bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucosal Immunization with Polyamine Transport Protein D (PotD) Protects Mice Against Nasopharyngeal Colonization with Streptococcus pneumoniae
Authors: Shah Pratik , Briles David E. , King Janice , Hale Yvette , Swiatlo Edwin
Published: January 2009

Streptococcus pneumoniae is an encapsulated pathogen that can cause invasive disease following colonization of the nasopharynx. Targeting colonization of mucosal surfaces may, therefore, be the best approach for vaccination to prevent pneumococcal invasive disease. Previous studies in our laboratory have shown that immunization with recombinant polyamine transport protein D (PotD) protects mice against systemic pneumococcal infections. In this study we investigated the efficacy of mucosal immunization with rPotD to protect against pneumococcal carriage and invasion in a murine model. Mice were intranasally immunized with either rPotD and cholera toxin B subunit (CTB) or CTB alone. Significantly less pneumococci were recovered from the nasopharynx of immunized mice compared to the control animals following intranasal challenge with either EF3030 (serotype 19F) ( P < 0.05) or an invasive serotype 4 isolate (TIGR4) ( P < 0.05). PotD immunized mice also had lesser bacteria in their sinus tissues ( P < 0.05), brains ( P < 0.05), lungs and olfactory bulbs following intranasal challenge with TIGR4. ELISA analysis demonstrated the presence of IgG antibodies to PotD in the serum and IgA antibodies in the saliva. These results indicate that mucosal immunization with PotD generates both mucosal and systemic immune responses and prevents establishment of nasopharyngeal carriage by multiple pneumococcal serotypes. Thus, PotD is a potentially important antigen for development of a pneumococcal protein vaccine.
Characteristics of multiple-diseased elderly in Swedish hospital care and clinical guidelines
Authors: Ekerstad Niklas , Edberg Annika , Carlsson Per
Published: January 2009

In Sweden, an expected growing gap between available resources and greater potential for medical treatment has brought evidence-based guidelines and priority setting into focus. There are problems, however, in areas where the evidence base is weak and underlying ethical values are controversial. Based on a specified definition of multiple-diseased elderly patients, the aims of this study are: (i) to describe and quantify inpatient care utilisation and patient characteristics, particularly regarding cardiovascular disease and co-morbidity; and (ii) to question the applicability of evidence-based guidelines for these patients with regard to the reported characteristics (i.e. age and co-morbidity), and to suggest some possible strategies in order to tackle the described problem and the probable presence of ageism. We used data from three sources: (a) a literature review, (b) a register study, based on a unique population-based register of inpatient care in Sweden, and (c) a national cost per patient database. The results show that elderly patients with multiple co-morbidities constitute a large and growing population in Swedish inpatient hospital care. They have multiple and complex needs and a large majority have a cardiovascular disease. There is a relationship between reported characteristics, i.e. age and co-morbidity, and limited applicability of evidence-based guidelines, and this can cause an under-use as well as an over-use of medical interventions. As future clinical studies will be rare due to methodological and financial factors, we consider it necessary to condense existing practical-clinical experiences of individual experts into consensus-based guidelines concerning elderly with multi-morbidity. In such priority setting, it will be important to consider co-morbidity and different degrees of frailty
Reactive Template Method to Synthesize Gold Nanoparticles with Controllable Size and Morphology Supported on Shells of Polymer Hollow Microspheres and Their Application for Aerobic Alcohol Oxidation in Water
Authors: Han Jie , Liu Yan , Guo Rong
Published: January 2009

A novel method has been developed to synthesize gold nanoparticles with tunable size and morphology supported on both inner and outer surfaces of poly(o‐phenylenediamine) (PoPD) hollow microspheres, which act as both reductant and template/stabilizer. The size of gold nanoparticles supported on shells of PoPD hollow microspheres can be tuned from 3 to 15 nm by changing the concentration of the gold source, HAuCl4. Gold nanorods supported on shells of PoPD hollow microspheres can also be fabricated by introducing a well‐known seed‐growth strategy. In addition, silver nanoparticles supported on shells of PoPD hollow microspheres can also be successfully fabricated using the same strategy, which indicates the diversity of this proposed method for polymer hollow microspheres supporting noble metal nanoparticles. The products are characterized by X‐ray diffraction and contact angle analysis. Furthermore, the catalytic activity of the obtained PoPD‐microsphere‐supported gold nanoparticles for aerobic alcohol oxidation is investigated. The results demonstrate that such polymer‐supported gold nanoparticles can be used as reusable catalysts with high catalytic activity for aerobic alcohol oxidation in water.
Organized Nanostructured Complexes of Polyoxometalates and Surfactants that Exhibit Photoluminescence and Electrochromism
Authors: Zhang Tierui , Liu Shaoqin , Kurth Dirk G. , Faul Charl F. J.
Published: January 2009

A variety of functional nanostructured organic/inorganic hybrid materials from the europium‐exchanged derivative of a Preyssler‐type polyoxometalate (POM), [EuP5W30O110]12−, and functional organic surfactants were prepared by the ionic self‐assembly (ISA) route. The effect of organic surfactants on the structure, photoluminescent, electrochemical and electrochromic properties of the POM anions was investigated in detail. All obtained hybrid materials are amphotropic, i.e., exhibit both thermotropic and lyotropic liquid‐crystalline phase behaviour. Investigations of their photophysical properties have shown that the interactions of the various surfactants with the polyanions influence the coordination environments and site symmetry of Eu3+ in different ways. The functional groups in the organic surfactants significantly influence the electrochromic properties and photoluminescence of POMs. Different from normal and pyridine‐containing complexes, no photoluminescence and no electrochromism were observed from the ferrocene‐containing complexes. This may be explained in view of charge transfer between the POM anion and the ferrocenyl group.
Threshold Voltage Shifts in Organic Thin‐Film Transistors Due to Self‐Assembled Monolayers at the Dielectric Surface
Authors: Possanner Stefan K. , Zojer Karin , Pacher Peter , Zojer Egbert , Schürrer Ferdinand
Published: January 2009

