ring closure yielding bright pink crystals of the intramolecular enol ester. Reaction of this activated but stable intermediate with ethanolamine leads to the title compound in good yield and purity without the necessity to remove coupling reagents or residual activating groups, such as N, N‐dialkyl ureas and fluorinated phenols.
Search for Histamine H3 Receptor Ligands with Combined Inhibitory Potency at HistamineN‐Methyltransferase: ω‐Piperidinoalkanamine Derivatives
Authors: Graßmann Sven , Apelt Joachim , Ligneau Xavier , Pertz Heinz H. , Arrang Jean‐Michel , Ganellin C. Robin , Schwartz Jean‐Charles , Schunack Walter , Stark Holger
Published: October 2004

In an effort to design new hybrid compounds with dual properties, i.e. binding affinity at histamine H3 receptors and inhibitory potency at the catabolic enzyme histamine Nτ‐methyltransferase (HMT), a novel series of 1‐substituted piperidine derivatives was synthesized. This alicyclic heterocycle is structurally linked via aminoalkyl spacers of variable lengths to additional aromatic carbo‐ or hetero‐cycles. These new hybrid drugs were pharmacologically evaluated regarding their binding affinities at recombinant human H3 receptors, stably expressed in CHO cells, and in a functional assay for their inhibitory potencies at rat kidney HMT. All compounds investigated proved to be H3 receptor ligands with binding affinities in the micro‐ to nanomolar concentration range despite significant differences in the type of the aromatic moiety introduced. The most potent compound in this series was the quinoline derivative 20 (Ki = 5.6 nM). Likewise, all new ligands studied showed impressive HMT inhibitory activities. Here, compounds 5, 10, 14 and 18—20 exhibited submicromolar potencies (IC50 = 0.061—0.56 μM). The aminomethylated quinoline 19 showed almost the same, well balanced nanomolar activities on both targets. In this study, new hybrid compounds with a dual mode biological action were developed. These pharmacological agents are valuable leads for further development and candidates for treatment of histamine‐dependent disorders.
Synthesis and Antimycobacterial Activity of Pyridylmethylsulfanyl and Naphthylmethylsulfanyl Derivatives of Benzazoles, 1, 2, 4‐Triazole, and Pyridine‐2‐carbothioamide/‐2‐carbonitrile
Authors: Zahajská Lenka , Klimešová Věra , Kočí Jan , Waisser Karel , Kaustová Jarmila
Published: October 2004

A set of four types of benzazoles, 1, 2, 4‐triazole, and pyridine‐2‐carbonitrile/‐2‐carbothioamide substituted with 1‐naphthylmethylsulfanyl or pyridylmethylsulfanyl was prepared to modify the structure of benzylsulfanyl derivatives of the above‐mentioned heterocycles. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration (MIC). The MIC values fall into a range of 2 to >1000 μmmol/L. Introduction of a pyridyl moiety into the molecule mostly decreased the activity. A naphthyl moiety did not influence the activity in comparison with a phenyl. The most active substances were 4‐(3‐pyridylmethylsulfanyl)pyridine‐2‐carbothioamide (7b) (MIC = 2 — >62.5 μmol/L) and 4‐(1‐naphthylmethylsulfanyl)pyridine‐2‐carbothioamide (7d) (MIC = 2 — >32 μmol/L).
Enhanced interleukin‐1β and interleukin‐18 release in a patient with chronic infantile neurologic, cutaneous, articular syndrome
Authors: Janssen Riny , Verhard Els , Lankester Arjan , ten Cate Rebecca , van Dissel Jaap T.
Published: October 2004

Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome is a severe inflammatory disease that recently was associated with mutations in CIAS1. It was hypothesized that these mutations may lead to enhanced inflammatory responses. Herein, we provide evidence that inflammation in the CINCA syndrome is characterized by enhanced interleukin‐1β (IL‐1β) and IL‐18 release upon stimulation of blood cells and show that this release is caspase 1 dependent.
Interferon‐α–inducible proteins are novel autoantigens in murine lupus
Authors: Hueber Wolfgang , Zeng Defu , Strober Samuel , Utz Paul J.
Published: October 2004

Objective

To investigate the spectrum of B cell autoimmunity in the recently described anti‐CD1–autoreactive T cell receptor (TCR)–transgenic murine lupus‐like (CD1 lupus‐like) model.

