bluuebunny/crossref_metadata_2025 huggingface dataset:
Requirement of type I interferon signaling for arthritis triggered by double‐stranded RNA
Authors: Magnusson Mattias , Zare Fariba , Tarkowski Andrej
Published: December 2005

Objective

Arthralgias and overt arthritides are often associated with viral infections. Viral infections expose the infected host to proinflammatory double‐stranded RNA (dsRNA), which can cause joint inflammation and is a potent activator of interferon‐α (IFNα). The aim of this study was to determine the role of IFNα and dsRNA‐related signaling molecules in the onset of joint inflammation induced by viral dsRNA.

Methods

IFNα and different forms of RNA were injected into the knee joints of wild‐type mice, mice lacking the type I interferon receptor (IFNAR−/−), and mice deficient in dsRNA‐dependent protein kinase (PKR−/−). Histologic evidence of joint damage and the ability of splenocytes to produce cytokines in response to dsRNA or IFNα were assessed.

Results

Viral dsRNA, but not short single‐stranded RNA, induced arthritis. The arthritis was aggravated by intracellular delivery of dsRNA. The expression of PKR was not mandatory for dsRNA‐induced joint inflammation. In contrast, IFNα/β signaling was important for dsRNA‐induced joint inflammation because IFNAR−/− mice did not develop arthritis. Furthermore, intraarticular deposition of IFNα induced arthritis in PKR−/− and control mice, whereas IFNAR−/− mice were protected. The arthritogenic effect of IFNα was attenuated by in vivo depletion of monocyte/macrophages.

Conclusion

Arthritis triggered by dsRNA is not dependent on the expression of the dsRNA‐signaling molecule PKR (or Toll‐like receptor 3, as previously shown), but is associated with the ability to produce type I IFN and is critically dependent on type I IFN receptor signaling. The intrinsic arthritogenic properties of IFNα implicate a role of this cytokine in joint manifestations triggered by various interferogenic stimuli.
Acute‐phase serum amyloid A stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an NF‐κB–dependent signal transduction pathway
Authors: Mullan Ronan H. , Bresnihan Barry , Golden‐Mason Lucy , Markham Trevor , O'Hara Rosemary , FitzGerald Oliver , Veale Douglas J. , Fearon Ursula
Published: December 2005

Objective

To examine the role of the acute‐phase protein serum amyloid A (A‐SAA) in regulating cell adhesion molecule expression, leukocyte recruitment, and angiogenesis in rheumatoid arthritis (RA).

Methods

Intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1), and matrix metalloproteinase 1 (MMP‐1) expression was examined in RA fibroblast‐like synoviocytes (FLS) and human microvascular endothelial cells (HMVECs) using flow cytometry and enzyme‐linked immunosorbent assay techniques. Peripheral blood mononuclear cell (PBMC) adhesion to FLS/HMVECs was determined by flow cytometry. Angiogenesis was examined using a Boyden chemotaxis chamber and Matrigel tubule formation. NF‐κB/IκBα mediation of the effects of A‐SAA was investigated using a specific NF‐κB inhibitor and Western blotting.

Results

A‐SAA significantly enhanced the time‐ and dose‐dependent expression of ICAM‐1 and VCAM‐1 as effectively as interleukin‐1β/tumor necrosis factor α. A‐SAA promoted the adhesion of PBMCs to FLS and HMVECs. In addition, A‐SAA at 10 μg/ml and 50 μg/ml significantly increased endothelial cell tube formation by 69% and 207%, respectively. At 50 μg/ml and 100 μg/ml, A‐SAA increased HMVEC migration by 188 ± 54% and 296 ± 71%, respectively (mean ± SEM). A‐SAA–induced expression of VCAM‐1, ICAM‐1, and MMP‐1 was down‐regulated by NF‐κB inhibition. Furthermore, A‐SAA induced IκBα degradation and NF‐κB translocation, suggesting that its proinflammatory effects are mediated in part by NF‐κB signaling.

Conclusion

Our findings demonstrate the ability of A‐SAA to induce adhesion molecule expression, angiogenesis, and matrix degradation, mechanisms that are mediated by NF‐κB. Targeting A‐SAA and its signaling pathways may represent a new therapeutic approach in the treatment of RA.
Elevated serum BAFF levels in patients with systemic sclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes
Authors: Matsushita Takashi , Hasegawa Minoru , Yanaba Koichi , Kodera Masanari , Takehara Kazuhiko , Sato Shinichi
Published: December 2005

Objective

To determine serum levels of BAFF, a potent B cell survival factor, in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc.

Methods

Serum BAFF levels in 83 patients with SSc were examined by enzyme‐linked immunosorbent assay (ELISA). In a longitudinal study, 131 serum samples obtained from 21 patients with SSc were analyzed. The expression of BAFF messenger RNA (mRNA) in the skin was quantified by real‐time reverse transcription–polymerase chain reaction. The expression of BAFF receptor (BAFFR) on CD19+ B cells was assessed by flow cytometry. The production of IgG and interleukin‐6 (IL‐6) by isolated B cells was examined by ELISA.

Results

Serum BAFF levels were elevated in SSc patients compared with healthy controls and correlated positively with the extent of skin fibrosis. Among the 21 patients with SSc in the longitudinal study, 7 had decreased BAFF levels, 11 had levels that remained unchanged, and 3 patients had increased levels. Decreasing BAFF levels were accompanied by regression of skin sclerosis, whereas increasing levels of BAFF were associated with the new onset or worsening of organ involvement. BAFF mRNA expression was up‐regulated in the affected skin of patients with early diffuse cutaneous SSc. BAFFR expression on B cells was increased in SSc patients relative to healthy controls. Furthermore, SSc B cells that were stimulated by BAFF exhibited an enhanced ability to produce IgG and IL‐6.

