bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral Statistics of the Triaxial Rigid Rotator: Semiclassical Origin of Their Pathological Behavior
Authors: Manfredi V. R. , Penna V. , Salasnich L.
Published: August 2003

In this paper we investigate the local and global spectral properties of the triaxial rigid rotator. We demonstrate that, for a fixed value of the total angular momentum, the energy spectrum can be divided into two sets of energy levels, whose classical analogs are librational and rotational motions. By using diagonalization, semiclassical and algebric methods, we show that the energy levels follow the anomalous spectral statistics of the one-dimensional harmonic oscillator.
Chemie und Biologie der DNA‐Reparatur
Authors: Schärer Orlando D.
Published: July 2003

Zahlreiche Agentien endogenen und exogenen Ursprungs schädigen die DNA in unserem Genom. Es existieren unterschiedliche Reparatursysteme, die Schäden in der DNA erkennen und durch eine Vielzahl von Reaktionssequenzen beheben können. Defekte DNA‐Reparaturproteine hängen mit einigen erblich bedingten Syndromen zusammen, die eine Prädisposition für Krebs aufweisen. Während die DNA‐Reparatur einerseits essenziell für eine gesunde Zelle ist, beeinträchtigen DNA‐Reparaturenzyme andererseits die Effizienz vieler Antitumorwirkstoffe, deren Wirkung auf der Schädigung von DNA beruht, sodass DNA‐Reparaturenzyme auch hinsichtlich des Wirkstoff‐Designs von großer Bedeutung sind. DNA‐Reparaturprozesse variieren stark in ihrer Art und Komplexität. Während in einem Fall nur ein einziges Enzym benötigt wird, ist an anderen Pfaden ein koordiniertes Zusammenspiel von dreißig oder mehr Proteinen beteiligt. Unser Kenntnisstand der genetischen, biochemischen und strukturellen Grundlagen der DNA‐Reparatur und damit verwandter Prozesse hat sich in den letzten Jahren stark verbessert. Dieser Aufsatz fasst die jüngsten Forschungsergebnisse auf diesem Gebiet zusammen.
Titelbild: Angew. Chem. 1/2003
Authors: Lin Hong , Danishefsky Samuel J.
Published: July 2003

Die Kunst der Synthese und die Schönheit der Natur machen die Attraktivität der Naturstoffsynthese aus. Das Titelbild zeigt Wilden Jasmin in voller Blüte, aus dessen Wurzeln das giftige Alkaloid Gelsemin isoliert werden kann. Seine Formel sowie die wichtiger Intermediate von Totalsynthesen sind über das Foto gelegt. Aus den Synthesen lässt sich lernen, welche Strategien am schnellsten und/oder effizientesten zum Ziel führen. Mehr über diesen Naturstoff und seine Totalsynthesen schildern S. J. Danishefsky und H. Lin auf Seite 38 ff.
Selektivität in der Analytischen Chemie
Authors: Danzer Klaus
Published: July 2003

Die korrekte Verwendung des Begriffs “Selektivität” in der Analytischen Chemie wird diskutiert, insbesondere seine Unterscheidung vom Begriff “Spezifität”. Des Weiteren wird eine Definition des Begriffs Selektivität gegeben und empfohlen, nur diesen Begriff in der Analytischen Chemie zu verwenden.

Die Begriffe Selektivität und Spezifität beschreiben unterschiedliche Eigenschaften analytischer Systeme. Sie sollten deshalb streng unterschieden werden; siehe dazu Lit. 32. In dieser Empfehlung geht es um Selektivität, und in diesem Sinne sollte Spezifität nicht verwendet werden.
Hadamard‐Transformations‐Flugzeitmassenspektrometrie: gesteigerte Signalintensität bei gleicher Messzeit
Authors: Zare Richard N. , Fernández Facundo M. , Kimmel Joel R.
Published: July 2003

Die Hadamard‐Transformations‐Flugzeit(HT‐TOF)‐Massenspektrometrie ist eine massenspektrometrische Methode, die kontinuierlich strahlende Ionenquellen mit der Puls‐Technik von Flugzeitmessungen kombiniert. Anders als die konventionelle TOF‐Massenspektrometrie hat die Hadamard‐Transformations‐Methode einen Auslastungszyklus von 50 % mit der Möglichkeit zur Erweiterung auf 100 %. Da es sich um ein Multiplex‐Verfahren handelt, ist das erreichbare Signal‐Rausch‐Verhältnis bedeutend höher als bei der konventionellen TOF‐Massenspektrometrie. Der vorliegende Kurzaufsatz stellt die grundlegenden Prinzipien der HT‐TOF‐Massenspektrometrie, des hohen Auslastungszyklus und des Signal‐Rausch‐Verhältnisses vor. Diese Vorteile eröffnen eine Spektrenaufnahmegeschwindigkeit, die schneller ist als die von vergleichbaren Geräten: Detektoren für Hochgeschwindigkeits‐Trennungen sind somit in greifbare Nähe gerückt.
Eine chemische Denksportaufgabe: die Totalsynthese von Gelsemin
Authors: Lin Hong , Danishefsky Samuel J.
Published: July 2003

Die Totalsynthese von Gelsemin und 21‐Oxogelsemin ist auf mehreren Wegen möglich. In diesem Aufsatz werden die zentralen Elemente der unterschiedlichen Synthesestrategien zusammengefasst und die Ansätze zum Aufbau des Bicyclo[3.2.1]octan‐Kerns, zur Einführung des quartären Brückenkopf‐Kohlenstoffatoms C20 bei der Bildung der Pyrrolidineinheit, zum Aufbau des Oxindol‐Rests und zum Ringschluss des Tetrahydropyranrings diskutiert.
Titelbild: Structure and Bonding of Pd@[Bi10]4+ in the Subbromide Bi14PdBr16 (Angew. Chem. 26/2003)
Authors: Ruck Michael , Dubenskyy Vitaly , Söhnel Tilo
Published: July 2003