Recently, it has been shown by several groups that the electrical characteristics of organic thin‐film transistors (OTFTs) can be significantly influenced by depositing self‐assembled monolayers (SAMs) at the organic semiconductor/dielectric interface. In this work, the effect of such SAMs on the transfer characteristics and especially on the threshold voltage of OTFTs is investigated by means of two‐dimensional drift‐diffusion simulations. The impact of the SAM is modeled either by a permanent space charge layer that can result from chemical reactions with the active material, or by a dipole layer representing an array of ordered dipolar molecules. It is demonstrated that, in both model cases, the presence of the SAM significantly changes the transfer characteristics. In particular, it gives rise to a modified, effective gate voltageVeffthat results in a rigid shift of the threshold voltage, ΔVth, relative to a SAM‐free OTFT. The achievable amount of threshold voltage shift, however, strongly depends on the actual role of the SAM. While for the investigated device dimensions, an organic SAM acting as a dipole layer can realistically shift the threshold voltage only by a few volts, the changes in the threshold voltage can be more than an order of magnitude larger when the SAM leads to charges at the interface. Based on the analysis of the different cases, a route to experimentally discriminate between SAM‐induced space charges and interface dipoles is proposed. The developed model allows for qualitative description of the behavior of organic transistors containing reactive interfacial layers; when incorporating rechargeable carrier trap states and a carrier density‐dependent mobility, even a quantitative agreement between theory and recent experiments can be achieved.
Magnesium Borohydride Confined in a Metal–Organic Framework: A Preorganized System for Facile Arene Hydroboration
Authors: Ingleson Michael J. , Barrio Jorge Perez , Bacsa John , Steiner Alexander , Darling George R. , Jones James T. A. , Khimyak Yaroslav Z. , Rosseinsky Matthew J.
Published: January 2009

In nächster Nähe: Anders als unter analogen Bedingungen in homogener Lösung reagiert Magnesiumborhydrid als Teil eines metall‐organischen Netzwerks mit Arenen unter Hydroborierung (siehe Schema). Die erforderliche Ausrichtung der reaktiven Gruppen im Netzwerk wird durch Metallkoordination und Diwasserstoffbrücken erzielt.

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Semisynthese eines homogenen Glycoprotein‐Enzyms: Ribonuclease C (Teil 2)
Authors: Piontek Christian , Varón Silva Daniel , Heinlein Christian , Pöhner Claudia , Mezzato Stefano , Ring Petra , Martin Andreas , Schmid Franz Xaver , Unverzagt Carlo
Published: January 2009

Aktives RNase‐Glycoprotein aus drei Segmenten: Das Glycoprotein‐Enzym Ribonuclease C mit einem komplexen nonasaccharidischen N‐Glycan wurde durch sequenzielle native chemische Ligation synthetisiert. Durch optimierte Ligations‐ und Isolierungsbedingungen konnte das aus 124 Aminosäuren bestehende Enzym effizient aufgebaut und zurückgefaltet werden.

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A Luminescent Microporous Metal–Organic Framework for the Fast and Reversible Detection of High Explosives
Authors: Lan Anjian , Li Kunhao , Wu Haohan , Olson David H. , Emge Thomas J. , Ki Woosoek , Hong Maochun , Li Jing
Published: January 2009

Ein hoch empfindlicher Sensor: Mit dem intensiv lumineszierenden mikroporösen Metall‐organischen Gerüst [Zn2(bpdc)2(bpee)] (bpdc=4,4′‐Biphenyldicarboxylat; bpee=1,2‐Bipyridylethen) lassen sich Dämpfe des Nitrosprengstoffs 2,4‐Dinitrotoluol und von 2,3‐Dimethyl‐2,3‐dinitrobutan, das Plastiksprengstoff als Markierung zugemischt wird, durch Redox‐Fluoreszenzlöschung sehr schnell, reversibel und mit unerreichter Empfindlichkeit nachweisen (siehe Spektren).

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Stabilisierung eines Thiolat→Dibrom‐Charge‐Transfer‐Addukts durch einen makrocyclischen Dinickel‐Komplex und dessen Überführung in einen Arensulfenylbromid‐Komplex
Authors: Steinfeld Gunther , Lozan Vasile , Krüger Hans‐Jörg , Kersting Berthold
Published: January 2009

Erstaunlich stabil sind die hier vorgestellten ersten Übergangsmetallkomplexe mit S‐Br‐Einheiten. Festes 2 verliert im Vakuum kein Br2, und festes 3 ist mindestens sechs Monate stabil. Die Bildung des ersten strukturell charakterisierten Übergangsmetall‐Arensulfenylbromid‐Komplexes 3 geht laut den Ergebnissen von Suszeptibilitätsmessungen mit einer Veränderung des Spingrundzustands von S=2 nach S=0 einher.