Conclusion

These results suggest that BAFF and its signaling in B cells contribute to B cell abnormalities and disease development in patients with SSc.
Anti–tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis
Authors: Catrina Anca Irinel , Klint Erik af , Ernestam Sofia , Catrina Sergiu‐Bogdan , Makrygiannakis Dimitrios , Botusan Ileana Ruxandra , Klareskog Lars , Ulfgren Ann‐Kristin
Published: December 2005

Objective

Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF)–blocking agents, including etanercept and infliximab, has resulted in reductions in the radiographic progression of RA. However, the exact mechanism by which this protection occurs has not been determined. In order to add to such knowledge, we investigated the effect of anti‐TNF therapy on the expression of osteoprotegerin (OPG) and receptor activator of NF‐κB ligand (RANKL) in synovial tissue.

Methods

The expression of OPG and RANKL in synovial biopsy specimens was evaluated by immunohistochemistry. Serial synovial biopsy specimens were obtained from 18 patients with RA, before and after treatment with etanercept (9 patients) or infliximab (9 patients). Biopsy specimens were evaluated by double‐blind semiquantitative analysis and image analysis. The in vitro effect of TNF antagonists on the RANKL/OPG expression in osteoblasts and endothelial cells was evaluated by Western blotting. Statistical analysis was performed using Wilcoxon's signed rank test, followed by the Bonferroni correction for multiple comparisons of paired samples. The results of in vitro experiments were evaluated by one‐way analysis of variance, with Tukey's post hoc test.

Results

Treatment with both infliximab and etanercept increased the expression of OPG in synovial tissue. After 8 weeks of treatment, neither infliximab nor etanercept influenced RANKL expression. In both groups of patients, the RANKL:OPG ratio decreased following therapy. In vitro, both of the TNF antagonists mimicked the in vivo effect, inducing a decrease in the RANKL:OPG ratio in TNF‐primed osteoblasts and endothelial cells.

Conclusion

Therapy with TNF antagonists in RA modulates the OPG/RANKL system, a potential mechanism that could explain the retardation of radiographic damage observed following anti‐TNF therapy.
Polymorphisms in the mannose‐binding lectin gene as determinants of age‐defined risk of coronary artery lesions in Kawasaki disease
Authors: Biezeveld Maarten H. , Geissler Judy , Weverling Gerrit Jan , Kuipers Irene M. , Lam Jan , Ottenkamp Jaap , Kuijpers Taco W.
Published: December 2005

Objective

To evaluate the relationship between polymorphisms in the gene coding for mannose‐binding lectin (MBL) and the occurrence of coronary artery lesions (CALs) among different age groups of patients with Kawasaki disease.

Methods

The frequencies of the genotypes, defined as mutations in codons 52, 54, and 57, and the functional promoter variants of the MBL2 gene were determined in 88 patients with acute Kawasaki disease (median age at onset 1.9 years). The possible influence of the MBL2 genotype on the development and progression of CALs in Kawasaki disease was assessed according to age categories and MBL genotypes in univariate and multivariate analyses.

Results

In patients younger than age 1 year, we found an increased risk of developing CALs in the presence of a variant MBL2 genotype (P = 0.008). In contrast, in patients older than age 1 year, we found an increased risk of CALs in those patients with the wild‐type genotype (P = 0.005).

Conclusion

Our findings indicate that MBL has an ambiguous role in Kawasaki disease and contributes differently to the pathophysiologic development of CALs, being protective in infants but potentially harmful in patients of older age. The data also imply that the standard treatment of intravenous immunoglobulins to reduce the development of lesions may not be as effective in the very young as it is in the older patients. For the very young, alternative or adjuvant treatment may be indicated, particularly in infants who are MBL‐deficient.
Associations between pain, function, and radiographic features in osteoarthritis of the knee
Authors: Szebenyi Béla , Hollander Anthony P. , Dieppe Paul , Quilty Brian , Duddy John , Clarke Shane , Kirwan John R.
Published: December 2005

Objective

To assess the associations between pain, loss of function, and radiographic changes in knee osteoarthritis (OA), taking into account both the patellofemoral and tibiofemoral compartments.

Methods

Both knees of 167 community‐based patients with OA in at least 1 of their knees were assessed. Pain was measured by visual analog scale, and function was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index. Anteroposterior standing radiographs with the knee in extension and lateral 30° flexion were obtained and assessed for the Kellgren/Lawrence score and for individual features (osteophytes, joint space narrowing, and subchondral bone sclerosis) in each compartment.

Results

Knees with structural changes in both compartments were more likely to be painful and to be associated with loss of function than were knees in which only 1 compartment was affected. The individual feature most strongly associated with pain was subchondral bone sclerosis.

Conclusion

Studies exploring the associations between structural and symptomatic knee OA need to include an assessment of the patellofemoral compartment, and individual radiographic features rather than a global severity score should be considered in these studies.
Interleukin‐6 modulates production of T lymphocyte–derived cytokines in antigen‐induced arthritis and drives inflammation‐induced osteoclastogenesis
Authors: Wong Peter K. K. , Quinn Julian M. W. , Sims Natalie A. , van Nieuwenhuijze Annemarie , Campbell Ian K. , Wicks Ian P.
Published: December 2005

Objective

To determine the cellular mediators of antigen‐induced arthritis (AIA) and the relative contribution of members of the interleukin‐6 (IL‐6) family and tumor necrosis factor (TNF) in AIA.

Methods

AIA was induced in mice deficient in T and B lymphocytes, IL‐6 (IL‐6−/−), TNF (TNF−/−), IL‐11 receptor, and oncostatin M receptor, by immunization with methylated bovine serum albumin (mBSA) followed 7 days later by intraarticular injection of mBSA. Arthritis severity was assessed histologically, and T lymphocyte responses were assessed in vitro. Anti‐TNF neutralizing antibody was administered to wild‐type mice during AIA. Bone marrow osteoclasts were generated in vitro via culture with RANKL and macrophage colony‐stimulating factor.