Endohedrale Cluster kommen in der Chemie häufiger vor als erwartet. Nach den Einschlussverbindungen der Fullerene wie He@C60 (links) und dem W@Au12‐Ikosaeder (rechts) stellen M. Ruck et al. nun auf S. 3086 ff. das im Subbromid Bi14PdBr16 vorliegende Polykation Pd@[Bi10]4+ (oben) vor. Es hat die Gestalt eines pentagonalen Antiprismas, eines bereits von Archimedes beschriebenen semiregulären Polyeders. Maßgebend für die Formulierung als Pd@[Bi10]4+ ist die Schwäche der Wechselwirkung zwischen dem zentralen Pd‐Atom und dem arachno‐Cluster [Bi10]4+.
Chemistry and Biology of DNA Repair
Authors: Schärer Orlando D.
Published: July 2003

Numerous agents of endogenous and exogenous origin damage DNA in our genome. There are several DNA‐repair pathways that recognize lesions in DNA and remove them through a number of diverse reaction sequences. Defects in DNA‐repair proteins are associated with several human hereditary syndromes, which show a marked predisposition to cancer. Although DNA repair is essential for a healthy cell, DNA‐repair enzymes counteract the efficiency of a number of important antitumor agents that exert their cytotoxic effects by damaging DNA. DNA‐repair enzymes are therefore also targets for drug design. DNA‐repair processes differ greatly in their nature and complexity. Whereas some pathways only require a single enzyme to restore the original DNA sequence, others operate through the coordinated action of 30 or more proteins. Our understanding of the genetic, biochemical, and structural basis of DNA repair and related processes has increased dramatically over the past decade. This review summarizes the latest developments in this field.
Cover Picture: Structure and Bonding of Pd@[Bi10]4+ in the Subbromide Bi14PdBr16 (Angew. Chem. Int. Ed. 26/2003)
Authors: Ruck Michael , Dubenskyy Vitaly , Söhnel Tilo
Published: July 2003

Endohedral clusters are more common in chemistry than expected, such as the inclusion compounds of fullerene (e.g., He@C60, left) and the recently discovered W@Au12 icosahedron (right). In the Communication by M. Ruck et al. on page 2978 ff., the Pd@[Bi10]4+ polycation (above) is presented, which has a pentagonal antiprismatic structure, a semiregular polyhedron first described by Archimedes. The relative weakness of the interaction between the Pd center and the arachno‐[Bi10]4+ unit is discussed.
Crystallographic report: Bis[tris(2‐pyridyl)amine]cadmium(II)‐di‐µ‐chloro‐dichloro‐cadmium(II), [(C5H4N)3N]2CdCl2CdCl2
Authors: Xie Yongshu , Liu Xueting , Ni Jia , Jiang Hui , Liu Qingliang
Published: July 2003

In the dinuclear molecule of [(C5H4N)3N]2CdCl2CdCl2, one cadmium is octahedrally coordinated by a Cl2N4 donor set and the other cadmium is tetrahedrally coordinated by four chlorine atoms. The dinuclear units are connected by π–π interactions to give a two‐dimensional network. Copyright © 2003 John Wiley & Sons, Ltd.
Metal‐stabilized rare tautomers: N4 metalated cytosine (M = Li+, Na+, K+, Rb+ and Cs+), theoretical views
Authors: Monajjemi Majid , Ghiasi Reza , Sadjadi M. A. Seyed
Published: July 2003

Ab initio calculations indicate that metalation of the exocyclic amino group of cytosine by the elements of Group IA (Li, Na, K, Rb and Cs) induces protonation of a nucleobase ring nitrogen atom, and hence causes a proton shift from an exocyclic to an endocyclic nitrogen atom. Thus, this metal‐assisted process leads to the generation of rare nucleobase tautomers. The calculations suggest that this kind of metalation increases the protonation energies of the aromatic ring of the nucleobase. The present study reports the quantum chemistry analysis of the metal‐assisted tautomerization. The calculations clearly demonstrate that metalation of the exocyclic amino group of the nucleobase significantly increases the protonation energy of the aromatic rings of the nucleobase. Also, absolute anisotropy shift, molecular orbital and natural bond orbital calculations are compatible with these results. Copyright © 2003 John Wiley & Sons, Ltd.
High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry
Authors: Maksymowych Walter P. , Reeve Jeff P. , Reveille John D. , Akey Joshua M. , Buenviaje Heidi , O'Brien Lori , Peloso Paul M. , Thomson Glen T. , Jin Li , Russell Anthony S.
Published: July 2003

Objective

To examine single‐nucleotide polymorphisms (SNPs) in the 3′ region of the IL1RN gene in a large Caucasoid case–control series and in ankylosing spondylitis (AS) families from Western Canada by use of high‐throughput MassArray matrix‐assisted laser desorption ionization–time‐of‐flight (MALDI‐TOF) mass spectrometry SNP typing.

