bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and properties of poly(ether imide)s derived from 2,5‐bis(3,4‐dicarboxyphenoxy)biphenyl dianhydride and aromatic ether–diamines
Authors: Hsiao Sheng‐Huei , Yang Chin‐Ping , Chen Yung‐Chung , Wang Hui‐Ming , Guo Wenjeng
Published: May 2009

A series of poly(ether imide)s (PEIs) with light colors and good mechanical properties were synthesized from 2,5‐bis(3,4‐dicarboxyphenoxy)biphenyl dianhydride and various aromatic ether–diamines via a conventional two‐step polymerization technique that included ring‐opening polyaddition at room temperature to poly(amic acid)s (PAAs) followed by thermal imidization. The precursor PAAs had inherent viscosities ranging from 0.71 to 1.19 dL/g and were solution‐cast and thermally cyclodehydrated to flexible and tough PEI films. All of the PEI films were essentially colorless, with ultraviolet–visible absorption cutoff wavelengths between 377 and 385 nm and yellowness index values ranging from 10.5 to 19.9. These PEIs showed high thermal stabilities with glass‐transition temperatures of 206–262°C and decomposition temperatures (at 10% weight loss) higher than 478°C. They also showed low dielectric constants of 3.39–3.72 (at 1 MHz) and low water absorptions below 0.85 wt %. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Effect of network relaxation on void propagation and failure in isotactic polypropylene at large strain
Authors: Na Bing , Lv Ruihua , Xu Wenfei
Published: May 2009

The important role of network relaxation in the voiding and fracture toughness of isotactic polypropylene (iPP) has been explored with video‐aid tensile tests, two‐dimensional small‐angle X‐ray scattering (2D‐SAXS) measurements, and morphological observations. The results indicated that macroscopic volume dilatation related to voiding became lower during large deformation of iPP sample with rich γ phase (denoted as γ‐iPP) cooled at 1°C/min, compared with one with exclusive α form (referred to α‐iPP) quenched in air. Furthermore, void propagation perpendicular to the tensile direction, demonstrated by Guinier approximation analysis of 2D‐SAXS results, was suppressed to a large extent in such a γ‐iPP sample. Less network relaxation, resulted from its peculiar crystalline and amorphous phases, was responsible for lower volume dilatation and slower void propagation in the γ‐iPP sample. Meanwhile, less network relaxation and suppressed transverse void propagation contributed to higher toughness in the γ‐iPP sample. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Photoluminescence of solution processed poly n‐vinyl carbazole films
Authors: Chung P. S. , Holloway P. H.
Published: May 2009

The photoluminescence (PL) of poly n‐vinyl carbazole (PVK) films formed by solution processing was investigated. PVK films were formed by spincasting onto bare glass or glass covered by films of indium tin oxide (ITO) and poly(3,4‐ethylenedioxythiophene): poly(styrenesulfonate)ethylene (PEDOT : PSS). Some of the spincast films were redissolved in chloroform solvent and redried both in the absence or presence of an electric field (6000 V/cm). The broad aggregate PL peak near 410 nm exhibited both blue and red shifts dependent upon the processing conditions. These shifts in PL were attributed to changes in the excimer populations associated with the molecular conformation of adjacent carbazole groups. The PL data were deconvoluted into two component peaks representing two excimers associated with overlap of only one (partial or P) or full overlap (F) of both aromatic rings on adjacent carbazole groups. It was concluded that the excimer population was dependent on the amount of residual solvent left in the film after processing and upon the type of substrate. The mechanism(s) controlling the molecular configurations was discussed. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Free‐radical retrograde‐precipitation copolymerization of vinyl acetate and acrylic acid
Authors: Caneba Gerard T. , Xu Zhiyong , Dar Yadunandan L.
Published: May 2009

Free‐radical chain polymerization kinetics of vinyl acetate (VA) and acrylic acid (AA) exhibit some unusual control features. The VA radicals have a high rate of chain transfer leading to relatively sluggish propagation rates. Polymerization of AA, however, is prone to autoacceleration behavior in bulk, solution, and precipitating media. Thus, conventional statistical copolymerization of VA and AA would result in the preferential formation of high AA content copolymer. However, when the reaction medium is chosen in such a way that the copolymer precipitates above the lower critical solution temperature (LCST), propagation control and even monomer sequence control are obtained. Under these conditions, when the VA charge is much greater than AA, a tapered block copolymer (VA‐t‐AA) is obtained. We report a single stage polymerization process for the synthesis of such materials. The presence of VA‐t‐AA products is verified by emulsification, solubility, fractionation, size exclusion chromatography, NMR, and thermal analyses. In addition, propagation control can virtually eliminate formation of bimodal MWD and random/homopolymer materials that are associated with various chain transfer mechanisms in conventional polymerization routes. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Resol/montmorillonite nanocomposites obtained by in situ polymerization
Authors: Rivero Guadalupe , Vázquez Analía , Manfredi Liliana B.
Published: May 2009

Nanocomposites based on resol resin and layered silicates were obtained by in situ polymerization. An increment in the viscosity and in the content of free formaldehyde in the prepolymer with the addition of clay was observed. It could be attributed to the entrance of small phenol molecules into the galleries modifying the concentration of reagent enabled to react outside the clay galleries.