Results

AIA was dependent on CD4+ T lymphocytes, but not CD8+ T lymphocytes or B cells. IL‐6−/− mice had reduced AIA severity and fewer osteoclasts at sites of bone erosion. This protective effect was not seen with a deficiency of other IL‐6 family members and was similar to that in TNF−/− mice or wild‐type mice receiving TNF blockade treatment. IL‐6−/− CD4+ T lymphocytes from draining lymph nodes had reduced antigen‐induced proliferation and produced less IL‐17 and less RANKL, relative to osteoprotegerin, than cells from wild‐type mice. Bone marrow from IL‐6−/− mice generated fewer osteoclasts in vitro than bone marrow from either wild‐type or TNF−/− mice.

Conclusion

AIA is driven by CD4+ T lymphocytes. IL‐6 is an important mediator of bone destruction in AIA because it regulates T lymphocyte production of key osteoclastogenic cytokines and inflammation‐induced bone marrow osteoclast differentiation. These findings have implications for reducing bone and joint damage in rheumatoid arthritis.
Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease
Authors: Trad Salim , Amoura Zahir , Beigelman Catherine , Haroche Julien , Costedoat Nathalie , Boutin Le Thi Huong Du , Cacoub Patrice , Frances Camille , Wechsler Bertrand , Grenier Philippe , Piette Jean‐Charles
Published: December 2005

Objective

To determine whether pulmonary arterial hypertension (PAH) is a prognostic factor for mortality in diffuse cutaneous systemic sclerosis (dcSSc), independent of interstitial lung disease (ILD).

Methods

ILD was diagnosed by high‐resolution computed tomography and PAH (pulmonary arterial systolic pressure [PASP] ≥45 mm Hg) by echocardiography. All patients with ILD underwent testing for total lung capacity (TLC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide.

Results

Eighty‐six patients with dcSSc (mean age at diagnosis 44.5 years) were followed up for a median of 72.5 months. ILD was found in 52 patients (60%) and PAH in 18 (21%). ILD was associated with PAH in 15 patients. Seventeen patients died (19.8%), 9 of whom had PAH (P = 0.001) and 10 of whom had ILD (P = 0.99). By multivariate analysis, age at SSc diagnosis and PAH were the only independent predictors of death (hazard ratio [HR] 1.057, 95% confidence interval [95% CI] 1.009–1.109, P = 0.020 and HR 4.09, 95% CI 1.47–11.5, P = 0.007, respectively). Mean TLC and mean FVC were similar in ILD patients with and those without PAH (P = 0.71 and P = 0.40, respectively). Among ILD patients, age at SSc diagnosis and PAH were again the sole predictors of death (HR 1.073, 95% CI 1.003–1.149, P = 0.042 and HR 5.07, 95% CI 1.09–23.8, P = 0.038, respectively). Twenty ILD patients received at least 6 monthly pulses of intravenous cyclophosphamide (CYC). In CYC‐treated patients with PAH (n = 8), PASP increased significantly during the CYC regimen (mean ± SD 55 ± 14.5 mm Hg; P = 0.015 versus baseline), while TLC remained stable during the same period.

Conclusion

These results indicate that, independent of ILD, PAH is a major prognostic factor for survival in dcSSc.
Accuracy of anti–ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: An international meta‐analysis
Authors: Karassa Fotini B. , Afeltra Antonella , Ambrozic Ales , Chang Deh‐Ming , De Keyser Filip , Doria Andrea , Galeazzi Mauro , Hirohata Shunsei , Hoffman Ilse E. A. , Inanc Murat , Massardo Loreto , Mathieu Alessandro , Mok Chi Chiu , Morozzi Gabriella , Sanna Giovanni , Spindler Alberto J. , Tzioufas Athanasios G. , Yoshio Taku , Ioannidis John P. A.
Published: December 2005

Objective

To quantitatively evaluate the diagnostic accuracy of antibodies to ribosomal P proteins (anti‐P) for neuropsychiatric systemic lupus erythematosus (NPSLE) in general, for psychosis, mood disorder, or both, and for other diffuse manifestations.

Methods

This international meta‐analysis combined standardized data from 1,537 lupus patients contributed by 14 research teams. Weighted estimation of sensitivity and specificity with fixed‐effects and random‐effects models, as well as summary receiver operating characteristic (SROC) curve analysis, was used to summarize test performance. The robustness of the overall estimates was examined in sensitivity analyses that included additional studies published up to November 1, 2004 in the Medline, EMBase, and Cochrane databases.

Results

Combining the data from the 14 teams, the weighted sensitivity and specificity estimates for the diagnosis of NPSLE were 26% (95% confidence interval [95% CI] 15–42%) and 80% (95% CI 74–85%), respectively. For psychosis, mood disorder, or both, the sensitivity and specificity were 27% (95% CI 14–47%) and 80% (95% CI 74–85%), respectively. For other diffuse manifestations, the sensitivity was 24% (95% CI 12–42%), and the specificity was 80% (95% CI 73–85%). The proportion of patients with anti‐P antibodies did not vary markedly across different presentations of NPSLE. Between‐study heterogeneity was substantial, but the SROC curves were consistent with the weighted estimates. In further analyses that included another 24 published studies, only the sensitivity for psychosis and/or mood disorder was slightly improved, but it was still suboptimal (42% [95% CI 30–53%]); the specificity remained essentially the same (81% [95% CI 76–85%]).