Methods

An association analysis was performed in a case–control cohort of 394 AS cases and 500 controls. Family‐based association analysis was performed in 58 simplex and 13 multiplex families. Three SNPs located in the 3′ region of the IL1RN gene (T/C at position 27810 in exon 4, T/C at position 30735 in exon 6, and G/C at position 31017 in exon 6) were examined by high‐throughput MassArray MALDI‐TOF mass spectrometry. Haplotype inference software programs were used to infer the most likely haplotypes and to compare haplotype frequencies, which were then further analyzed in family‐based association studies by transmission disequilibrium tests.

Results

The frequency of allele C at SNP position 30735 in exon 6 was significantly increased in AS cases (35.1%) versus controls (27.8%), as was the phenotype frequency (61.7% versus 48.6%). A significantly increased frequency of SNP allele G at position 31017 in exon 6 in cases (32.9%) versus controls (28.3%) was also noted. A highly significant difference in the overall distribution of haplotype frequencies was evident between cases and controls, with significant increases in the frequencies of the 27810C/30735C/31017C and 27810C/30735T/31017G haplotypes, but a significant reduction in the estimated frequency of the 27810C/30735T/31017C haplotype, in the AS cases. Estimation of haplotype frequencies based on 2 SNP markers indicated a highly significant increase in the 30735C/31017C haplotype and a highly significant decrease in the 30735T/31017C haplotype in cases compared with controls. Preliminary evidence for reduced transmission of the 27810C/30735T/31017C 3‐marker haplotype was also found in family‐based association analyses.

Conclusion

Our data establish a highly significant disease association with markers in the IL1RN gene. In the absence of nonsynonymous coding sequence substitutions, it is possible that the primary disease‐associated locus regulates gene expression. Association with specific haplotypes raises the possibility that the primary disease locus is in linkage disequilibrium with a specific combination(s) of markers in the IL1RN gene.
Antiphospholipid antibodies in pediatric and adult patients with rheumatic disease are associated with parvovirus B19 infection
Authors: von Landenberg Philipp , Lehmann Hartwig W. , Knöll Antje , Dorsch Simone , Modrow Susanne
Published: July 2003

Objective

To show a possible association between parvovirus B19 infection and the presence of antiphospholipid antibodies (aPL) in patients with rheumatic diseases.

Methods

Serum samples obtained from 88 children with various forms of juvenile rheumatic disease and from 40 adults with systemic lupus erythematosus, the antiphospholipid syndrome, or other rheumatic disease, who had previously been tested and shown to be positive for IgG aPL, were analyzed for the presence of B19 DNA, for antibodies against the B19 viral proteins VP1, VP2, and NS1, and for IgG aPL (anticardiolipin, anti–β2‐glycoprotein I, and antiphosphatidylserine). As controls, serum samples obtained from 135 children with noninflammatory bone diseases or growth retardation were also analyzed.

Results

Twenty‐four (27%) of the 88 children with rheumatic diseases had detectable amounts of IgG aPL. Fourteen (58%) of these 24 IgG aPL–positive patients showed IgG against VP1/VP2 and viral genomes, indicating the presence of acute (2 patients) or persistent (12 patients) infection. Past parvovirus B19 infection was identified in 7 (29%) of 24 IgG aPL–positive children, as indicated by VP1/VP2‐specific IgG in the absence of viral DNA. Three (12%) of 24 IgG aPL–positive children had not been infected with B19. Sixty‐nine (51%) of 135 control children displayed VP1/VP2‐specific IgG. Three (2%) of these 135 children were IgG aPL positive (2 children had past parvovirus B19 infection, and 1 was negative for parvovirus B19). Analysis of the parvovirus B19 status of 40 adult IgG aPL–positive patients showed that 33 (83%) were anti–IgG VP1/VP2–positive, and viral DNA was detected in 11 patients (28%). Ten of these 11 viremic patients were in the subgroup of 28 IgG aPL–positive SLE patients.

Conclusion

Antiphospholipid antibodies are preferentially found in serum of children with juvenile idiopathic arthritis who have been previously infected with parvovirus B19 and have established, persistent infection. Adult patients with IgG aPL positivity have a high incidence of persistent parvovirus B19 infection. We conclude that parvovirus B19 might be directly involved in the elicitation of autoimmune reactions partly mediated by aPL.
Doppler sonographic findings in the long bicipital tendon sheath in patients with rheumatoid arthritis as compared with patients with degenerative diseases of the shoulder
Authors: Strunk Johannes , Lange Uwe , Kürten Bernhard , Schmidt Klaus Louis , Neeck Gunther
Published: July 2003

Objective

To compare power Doppler sonography (PDS) findings inside the bicipital tendon sheath in patients with rheumatoid arthritis (RA) and degenerative disorders of the shoulder, in order to evaluate the diagnostic value of PDS in distinguishing between inflammatory and noninflammatory shoulder pain.

Methods

The glenohumeral joints of 41 consecutive patients with shoulder pain were examined by ultrasound. Using ventral transverse and longitudinal scanning, the vascularity near and/or inside the bicipital tendon sheath was visualized by PDS. One fully trained and experienced examiner performed the sonography. Representative images were digitally stored and were read, under blinded conditions, by 2 independent investigators, who categorized the Doppler signals as being either inside or outside the tendon sheath.

Results

Biceps tendon sheath effusion, represented by the typical hypoechoic rim, was found in 95.8% of the RA patients (23 of 24) and in 58.8% of the patients with degenerative disorders (10 of 17). PDS signals were localized to inside the tendon sheath in 22 of the RA patients (91.7%) and in none of the patients with degenerative disorders. Although no PDS signal was found inside the tendon sheath in patients with degenerative disorders, in 9 of these patients (52.9%), signals could be localized to the environment of the tendon sheath.