The composites were cured by temperature and it was observed that the type of clay affect their dispersion in the polymer. The unmodified Cloisite® Na+ montmorillonite (CNa) was the best dispersed in the polymeric matrix, whereas the modified montmorillonites (MMTs) showed an interlayer contraction after curing. It seems to be due to the loss of modifiers from the clay or to the different rate of curing inside and outside the galleries. In addition, the composite containing CNa presented higher crosslinking density than the others with modified MMTs. More adhesive strength was observed in that composite as well. It was related with the void content and the polarity of the samples. These results were compared with the ones obtained when the nanocomposites were synthesized by mixing the clay with the prepolymer. The nanocomposites with the addition of CNa showed similar properties independent of the way of synthesis used. However, it seems that the modified clays are better dispersed by mixing with the prepolymer than by in situ polymerization. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
The Developing Left Superior Cervical Ganglion of Pacas (Agouti paca)
Authors: Melo Samanta Rios , Nyengaard Jens Randel , da Roza Oliveira Felipe , Ladd Fernando Vagner Lobo , Abrahão Luciana Maria Bigaram , Machado Márcia R.F. , Sasahara Tais H.C. , de Melo Mariana Pereira , Ribeiro Antonio Augusto C.M.
Published: May 2009

In this study the main question investigated was the number and size of both binucleate and mononucleate superior cervical ganglion (SCG) neurons and, whether post‐natal development would affect these parameters. Twenty left SCGs from 20 male pacas were used. Four different ages were investigated, that is newborn (4 days), young (45 days), adult (2 years), and aged animals (7 years). By using design‐based stereological methods, that is the Cavalieri principle and a physical disector combined with serial sectioning, the total volume of ganglion and total number of mononucleate and binucleate neurons were estimated. Furthermore, the mean perikaryal (somal) volume of mononucleate and binucleate neurons was estimated using the vertical nucleator. The main findings of this study were a 154% increase in the SCG volume, a 95% increase in the total number of mononucleate SCG neurons and a 50% increase in the total volume of SCG neurons. In conclusion, apart from neuron number, different adaptive mechanisms may coexist in the autonomic nervous system to guarantee a functional homeostasis during ageing, which is not always associated with neuron losses. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.
The Collagen Receptor DDR2 Is Expressed During Early Cardiac Development
Authors: Goldsmith Edie C. , Zhang Xiadong , Watson James , Hastings Josh , Potts Jay D.
Published: May 2009

Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase which has been shown to regulate cell migration upon binding its ligand, collagen. Expression studies determined that DDR2 mRNA and protein are present in the atrioventricular canal during epithelial‐mesenchymal transformation (EMT) and the receptor is expressed in both activated endothelial and migrating mesenchymal cells in vivo. Anat Rec, 2010. © 2009 Wiley‐Liss, Inc.
The effect of calorie restriction on growth and development in silkworm, Bombyx mori
Authors: Li Yijia , Chen Keping , Yao Qin , Li Jun , Wang Yong , Liu Haijun , Zhang Chiyu , Huang Guoping
Published: May 2009

Caloric restriction (CR) is known to extend the life span in different species from yeast to mammals. In this report, a simple organism silkworm (Bombyx mori) was used to study the effect of moderate CR on the growth and development processes of insects. Here we show that an extension of life span upon moderate CR was observed in the silkworm. The total protein level in the 5th instar larvae hemolymph appeared to decline significantly under CR. SDS‐PAGE analysis showed that the influence of CR was sex‐dependent. The CR effects on female animals were much more significant than on the males. The MALDI‐TOF MS study identified 16 proteins that expressed differentially among six groups of the male or female larvae fed at different time frequencies. Four of them, storage protein 1 (SP1), arylphorin (SP2), imaginal disk growth factor (IDGF), and 30‐kDa lipoprotein, showed significant differences. It was demonstrated that these four proteins were up‐regulated when the larvae were over‐fed and down‐regulated when the larvae were less‐fed. © 2009 Wiley Periodicals, Inc.
The mode of action of venom from the endoparasitic wasp Pimpla hypochondriaca (Hymenoptera: Ichneumonidae) involves Ca+2‐dependent cell death pathways
Authors: Rivers David B. , Dani M. Paulina , Richards Elaine H.
Published: May 2009