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Shape‐Selective Interception by Hydrocarbons of the O2‐Derived Oxidant of a Biomimetic Nonheme Iron Complex
Authors: Mukherjee Anusree , Martinho Marlène , Bominaar Emile L. , Münck Eckard , Que Lawrence
Published: January 2009

Wählerisches Ferryl: [Fe(Tp)(BF)] (Tp=Hydrotris(3,5‐diphenylpyrazolyl)borat; BF=Benzoylformiat) liefert mit O2 ein Oxidationsmittel (siehe Bild; O rot, rosa, Fe gelb, N blau, C grau, H weiß), das Kohlenwasserstoffe formselektiv oxidiert. Die Ursache hierfür ist eine durch zwei Phenylgruppen des Tp‐Liganden gebildete Spalte, die abgeflachte spheroidale Substrate bevorzugt.

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Addition of Hydrogen or Ammonia to a Low‐Valent Group 13 Metal Species at 25 °C and 1 Atmosphere
Authors: Zhu Zhongliang , Wang Xinping , Peng Yang , Lei Hao , Fettinger James C. , Rivard Eric , Power Philip P.
Published: January 2009

Unter milden Bedingungen: Die niedervalente Arylgallium(I)‐Spezies :GaAr′ (Ar′=2,6‐(2,6‐iPr2C6H3)2C6H3) geht bei Raumtemperatur und einem Druck von 1 atm eine Addition an H2 oder NH3 ein, wobei 1 bzw. 2 gebildet wird (siehe Schema). Beide Produkte wurden durch Röntgenkristallographie sowie NMR‐ und IR‐Spektroskopie charakterisiert.

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Magnesium Borohydride Confined in a Metal–Organic Framework: A Preorganized System for Facile Arene Hydroboration
Authors: Ingleson Michael J. , Barrio Jorge Perez , Bacsa John , Steiner Alexander , Darling George R. , Jones James T. A. , Khimyak Yaroslav Z. , Rosseinsky Matthew J.
Published: January 2009

In close quarters: When confined in a metal–organic framework, magnesium borohydride reacts with arenes by a hydroboration pathway (see scheme), in contrast to its reactivity under analogous homogeneous solution‐phase conditions. Framework‐imposed organization of the reactive groups is required, which is achieved by a combination of the metal coordination and two hydrogen bonds.

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A Luminescent Microporous Metal–Organic Framework for the Fast and Reversible Detection of High Explosives
Authors: Lan Anjian , Li Kunhao , Wu Haohan , Olson David H. , Emge Thomas J. , Ki Woosoek , Hong Maochun , Li Jing
Published: January 2009

Sensors and sensitivity: A highly luminescent microporous metal–organic framework, [Zn2(bpdc)2(bpee)] (bpdc=4,4′‐biphenyldicarboxylate; bpee=1,2‐bipyridylethene), is capable of very fast and reversible detection of the vapors of the nitroaromatic explosive 2,4‐dinitrotoluene and the plastic explosive taggant 2,3‐dimethyl‐2,3‐dinitrobutane, through redox fluorescence quenching with unprecedented sensitivity (see spectra).

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CF Activation at Rhodium Boryl Complexes: Formation of 2‐Fluoroalkyl‐1,3,2‐Dioxaborolanes by Catalytic Functionalization of Hexafluoropropene
Authors: Braun Thomas , Ahijado Salomon Marcel , Altenhöner Kai , Teltewskoi Michael , Hinze Silke
Published: January 2009

Fluorinated building blocks by CF bond cleavage: Catalytic CF activation reactions that give novel dioxaborolanes have been developed (see scheme). The reactions proceed at room temperature, and catalytic intermediates are presumably rhodium hydride and boryl species.

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Rheumatology fellows' perception on training and careers in academia: The American College of Rheumatology Fellow Research and Academic Training Survey
Authors:   The Young Investigator Subcommittee of the American College of Rheumatology Committee on Research
Published: January 2009

Objective

To examine the perceptions of rheumatology fellows regarding their research training, mentoring, and interest in a career in academia.

Methods

We solicited by e‐mail 386 fellows in the American College of Rheumatology 2005–2006 fellow database to take an anonymous Internet‐based survey addressing the topics of research training, mentoring, and interest in an academic career.

Results

We received 176 responses (50% response rate after excluding invalid contacts) to the survey. During their training, 58% of fellows reported an interest in academia and 21% in research. There was great satisfaction with mentoring. However, there were concerns about academic salaries, with 50% of respondents stating a preference for a higher paying community position. Furthermore, there were substantial concerns about the difficulty of generating funds to cover salaries. In addition, several respondents viewed an academic career as incompatible with starting a family. Compared with male fellows, female fellows were more likely to want a career in academics, were less concerned about academic salaries, and were more concerned about funding and family life.

Conclusion

Despite an interest in academia and satisfaction with current mentoring, several barriers to academia were identified among rheumatology fellows. The concern that academia and family life are incompatible needs further attention. University deans should consider reevaluating promotion programs to make allowances for family and parenting demands. Rheumatology division chairs should better promote the nonfinancial rewards of a career in academia. Programs such as the National Institutes of Health Loan Repayment Program should be strongly advertised to interested applicants with financial concerns.
Proinflammatory role of the Th17 cytokine interleukin‐22 in collagen‐induced arthritis in C57BL/6 mice
Authors: Geboes Lies , Dumoutier Laure , Kelchtermans Hilde , Schurgers Evelien , Mitera Tania , Renauld Jean‐Christophe , Matthys Patrick
Published: January 2009

Objective

To investigate the role of interleukin‐22 (IL‐22) in collagen‐induced arthritis (CIA), an animal model of rheumatoid arthritis.