Conclusion

PDS demonstrates vascularity in the long bicipital tendon sheath of patients with RA, but not in those with degenerative shoulder disorders.
Heterogeneous requirement of IκB kinase 2 for inflammatory cytokine and matrix metalloproteinase production in rheumatoid arthritis: Implications for therapy
Authors: Andreakos Evangelos , Smith Clive , Kiriakidis Serafim , Monaco Claudia , de Martin Rainer , Brennan Fionula M. , Paleolog Ewa , Feldmann Marc , Foxwell Brian M.
Published: July 2003

Objective

To investigate the potential role of IκB kinase 1 (IKK‐1) and IKK‐2 in the regulation of nuclear factor κB (NF‐κB) activation and the expression of tumor necrosis factor α (TNFα), as well as interleukin‐1β (IL‐1β), IL‐6, IL‐8, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), in rheumatoid arthritis (RA).

Methods

Recombinant adenoviruses expressing β‐galactosidase, dominant‐negative IKK‐1 and IKK‐2, or IκBα were used to infect ex vivo RA synovial membrane cultures and synovial fibroblasts obtained from patients with RA undergoing joint replacement surgery, or human dermal fibroblasts, human umbilical vein endothelial cells (HUVECs), and monocyte‐derived macrophages from healthy volunteers. Then, their effect on the spontaneous or stimulus‐induced release of inflammatory cytokines, VEGF, and MMPs from RA synovial membrane cells was examined.

Results

IKK‐2 was not required for lipopolysaccharide (LPS)–induced NF‐κB activation or TNFα, IL‐6, or IL‐8 production in macrophages, but was essential for this process in response to CD40 ligand, TNFα, and IL‐1. In synovial fibroblasts, dermal fibroblasts, and HUVECs, IKK‐2 was also required for LPS‐induced NF‐κB activation and IL‐6 or IL‐8 production. In RA synovial membrane cells, IKK‐2 inhibition had no effect on spontaneous TNFα production but significantly reduced IL‐1β, IL‐6, IL‐8, VEGF, and MMPs 1, 2, 3, and 13.

Conclusion

Our study demonstrates that IKK‐2 is not essential for TNFα production in RA. However, because IKK‐2 regulates the expression of other inflammatory cytokines (IL‐1β, IL‐6, and IL‐8), VEGF, and MMPs 1, 2, 3, and 13, which are involved in the inflammatory, angiogenic, and destructive processes in the RA joint, it may still be a good therapeutic target.
Estrogen receptor α gene haplotype is associated with radiographic osteoarthritis of the knee in elderly men and women
Authors: Bergink Arjan P. , van Meurs Joyce B. , Loughlin John , Arp Pascal P. , Fang Yue , Hofman Albert , van Leeuwen Johannes P. T. M. , van Duijn Cornelia M. , Uitterlinden André G. , Pols Huibert A. P.
Published: July 2003

Objective

Genetic influences have been shown to play an important role in the etiology of osteoarthritis (OA), but the genes involved are ill‐defined. We studied the association between polymorphisms in the estrogen receptor α (ERα) gene and the prevalence of radiographic OA of the knee.

Methods

The study group comprised 1,483 men and women from the Rotterdam Study. Direct molecular haplotyping was used to determine the relationship between 2 polymorphisms in the ERα gene (the Pvu II and Xba I restriction fragment–length polymorphisms). Radiographs of the knee were evaluated according to the Kellgren/Lawrence (K/L) score, along with separate scores for osteophytosis and joint space narrowing.

Results

Three different haplotype alleles were identified: px (54%), PX (34%), and Px (12%). Allele PX was associated with an increased prevalence of radiographic knee OA (K/L score ≥2). The prevalence of radiographic OA was 22% among subjects without allele PX, 24% among those carrying 1 copy, and 35% among subjects carrying 2 copies. The corresponding odds ratios, after adjustment for confounding factors, were 1.3 (95% confidence interval [95% CI] 0.9–1.7) for heterozygotes and 2.2 (95% CI 1.5–3.4) for homozygotes. Separate analyses for men and women showed similar risk estimates. The association appeared to be driven by osteophytosis and is somewhat consistent with the association observed in previous studies of these polymorphisms in relation to OA.

Conclusion

This study shows that polymorphisms in the ERα gene are associated with radiographic OA of the knee, and in particular with osteophytosis, in both elderly men and elderly women.
Role of Crk‐associated substrate lymphocyte type in the pathophysiology of rheumatoid arthritis in tax transgenic mice and in humans
Authors: Miyake‐Nishijima Rikako , Iwata Satoshi , Saijo Shinobu , Kobayashi Hiroshi , Kobayashi Seiji , Souta‐Kuribara Akiko , Hosono Osamu , Kawasaki Hiroshi , Tanaka Hirotoshi , Ikeda Eiji , Okada Yasunori , Iwakura Yoichiro , Morimoto Chikao
Published: July 2003

Objective

To investigate the role of Crk‐associated substrate lymphocyte type (Cas‐L), a downstream signaling molecule of β1 integrins, in the pathophysiology of rheumatoid arthritis (RA).

Methods

We analyzed human T lymphotropic virus type I (HTLV‐I) tax transgenic mice as well as samples from human RA patients. Splenocytes from tax transgenic mice were cultured on mouse endothelial cell–covered Transwell inserts, and cells migrating through the endothelial monolayer were counted. Biochemical studies were performed to analyze the protein expression and tyrosine phosphorylation of Cas‐L. Immunohistochemical analysis was performed to detect Cas‐L–positive cells that had infiltrated into the joints.