The endoparasitoid Pimpla hypochondriaca injects venom during oviposition to condition its lepidopteran hosts. Venom is a complex mixture of proteins and polypeptides, many of which have been identified as enzymes, including phenoloxidase, endopeptidase, aminopeptidase, hydrolase, and angiotensin‐converting enzyme. Constituents of the venom have been shown to possess cytolytic and paralytic activity, but the modes of action of factor(s) responsible for exerting such effects have not been deciphered. In this study, we examined the mode of action of isolated venom using cultured cells (BTI‐TN‐5B1‐4). A series of blockage and inhibition assays were performed using a potent inhibitor (phenylthiourea, PTU) of venom phenoloxidase, and anti‐calreticulin antibodies. Monolayers exposed to venom alone were highly susceptible with more than 84.6±2.3% dead within 15 min. Susceptible cells displayed a retraction of cytoplasmic extensions, rounding, and swelling prior to lysis in more than half (55.7±1.7%) of the dying cells. Within 15 min of exposure to venom, cells displayed qualitative increases in [Ca+2]i as evidenced by staining with the calcium‐sensitive probe fluo‐4 AM, and mitochondrial membrane potential (ΔΨm) was undetectable by 5 min post‐treatment with venom. These venom‐mediated changes occurred regardless of whether an external source of calcium was present, or whether venom was pre‐treated with PTU. In contrast, venom toxicity was attenuated by treatment with anti‐calreticulin antibodies. Not only did fewer cells die when exposed to antibody‐treated venom but also cell swelling diminished and no increases in intracellular calcium were detected. A possible mode of action for the venom is discussed. © 2009 Wiley Periodicals, Inc.
Pyrazolo[3,4‐d]pyrimidine Derivatives as COX‐2 Selective Inhibitors: Synthesis and Molecular Modelling Studies
Authors: Raffa Demetrio , Maggio Benedetta , Plescia Fabiana , Cascioferro Stella , Raimondi Maria Valeria , Plescia Salvatore , Cusimano Maria Grazia
Published: May 2009

The pyrazolo[3,4‐d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti‐inflammatory activity of 5‐benzamido‐pyrazolo[3,4‐d]pyrimidin‐4‐one derivatives and considering the easy synthesis of this class of compounds, a set of new 5‐benzamido‐1H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones has been prepared in 42‐80% yields by reacting 5‐aminopyrazole‐4(N‐benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a–d, and 11a, b revealed a superior inhibitory profile against COX‐2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.
Synthesis and Antibacterial Activity of a New Series of 3‐[3‐(Substituted Phenyl)‐1‐Isonicotinoyl‐1H‐Pyrazol‐5‐yl]‐2H‐Chromen‐2‐one Derivatives
Authors: Aragade Prashant , Maddi Veeresh , Khode Suresh , Palkar Mahesh , Ronad Pradeepkumar , Mamledesai Shivalingarao , Satyanarayana Darbhamulla
Published: May 2009

A novel series of 3‐[3‐(substituted phenyl)‐1‐isonicotinoyl‐1H‐pyrazol‐5‐yl]‐2H‐chromen‐2‐one derivatives 4a–k have been synthesized by the reaction of 3‐[2,3‐dibromo‐3‐(substituted phenyl) propanoyl]‐2H‐chromen‐2‐one 3a–k and isonicotinic acid hydrazide in the presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in‐vitro antibacterial activity against Gram‐positive and Gram‐negative bacteria. Among the series, compounds 4e, 4i, and 4k displayed an encouraging antibacterial activity profile as compared to the reference drug ampicillin against tested bacterial strains.
Generation and Evaluation of a Homology Model of PfGSK‐3
Authors: Kruggel Sebastian , Lemcke Thomas
Published: May 2009

Plasmodial GSK‐3 is a potential new target for malaria therapy. For a structure‐based design project, the three‐dimensional information of the designated target is needed. Unfortunately, experimental structure data for plasmodial GSK‐3 is not yet available. Homology building can be used to generate such three‐dimensional structure data using structure information of a homologous protein. GSK‐3 possesses a very flexible ATP‐binding site, a fact reflected in the variety of X‐ray structures of the human GSK‐3β which are deposited in the protein data base and are crystallized with different ligands. We used ten different HsGSK‐3β templates for the model building of plasmodial GSK‐3 and generated 200 models for each template with different modeling protocols. The quality of the models was evaluated with different tools. The results of these evaluations were used to calculate a rank‐by‐rank consensus score. The top models of this were used to compile an ensemble of PfGSK‐3 models that reflect the flexibility of the ATP‐binding site and that will be used for the structure‐based design of potential ATP‐binding site inhibitors of PfGSK‐3.
Autoimmune regulator controls T cell help for pathogenetic autoantibody production in collagen‐induced arthritis
Authors: Campbell Ian K. , Kinkel Sarah A. , Drake Sarah F. , Nieuwenhuijze Annemarie Van , Hubert François‐Xavier , Tarlinton David M. , Heath William R. , Scott Hamish S. , Wicks Ian P.
Published: May 2009

Objective

Autoimmune regulator (Aire) promotes the ectopic expression of tissue‐restricted antigens in medullary thymic epithelial cells (mTECs), leading to negative selection of autoreactive T cells. This study was undertaken to determine whether loss of central tolerance renders Aire‐deficient (Aire−/−) mice more susceptible to the induction of autoimmune arthritis.

Methods

Medullary TECs were isolated from Aire−/− and wild‐type C57BL/6 mice for gene expression analysis. Collagen‐induced arthritis (CIA) was elicited by injection of chick type II collagen (CII) in adjuvant. Cellular and humoral immune responses to CII were evaluated. Chimeric mice were created by reconstituting lymphocyte‐deficient mice with either Aire−/− or wild‐type CD4 T cells and wild‐type B cells.

Results

Wild‐type, but not Aire−/−, mTECs expressed the CII gene Col2a1. Aire−/− mice developed more rapid and severe CIA, showing elevated serum anti‐CII IgG levels, with earlier switching to arthritogenic IgG subclasses. No evidence was found of enhanced T cell responsiveness to CII in Aire−/− mice; however, Aire−/− CD4 T cells were more efficient at stimulating wild‐type B cells to produce anti‐CII IgG following immunization of chimeric mice with CII.