Methods

C57BL/6 mice were immunized with type II collagen (CII) in Freund's incomplete adjuvant with added Mycobacterium tuberculosis, and levels of IL‐22 and its specific receptor, IL‐22 receptor type I (IL‐22RI), were measured in sera and tissue by enzyme‐linked immunosorbent assay and real‐time quantitative polymerase chain reaction analysis. Clinical and histologic signs of arthritis were recorded and compared with those in C57BL/6 mice deficient in the IL‐22 gene (IL‐22–/–). Humoral and cellular immune responses against CII were analyzed. In vitro osteoclastogenesis assays were performed on splenocytes.

Results

Upon immunization with CII in Freund's incomplete adjuvant plus heat‐killed Mycobacterium tuberculosis, sera from C57BL/6 mice were found to contain high levels of IL‐22, and the specific IL‐22RI was expressed in lymphoid tissue, including splenocytes. IL‐22–/– mice were less susceptible to CIA than were wild‐type mice, as evidenced by their decreased incidence of arthritis and decreased pannus formation. Remarkably, the less severe form of arthritis in IL‐22–/– mice was associated with increased production of CII‐specific and total IgG antibodies, whereas cellular CII responses were unchanged. In vitro, IL‐22 was found to promote osteoclastogenesis, a process that might contribute to its proinflammatory activity in CIA.

Conclusion

Endogenous IL‐22 plays a proinflammatory role in CIA in C57BL/6 mice. Our data also indicate that IL‐22 promotes osteoclastogenesis and regulates antibody production.
Molecular framework for response to imatinib mesylate in systemic sclerosis
Authors: Chung Lorinda , Fiorentino David F. , BenBarak Maya J. , Adler Adam S. , Mariano Melissa M. , Paniagua Ricardo T. , Milano Ausra , Connolly M. Kari , Ratiner Boris D. , Wiskocil Robert L. , Whitfield Michael L. , Chang Howard Y. , Robinson William H.
Published: January 2009

Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet‐derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRβ and Abl with imatinib therapy. By gene expression profiling, an imatinib‐responsive signature specific to dcSSc was identified (P < 10−8). The response of these patients and the findings of the analyses suggest that PDGFRβ and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.
Increased expression of the Akt/PKB inhibitor TRB3 in osteoarthritic chondrocytes inhibits insulin‐like growth factor 1–mediated cell survival and proteoglycan synthesis
Authors: Cravero John D. , Carlson Cathy S. , Im Hee‐Jeong , Yammani Raghunatha R. , Long David , Loeser Richard F.
Published: January 2009

Objective

The chondrocyte response to insulin‐like growth factor 1 (IGF‐1) is reduced with aging and in osteoarthritis (OA). IGF‐1 signals through the phosphatidylinositol 3‐kinase/Akt pathway. TRB3, a tribbles homolog, has been shown to inhibit IGF‐1–mediated activation of Akt in HEK 293 cells. This study was undertaken to determine if TRB3 is expressed in chondrocytes, and whether the chondrocyte response to IGF‐1 is reduced by TRB3.

Methods

Human articular cartilage was obtained from normal tissue donors and from patients with OA at the time of knee replacement surgery. TRB3 was assessed in the tissue samples by reverse transcription–polymerase chain reaction, immunoblotting, and immunohistochemistry. Overexpression of TRB3 was induced by transient transfection to determine the effects of TRB3 on cell survival and proteoglycan synthesis.

Results

TRB3 messenger RNA was detected in normal human chondrocytes. TRB3 protein levels were low in cells from normal cartilage but significantly increased in cells from OA cartilage. Incubation with 2 agents that induce endoplasmic reticulum stress, tunicamycin and thapsigargin, increased TRB3 levels in normal cells. Overexpression of TRB3 inhibited Akt phosphorylation and reduced chondrocyte survival and proteoglycan synthesis.

Conclusion

These results are the first to demonstrate that TRB3 is present in human chondrocytes, and that the level of TRB3 is increased in OA cartilage and in isolated OA chondrocytes. Because it is an inhibitor of Akt activation, elevated TRB3 production could play a role in the increased cell death and reduced response to IGF‐1 observed in OA cartilage.
α‐melanocyte–stimulating hormone suppresses bleomycin‐induced collagen synthesis and reduces tissue fibrosis in a mouse model of scleroderma: Melanocortin peptides as a novel treatment strategy for scleroderma?
Authors: Kokot Agatha , Sindrilaru Anca , Schiller Meinhard , Sunderkötter Cord , Kerkhoff Claus , Eckes Beate , Scharffetter‐Kochanek Karin , Luger Thomas A. , Böhm Markus
Published: January 2009

Objective

Recently, we found that human dermal fibroblasts (HDFs) express melanocortin 1 receptors (MC‐1R) that bind α‐melanocyte–stimulating hormone (α‐MSH). In search of novel therapies for scleroderma (systemic sclerosis [SSc]), we used the bleomycin (BLM) model to investigate the effects of α‐MSH on collagen synthesis and fibrosis.

Methods

Collagen expression in HDFs was determined by real‐time reverse transcription–polymerase chain reaction (RT‐PCR) and Western blot analyses. Signal transduction studies included pharmacologic blockade, immunofluorescence analysis, Western blotting, and reporter–promoter assays. Oxidative stress was measured by fluorescence‐activated cell sorter analysis, and anti–oxidative enzyme levels were determined by real‐time RT‐PCR and Western blot analyses. The effect of α‐MSH in the BLM mouse model of scleroderma was assessed by histologic, immunohistochemical, real‐time RT‐PCR, and protein analyses. Expression of MC‐1R and pro‐opiomelanocortin (POMC) in skin and HDF samples from patients with SSc was determined by RT‐PCR and compared with that in samples from normal controls.