Methods

Lethally irradiated BALB/c/nu/nu mice were injected intravenously with donor BALB/c bone marrow and spleen cells expressing TCRα and TCRβ transgenes that recognize CD1d. Sera from adoptive host animals that developed lupus (i.e., CD1 lupus mice) were collected at serial time points and analyzed by Western blotting and immunoprecipitation, using protein extracts prepared from NIH3T3 mouse fibroblasts and EL‐4 lymphocytes, respectively. Sera obtained from older animals in several models of spontaneous lupus (NZB/NZW, MRL++, and MRL/lpr mice), unmanipulated BALB/c/nu/nu mice, and normal BALB/c mice were used as controls.

Results

Analyses demonstrated that the prominent targets of autoantibodies in the CD1 lupus‐like model are interferon‐α (IFNα)–inducible antigens. Biochemical and serologic characterizations identified one antigen as belonging to the interferon‐inducible 202 (Ifi202) subfamily of proteins within the Ifi200 family, and a second antigen as a member of the 70‐kd heat‐shock protein family. Autoantibodies directed against these antigens were rapidly produced at an early stage of disease. Anti‐p50 autoantibodies were present in sera from 7 (78%) of 9 CD1 lupus mice that developed severe kidney disease.

Conclusion

IFNα‐inducible proteins represent a novel class of autoantigens in murine lupus, and the findings suggest additional roles for IFNα in this disease. Since Ifi202 autoantigens are encoded by the murine non–major histocompatibility complex lupus‐susceptibility gene locus Ifi202, these data provide a link between recent advances in lupus genetics and the formation of autoantibodies.
Severity of murine collagen‐induced arthritis correlates with increased CYP7B activity: Enhancement of dehydroepiandrosterone metabolism by interleukin‐1β
Authors: Dulos John , Verbraak Evert , Bagchus Wilma M. , Boots Annemieke M. H. , Kaptein Allard
Published: October 2004

Objective

The endogenous steroid dehydroepiandrosterone (DHEA) has been reported to play a role in rheumatoid arthritis (RA). DHEA is metabolized by the P450 enzyme CYP7B into 7α‐OH‐DHEA, which has immunostimulating properties. This study was undertaken to investigate the putative role of CYP7B in arthritis using murine collagen‐induced arthritis (CIA), an interleukin‐1β (IL‐1β)–dependent model.

Methods

DBA/1J mice were immunized and administered a booster with type II collagen. The presence of 7α‐OH‐DHEA was determined in both arthritic and nonarthritic joints and the serum of CIA mice by radioimmunoassay. CYP7B messenger RNA (mRNA) expression was analyzed in synovial biopsy samples, and in fibroblast‐like synoviocytes (FLS) isolated from these synovial biopsy samples, by reverse transcriptase–polymerase chain reaction (RT‐PCR). In addition, the regulatory role of IL‐1β on CYP7B activity in FLS was determined using RT‐PCR, Western blotting, and high‐performance liquid chromatography.

Results

In knee joint synovial biopsy samples from arthritic mice, 7α‐OH‐DHEA levels were 5‐fold higher than in nonarthritic mice. Elevated levels of 7α‐OH‐DHEA were accompanied by an increase in CYP7B mRNA expression and were positively correlated with disease severity. In serum, no differences in 7α‐OH‐DHEA levels were observed between arthritic and nonarthritic mice. Incubation of FLS with IL‐1β resulted in a dose‐dependent increase in 7α‐OH‐DHEA formation. In addition, IL‐1β enhanced CYP7B mRNA and CYP7B protein levels in FLS.

Conclusion

Disease progression in CIA is correlated with enhanced CYP7B activity, which leads to locally enhanced 7α‐OH‐DHEA levels. Elevated IL‐1β levels within the arthritic joint may regulate this increase in CYP7B activity.
Intramolecular T cell spreading in unprimed MRL/lpr mice: Importance of the U1‐70k protein sequence 131–151
Authors: Monneaux Fanny , Parietti Véronique , Briand Jean‐Paul , Muller Sylviane
Published: October 2004

Objective

To analyze spontaneous T cell spreading against determinants of the U1‐70K protein in young autoimmune MRL/lpr lupus mice, in comparison with the T cell spreading occurring in normal BALB/c mice immunized with peptide 131–151 of this protein.

Methods

Peripheral blood lymphocytes (PBLs) from both unprimed MRL/lpr mice and immunized BALB/c mice were tested for their ability to proliferate ex vivo in response to 18 overlapping peptides of the U1‐70K spliceosomal protein, using assays for lymphocyte proliferation and secretion of interleukin‐2.

Results

The proliferative response to peptides of the U1‐70K protein evolved rapidly in MRL/lpr mice tested at different ages. At least 5 peptides were recognized by PBLs from 8‐week‐old autoimmune mice, whereas a different peptide was recognized by PBLs from MRL/lpr mice at 12 weeks of age. At 15 weeks, the proliferative response was weak or negative when assessed with any of the test peptides. At least 2 major peptides recognized by MRL/lpr PBLs were also recognized by PBLs generated in the BALB/c mice primed with peptide 131–151. We further demonstrated that, in preautoimmune MRL/lpr mice, repeated administration of phosphorylated peptide 131–151 (called P140), which was shown previously to be protective, transiently abolished T cell intramolecular spreading to other regions of the 70K protein.