Conclusion

Our findings indicate that Aire‐dependent expression of CII occurs in mTECs, implying that there is central tolerance to self antigens found in articular cartilage. Reduced central tolerance to CII in Aire−/− mice manifests as increased CD4 T cell help to B cells for cross‐reactive autoantibody production and enhanced CIA. Aire and central tolerance help prevent cross‐reactive autoimmune responses to CII initiated by environmental stimuli and limit spontaneous autoimmunity.
Relationships between the fibromyalgia impact questionnaire, tender point count, and muscle strength in female patients with fibromyalgia: A cohort study
Authors: Henriksen Marius , Lund Hans , Christensen Robin , Jespersen Anders , Dreyer Lene , Bennett Robert M. , Danneskiold‐SamsØe Bente , Bliddal Henning
Published: May 2009

Objective

To test the hypothesis that fibromyalgia (FM) patients with reduced lower extremity strength are more symptomatic and tender than FM patients with normal muscle strength.

Methods

A total of 840 FM patients and 122 healthy subjects were evaluated between 1998 and 2005. All of the patients completed version 1 of the Fibromyalgia Impact Questionnaire (FIQ) and were assessed for tender points and knee muscle strength. All subjects underwent bilateral isokinetic knee muscle strength testing in flexion and extension. Normative knee muscle strength values were calculated from the healthy subjects, and the FM cohort was divided in 2 groups: 1) patients with normal muscle strength and 2) patients with low muscle strength (2 SDs below normal). The clinical characteristics of these 2 groups were compared.

Results

Significantly reduced knee muscle strength was found in 52% of the patients. There were no clinically significant differences between patients with low versus normal muscle strength. There were no clinically significant correlations between total FIQ score, tender point count, and muscle strength. Only 4.6% of the FIQ scores and 5.1% of the tender point counts were explained by muscle strength.

Conclusion

Significantly reduced knee muscle strength was found in more than half of the patients. Patients with subnormal muscle strength were not more symptomatic or tender than patients with normal muscle strength. There were no clinically significant correlations between FIQ, tender point count, and muscle strength; therefore, reduced knee muscle strength appears to be a common objective abnormality in FM that is independent of measurements of disease activity. The implication of this finding in regard to the clinical assessment of FM needs further study.
Is adiposity an under‐recognized risk factor for tendinopathy? A systematic review
Authors: Gaida James E. , Ashe Maureen C. , Bass Shona L. , Cook Jill L.
Published: May 2009

Objective

Tendon injuries have been reported to occur more frequently in individuals with increased adiposity. Treatment also appears to have poorer outcomes among these individuals. Our objective was to examine the extent and consistency of associations between adiposity and tendinopathy.

Methods

A systematic review of observational studies was conducted. Eight electronic databases were searched (Allied and Complementary Medicine, Biological Abstracts, CINAHL, Current Contents, EMBase, Medline, SPORTDiscus, and Web of Science) and citation tracking was performed on included reports. Studies were included if they compared adiposity between subjects with and without tendon injury or examined adiposity as a predictor of conservative treatment success.

Results

Four longitudinal cohorts, 14 cross‐sectional studies, 8 case–control studies, and 2 interventional studies (28 in total) met the inclusion criteria, providing a total of 19,949 individuals. Forty‐two subpopulations were identified, 18 of which showed elevated adiposity to be associated with tendon injury (43%). Sensitivity analyses indicated a clustering of positive findings among studies that included clinical patients (81% positive) and among case–control studies (77% positive).

Conclusion

Elevated adiposity is frequently associated with tendon injury. Published reports suggest that elevated adiposity is a risk factor for tendon injury, although this association appears to vary depending on aspects of study design and measurement. Adiposity is of particular interest in tendon research because, unlike a number of other reported risk factors for tendon injury, it is somewhat preventable and modifiable. Further research is required to determine if reducing adiposity will reduce the risk of tendon injury or improve the results of treatment.
Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus
Authors: Bachen Elizabeth A. , Chesney Margaret A. , Criswell Lindsey A.
Published: May 2009

Objective

To examine the lifetime prevalence of mood and anxiety disorders in patients with systemic lupus erythematosus (SLE). Demographic and disease‐related variables were examined for association with lifetime major depressive disorder (MDD) and the presence of any mood or anxiety disorder.

Methods

Three hundred twenty‐six white women with SLE completed the Composite International Diagnostic Interview and the Systemic Lupus Activity Questionnaire, a self‐report measure of SLE disease activity. The binomial test was used to compare the prevalence of psychiatric diagnoses in patients with SLE with a population sample of white women.

Results

Sixty‐five percent of the participants received a lifetime mood or anxiety diagnosis. MDD (47%), specific phobia (24%), panic disorder (16%), obsessive‐compulsive disorder (9%), and bipolar I disorder (6%) were more common among patients with SLE than among other white women (P = 0.00009 for specific phobia; for all other values P = 0.00001). Although most patients with histories of mood disorders reported their psychiatric symptoms to a medical provider, a substantial number of patients with anxiety disorders did not. Self‐reported disease activity was associated with a lifetime history of MDD (P = 0.001) and presence of a mood or anxiety disorder (P = 0.001), after controlling for demographic and clinical characteristics.