Results

Treatment with α‐MSH (and related peptides) suppressed BLM‐induced expression of type I and type III collagen in HDFs, and this effect was cAMP‐dependent. Neither BLM nor α‐MSH altered Smad signaling, but antioxidants inhibited BLM‐induced collagen expression in vitro. In addition, α‐MSH suppressed BLM‐induced oxidative stress and enhanced the expression of superoxide dismutase 2 (SOD2) and heme oxygenase 1 (HO‐1). In the BLM mouse model, α‐MSH reduced skin fibrosis and collagen content and increased tissue levels of SOD2 and HO‐1. In skin and HDFs from patients with SSc, both MC‐1R and POMC messenger RNAs were detected, but there were no differences compared with healthy controls.

Conclusion

Alpha‐melanocyte–stimulating hormone and related peptides that exert their effects via MC‐1R may provide a novel antifibrogenic therapeutic tool for the treatment of fibrotic diseases such as scleroderma.
Depression, medication adherence, and service utilization in systemic lupus erythematosus
Authors: Julian Laura J. , Yelin Edward , Yazdany Jinoos , Panopalis Pantelis , Trupin Laura , Criswell Lindsey A. , Katz Patricia
Published: January 2009

Objective

Forgetting to take medications is an important cause of nonadherence. This study evaluated factors associated with forgetting to take medications in a large cohort of persons with systemic lupus erythematosus (SLE) participating in the University of California, San Francisco Lupus Outcomes Study (LOS). Relationships among adherence problems and service utilization (outpatient visits, emergency department visits, and hospitalizations) were also evaluated.

Methods

The cohort consisted of 834 LOS participants who provided self‐reported frequency of forgetting to take medications as directed. Predictors of adherence and service utilization patterns included self‐reported sociodemographics, disease‐related characteristics (e.g., disease activity, recent SLE flare), and mental health characteristics (Center for Epidemiologic Studies Depression Scale and cognitive function screen). Health care utilization patterns included the presence and quantity of visits to rheumatologists, primary care physicians, other care providers, emergency departments, and hospitalizations.

Results

Forty‐six percent of the LOS cohort reported forgetting to take medications at least some of the time. Depressive symptom severity was a strong predictor of adherence difficulties (odds ratio [OR] 1.04, 95% confidence interval [95% CI] 1.02–1.05; P < 0.0001) after accounting for all other predictors. Persons reporting adherence difficulties had significantly greater numbers of outpatient rheumatology and primary care visits, and were more likely to visit the emergency department (OR 1.45, 95% CI 1.04–2.04; P = 0.03).

Conclusion

Depression may be an important cause of medication adherence problems, and difficulties with adherence are significantly associated with high‐cost service utilization, specifically emergency department visits. In an era of rapidly evolving treatments for lupus, identifying patients at risk for adherence problems may decrease medical expenditures and improve patient outcomes in SLE.
Study of functional variants of the BANK1 gene in rheumatoid arthritis
Authors: Orozco Gisela , Abelson Anna‐Karin , González‐Gay Miguel A. , Balsa Alejandro , Pascual‐Salcedo Dora , García Antonio , Fernández‐Gutierrez Benjamín , Petersson Ingemar , Pons‐Estel Bernardo , Eimon Alicia , Paira Sergio , Scherbarth Hugo R. , Alarcón‐Riquelme Marta , Martín Javier
Published: January 2009

Objective

To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA).

Methods

Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single‐nucleotide polymorphisms (SNPs) using a TaqMan 5′‐allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi‐square test.

Results

We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03–1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00–1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04–1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07–1.29]) with RA in the pooled analysis. In a 3‐SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04–1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74–0.92]).

Conclusion

These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.
Replication of the association between the C8orf13–BLK region and systemic lupus erythematosus in a Japanese population
Authors: Ito Ikue , Kawasaki Aya , Ito Satoshi , Hayashi Taichi , Goto Daisuke , Matsumoto Isao , Tsutsumi Akito , Hom Geoffrey , Graham Robert R. , Takasaki Yoshinari , Hashimoto Hiroshi , Ohashi Jun , Behrens Timothy W. , Sumida Takayuki , Tsuchiya Naoyuki
Published: January 2009

Objective

Recent genome‐wide association studies identified an association between single‐nucleotide polymorphisms (SNPs) in the C8orf13 region of BLK, the B lymphoid tyrosine kinase gene, with systemic lupus erythematosus (SLE) in Caucasians. The purpose of this study was to evaluate the significance of this region in the genetic background of Japanese patients with SLE.

Methods

Fourteen tag SNPs in the C8orf13–BLK region were genotyped in 327 Japanese patients with SLE and 322 healthy Japanese controls. The population‐attributable risk percentage (PAR%) of rs13277113 in Japanese was compared with that in Caucasians as well as with that of other SLE susceptibility genes in Japanese.

Results

As in Caucasians, rs13277113A demonstrated the strongest association in Japanese (P = 1.73 × 10–6 for the genotype frequency, P = 4.75 × 10–7 for the allele frequency, odds ratio [OR] 2.44 [95% confidence interval (95% CI) 1.43–4.16]). The association in Japanese was consistent with a recessive model (P = 2.74 × 10–7, OR 2.27 [95% CI 1.66–3.11]). In contrast to the Caucasian population, this risk allele was the major allele in the Japanese population. Because both the risk allele frequency and the OR were higher in Japanese than in Caucasians, the PAR% of rs13277113 was estimated to be much higher in Japanese (35.4%) than in Caucasians (16.2%), and the second highest among the 6 confirmed SLE susceptibility genes in Japanese.