Conclusion

Anti‐P antibody testing has limited diagnostic value for NPSLE, and it is not helpful in differentiating among various disease phenotypes.
Zum Tragverhalten flacher Schalentragwerke unter Kriechbeanspruchung
Authors: Bockhold Jörg
Published: December 2005

Die wirklichkeitsnahe Vorhersage des Tragverhaltens von Schalentragwerken aus Stahlbeton stellt nach wie vor einen hohen Anspruch an den planenden Ingenieur. In diesem Beitrag werden beispielhaft anhand einer flachen zylindrischen Dachschale die unterschiedlichen Einflüsse auf die Langzeittragfähigkeit beulgefährdeter Strukturen vorgestellt und auf die besondere Bedeutung des Betonkriechens im Hinblick auf ein Dauerstandversagen des Tragwerkes hingewiesen.
Tragverhalten von Kunststoffdübeln in gerissenem Beton
Authors: Pregartner Thilo , Eligehausen Rolf
Published: December 2005

Kunststoffdübel bestehen aus einer Dübelhülse aus Kunststoff und einem Spreizelement aus Stahl. Das Spreizelement wird drehend oder schlagend in die Kunststoffhülse eingetrieben. Dabei wird dem Kunststoff eine radiale Dehnung aufgeprägt.

Das viskoelastische Verformungsverhalten des Kunststoffes beeinflußt stark das Tragverhalten von Kunststoffdübeln in ungerissenem und gerissenem Beton. In ungerissenem Beton nimmt die Spreizkraft mit zunehmender Zeit infolge Relaxation des Kunststoffes ab. Ein Riß, der durch die Achse des Bohrlochs eines Kunststoffdübels läuft, reduziert die Spreizkraft des Dübels weiter. Bei konstanter Rißbreite nimmt die Spreizkraft des Dübels mit zunehmender Zeit nach der Rißöffnung jedoch wieder zu. Der Reibkoeffizient zwischen Dübelhülse und Beton steigt im ungerissenen und gerissenen Beton mit der Zeit an. Dadurch wachsen auch die Herausziehlasten im gerissenen und ungerissenen Beton mit der Zeit an.
Zur Torsionsbemessung von Stahlbeton‐ und Spannbetonbalken nach DIN 1045‐1
Authors: Zedler Thomas , Stangenberg Friedhelm
Published: December 2005

Für die Torsionsbemessung ist nach DIN 1045‐1 neben einer Ermittlung des Druckstrebenwinkels nach Gl. (73) auch der vereinfachte Ansatz eines Neigungswinkels von 45° zulässig. Untersuchungen zeigten, daß bei bestimmten Belastungskombinationen die beiden Verfahren nicht alternativ angewandt werden sollten. Zudem zeigt sich eine generelle Überschätzung der Druckstrebentragfähigkeit unter Torsion nach DIN 1045‐1.

Vor dem Hintergrund dieser Ergebnisse werden ein Vorschlag zur Bestimmung des Druckstrebenwinkels für die Torsions‐ und Torsions‐Interaktionsbemessung sowie ein Ansatz zur Beschreibung der Geometrie des effektiven Hohlkastens vorgestellt. Vergleichend werden die Ergebnisse einer Auswertung der Datenbank nach Eurocode 2 in seiner Neufassung vom April 2002 dargestellt.
Die Massivbaukonstruktion der Frankfurter Commerzbank‐Arena
Authors: Retzepis Ioannis , Beier Gunther , Constantinescu Dan
Published: December 2005

Die Massivbaukonstruktion der Frankfurter Commerzbank‐Arena (vormals Waldstadion) ist weitgehend eine Fertigteilkonstruktion. Dies war primär aus Bauzeitgründen notwendig und sicherte gleichzeitig die geforderte hohe Qualität der Sichtbetonoberflächen. Außerdem durfte während der Bauarbeiten der Spielbetrieb nicht beeinträchtigt werden. Diese Bedingungen haben das Konzept der gesamten Konstruktion maßgeblich beeinflußt. Der Aufsatz beschreibt die Grundlagen des Tragsystems der Tribünen – die auch die Dachlasten abtragen – und der weiteren Massivkonstruktionen (Medientürme, Tiefgarage usw.), insbesondere die Abtragung der Vertikal‐ und Horizontallasten sowie die statisch‐konstruktive Ausbildung der Fertigteile und deren Anschlüsse.
Umbau der Stadthalle Bremen zum AWD‐Dome
Authors: Eisele Manfred , Bachmann Hubert
Published: December 2005

Die im Jahr 1964 erstellte Stadthalle in Bremen wurde zur Vergrößerung des Fassungsvermögens umgestaltet. Nach Abbruch der Giebelwände und des zwischen Nord‐ und Südböcken aufgespannten Hängedachs, werden an der Nord‐ und Südseite zusätzliche Zuschauertribünen über den bestehenden eingebaut und ein neues Dach aus Stahl‐Fachwerk‐Bindern aufgesetzt. Die ausführende Firma beschließt, die neuen Giebelwände in Stahlbetonfertigteil‐Bauweise zu erstellen. Der Aufsatz beschreibt die ungewöhnlichen statischen Systeme und aufwendigen Detaillösungen. Durch eine lange Planungsphase und den hohen Vorfertigungsgrad war eine kurze Bauzeit realisierbar.
Isostructurality, Polymorphism and Mechanical Properties of Some Hexahalogenated Benzenes: The Nature of Halogen⋅⋅⋅Halogen Interactions
Authors: Reddy C. Malla , Kirchner Michael T. , Gundakaram Ravi C. , Padmanabhan K. Anantha , Desiraju Gautam R.
Published: December 2005