Conclusion

Several mood and anxiety disorders were more common in women with SLE compared with the general population, and disease activity may contribute to this higher risk. Brief self‐report questionnaires may help providers identify patients with these conditions, particularly when patients are reluctant to disclose their symptoms.
Time course and nature of brain atrophy in the MRL mouse model of central nervous system lupus
Authors: Sled John G. , Spring Shoshana , van Eede Matthijs , Lerch Jason P. , Ullal Sangeeta , Sakic Boris
Published: May 2009

Objective

Similar to patients with systemic lupus erythematosus, autoimmune MRL/lpr mice spontaneously develop behavioral deficits and pathologic changes in the brain. Given that the disease‐associated brain atrophy in this model is not well understood, the present study was undertaken to determine the time course of morphometric changes in major brain structures of autoimmune MRL/lpr mice.

Methods

Computerized planimetry and high‐resolution magnetic resonance imaging (MRI) were used to compare the areas and volumes of brain structures in cohorts of mice that differ in severity of lupus‐like disease.

Results

A thinner cerebral cortex and smaller cerebellum were observed in the MRL/lpr substrain, even before severe autoimmunity developed. With progression of the disease, the brain area of coronal sections became smaller and the growth of the hippocampus was retarded, which likely contributed to the increase in the ventricle area:brain area ratio. MRI revealed reduced volume across different brain regions, with the structures in the vicinity of the ventricular system particularly affected. The superior colliculus, periaqueductal gray matter, pons, and midbrain were among the regions most affected, whereas the volumes of the parietal‐temporal lobe, parts of the cerebellum, and lateral ventricles in autoimmune MRL/lpr mice were comparable with values in congenic controls.

Conclusion

These results suggest that morphologic alterations in the brains of MRL/lpr mice are a consequence of several factors, including spontaneous development of lupus‐like disease. A periventricular pattern of parenchymal damage is consistent with the cerebrospinal fluid neurotoxicity, limbic system pathologic features, and deficits in emotional reactivity previously documented in this model.
Large‐scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand
Authors: Evangelou Evangelos , Chapman Kay , Meulenbelt Ingrid , Karassa Fotini B. , Loughlin John , Carr Andrew , Doherty Michael , Doherty Sally , Gómez‐Reino Juan J. , Gonzalez Antonio , Halldorsson Bjarni V. , Hauksson Valdimar B. , Hofman Albert , Hart Deborah J. , Ikegawa Shiro , Ingvarsson Thorvaldur , Jiang Qing , Jonsdottir Ingileif , Jonsson Helgi , Kerkhof Hanneke J. M. , Kloppenburg Margreet , Lane Nancy E. , Li Jia , Lories Rik J. , van Meurs Joyce B. J. , Näkki Annu , Nevitt Michael C. , Rodriguez‐Lopez Julio , Shi Dongquan , Slagboom P. Eline , Stefansson Kari , Tsezou Aspasia , Wallis Gillian A. , Watson Christopher M. , Spector Tim D. , Uitterlinden Andre G. , Valdes Ana M. , Ioannidis John P. A.
Published: May 2009

Objective

GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large‐scale meta‐analysis of individual‐level data.

Methods

Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex‐specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed‐effects and random‐effects models for allele‐based effects, and also for haplotype effects for FRZB.

Results

A significant random‐effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between‐study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between‐study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).

Conclusion

Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
Risks of rheumatic diseases in first‐ and second‐generation immigrants in Sweden: A nationwide followup study
Authors: Li Xinjun , Sundquist Jan , Sundquist Kristina
Published: May 2009

Objective

To examine whether there is an association between country of birth in first‐generation immigrants and first hospitalization for a rheumatic disease, and to study whether any such association remains in second‐generation immigrants.

Methods

In this followup study, the Swedish MigMed database at the Karolinska Institute in Stockholm was used to identify all primary hospital diagnoses of rheumatic diseases in first‐ and second‐generation immigrants in Sweden between January 1, 1964 and December 31, 2004. Incidence ratios, standardized with regard to age, geographic region, and socioeconomic status, were estimated by sex in first‐ and second‐generation immigrants.

Results

First‐generation immigrants from Iraq had a higher risk of rheumatoid arthritis than did subjects in the native‐born Swede reference group, and the risk of systemic lupus erythematosus was increased in immigrants from Iraq and Africa; these raised risks persisted in the second generation. The lower risk of rheumatoid arthritis in some first‐generation immigrants disappeared in the second generation. In groups of second‐generation immigrants, the risk of ankylosing spondylitis was similar to the risk in the corresponding parental groups. Polish‐born immigrants and second‐generation Yugoslavs and Russians showed a significantly increased risk of systemic sclerosis. The raised risk of systemic sclerosis did not persist in the second generation, but was clustered in groups involved in certain blue collar occupations.