Conclusion

The association of the C8orf13–BLK region with SLE was replicated in a Japanese population. Contribution of this region to the genetic predisposition to SLE appeared to be greater in Japanese than in Caucasians.
Involvement of the notch pathway in the regulation of matrix metalloproteinase 13 and the dedifferentiation of articular chondrocytes in murine cartilage
Authors: Blaise Régis , Mahjoub Mouna , Salvat Colette , Barbe Ullah , Brou Christel , Corvol Marie‐Thérèse , Savouret Jean‐François , Rannou François , Berenbaum Francis , Bausero Pedro
Published: January 2009

Objective

To demonstrate the activation of the Notch signaling pathway during changes in the phenotype of chondrocytes in vitro, and to assess the influence of Notch on the production of chondrocyte markers.

Methods

Serial monolayer primary cultures of murine articular chondrocytes (MACs), as a model of chondrocyte dedifferentiation, were prepared. MACs were cultured with or without a Notch inhibitor and transfected with different Notch‐expressing vectors. The Notch pathway and chondrocyte marker profiles were assessed by quantitative reverse transcription–polymerase chain reaction, immunoblotting, and immunocytochemistry.

Results

Successive passages of MACs resulted in a loss of type II collagen and aggrecan (chondrocyte differentiation markers), an increase in type I collagen (dedifferentiation marker), an increase in Notch ligands, and augmented target gene activity. The Notch inhibitor decreased the type II collagen protein content but had no effect on Col2a1 messenger RNA, while transfection with the constitutive active forms of the Notch1 receptor led to a decrease in type II collagen in transfected cells. In assays to investigate the mechanism of type II collagen breakdown, matrix metalloproteinase 13 (MMP‐13) synthesis was regulated in a Notch‐dependent manner, whereas MMP‐2 synthesis was unchanged.

Conclusion

The Notch signaling pathway is associated with decreased type II collagen production during the dedifferentiation of MACs in vitro. This may be correlated with the increase in MMP‐13 production linked to activation of Notch.
Alteration of articular cartilage frictional properties by transforming growth factor β, interleukin‐1β, and oncostatin M
Authors: Gleghorn Jason P. , Jones Aled R. C. , Flannery Carl R. , Bonassar Lawrence J.
Published: January 2009

Objective

To evaluate the functional effects of transforming growth factor β1 (TGFβ1), interleukin‐1β (IL‐1β), and oncostatin M (OSM) on the frictional properties of articular cartilage and to determine the role of cytokine‐mediated changes in cartilage frictional properties by extracting and redepositing lubricin on the surface of cartilage explants.

Methods

Neonatal bovine cartilage explants were cultured in the presence or absence of 10 ng/ml of TGFβ1, IL‐1β, or OSM over 48 hours. Boundary lubrication tests were conducted to determine the effects of endogenously produced surface localized lubricin and of exogenous lubricin at the tissue surface and in the lubricant solution. The initial friction coefficient (μ0), equilibrium friction coefficient (μeq), and Young's modulus (EY) were determined from the temporal load data.

Results

IL‐1β and OSM decreased tissue glycosaminoglycan (GAG) content by ∼20% over 48 hours and decreased EY to a similar extent (11–17%), but TGFβ did not alter GAG content or EY. Alterations in proteoglycan content corresponded to changes in μ0, but endogenous lubricin decreased boundary mode μeq. The addition of exogenous lubricin, either localized at the tissue surface or in the lubricating solution, did not modulate μ0, but it did lower μeq in cytokine‐treated cartilage.

Conclusion

This study provides new insight into the functional consequences of cytokine‐mediated changes in friction coefficient. In combination with established pathways of cytokine‐mediated lubricin metabolism, these data provide evidence of distinct biochemical origins of boundary and biphasic pressure‐mediated lubrication mechanisms in cartilage, with boundary lubrication regulated by surface accumulation of lubricants and biphasic lubrication controlled by factors such as GAG content that affect water movement through the tissue.
HLA–E gene polymorphism associated with susceptibility to kawasaki disease and formation of coronary artery aneurysms
Authors: Lin Y.‐J. , Wan L. , Wu J.‐Y. , Sheu J. J.‐C. , Lin C.‐W. , Lan Y.‐C. , Lai C.‐H. , Hung C.‐H. , Tsai Y. , Tsai C.‐H. , Lin T.‐H. , Lin J.‐G. , Hsueh K.‐C. , Huang Y.‐M. , Chang J.‐S. , Tsai F.‐J.
Published: January 2009

Objective

Kawasaki disease (KD) is a pediatric systemic vasculitis of unknown cause for which a genetic influence is supposed. The purpose of this study was to identify possible genetic variants in the major histocompatibility complex (MHC) region that are associated with KD and the development of coronary artery aneurysms (CAAs) in a Taiwanese population.

Methods

The 168 genetic variants covering the MHC locus were analyzed in an association study of a Taiwanese cohort of 93 KD patients and 680 unrelated healthy children matched for sex and age with the study patients.