The nature of intermolecular interactions between halogen atoms, X⋅⋅⋅X (X=Cl, Br, I), continues to be of topical interest because these interactions may be used as design elements in crystal engineering. Hexahalogenated benzenes (C6Cl6−nBrn, C6Cl6−nIn, C6Br6−nIn) crystallise in two main packing modes, which take the monoclinic space group P21/n and the triclinic space group P$\bar 1$. The former, which is isostructural to C6Cl6, is more common. For molecules that lack inversion symmetry, adoption of this monoclinic structure would necessarily lead to crystallographic disorder. In C6Cl6, the planar molecules form Cl⋅⋅⋅Cl contacts and also π⋅⋅⋅π stacking interactions. When crystals of C6Cl6 are compressed mechanically along their needle length, that is, [010], a bending deformation takes place, because of the stronger interactions in the stacking direction. Further compression propagates consecutively in a snakelike motion through the crystal, similar to what has been suggested for the motion of dislocations. The bending of C6Cl6 crystals is related to the weakness of the Cl⋅⋅⋅Cl interactions compared with the stronger π⋅⋅⋅π stacking interactions. The triclinic packing is less common and is restricted to molecules that have a symmetrical (1,3,5‐ and 2,4,6‐) halogen substitution pattern. This packing type is characterised by specific, polarisation‐induced X⋅⋅⋅X interactions that result in threefold‐symmetrical X3 synthons, especially when X=I; this leads to a layered pseudohexagonal structure in which successive planar layers are inversion related and stacked so that bumps in one layer fit into the hollows of the next in a space‐filling manner. The triclinic crystals shear on application of a mechanical stress only along the plane of deformation. This shearing arises from the sliding of layers against one another. Nonspecificity of the weak interlayer interactions here is demonstrated by the structure of twinned crystals of these compounds. One of the compounds studied (1,3,5‐tribromo‐2,4,6‐triiodobenzene) is dimorphic, adopting both the monoclinic and triclinic structures, and the reasons for polymorphism are suggested. To summarise, both chemical and geometrical models need to be considered for X⋅⋅⋅X interactions in hexahalogenated benzenes. The X⋅⋅⋅X interactions in the monoclinic group are nonspecific, whereas in the triclinic group some X⋅⋅⋅X interactions are anisotropic, chemically specific and crystal‐structure directing.
Substituted Isoxazoles as Potent Inhibitors of p38 MAP Kinase
Authors: Laufer Stefan A. , Margutti Simona , Fritz Martina D.
Published: December 2005

In a continuous effort to develop improved p38 MAP (mitogen‐activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxazole ring as a bioisosteric replacement for the imidazole ring of SB‐203580. 3,4‐ and 4,5‐disubstituted as well as 3,4,5‐trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme‐linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4 a displays a highly promising profile for development as an anti‐inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC50 toward isolated p38 MAP kinase.
MS‐Binding Assays: Kinetic, Saturation, and Competitive Experiments Based on Quantitation of Bound Marker as Exemplified by the GABA Transporter mGAT1
Authors: Zepperitz Christine , Höfner Georg , Wanner Klaus T.
Published: December 2005

A new kind of binding assay is described in which the amount of a nonlabeled marker bound to the target is quantified by LC–ESI‐MS–MS. This new approach was successfully implemented with nonlabeled NO 711 as marker and the GABA transporter subtype mGAT1 as target. The native marker bound to the target was liberated from the receptor protein by methanol denaturation after filtration. A reliable and sensitive LC–ESI‐MS–MS method for the quantitation of NO 711 was developed, and data from mass spectrometric detection were analyzed by nonlinear regression. Kinetic MS‐binding experiments yielded values for k+1 and k−1, while in saturation MS‐binding experiments, Kd and Bmax values were determined. In competitive MS‐binding experiments, Ki values were obtained for various test compounds covering a broad range of affinities for mGAT1. All experiments were performed in 96‐well plate format with a filter plate for the separation step which improved the efficiency and throughput of the procedure. The method was validated by classical radioligand‐binding experiments with the labeled marker [3H2]NO 711 in parallel. The results obtained from MS‐binding experiments were found to be in good agreement with the results of the radioligand‐binding assays. The new kind of MS‐binding assay presented herein is further adapted to the conventional radioligand‐binding assay in that the amount of bound marker is securely quantified. This promises easy implementation in accordance with conventional binding assays without the major drawbacks that are inherent in radioligand or fluorescence binding assays. Therefore, MS‐binding assays are a true alternative to classical radioligand‐binding assays.
Individual‐, neighborhood‐, and state‐level socioeconomic predictors of cervical carcinoma screening among U.S. black women
Authors: Datta Geetanjali D. , Colditz Graham A. , Kawachi Ichiro , Subramanian S.V. , Palmer Julie R. , Rosenberg Lynn
Published: December 2005

BACKGROUND

Cervical carcinoma is the fifth most common cancer among African American women in the U.S. Although the Papanicolaou (Pap) smear is an efficacious screening tool in the early detection of the disease, disparities are known to persist in the utilization of this procedure across socioeconomic groups.

METHODS

Data regarding cervical carcinoma screening and covariates were obtained from the 59,090 Black Women's Health Study participants across the U.S. via a mailed questionnaire in 1995. Logistic regression and multilevel techniques were used to assess the independent effects of the covariates on nonrecent cervical carcinoma screening.

RESULTS

In all, 8.3% of the 40,009 women in the present analysis had not undergone a Pap smear examination within the previous 2 years (nonrecent screening). Lower educational attainment, older age, obesity, smoking, and neighborhood poverty were found to be independently related to increased risk of nonrecent screening. The adjusted odds ratio for nonrecent screening was 1.2 (95% confidence interval [95% CI], 1.1–1.4) for women residing in neighborhoods with 20% or more poverty compared with those in neighborhoods with less than 5% poverty. State of residence was also associated with nonrecent cervical carcinoma screening.