Results

Migratory activity of splenocytes from tax transgenic mice with arthritis (ATg) was much higher than that of tax transgenic mice without arthritis (NTg) and littermate control mice. The expression of Cas‐L protein and its tyrosine phosphorylation were increased in ATg mice compared with NTg and control mice, and this was accompanied by enhanced autophosphorylation of Fyn and Lck. Immunohistochemical analysis demonstrated a large number of Cas‐L–positive lymphocytes migrating into the affected joints. Furthermore, in human RA, Cas‐L–positive lymphocytes were shown to infiltrate to the inflammatory lesions.

Conclusion

These results strongly suggest that Cas‐L plays an important role in the pathophysiology of RA.
Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman
Authors: García‐Pavía Pablo , Torres Rosa J. , Rivero Manuel , Ahmed Maqbool , García‐Puig Juan , Becker Michael A.
Published: July 2003

Overactivity of phosphoribosylpyrophosphate synthetase (PRS) is an X chromosome–linked disorder of purine metabolism that is characterized by gout with uric acid overproduction and, in some families, neurodevelopmental impairment. We present the case of a 24‐year‐old Spanish woman with renal colic and hyperuricemia, which first manifested at age 11 years. Results of enzymatic and genetic studies supported the view that accelerated purine nucleotide and uric acid production in this woman resulted from defective allosteric regulation of PRS activity, which is, in turn, a consequence of a mutation in one of the patient's PRPS1 genes: an A‐to‐T substitution at nucleotide 578, encoding leucine for histidine at amino acid residue 192 of the mature PRS1 isoform. A previous example of disordered regulation of PRS1 activity in a family with a different substitution at the same amino acid residue strengthens this proposed mechanism. This is the first reported instance of PRS overactivity in which the propositus and sole affected family member is a woman.
Role of the Fcγ receptor IIA polymorphism in the antiphospholipid syndrome: An international meta‐analysis
Authors: Karassa Fotini B. , Bijl Marc , Davies Kevin A. , Kallenberg Cees G. M. , Khamashta Munther A. , Manger Karin , Michel Marc , Piette Jean‐Charles , Salmon Jane E. , Song Yeong Wook , Tsuchiya Naoyuki , Yoo Dae‐Hyun , Ioannidis John P. A.
Published: July 2003

Objective

To assess the impact of the FcγRIIA‐R/H131 polymorphism on the risk for antiphospholipid syndrome (APS), both primary and secondary to systemic lupus erythematosus (SLE).

Methods

This international meta‐analysis combined data from 9 research teams. FcγRIIA‐R/H131 genotypes were determined in 481 APS cases (206 with primary APS), 1,420 SLE controls, and 1,655 disease‐free controls. Data were combined using fixed‐effects and random‐effects models.

Results

Compared with disease‐free controls, the RR genotype was enriched in the entire group of APS cases (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.28–2.14); this was driven mostly by patients with secondary APS (OR 1.95, 95% CI 1.45–2.63). The excess of RR homozygotes but not heterozygotes among APS patients suggested a recessive mode of inheritance, rather than the additive model seen for SLE susceptibility, where RR conferred greatest risk, and RH intermediate risk, for SLE. This probably reflected the additional influence of another opposing genetic effect of HH homozygosity on APS predisposition (OR 0.72 for RH versus HH, 95% CI 0.55–0.96). Among SLE patients, those with APS were more frequently HH homozygotes than heterozygotes (OR 0.56 for RH versus HH, 95% CI 0.39–0.81). HH homozygosity also tended to predominate in primary APS compared with secondary APS (OR 0.50 for RR versus HH, 95% CI 0.25–0.99 by fixed‐effects model). There was no significant between‐study heterogeneity for any of these effects.

Conclusion

The FcγRIIA‐R/H131 polymorphism is an important determinant of predisposition to APS, with different influences on SLE and APS susceptibility per se.
Increased asymmetric dimethylarginine and endothelin 1 levels in secondary Raynaud's phenomenon: Implications for vascular dysfunction and progression of disease
Authors: Rajagopalan Sanjay , Pfenninger Dana , Kehrer Christine , Chakrabarti Anjan , Somers Emily , Pavlic Robert , Mukherjee Debabrata , Brook Robert , D'Alecy Louis G. , Kaplan Mariana J.
Published: July 2003

Objective

To compare microvascular and macrovascular functions in a cohort of patients with primary and secondary Raynaud's phenomenon (RP) who were matched for demographic, risk factor, and severity profiles.

Methods

Forty patients with primary or secondary RP matched for vascular risk factors and severity scores underwent testing of endothelial function and cold pressor responsiveness of the brachial artery. Microvascular perfusion of the digital vasculature was assessed using laser Doppler fluxmetry in response to reactive hyperemia. Plasma was assayed for endothelin 1 (ET‐1), asymmetric dimethylarginine (ADMA), intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM‐1), and monocyte chemoattractant protein 1 (MCP‐1).

Results

Patients with RP had abnormal vasoconstrictor responses to cold pressor tests (CPT) that were similar in primary and secondary RP. There were no differences in median flow‐mediated and nitroglycerin‐mediated dilation or CPT of the brachial artery in the 2 populations. Patients with secondary RP were characterized by abnormalities in microvascular responses to reactive hyperemia, with a reduction in area under the curve adjusted for baseline perfusion, but not in time to peak response or peak perfusion ratio. Plasma ET‐1, ADMA, VCAM‐1, and MCP‐1 levels were significantly elevated in secondary RP compared with primary RP. There was a significant negative correlation between ET‐1 and ADMA values and measures of microvascular perfusion but not macrovascular endothelial function.