Results

Eleven single‐nucleotide polymorphisms (SNPs) were associated with the occurrence of KD. The SNP located at the 3′‐untranslated region of HLA–E (rs2844724) was highly associated (P < 1 × 10−7). In addition, the frequency of the C allele was higher in KD patients without CAAs than in controls (P < 0.001) due to a significantly increased frequency of the CC and CT genotypes. Plasma levels of soluble HLA–E were significantly higher in KD patients than in controls regardless of the presence of CAAs. Furthermore, there was a trend toward higher plasma levels of soluble HLA–E in KD patients with the CT and TT genotypes of the HLA–E gene polymorphism.

Conclusion

Our results suggest that the HLA–E gene polymorphism may play a role in the pathogenesis of KD.
Efficacy of multicomponent treatment in fibromyalgia syndrome: A meta‐analysis of randomized controlled clinical trials
Authors: Häuser Winfried , Bernardy Kathrin , Arnold Bernhard , Offenbächer Martin , Schiltenwolf Marcus
Published: January 2009

Objective

To systematically review the efficacy of multicomponent treatment of fibromyalgia syndrome (FMS).

Methods

We screened Medline, PsychINFO, Scopus, and the Cochrane Library (through December 2007), as well as reference sections of original studies, reviews, and evidence‐based guidelines. Randomized controlled trials (RCTs) on the multicomponent treatment (at least 1 educational or other psychological therapy with at least 1 exercise therapy) of FMS were analyzed.

Results

We included 9 (of 14) RCTs with 1,119 subjects (median treatment time 24 hours) in the meta‐analysis. Effects were summarized using standardized mean differences (SMDs) or weighted mean differences (WMDs). There was strong evidence that multicomponent treatment reduces pain (SMD −0.37; 95% confidence interval [95% CI] −0.62, −0.13), fatigue (WMD −0.85; 95% CI −1.50, −0.20), depressive symptoms (SMD −0.67; 95% CI −1.08, −0.26), and limitations to health‐related quality of life (HRQOL) (SMD −0.59; 95% CI −0.90, −0.27) and improves self‐efficacy pain (SMD 0.54; 95% CI 0.26, 0.82) and physical fitness (SMD 0.30; 95% CI 0.02, 0.57) at posttreatment. There was no evidence of its efficacy on pain, fatigue, sleep disturbances, depressive symptoms, HRQOL, or self‐efficacy pain in the long term. There was strong evidence that positive effects on physical fitness (SMD 0.30; 95% CI 0.09, 0.51) can be maintained in the long term (median followup 7 months).

Conclusions

There is strong evidence that multicomponent treatment has beneficial short‐term effects on the key symptoms of FMS. Strategies to maintain the benefits of multicomponent treatment in the long term need to be developed.
Time to diagnosis in systemic sclerosis: Is sex a factor?
Authors: Hudson Marie , Thombs Brett , Baron Murray ,   The Canadian Scleroderma Research Group
Published: January 2009

Objective

To determine whether sex plays a role in the time to diagnosis of systemic sclerosis (SSc).

Methods

In the Canadian Scleroderma Research Group registry, dates of onset of Raynaud's phenomenon, the first non–Raynaud's disease symptom, and diagnosis were recorded based on patient reports. Association between sex and time to diagnosis was assessed for the group as a whole and stratified based on extent of skin involvement, either limited or diffuse.

Results

Of the 408 patients studied (347 women, 61 men, 44% with diffuse cutaneous SSc), the time to diagnosis after the onset of Raynaud's phenomenon was significantly longer for women than men (log rank P = 0.001), but not significantly different after the onset of the first non–Raynaud's disease manifestation. In an analysis stratified by limited or diffuse status, the time to diagnosis from onset of Raynaud's phenomenon was also significantly longer for women than men with diffuse cutaneous SSc (log rank P = 0.008). A trend toward a longer period between onset of Raynaud's phenomenon and SSc diagnosis was observed in women compared with men with limited cutaneous SSc (median 4.6 years in women versus 2.1 years in men; P = 0.085), and there was no sex difference in time to diagnosis after the onset of the first non–Raynaud's disease manifestation.

Conclusion

In SSc, the time to diagnosis is longer for women than men after the onset of Raynaud's phenomenon, suggesting that there may be possible biologic differences in the progression of disease or in the health care trajectories of men and women with early SSc.
Role of placenta growth factor and its receptor flt‐1 in rheumatoid inflammation: A link between angiogenesis and inflammation
Authors: Yoo Seung‐Ah , Yoon Hyung‐Ju , Kim Hyun‐Sook , Chae Chi‐Bom , De Falco Sandro , Cho Chul‐Soo , Kim Wan‐Uk
Published: January 2009

Objective

To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt‐1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA).

Methods

Expression of PlGF and flt‐1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme‐linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor α (TNFα), and interleukin‐6 (IL‐6) in culture supernatants of either mononuclear cells or synoviocytes. The flt‐1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti‐CII antibody.

Results

PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast‐like synoviocytes (FLS). When stimulated with IL‐1β, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFα and IL‐6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin‐dependent pathway. The response to PlGF was associated with increased expression of flt‐1 on RA monocytes, which could be induced by IL‐1β and TNFα. A novel anti–flt‐1 hexapeptide, GNQWFI, abrogated the PlGF‐induced increase in TNFα and IL‐6 production, and also suppressed CII‐induced arthritis and serum IL‐6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti‐CII antibody–induced arthritis in mice.

