bluuebunny/crossref_metadata_2025 huggingface dataset:
Selection of line‐transect methods for estimating the density of group‐living animals: lessons from the primates
Authors: Marshall Andrew R. , Lovett Jon C. , White Piran C.L.
Published: January 2008

We review the four major contemporary methods for estimating density of group‐living animals from line‐transect sampling: perpendicular modelling of group centers, perpendicular modelling of center of measurable individuals, strip transects and animal–observer distance. The efficacy of each method is evaluated to produce a simple selection guide. We review the literature and use field data from the Udzungwa Mountains, Tanzania. The review is relevant to all group‐living animals; however, examples are drawn from the primates. Perpendicular methods have better mathematical justification than non‐perpendicular methods. For perpendicular methods using detection function models, it is preferable to measure group location using center of measurable individuals, as group centers are hard to estimate. The assumptions of detection function models are often broken in poor visibility habitats or with unhabituated animals. Alternatively strip transects may be used where there are reliable data on group spread and/or visibility. Strip transects are also the most practical, along with the animal–observer method; however, the latter lacks mathematical justification. We conclude that there are arguments for continued use of all four methods. In certain situations the use of raw encounter rates may also be considered. The appropriate method is determined by minimizing bias and considering time, resources and field conditions. Am. J. Primatol. 70:452–462, 2008. © 2008 Wiley‐Liss, Inc.
Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson's disease
Authors: Martin W. R. Wayne , Wieler Marguerite , Stoessl A. Jon , Schulzer Michael
Published: January 2008

Objective

To determine the sensitivity of positron emission tomography with11C‐labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD.

Methods

Untreated patients with early PD (n = 27) and age‐matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale.

Results

Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p< 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation.

Interpretation

Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible “floor” effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident. Ann Neurol 2008
Lewis‐Base‐Katalyse in der organischen Synthese
Authors: Denmark Scott E. , Beutner Gregory L.
Published: January 2008

Das Erbe von Gilbert Newton Lewis (1875–1946) ist im Wörterbuch der chemischen Bindung und Reaktivität allgegenwärtig. Die Bedeutung seines Konzepts der Donor‐Akzeptor‐Bindung kommt in den eponymen Grundbegriffen für Elektronenpaarakzeptoren (Lewis‐Säuren) und ‐donoren (Lewis‐Basen) zum Ausdruck. Lewis erkannte, dass Säuren nicht automatisch Wasserstoff enthalten müssen (Brønsted‐Säuren) und trug so zum Sturz des “modernen Protonenkults” bei. Seine Entdeckung läutete zunächst die Entwicklung von Lewis‐Säuren als Reagentien und Katalysatoren für organische Reaktionen ein, in den letzten Jahren wurde aber offensichtlich, dass für diese Zwecke auch Lewis‐Basen eingesetzt werden können. Bezüglich der Beschleunigung chemischer Reaktionen ergänzen Lewis‐Basen die entsprechenden Lewis‐Säuren nicht nur elektronisch: Tatsächlich können Lewis‐Basen die Elektrophilie wie auch die Nucleophilie der Verbindungen verstärken, an die sie gebunden werden. Diese unterschiedliche Reaktivität resultiert in einer bemerkenswerten Vielfalt Lewis‐Base‐katalysierter Reaktionen.
Lewis Base Catalysis in Organic Synthesis
Authors: Denmark Scott E. , Beutner Gregory L.
Published: January 2008

The legacy of Gilbert Newton Lewis (1875–1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor–acceptor bonding is evident in the eponymous foundations of electron‐pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Brønsted acids), and helped overthrow the “modern cult of the proton”. His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.
A sodium dodecyl sulfate–polyacrylamide gel electrophoresis–liquid chromatography tandem mass spectrometry analysis of bovine cartilage tissue response to mechanical compression injury and the inflammatory cytokines tumor necrosis factor α and interleukin‐1β
Authors: Stevens Anna L. , Wishnok John S. , Chai Diana H. , Grodzinsky Alan J. , Tannenbaum Steven R.
Published: January 2008

Objective

To compare the response of chondrocytes and cartilage matrix to injurious mechanical compression and treatment with interleukin‐1β (IL‐1β) and tumor necrosis factor α (TNFα), by characterizing proteins lost to the medium from cartilage explant culture.

Methods

Cartilage explants from young bovine stifle joints were treated with 10 ng/ml of IL‐1β or 100 ng/ml of TNFα or were subjected to uniaxial, radially‐unconfined injurious compression (50% strain; 100%/second strain rate) and were then cultured for 5 days. Pooled media were subjected to gel‐based separation (sodium dodecyl sulfate–polyacrylamide gel electrophoresis) and analysis by liquid chromatography tandem mass spectrometry, and the data were analyzed by Spectrum Mill proteomics software, focusing on protein identification, expression levels, and matrix protein proteolysis.