Conclusion

Country of birth affected the risk of rheumatic disease. These findings indicate that both genetic and environmental factors are involved in the etiology of specific rheumatic diseases.
Incomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigree
Authors: Saulsbury Frank T. , Wouters Carine H. , Martin Tammy M. , Austin Carrie R. , Doyle Trudy M. , Goodwin Kelly A. , Rosé Carlos D.
Published: May 2009

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6‐year‐old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 “Blau mutations.”
Anaerobic‐to‐aerobic power ratio in children with juvenile idiopathic arthritis
Authors: van Brussel Marco , van Doren Lieke , Timmons Brian W. , Obeid Joyce , van der Net Janjaap , Helders Paul J. M. , Takken Tim
Published: May 2009

Objective

To examine the anaerobic‐to‐aerobic power ratio in children with juvenile idiopathic arthritis (JIA) compared with healthy peers.

Methods

Sixty‐two patients with JIA (mean ± SD age 11.9 ± 2.1 years, range 7.2–15.9 years) with varying severity of disease and 50 healthy children (mean ± SD age 12.1 ± 2.1, range 8.4–15.9 years) participated in this study. Anaerobic power was measured using the Wingate Anaerobic Exercise Test. Aerobic power was measured using a cardiopulmonary exercise test. The power ratio was calculated as the ratio between the anaerobic mechanical power and aerobic mechanical power in watts.

Results

Mean ± SD anaerobic‐to‐aerobic power ratio and peak anaerobic‐to‐aerobic ratios in children with JIA were 1.98 ± 0.51 and 3.28 ± 1.15, respectively. Compared with healthy children these differences were not statistically significant (P = 0.52 and P = 0.99, respectively). The differences in these ratios were not statistically significant when corrected for age, height, and body mass. Statistical analyses showed no significant difference between disease‐onset types of JIA for mean anaerobic‐to‐aerobic power ratio and peak anaerobic‐to‐aerobic ratio, respectively. Furthermore, there was no significant difference in the development of the power ratios between children with JIA and healthy controls, or between girls and boys.

Conclusion

This cross‐sectional study suggests that the development of the anaerobic‐to‐aerobic power ratio is not statistically different in children with JIA compared with healthy peers. Exercise training of the anaerobic capacity through interval training, along with aerobic exercise training, seems warranted in the exercise therapy programs of children with JIA.
Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: A single center study of a cohort of 71 subjects
Authors: Colina Matteo , Govoni Marcello , Orzincolo Carlo , Trotta Francesco
Published: May 2009

Objective

To assess the basic features and outcomes of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome.

Methods

We identified all patients seen in our unit between 1990 and 2008 diagnosed according to the proposed inclusion criteria with SAPHO syndrome, who had a followup of at least 2 years.

Results

Seventy‐one patients (48 women, 23 men) with SAPHO syndrome were identified. The median disease duration at the end of followup was 10 years (interquartile range [IQR] 7–15 years), and the median followup duration was 11 years (IQR 6–11.5 years). Six patients were diagnosed with Crohn's disease. Fourteen patients had never had cutaneous involvement, but 8 patients presented >1 skin manifestation. Nine patients (13%) presented a limited (<6 months) monophasic disease course, 25 cases (35%) had a relapsing–remitting course, and 37 patients (52%) had an acute painful phase with a prolonged course lasting >6 months. A total of 4% of the patients were HLA–B27 positive. Female sex (odds ratio [OR] 7.2, 95% confidence interval [95% CI] 2.2–22.9) and the presence at onset of anterior chest wall (ACW) involvement (OR 5.7, 95% CI 1.8–18.1), peripheral synovitis (P = 0.0036), skin involvement (OR 10.3, 95% CI 3.4–31.1), and high values of acute‐phase reactants (OR 7.7, 95% CI 2.7–22) were correlated with a chronic disease course and involvement of new osteoarticular sites.

Conclusion

A chronic course is the more common evolution of SAPHO syndrome. Female sex, elevated erythrocyte sedimentation rate and C‐reactive protein values, ACW involvement, peripheral synovitis, and skin involvement at the onset seem to be associated with a chronic course.
The knee pain map: Reliability of a method to identify knee pain location and pattern
Authors: Thompson Laura R. , Boudreau Robert , Hannon Michael J. , Newman Anne B. , Chu Constance R. , Jansen Mary , Nevitt Michael C. , Kwoh C. Kent
Published: May 2009

Objective

To describe the location and pattern of knee pain in patients with chronic, frequent knee pain using the Knee Pain Map, and to evaluate the inter‐ and intrarater reliability of the map.

Methods

A cohort of 799 participants from the University of Pittsburgh Osteoarthritis Initiative Clinical Center who had knee pain in the last 12 months were studied. Trained interviewers assessed and recorded participant‐reported knee pain patterns into 8 local areas, 4 regional areas, or as diffuse. Inter‐ and intrarater reliability were assessed using Fleiss' kappa.

Results

Participants most often reported localized (69%) followed by regional (14%) or diffuse (10%) knee pain. In those with localized pain, the most commonly reported locations were the medial (56%) and lateral (43%) joint lines. In those with regional pain, the most commonly reported regions were the patella (44%) and medial region (38%). There was excellent interrater reliability for the identification of localized and regional pain patterns (κ = 0.7–0.9 and 0.7–0.8, respectively). The interrater reliability for specific locations was also excellent (κ = 0.7–1.0) when the number of participants with pain in a location was >4. For regional pain, the kappa for specific regions varied from 0.7–1.0.