Conclusion

Our data suggest that enhanced expression of PlGF and flt‐1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti–flt‐1 peptide, GNQWFI, may be an effective strategy for the treatment of RA.
Land‐based versus water‐based rehabilitation following total knee replacement: A randomized, single‐blind trial
Authors: Harmer Alison R. , Naylor Justine M. , Crosbie Jack , Russell Tyson
Published: January 2009

Objective

To compare outcomes between land‐based and water‐based exercise programs delivered in the early subacute phase up to 6 months after total knee replacement (TKR).

Methods

Two weeks after surgery (baseline), 102 patients were randomized to participate in either land‐based (n = 49) or water‐based (n = 53) exercise classes. Treatment parameters were guided by current clinical practice protocols. Therefore, each study arm involved 1‐hour sessions twice a week for 6 weeks, with patient‐determined exercise intensity. Session attendance was recorded. Outcomes were measured at baseline and at 8 and 26 weeks postsurgery. Outcomes included distance on the 6‐Minute Walk test, stair climbing power (SCP), the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (n = 85 English‐proficient patients), visual analog scale for joint pain, passive knee range of motion, and knee edema (circumference). Planned orthogonal contrasts, with an intent‐to‐treat approach, were used to analyze the effects of time and time‐group interactions.

Results

Compliance in both groups was excellent with 81% attending 8 or more sessions. Loss to followup was 5%. Significant improvements were observed across time in all outcomes at 8 weeks, with further improvements evident in all variables (except WOMAC pain) at 26 weeks. Minor between‐group differences were evident for 4 outcomes (SCP, WOMAC stiffness, WOMAC function, and edema) but these appear clinically insignificant.

Conclusion

A short‐term, clinically pragmatic program of either land‐based or water‐based rehabilitation delivered in the early phase after TKR was associated with comparable outcomes at the end of the program and up to 26 weeks postsurgery.
Synthesis, Characterization, and DNA‐Binding Studies of Mononuclear Copper(II)–Phenanthroline–Tyrosine Complex
Authors: Reddy Pulimamidi R. , Manjula Pallerla
Published: January 2009

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The mononuclear complex [CuII(phen)(L‐Tyr)(H2O)] was synthesized and structurally characterized by elemental analysis, magnetic susceptibility, UV/VIS, IR, and EPR spectroscopy, and ESI mass spectrometry. The electronic and EPR spectral data suggest a square‐pyramidal geometry around CuII. Absorption spectra, thermal denaturation, and fluorescence‐spectroscopic studies were conducted to assess the interaction of the CuII complex with calf thymus DNA (CT DNA). The intrinsic binding constant for CT DNA/complex (Kb=3750 M−1) and Stern–Volmer quenching constant (K=0.39) were determined.
Nitration of Alkyl Benzoates with Mixed Acid
Authors: Klais O. , Hoffmann H. , Kyaw Naing E.
Published: January 2009

The nitration of (substituted) benzoic acid esters is usually performed in fed‐batch operation. The ester is solved in sulfuric acid charged first. The nitric acid dosed keeps the reaction temperature under control. The safety regarding uncontrolled reaction conditions was investigated under variation of the ratio of nitric acid to charged aromatic compound. A significant decrease in thermal stability of the reaction mixture was observed with excess of nitric acid. Safe operation cannot be assumed in general when the acid is close to or exceeds 10 % molar ratio. The investigation was restricted to aromatic carboxylic acid alkyl esters which form homogeneous mixtures with sulfuric acid. The thermal stability was investigated by differential thermal analysis (closed systems), adiabatic storage tests, and dynamic calorimeters. The reaction products were analyzed by means of NMR and mass spectrometry. The experiments showed that the formation of dinitro compounds cannot cause the thermal instability alone. The formation of dinitro compounds starts at temperatures above the reaction conditions. Another component is responsible for the thermal instability which accumulates in the presence of an ester group at excess nitric acid. It could be deduced that the decomposition reaction is primarily caused by the reaction of surplus nitryl cation (NO2+ ion) with the nitrated carboxylic acid ester in the presence of sulfuric acid. The decomposition temperature of the reaction mixture depends on the nature of the ester group and the type and number of further substituents on the aromatic ring.
Stereo‐ and Regioselectivity in an Intramolecular Nitrone–Alkene Cycloaddition of Hept‐6‐enoses with a trans‐Acetonide Blocking Group
Authors: Shing Tony K. M. , Wong Wai F. , Ikeno Taketo , Yamada Tohru
Published: January 2009

From sugar to cycloadduct: The effect of the trans‐acetonide blocking group and the stereochemistry of the substituents on the regio‐ and stereoselectivity in the intramolecular nitrone–alkene cycloaddition (INAC) reaction of hept‐6‐enoses (see scheme) is reported and studied by using theoretical analysis.

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The positional effect of the trans‐acetonide blocking group and the effect of the stereochemistry of the substituents on the regio‐ and stereoselectivity in intramolecular nitrone–alkene cycloaddition (INAC) reactions of hept‐6‐enoses are reported. Hept‐6‐enoses with a 2,3‐trans‐acetonide group were reacted with N‐alkyl hydroxylamine to give a mixture of exo and endo cycloadducts (cyclohexanols and cycloheptanols, respectively). Complete formation of endo cycloadducts (cycloheptanols) was realized for the INAC reaction of hept‐6‐enoses containing a 3,4‐trans‐O‐isopropylidene ring. Similarly, reaction of a hept‐6‐enose possessing a 4,5‐trans‐acetonide group surprisingly afforded exo cycloadducts (cyclohexanols) exclusively. The regio‐ and stereochemical outcomes of these reactions were rationalized on the basis of transition‐state energies obtained by computation.