Conclusion

Secondary RP is characterized by elevations in plasma ET‐1 and ADMA levels that may contribute to alterations in cutaneous microvascular function.
Reconstitution of deficient T cell receptor ζ chain restores T cell signaling and augments T cell receptor/CD3–induced interleukin‐2 production in patients with systemic lupus erythematosus
Authors: Nambiar Madhusoodana P. , Fisher Carolyn U. , Warke Vishal G. , Krishnan Sandeep , Mitchell Jeanne P. , Delaney Nancy , Tsokos George C.
Published: July 2003

Objective

T cells from a majority of patients with systemic lupus erythematosus (SLE) display antigen receptor–mediated signaling aberrations associated with defective T cell receptor (TCR) ζ chain, a subunit of the TCR/CD3 complex. This study was undertaken to explore the possibility that forced expression of TCR ζ chain may reverse the known signaling abnormalities and defective interleukin‐2 (IL‐2) production in SLE T cells.

Methods

Freshly isolated SLE T cells were transfected with TCR ζ chain construct in a eukaryotic expression vector at high efficiency, by a recently developed nucleoporation technique. Restoration of TCR/CD3‐mediated signaling was studied in the ζ chain–transfected cells.

Results

In SLE T cells transfected with TCR ζ chain, surface expression of TCR chain was increased and the TCR/CD3‐induced increased free intracytoplasmic calcium concentration response was normalized, as was hyperphosphorylation of cellular substrates. Simultaneously, the previously noted increased expression of the Fc receptor γ chain was diminished in SLE T cells transfected with the ζ chain expression vector, and the surface membrane clusters of cell signaling molecules were redistributed to a more continuous pattern. TCR ζ chain replacement also augmented the expression of diminished TCR/CD3‐mediated IL‐2 production in SLE T cells, associated with increased expression of the p65 subunit of nuclear factor κB in the nuclear fractions of these T cells.

Conclusion

These results suggest that reconstitution of deficient TCR ζ chain can reverse the TCR/CD3‐mediated signaling abnormalities as well as the defective IL‐2 production in T cells of patients with SLE.
Human α‐enolase from endothelial cells as a target antigen of anti–endothelial cell antibody in Behçet's disease
Authors: Lee Kwang Hoon , Chung Hae‐Shin , Kim Hyoung Sup , Oh Sang‐Ho , Ha Moon‐Kyung , Baik Ja‐Hyun , Lee Sungnack , Bang Dongsik
Published: July 2003

Objective

To identify and recombine a protein of the human dermal microvascular endothelial cell (HDMEC) that specifically reacts with anti–endothelial cell antibody (AECA) in the serum of patients with Behçet's disease (BD), and to evaluate the usefulness of this protein in BD.

Methods

The proteomics technique, with 2‐dimensional gel electrophoresis and matrix‐assisted laser desorption ionization−time‐of‐flight (MALDI‐TOF) mass spectrometry, was used to identify and recombine HDMEC antigen. Western blotting and enzyme‐linked immunosorbent assay (ELISA) of recombinant protein isolated by gene cloning were performed on serum from healthy controls, patients with BD, and patients with other rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus, and Wegener's granulomatosis).

Results

Eighteen of 40 BD patients had serum IgM antibody to HDMEC antigen. The purified protein that reacted with AECA in BD patient sera was found to be α‐enolase by 2‐dimensional gel electrophoresis followed by immunoblotting and MALDI‐TOF mass spectrometry. Recombinant α‐enolase protein was isolated and refined by gene cloning. On Western blots, AECA‐positive IgM from the sera of patients with active BD reacted strongly with recombinant human α‐enolase. BD patient sera positive for anti–α‐enolase did not react with human γ‐enolase. On dot‐blotting, reactivity to human α‐enolase was detected only in the IgM‐positive group. Fifteen of the 18 AECA‐positive sera that were positive for the HDMEC antigen showed reactivity to recombinant α‐enolase IgM antibody by ELISA.

Conclusion

The α‐enolase protein is the target protein of serum AECA in BD patients. This is the first report of the presence of IgM antibodies to α‐enolase in endothelial cells from the serum of BD patients. Although further studies relating this protein to the pathogenesis of BD will be necessary, α‐enolase and its antibody may prove useful in the development of new diagnostic and treatment modalities in BD.
Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects
Authors: del Rincón Inmaculada , Williams Ken , Stern Michael P. , Freeman Gregory L. , O'Leary Daniel H. , Escalante Agustín
Published: July 2003

Objective

To examine the relationship between markers of systemic inflammation and carotid atherosclerosis in patients with rheumatoid arthritis (RA) and healthy controls.

Methods

Carotid artery intima‐media thickness (IMT) and carotid plaque were measured using high‐resolution B‐mode ultrasound in 204 patients with RA, ages 40–85, and 102 age‐ and sex‐matched healthy persons. No subject in either group had ever smoked cigarettes. Erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP) were used to measure systemic inflammation. The relationship of the carotid artery IMT and carotid plaque to inflammation markers was examined, adjusting for age, sex, RA versus control status, and the cardiovascular (CV) risk factors hypercholesterolemia, systolic blood pressure, diabetes mellitus, and body mass index (BMI).