CONCLUSION

These results suggest that among black women, residence in high‐poverty (20%) neighborhoods is associated with an increased risk of nonrecent cervical carcinoma screening, independent of individual level risk factors. Cancer 2006. © 2005 American Cancer Society.
Basal forebrain cholinergic system of the anuran amphibian Rana perezi: Evidence for a shared organization pattern with amniotes
Authors: Sánchez‐Camacho Cristina , López Jesús M. , González Agustín
Published: December 2005

The organization of the basal forebrain cholinergic system (BFCS) in the frog was studied by means of choline acetyltransferase (ChAT) immunohistochemistry. The BFCS was observed as a conspicuous cholinergic cell population extending through the diagonal band, medial septal nucleus, bed nucleus of the stria terminalis, and pallidal regions. Abundant fiber labeling was also found around the labeled cell bodies. The combination of retrograde tract tracing with dextran amines and ChAT immunohistochemistry revealed intraseptal and intra‐BFCS cholinergic connections. In addition, an extratelencephalic cholinergic input from the laterodorsal tegemental nucleus was demonstrated. The possible influence of monoaminergic inputs on the BFCS neurons was examined by means of tyrosine hydroxylase and serotonin immunohistochemistry combined with ChAT immunolabeling. Our results showed that catecholaminergic fibers overlapped the BFCS, with the exception of the medial septal nucleus. Serotoninergic innervation was widespread, but less abundant in the caudal extent of the BFCS. Taken together, our results on the localization of the cholinergic neurons in the basal forebrain and their relationship with cholinergic, catecholaminergic, and serotoninergic afferents have shown numerous common features with amniotes. In particular, anurans and mammals (for which most data is available) share a strikingly comparable organization pattern of the BFCS. J. Comp. Neurol. 494:961–975, 2006. © 2005 Wiley‐Liss, Inc.
Development of the commissure of the superior colliculus in the hamster
Authors: Chebat Daniel‐Robert , Boire Denis , Ptito Maurice
Published: December 2005

The development of the corpus callosum (CC) and the anterior commissure (CA) is well known in a wide variety of species. No study, however, has described the development of the commissure of the superior colliculus (CSC) from embryonic state to adulthood in mammals. In this study, by using the lipophylic tracer DiI, we investigated the ontogeny of this mesencephalic commissure in the hamster at various ages. The development of axonal terminals, growth cone morphologies, and axons branching were described for the superior colliculus (SC) contralateral to the tracer injection. The first CSC axons cross the midline at embryonic day 11 (E‐11) and grow further into the intermediate layers of the contralateral SC between E‐12 and E‐14. There is little axon growth therein between E‐14 and the day of birth (P‐0). Growth cones at the tip of these axons adopt complex morphologies at E‐12 and progressively simplify until P‐0. Pioneer axons are clearly visible between E‐14 and P‐1. These are followed by other axons progressively more numerous between P‐0 and P‐5. Axons do not show any branching until P‐2. Between P‐3 and P‐9, the axons progressively arborize in the intermediate layers. Some axons reach the superficial layers at P‐5, and they become more numerous around P‐11, and only a few axons remain therein by P‐21. Myelinated axons appear at P11 and are very dense at P‐21. Our results indicate that the CSC follows developmental schemes similar to those of the CC and the AC but that initial axon midline crossing occurs earlier. J. Comp. Neurol. 494:887–902, 2006. © 2005 Wiley‐Liss, Inc.
Small GTP‐binding protein RhoB is expressed in glial müller cells in the vertebrate retina
Authors: Santos‐Bredariol Andréa Silveira , Belmonte Mônica Aparecida , Kihara Alexandre Hiroaki , Santos Marinilce Fagundes , Hamassaki Dânia Emi
Published: December 2005

Among several small Rho GTPases observed in the chick retina, RhoB was transiently expressed during development and mainly present in glial Müller cells in the adult. The aim of this study was to compare the distribution of RhoB in the chick and mouse adult retinas and to study its potential role in the maintenance of cell morphology. The distribution of RhoB was studied in situ and pure Müller cell cultures were submitted to Clostridium difficile toxin A and lysophosphatidic acid (LPA) treatment in order to inactivate and activate Rho proteins, respectively. Cell morphology, F‐actin arrangement, RhoB, and vimentin distribution were studied by immunofluorescence and confocal microscopy. The results showed that, in both species, all vimentin‐containing cells also expressed RhoB in situ and in vitro. Toxin A promoted cell rounding and detachment due to actin depolymerization, changing the distribution of RhoB only in chick cells. In serum‐starved cells LPA stimulated actin polymerization and cell spreading, but only in chick cells was RhoB distribution recruited to expanding cellular processes and newly formed focal adhesions. These data suggest that, although RhoB is expressed by Müller cells in chick and mouse, its role in the maintenance of cellular morphology and regulation may be different. In addition, we show that RhoB may be an interesting Müller cell marker in the adult retina. J. Comp. Neurol. 494:976–985, 2006. © 2005 Wiley‐Liss, Inc.
Maternal influences on adult stress and anxiety‐like behavior in C57BL/6J and BALB/CJ mice: A cross‐fostering study
Authors: Priebe Kristianne , Brake Wayne G. , Romeo Russell D. , Sisti Helene M. , Mueller Astrid , McEwen Bruce S. , Francis Darlene D.
Published: December 2005

The quality of maternal care during early life has a dramatic impact on later stress reactivity and anxiety. Two inbred mouse strains, C57BL/6J and BALB/cJ, differ in levels of maternal care, stress reactivity, and anxiety‐like behavior in adulthood. However, the relative contribution of early environmental factors and genetic predisposition to differences in these strains is not known. Maternal care, plasma corticosterone levels, emotionality, and hippocampal and paraventricular nucleus (PVN) glucocorticoid receptor mRNA levels were measured in adult C57BL/6J and BALB/cJ mice. Litters were then cross‐fostered and anxiety‐like behavior and stress reactivity was assessed in adulthood. Significantly less maternal care and elevated stress‐induced corticosterone and emotionality was observed in BALB/cJ compared to C57BL/6J mice. Yet, no strain differences were found in hippocampal or paraventricular nucleus glucocorticoid receptor mRNA levels. Cross‐fostering did alter anxiety‐like behavior and basal corticosterone levels, which suggests that while genetic differences account for some of the variations between these two strains early rearing conditions also contribute. © 2005 Wiley Periodicals, Inc. Dev Psychobiol 48: 95–96, 2006.
Carboxylate‐Containing Tin(IV) Isopropoxides: Synthesis and Characterization of [Sn(OiPr)2(O2CR)2]2 [R = (CH3)CCH2, C6H5, CH3]
Authors: Martinez‐Ferrero Eugenia , Boubekeur Kamal , Ribot François
Published: December 2005