Conclusion

The majority of participants could identify the location of their knee pain, and trained interviewers could reliably record those locations. The variation in locations suggests that there are multiple sources of pain in knee OA. Additional studies are needed to determine whether specific knee pain patterns correlate with discrete pathologic findings on radiographs or magnetic resonance images.
Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint
Authors: Davies Mark R. , Ribeiro Lyn Rosenbrier , Downey‐Jones Mark , Needham Maurice R. C. , Oakley Caroline , Wardale John
Published: May 2009

Objective

Vitamin A derivatives, including all‐trans‐retinoic acid (ATRA), have a well‐established role during skeletal development and limb formation and have been shown to have profound effects on chondrocyte phenotype. The aim of this study was to elucidate the effects of retinoids and components of the retinoid metabolic pathway on chondrocyte phenotype in the tibiofemoral joints of patients with osteoarthritis (OA), to show that the retinoids can have multiple effects relevant to the OA disease process.

Methods

Human explant tissue and a chondrocyte‐like cell line were treated with ATRA, and the responses of 4 key markers of chondrocyte phenotype were analyzed. In addition, the effects of ATRA on a number of novel genes associated with OA were assessed using a low‐density microarray containing 80 disease marker genes.

Results

Vitamin A metabolite levels were elevated in synovial fluid, serum, and cartilage from patients with OA. Expression profiling of a retinoic acid receptor α coactivator protein, P/CAF, demonstrated elevated expression in patients with OA, suggesting the potential for increased signaling via the retinoid receptors in the disease. ATRA increased the levels of matrix metalloproteinase 13 and aggrecanase activity in human cartilage explants and in a human chondrocyte cell line. Furthermore, ATRA altered the expression of a wide range of relevant genes, including the types I, II, IX, and XI collagen genes, toward a nonchondrogenic and OA‐like phenotype.

Conclusion

These results suggest that retinoid signaling could have a central role in OA, and that components of the pathway may provide potential disease biomarkers or targets for therapeutic intervention.
The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis
Authors: Solomon Daniel H. , Finkelstein Joel S. , Shadick Nancy , LeBoff Meryl S. , Winalski Carl S. , Stedman Margaret , Glass Roberta , Brookhart M. Alan , Weinblatt Michael E. , Gravallese Ellen M.
Published: May 2009

Objective

Among rheumatoid arthritis (RA) patients who have had the disease for 10 years, more than half have focal erosions, and the risk of fracture is doubled. However, there is little information about the potential relationship between focal erosions and bone mineral density (BMD). The aim of this study was to determine whether lower BMD is associated with higher erosion scores among patients with RA.

Methods

We enrolled 163 postmenopausal women with RA, none of whom were taking osteoporosis medications. Patients underwent dual x‐ray absorptiometry at the hip and spine and hand radiography, and completed a questionnaire. The hand radiographs were scored using the Sharp method, and the relationship between BMD and erosions was measured using Spearman's correlation coefficients and adjusted linear regression models.

Results

Patients had an average disease duration of 13.7 years, and almost all were taking a disease‐modifying antirheumatic drug. Sixty‐three percent were rheumatoid factor (RF) positive. The median modified Health Assessment Questionnaire score was 0.7, and the average Disease Activity Score in 28 joints was 3.8. The erosion score was significantly correlated with total hip BMD (r = −0.33,P< 0.0001), but not with lumbar spine BMD (r = −0.09,P= 0.27). Hip BMD was significantly lower in RF‐positive patients versus RF‐negative patients (P= 0.02). In multivariable models that included age, body mass index, and cumulative oral glucocorticoid dose, neither total hip BMD nor lumbar spine BMD was significantly associated with focal erosions.

Conclusion

Our results suggest that hip BMD is associated with focal erosions among postmenopausal women with RA, but that this association disappears after multivariable adjustment. While BMD and erosions may be correlated with bone manifestations of RA, their relationship is complex and influenced by other disease‐related factors.
The critical role of kinase activity of interleukin‐1 receptor–associated kinase 4 in animal models of joint inflammation
Authors: Koziczak‐Holbro Magdalena , Littlewood‐Evans Amanda , Pöllinger Bernadette , Kovarik Jiri , Dawson Janet , Zenke Gerhard , Burkhart Christoph , Müller Matthias , Gram Hermann
Published: May 2009

Objective

We have previously reported that the kinase activity of interleukin‐1 receptor–associated kinase 4 (IRAK‐4) is important for Toll‐like receptor and interleukin‐1 receptor signaling in vitro. Using mice devoid of IRAK‐4 kinase activity (IRAK‐4 KD mice), we undertook this study to determine the importance of IRAK‐4 kinase function in complex disease models of joint inflammation.

Methods

IRAK‐4 KD mice were subjected to serum transfer–induced (K/BxN) arthritis, and migration of transferred spleen lymphocytes into joints and cartilage and bone degradation were assessed. T cell response in vivo was tested in antigen‐induced arthritis (AIA) by measuring the T cell–dependent antigen‐specific IgG production and frequency of antigen‐specific T cells in the spleen and lymph nodes. T cell allogeneic response was tested in vitro by mixed lymphocyte reaction (MLR).