Results

A significant linear trend for increased carotid artery IMT was associated with increasing ESR and CRP categories (r = 0.16, P = 0.004 for ESR, and r = 0.13, P = 0.02 for CRP). These trends did not differ among RA cases and controls, and were independent of age, sex, and CV risk factors. The difference in carotid artery IMT between the lowest and highest categories of ESR was 0.221 mm (95% confidence interval [95% CI] 0.767–1.020, P = 0.02). The difference between extreme CRP categories was 0.275 mm (95% CI 0.039–0.509, P = 0.02). Both remained significant after CV risk factor adjustment. Carotid plaque displayed a similar relationship to markers of inflammation.

Conclusion

Increased carotid artery IMT and the presence of carotid plaque are associated with markers of systemic inflammation in patients with RA and in healthy subjects. This observation is consistent with hypotheses that assign a role to systemic inflammation in atherosclerosis, and may have implications regarding RA and other chronic inflammatory diseases.
Early and extensive erosiveness in peripheral joints predicts atlantoaxial subluxations in patients with rheumatoid arthritis
Authors: Neva Marko Henrik , Isomäki Pia , Hannonen Pekka , Kauppi Markku , Krishnan Eswar , Sokka Tuulikki
Published: July 2003

Objective

To study the prevalence of cervical spine subluxations and predictive factors for atlantoaxial subluxations (including anterior atlantoaxial subluxation and atlantoaxial impaction, i.e., vertical subluxation) in patients with rheumatoid arthritis (RA) who were treated early and continuously with disease‐modifying antirheumatic drugs for 8–13 years.

Methods

Radiographs of the cervical spine were obtained in 103 of 110 patients (the 110 surviving patients of the original 135‐patient cohort) at their 8–13‐year followup visits. The prevalence of cervical spine subluxations was determined. Demographic variables and the first 5‐year serial data concerning disease course were analyzed in a logistic regression model to find predictive factors for atlantoaxial subluxations.

Results

Atlantoaxial subluxations were found in 14 patients (14%), and 5 patients (5%) had subaxial subluxations. Older age at baseline, greater disease activity during the first 5 years, and early erosiveness in peripheral joints predicted the development of atlantoaxial subluxations. Patients who had ≥10% of the maximum possible radiographic damage (by Larsen score) in peripheral joints at 5 years were 15.9 times more likely to develop atlantoaxial subluxations at 8–13 years than patients whose peripheral joint damage remained <10% of the maximum.

Conclusion

Compared with historical control RA cohorts, a lower prevalence of cervical spine destruction was found in the present group of patients. Rapid erosiveness in peripheral joints was the best predictor for atlantoaxial subluxations. Extensive erosiveness in peripheral joints should alert rheumatologists to the possible development of atlantoaxial subluxations in patients with RA.
Complete remission of experimental arthritis by joint targeting of glucocorticoids with long‐circulating liposomes
Authors: Metselaar Josbert M. , Wauben Marca H. M. , Wagenaar‐Hilbers Josee P. A. , Boerman Otto C. , Storm Gert
Published: July 2003

Objective

To increase the therapeutic activity of glucocorticoids in experimental arthritis by encapsulation in long‐circulating polyethylene glycol liposomes, which have shown the ability to preferentially accumulate in inflamed joints after intravenous administration.

Methods

Rats with adjuvant‐induced arthritis (AIA) were treated intravenously with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of disease. The effect on paw inflammation scores during the weeks after treatment was evaluated. Liposome biodistribution and joint localization were investigated by labeling the preparation with radioactive 111In‐oxine. By studying PLP encapsulated in other types of liposomes, which show a distinctive tissue distribution pattern and reduced accumulation in inflamed joints, the importance of targeted delivery to inflamed joints for achieving an increased therapeutic effect was illustrated.

Results

Liposomal PLP proved to be highly effective in the rat AIA model. A single injection of 10 mg/kg resulted in complete remission of the inflammatory response for almost a week. In contrast, the same dose of unencapsulated PLP did not reduce inflammation, and only a slight effect was observed after repeated daily injections. Evidence was found that preferential glucocorticoid delivery to the inflamed joint was the key factor explaining the observed strong therapeutic benefit obtained with the liposomal preparation, while other possible mechanisms, such as splenic accumulation or prolonged release of prednisolone in the circulation, were excluded.

Conclusion

Targeted delivery using long‐circulating liposomes is a promising, novel means to successfully intervene in arthritis with glucocorticoid therapy.
Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice
Authors: Schett Georg , Redlich Kurt , Hayer Silvia , Zwerina Jochen , Bolon Brad , Dunstan Colin , Görtz Birgit , Schulz Andreas , Bergmeister Helga , Kollias Giorgos , Steiner Günter , Smolen Josef S.
Published: July 2003

Objective

To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.

Methods

We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.

Results

Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (−37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (−85%) compared with wild‐type controls. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast‐mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF‐mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast‐mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin‐1β (IL‐1β), and IL‐6. However, OPG decreased bone formation parameters (osteoblast‐covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti‐TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti‐TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.

Conclusion

OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.
Salmonella septicemia in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: Association with decreased interferon‐γ production and toll‐like receptor 4 expression
Authors: Netea Mihai G. , Radstake Timothy , Joosten Leo A. , van der Meer Jos W. M. , Barrera Pilar , Kullberg Bart Jan
Published: July 2003

Objective

Patients treated with antibodies to tumor necrosis factor α (TNFα) have an increased susceptibility to intracellular infections. We describe 2 patients with rheumatoid arthritis (RA) who developed Salmonella septicemia during anti‐TNF treatment. The aim of this study was to identify the mechanisms involved in the increased susceptibility of anti‐TNF–treated patients to intracellular microorganisms.