Tin(IV) isopropoxide solvate has been modified by treatment with methacrylic, benzoic and acetic acid. For carboxylate to tin ratios ranging from 1.4 to 2, a dimer, namely [Sn(μ2‐OiPr)(OiPr)(O2CR)2]2 [R = (CH3)CCH2, C6H5, CH3], is isolated. Its structure, as determined by X‐ray diffraction on the methacrylate derivative, is based on two seven‐coordinate tin atoms, terminal and bridging isopropoxy ligands, and purely chelating carboxylates. These compounds have also been characterized by 119Sn, 1H, and 13C solution NMR and 119Sn CP‐MAS NMR spectroscopy. The possible use of this dimer as a precursor for carboxylate‐modified tin–oxo clusters has been tested. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Synthesis and Mass Spectrometric Analysis of CyclostellettaminesH, I, K and L
Authors: Grube Achim , Timm Christoph , Köck Matthias
Published: December 2005

Very recently the new cyclostellettamines H, I, K and L were identified from a Brazilian sponge of the genus Pachychalina. They were isolated together with the known cyclostellettamines A–G in a mixture of only 1.5 mg. To obtain further material for biological investigations, the synthesis of the four new cyclostellettamines has been carried out. Since mass spectrometry plays an essential role in identifying these compounds a systematic analysis of the cyclostellettamines is discussed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
New Cyclization Mode of [N‐(Diarylmethyleneamino)carbonimidoyl]ketenes: Synthesis of 9H‐Pyrazolo[3,2‐b][1,3]benzoxazines
Authors: Lisowskaya Natalia A. , Alajarin Mateo , Sanchez‐Andrada Pilar
Published: December 2005

The thermal decarbonylation of methyl 3‐acyl‐1‐[o‐bromophenyl(phenyl)methyleneamino]‐4,5‐dioxo‐4,5‐dihydro‐1H‐pyrrole‐2‐carboxylates2aand2bgave the novel methyl 3‐acyl‐9‐hydroxy‐9‐phenyl‐9H‐pyrazolo[3,2‐b][1,3]benzoxazine‐2‐carboxylates4aand4b, the structures of which were determined by X‐ray crystallography. The proposed mechanism for this conversion, involving the [N‐(o‐bromo‐α‐phenylbenzylideneamino)carbonimidoyl]ketenes5and the mesomeric betaines6as intermediates, has been investigated by ab initio and DFT calculations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Asymmetric Synthesis of 3‐Substituted γ‐ and δ‐Sultams
Authors: Enders Dieter , Moll Alexander , Bats Jan W.
Published: December 2005

An efficient and flexible asymmetric synthesis of various 3‐substituted γ‐ and δ‐sultams is described. The key step is a diastereoselective nucleophilic 1,2‐addition of various organocerium compounds to the CN double bond of ω‐SAMP‐hydrazonosulfonates. The resulting hydrazines were obtained in good to excellent diastereomeric excesses (de = 78 to ≥ 96 %). Removal of the chiral auxiliary by reductive N,N‐bond cleavage afforded the corresponding aminosulfonates without racemisation. Ester hydrolysis and subsequent treatment of the resulting sulfonic acids with phosgene in toluene led to the aminosulfonyl chlorides, which were cyclised to the title compounds in good to excellent overall yields (39–51 %) and high enantiomeric excesses (ee = 78–99 %). The absolute configuration was determined by X‐ray structure analysis and is in accordance with the postulated mechanism for the diastereoselective 1,2‐addition. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Fine mapping of disease genes via haplotype clustering
Authors: Waldron E.R.B. , Whittaker J.C. , Balding D.J.
Published: December 2005

We propose an algorithm for analysing SNP‐based population association studies, which is a development of that introduced by Molitor et al. [2003: Am J Hum Genet 73:1368–1384]. It uses clustering of haplotypes to overcome the major limitations of many current haplotype‐based approaches. We define a between‐haplotype score that is simple, yet appears to capture much of the information about evolutionary relatedness of the haplotypes in the vicinity of a (unobserved) putative causal locus. Haplotype clusters can then be defined via a putative ancestral haplotype and a cut‐off distance. The number of an individual's two haplotypes that lie within the cluster predicts the individual's genotype at the causal locus. This predicted genotype can then be investigated for association with the phenotype of interest. We implement our approach within a Markov‐chain Monte Carlo algorithm that, in effect, searches over locations and ancestral haplotypes to identify large, case‐rich clusters. The algorithm successfully fine‐maps a causal mutation in a test analysis using real data, and achieves almost 98% accuracy in predicting the genotype at the causal locus. A simulation study indicates that the new algorithm is substantially superior to alternative approaches, and it also allows us to identify situations in which multi‐point approaches can substantially improve over single‐SNP analyses. Our algorithm runs quickly and there is scope for extension to a wide range of disease models and genomic scales. Genet. Epidemiol. 2006. © 2005 Wiley‐Liss, Inc.
A multimarker regression‐based test of linkage for affected sib‐pairs at two linked loci
Authors: Barber Mathew J. , Todd John A. , Cordell Heather J.
Published: December 2005

We address the analytical problem of evaluating the evidence for linkage at a test locus while taking into account the effect of a known linked disease locus. The method we propose is a multimarker regression approach that models the identity‐by‐descent states for affected sib‐pairs at a series of linked markers in terms of the identity‐by‐descent state at the known disease locus. Our method allows analysis to be performed at a test location (or a series of locations) without the requirement that identity‐by‐descent be directly observed at either the test or the known conditioning locus. An advantage of our method is that identity‐by‐descent states from multiple markers are included simultaneously in the test of linkage, without recourse to multipoint imputation. The properties and power of the method are examined under various null and alternative hypotheses. The method is applied to data from a study of 1056 type 1 diabetes families to examine the evidence for an additional putative locus (IDDM15) on chromosome 6q, linked to IDDM1 in the HLA region on chromosome 6p. After accounting for the strong effect of IDDM1 and the differing rates of male and female recombination in the region, we find only marginal evidence for IDDM15 (P=0.03 to 0.002, using different methods) approximately 15 cM centromeric of the original localisation. Genet. Epidemiol. 2006. © 2005 Wiley‐Liss, Inc.
On the Occasion of the 65th Birthday of Dr. Ferdinand Näf
Authors: Snowden Roger
Published: December 2005