Conclusion

This is the first study to demonstrate that intramolecular T cell spreading effectively occurs in MRL/lpr mice with lupus, and that region 131–151 is important in the cascade of events observed in the murine lupus response. This sequence might originate a mechanism of tolerance spreading that leads to the beneficial effect observed in MRL/lpr mice after treatment with the phosphorylated peptide 131–151.
Systemic lupus erythematosus genome scan: Support for linkage at 1q23, 2q33, 16q12–13, and 17q21–23 and novel evidence at 3p24, 10q23–24, 13q32, and 18q22–23
Authors: Cantor Rita M. , Yuan Jinying , Napier Susan , Kono Naoko , Grossman Jennifer M. , Hahn Bevra H. , Tsao Betty P.
Published: October 2004

Objective

To identify chromosome regions likely to harbor genes that predispose to the development of systemic lupus erythematosus (SLE) by analyzing a full genome scan in nuclear families ascertained for siblings with SLE.

Methods

Approximately 400 multiallelic markers spaced an average of 10 cM apart were genotyped in a multiethnic panel of 238 individuals from 62 multiplex SLE families having 88 affected sibling pairs and 456 total sibling pairs. Findings were analyzed by 2 model‐free statistical linkage procedures.

Results

Evidence supporting linkage to 4 previously reported (1q23, 2q33, 16q12–13, and 17q21–23) and 4 novel (3p24, 10q23–24, 13q32, and 18q22–23) chromosome regions was revealed. Stratification by family ethnicity indicated that linkage to 3 regions, 2q33, 10q23–24, and 18q22–23, was derived primarily from the Caucasian families, while linkage to 17q21–23 was seen primarily in the non‐Caucasian families.

Conclusion

Linkage to the same chromosome regions in independent cohorts is a critical step in finding the genes that predispose to a complex disorder such as SLE. Four linked regions also seen in independent SLE cohorts lend credibility to the 4 novel regions identified by these analyses. Substantial linkage information was gleaned by genotyping and analyzing the unaffected siblings. These results provide additional evidence that the SLE clinical phenotype is genetically complex, multigenic, and heterogeneous.
The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate‐treated rheumatoid arthritis
Authors: Morgan Sarah L. , Oster Robert A. , Lee Jeannette Y. , Alarcón Graciela S. , Baggott Joseph E.
Published: October 2004

Objective

To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5‐aminoimidazole‐4‐carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism.

Methods

Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24‐hour urinary AICA and adenosine excretion levels, respectively.

Results

At the end of 6 weeks, 24‐hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels.

Conclusion

The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase–catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.
Combined effects of an anticoagulant and a lipid‐lowering agent on the prevention of steroid‐induced osteonecrosis in rabbits
Authors: Motomura Goro , Yamamoto Takuaki , Miyanishi Keita , Jingushi Seiya , Iwamoto Yukihide
Published: October 2004

Objective

To investigate the effects of combination treatment with an anticoagulant (warfarin) plus a lipid‐lowering agent (probucol) on the prevention of steroid‐induced osteonecrosis (ON) in rabbits.

Methods

Adult male Japanese white rabbits were injected once intramuscularly with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were then divided into 4 groups and treated as follows: one group received warfarin plus probucol (WP; n = 25), one received probucol alone (PA; n = 30), one received warfarin alone (WA; n = 26), and one received no treatment (nonprophylactic [NP]; n = 20). Two weeks after the steroid injection, the femora and humeri were examined histopathologically for the presence of ON. The sizes of the bone marrow fat cells were examined morphologically. Hematologic examinations were performed before and after the steroid injection.

Results

The incidence of ON in the WP group (5%) was significantly lower than that observed in the NP group (70%). While the incidence rates of ON in the PA (38%) and WA (33%) groups were also significantly lower than that in the NP group, they were significantly higher than that observed in the WP group. The sizes of the bone marrow fat cells in both the WP (53.5 ± 4.1 μm) and the PA (52.0 ± 5.0 μm) groups were significantly smaller than those in the NP group (60.0 ± 4.0 μm). We also observed a prolongation of the prothrombin time and a reduction in the plasma lipid levels in the WP group during the study.

Conclusion

This study experimentally confirmed that the combined use of an anticoagulant and a lipid‐lowering agent helps prevent steroid‐induced ON in rabbits.