Methods

We evaluated an additional 6 RA patients receiving anti‐TNF antibodies, 5 RA patients not receiving anti‐TNF therapy, and 6 age‐ and sex‐matched healthy volunteers. The in vitro production of cytokines (interleukin‐1β [IL‐1β], IL‐6, interferon‐γ [IFNγ], and IL‐10) upon bacterial stimulation of whole blood and the expression of Toll‐like receptor 4 (TLR‐4) on dendritic cells from RA patients treated with infliximab, RA patients not treated with infliximab, and healthy controls were compared.

Results

Stimulation with heat‐killed Salmonella typhimurium or Candida albicans led to a significantly decreased production of IFNγ, but not to a decreased production of IL‐10, IL‐β, or IL‐6, in anti‐TNF–treated RA patients compared with RA patients who were not receiving anti‐TNF antibodies and compared with healthy controls. TNF‐blocking treatment ex vivo significantly inhibited TLR‐4 expression on dendritic cells from RA patients and healthy controls.

Conclusion

Since recognition of microorganisms by TLR‐4 and activation of phagocytes by IFNγ are essential mechanisms for the defense against intracellular and fungal pathogens, we propose that this pathway is crucial for the increased susceptibility to these microorganisms in patients receiving anti‐TNF therapy.
Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts
Authors: Mori Yasuji , Chen Shu‐Jen , Varga John
Published: July 2003

Objective

Scleroderma is characterized by excessive synthesis and accumulation of matrix proteins in lesional tissues. Transforming growth factor β (TGFβ) plays a central role in the pathogenesis of fibrosis by inducing and sustaining activation of fibroblasts; however, the underlying mechanisms are poorly understood. We undertook this study to examine the expression and function of SMADs, recently characterized intracellular effectors of TGFβ signaling, in scleroderma fibroblasts.

Methods

Primary dermal fibroblasts obtained from 14 patients with scleroderma and from 4 healthy adult volunteers were studied. Northern analysis was used to determine the expression of endogenous SMAD messenger RNA (mRNA), and Western analysis was used to determine SMAD protein expression. Intracellular compartmentalization of cellular SMAD proteins in the presence and absence of TGFβ was studied by antibody‐mediated immunofluorescence confocal microscopy. The effect of TGFβ blockade on SMAD subcellular distribution was determined using anti‐TGFβ antibodies as well as a dominant‐negative TGFβ receptor type II (TGFβRII) vector to disrupt TGFβ responses. SMAD‐regulated luciferase reporter expression was examined to investigate the potential functional significance of activation and nuclear accumulation of endogenous SMADs in scleroderma fibroblasts.

Results

Protein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts compared with those from healthy controls. In sharp contrast to control fibroblasts, which displayed predominantly cytoplasmic localization of SMAD3/4 in the absence of exogenous TGFβ, in scleroderma fibroblasts SMAD3 and SMAD4 consistently showed elevated nuclear localization. Furthermore, phosphorylated SMAD2/3 levels were elevated and nuclear localization of phosphorylated SMAD2/3 was increased, suggesting activation of the SMAD pathway in scleroderma fibroblasts. Blockade of autocrine TGFβ signaling with antibodies or by expression of dominant‐negative TGFβRII failed to normalize SMAD subcellular distribution, suggesting that elevated nuclear SMAD import was due to alterations downstream of the TGFβ receptors. The activity of a SMAD‐responsive minimal promoter–reporter construct was enhanced in transiently transfected scleroderma fibroblasts.

Conclusion

This study is the first to demonstrate apparently ligand‐independent constitutive activation of the intracellular TGFβ/SMAD signaling axis in scleroderma fibroblasts. SMAD signaling may be a mechanism contributing to the characteristic phenotype of scleroderma fibroblasts and playing a role in the pathogenesis of fibrosis.
Association of the –2849 interleukin‐10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis
Authors: Lard L. R. , van Gaalen F. A. , Schonkeren J. J. M. , Pieterman E. J. , Stoeken G. , Vos K. , Nelissen R. G. H. H. , Westendorp R. G. J. , Hoeben R. C. , Breedveld F. C. , Toes R. E. M. , Huizinga T. W. J.
Published: July 2003

Objective

To analyze the –2849 A/G interleukin‐10 (IL‐10) promoter polymorphism, which is associated with high (AG/GG) and low (AA) IL‐10 production, in a cohort of rheumatoid arthritis (RA) patients and controls in order to gain a better understanding of its role in the incidence and progression of RA.

Methods

Allele frequencies of the promoter polymorphism –2849 A/G and carriage rates were compared in 283 RA patients, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The rate of joint damage and baseline levels of IgG and IgM rheumatoid factors and anti–citrullinated peptide antibodies were measured and were correlated with the IL‐10 gene polymorphism. Furthermore, the correlation between the invasiveness of fibroblast‐like synoviocytes (FLS) and the −2849 IL‐10 genotype was tested.

Results

The IL‐10 genotype was not associated with the incidence of RA, but instead, correlated with disease progression, as determined by the extent of joint destruction. A higher rate of joint destruction was observed in patients with the genotype associated with high IL‐10 production. Since FLS are thought to be involved in joint destruction, we analyzed IL‐10 genotypes in conjunction with FLS invasiveness. Although adenoviral gene transfer of IL‐10 to FLS inhibited their invasiveness, no differences were observed in vitro in the FLS from RA patients who were –2849 non‐G carriers compared with those who were G carriers. Instead, patients with the –2849 AG/GG genotype, which is associated with high IL‐10 production, had higher autoantibody titers at baseline.

Conclusion

The –2849 IL‐10 promoter polymorphism is associated with autoantibody production and subsequent joint damage in RA.