Results

Lipopolysaccharide‐induced local neutrophil influx into subcutaneous air pouches was impaired in IRAK‐4 KD mice. These mice were also protected from inflammation in the K/BxN and AIA models, as shown by reduced swelling of joints. Histologic analysis of joints of K/BxN serum–injected mice revealed that bone erosion, osteoclast formation, and cartilage matrix proteoglycan loss were reduced in IRAK‐4 KD mice. Assessment of T cell response by MLR, by frequency of antigen‐specific clones, and by production of antigen‐specific IgG did not reveal substantial differences between IRAK‐4 KD and wild‐type mice.

Conclusion

These results demonstrate that IRAK‐4 is a key component for the development of proarthritis inflammation, but that it is not crucial for T cell activation. Therefore, the kinase function of IRAK‐4 appears to be an attractive therapeutic target in chronic inflammation.
Impact of medicare part D on access to and cost sharing for specialty biologic medications for beneficiaries with rheumatoid arthritis
Authors: Polinski Jennifer M. , Mohr Penny E. , Johnson Lorraine
Published: May 2009

Objective

Many worry that the use of specialty tiering for biologic disease‐modifying antirheumatic drugs (DMARDs) by Medicare Part D plans imposes a heavy financial burden on beneficiaries with rheumatoid arthritis (RA). To date, no one has examined the cost‐sharing structures for biologic DMARDs in Part D plans or the resulting cost burden for patients.

Methods

We followed 14,929 vulnerable, low‐income patients with RA who were enrolled in the Medicare Replacement Drug Demonstration (MRDD) in 2005. As the MRDD population transitioned into Part D in 2006, we examined correlates of Part D enrollment and compared the cost‐sharing provisions for biologic DMARDs in the Medicare Advantage and stand‐alone plans. We simulated the out‐of‐pocket costs of beneficiaries under 3 cost‐sharing scenarios.

Results

Eighty‐one percent of MRDD beneficiaries with RA enrolled in Part D. Enrollment predictors were female sex (odds ratio [OR] 1.48, 95% confidence interval [95% CI] 1.32–1.67), prior MRDD benefit use (OR 2.29, 95% CI 2.04–2.58), other self‐reported drug coverage (OR 1.53, 95% CI 1.36–1.71), and receiving an MRDD subsidy (OR 2.00, 95% CI 1.74–2.30). Compared with stand‐alone plans, Medicare Advantage plans had lower deductibles, lower premiums, and fewer prior authorization, step therapy, and quantity limit restrictions. However, ∼75% of all plans used coinsurance as the preferred form of cost sharing. Out‐of‐pocket costs exceeded $4,000 annually in all cost‐sharing scenarios.

Conclusion

Most MRDD beneficiaries with RA enrolled in Part D. Although plans assume some costs for biologic DMARDs, the majority of costs are shifted to beneficiaries and to Medicare. Such cost shifting may place these medications out of the beneficiary's financial reach and expose Medicare to high financial liability.
Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis
Authors: Shen Hui , Goodall Jane C. , Hill Gaston J. S.
Published: May 2009

Objective

To analyze the frequency, surface phenotype, and cytokine secretion of CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared with both healthy control subjects and patients with rheumatoid arthritis (RA).

Methods

Eight‐color flow cytometry was used to analyze the surface phenotype and cytokine production of PBMCs from 20 patients with AS, 12 patients with RA, and 16 healthy control subjects, following stimulation ex vivo with phorbol myristate acetate and ionomycin for 5 hours. Secretion of interleukin‐17 (IL‐17) by PBMCs was measured by enzyme‐linked immunosorbent assay, following stimulation with anti‐CD3/CD28 for 4 days.

Results

The percentages of IL‐17–positive CD4+ T cells and IL‐22–positive CD4+ T cells were increased in the PBMCs of both patients with AS and patients with RA compared with healthy control subjects, whereas there were no differences in the percentages of interferon‐γ (IFNγ)–positive or IL‐10–positive CD4+ T cells. Likewise, concentrations of IL‐17 in supernatants from patients with AS were significantly higher compared with those from healthy control subjects. In patients with RA, the concentrations of IL‐17 were increased but not significantly. There was a correlation between the percentages of IL‐17–positive CD4+ T cells detected in PBMCs and the amounts of IL‐17 in culture supernatants (r = 0.414, P = 0.0034). All IL‐17–producing cells were CD4+CD45RO+; most expressed both CCR6 and CCR4, but only 50% expressed the IL‐23 receptor (IL‐23R). Nevertheless, there was a positive relationship between the percentage of IL‐23R–positive CD4+ T cells and the frequency of IL‐17–positive CD4+ T cells or IL‐22–positive CD4+ T cells (r = 0.57, P < 0.0001 and r = 0.46, P = 0.001, respectively). A significant proportion of cells that produced IL‐17 also produced IL‐22 and IFNγ, but none produced IL‐10.

Conclusion

The frequencies of IL‐17–positive and IL‐22–positive CD4+ T cells were increased in PBMCs from patients with AS and patients with RA, resulting in secretion of higher quantities of IL‐17 by PBMCs following stimulation. These data support the hypothesis that Th17 cells, particularly when present in excess of IL‐10–producing cells, are involved in the pathogenesis of inflammatory arthritis.