The following six publications in this issue of Helvetica Chimica Acta are dedicated to Dr. Ferdinand Näf who was Corporate Vice President of R & D at Firmenich (1989–2005).
Tumor‐Promoting Diterpene Esters from Latex of Euphorbia cauducifolia L.
Authors: Baloch Imam Bakhsh , Baloch Musa Kaleem , Najam us Saqib Qazi
Published: December 2005

Tumor‐promoting characteristics of seven esters, 1–7, obtained from the latex of Euphorbia cauducifolia L. was appraised by carrying out NMRI mice back skin. The structures of 1–7 were elucidated by spectroscopic techniques like 1H‐ and 13C‐NMR, 2D‐NMR (HMQC, HMBC, HOHAHA (homonuclear Hartmann–Hahn), NOESY, and NOE), FT‐IR, UV, and MS as esters of 17‐hydroxyingenol, namely 17‐[(2Z,4E,6Z)‐deca‐2,4,6‐trienoyloxy]ingenol (1), 3‐O‐angeloyl‐17‐[(2Z,4E,6Z)‐deca‐2,4,6‐trienoyloxy]ingenol (2), 3‐O‐acetyl‐20‐O‐angeloyl‐17‐hydroxyingenol (3), 17‐(acetyloxy)‐3‐O‐angelyl‐ingenol (4), 20‐O‐acetyl‐3‐O‐angeloyl‐17‐hydroxyingenol (5), 3‐O‐angelyl‐17‐(benzoyloxy)ingenol (6) and 20‐O‐acetyl‐3‐O‐angelyl‐17‐(benzoyloxy)ingenol (7). Compounds 1–4 were isolated for the first time, whereas 5–7 are known metabolites but detected for the first time in this plant. Biological investigations revealed that these compounds are tumor promoters.
Tumour‐cell apoptosis after cisplat in treatment is not telomere dependent
Authors: Jeyapalan Jessie C. , Saretzki Gabriele , Leake Alan , Tilby Michael J. , von Zglinicki Thomas
Published: December 2005

Cisplatin is a major chemotherapeutic agent, especially for the treatment of neuroblastoma. Telomeres with their sequence (TTAGGG)n are probable targets for cisplatin intrastrand cross‐linking, but the role of telomeres in mediating cisplatin cytotoxicity is not clear. After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, ∼4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, ∼80 kbp). There was no induction of telomeric single strand breaks, telomeric overhangs were not degraded and telomerase activity was down‐regulated only after massive onset of apoptosis. In contrast, cisplatin induced a delayed formation of DNA strand breaks and induced DNA damage foci containing γ‐H2A.X at nontelomeric sites. Interstitial DNA damage appears to be more important than telomere loss or telomeric damage as inducer of the signal pathway towards apoptosis and/or growth arrest in cisplatin‐treated tumour cells. © 2005 Wiley‐Liss, Inc.
Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3‐FKHR positive and negative tumors
Authors: De Pittà Cristiano , Tombolan Lucia , Albiero Giada , Sartori Francesca , Romualdi Chiara , Jurman Giuseppe , Carli Modesto , Furlanello Cesare , Lanfranchi Gerolamo , Rosolen Angelo
Published: December 2005

We analyzed the expression signatures of 14 tumor biopsies from children affected by alveolar rhabdomyosarcoma (ARMS) to identify genes correlating to biological features of this tumor. Seven of these patients were positive for the PAX3‐FKHR fusion gene and 7 were negative. We used a cDNA platform containing a large majority of probes derived from muscle tissues. The comparison of transcription profiles of tumor samples with fetal skeletal muscle identified 171 differentially expressed genes common to all ARMS patients. The functional classification analysis of altered genes led to the identification of a group of transcripts (LGALS1, BIN1) that may be relevant for the tumorigenic processes. The muscle‐specific microarray platform was able to distinguish PAX3‐FKHR positive and negative ARMS through the expression pattern of a limited number of genes (RAC1, CFL1, CCND1, IGFBP2) that might be biologically relevant for the different clinical behavior and aggressiveness of the 2 ARMS subtypes. Expression levels for selected candidate genes were validated by quantitative real‐time reverse‐transcription PCR. © 2005 Wiley‐Liss, Inc.
Polymorphisms in the growth hormone receptor: A case‐control study in breast cancer
Authors: Wagner Kerstin , Hemminki Kari , Grzybowska Ewa , Bermejo Justo Lorenzo , Butkiewicz Dorota , Pamula Jolanta , Pekala Wioletta , Försti Asta
Published: December 2005

The human growth hormone receptor (GHR) mediates the effects of growth hormone (GH1), starting a signalling cascade that is involved in the regulation of proliferation, differentiation and apoptosis. Recently, an isoform of the GHR gene lacking exon 3 (GHRd3) was associated with accelerated responsiveness to growth hormone. In this study, we investigated the association of the GHRd3 polymorphism with breast cancer risk and performed a haplotype analysis with 3 additional single nucleotide polymorphisms (SNPs) (Gly186Gly, Cys440Phe and Ile544Leu) in the GHR coding region in a Polish cohort. We did not observe any effect of the 4 polymorphisms on breast cancer risk. Neither did the 3 most common haplotypes influence breast cancer risk. However, a rare haplotype (dGGC), containing the GHRd3 allele, was associated with a decreased breast cancer risk (OR 0.30, 95% CI 0.11–0.80). © 2005 Wiley‐Liss, Inc.