Results

More than 250 proteins were detected, including extracellular matrix (ECM) structural proteins, pericellular matrix proteins important in cell–cell interactions, and novel cartilage proteins CD109, platelet‐derived growth factor receptor–like, angiopoietin‐like 7, and adipocyte enhancer binding protein 1. IL‐1β and TNFα caused increased release of chitinase 3–like protein 1 (CHI3L1), CHI3L2, complement factor B, matrix metalloproteinase 3, ECM‐1, haptoglobin, serum amyloid A3, and clusterin. Injurious compression caused the release of intracellular proteins, including Grp58, Grp78, α4‐actinin, pyruvate kinase, and vimentin. Injurious compression also caused increased release and evidence of proteolysis of type VI collagen subunits, cartilage oligomeric matrix protein, and fibronectin.

Conclusion

Overload compression injury caused a loss of cartilage integrity, including matrix damage and cell membrane disruption, which likely occurred through strain‐induced mechanical disruption of cells and matrix. IL‐1β and TNFα caused the release of proteins associated with an innate immune and stress response by the chondrocytes, which may play a role in host defense against pathogens or may protect cells against stress‐induced damage.
Serum uric acid is an independent predictor of all‐cause mortality in patients at high risk of cardiovascular disease: A preventive cardiology information system (PreCIS) database cohort study
Authors: Ioachimescu Adriana G. , Brennan Danielle M. , Hoar Brian M. , Hazen Stanley L. , Hoogwerf Byron J.
Published: January 2008

Objective

Uric acid is a product of the activity of xanthine oxidase, an enzyme linked to oxidative stress, endothelial dysfunction, and heart failure. It is unclear whether adding uric acid levels to the assessment of cardiovascular risk might contribute to the improved ability to stratify cardiovascular risk. The purpose of this study was to evaluate the prognostic value of serum uric acid levels in a large cohort of men and women at high risk of cardiovascular disease.

Methods

Serum uric acid levels were determined in all patients seen for primary/secondary cardiovascular disease prevention at the Cleveland Clinic Section of Preventive Cardiology and Rehabilitation between 1998 and 2004, and all data were entered into the Preventive Cardiology Information System (PreCIS) database. Vital status of the patients was determined through the Social Security Death Index. Death from all causes was summarized across quartiles of uric acid values.

Results

A total of 3,098 patients (age range 18–87 years) were identified in the database, among whom 43% had cardiovascular disease. There were 156 deaths (5%) during the 14,262 person‐years of followup. For each 1‐mg/dl increase in the serum uric acid level, there was a 39% increase in the risk of death (by Cox regression analysis). After adjusting for age, sex, smoking status, alcohol consumption, weight, body mass index, waist circumference, blood pressure, history of cardiovascular disease, estimated glomerular filtration rate, levels of cholesterol fractions, and plasma glucose levels, the serum uric acid level continued to predict the risk of death (hazard ratio = 1.26 [95% confidence interval 1.15–1.38], P < 0.001). This association was present regardless of diuretic use. Concordance index (C statistic) analyses showed that uric acid significantly improved the predictive accuracy of a model that included Framingham Heart Study score factors, metabolic syndrome components, and fibrinogen levels.

Conclusion

Serum uric acid levels are an independent predictor of death in patients at high risk of cardiovascular disease. Further studies are warranted to evaluate its prognostic implications and potential utility in the monitoring of therapy.
Cell‐based resurfacing of large cartilage defects: Long‐term evaluation of grafts from autologous transgene‐activated periosteal cells in a porcine model of osteoarthritis
Authors: Gelse Kolja , Mühle Christiane , Franke Oliver , Park Jung , Jehle Marc , Durst Karsten , Göken Mathias , Hennig Friedrich , Mark Klaus Von Der , Schneider Holm
Published: January 2008

Objective

To investigate the potential of transgene‐activated periosteal cells for permanently resurfacing large partial‐thickness cartilage defects.

Methods

In miniature pigs, autologous periosteal cells stimulated ex vivo by bone morphogenetic protein 2 gene transfer, using liposomes or a combination of adeno‐associated virus (AAV) and adenovirus (Ad) vectors, were applied on a bioresorbable scaffold to chondral lesions comprising the entire medial half of the patella. The resulting repair tissue was assessed, 6 and 26 weeks after transplantation, by histochemical and immunohistochemical methods. The biomechanical properties of the repair tissue were characterized by nanoindentation measurements. Implants of unstimulated cells and untreated lesions served as controls.

Results

All grafts showed satisfactory integration into the preexisting cartilage. Six weeks after transplantation, AAV/Ad‐stimulated periosteal cells had adopted a chondrocyte‐like phenotype in all layers; the newly formed matrix was rich in proteoglycans and type II collagen, and its contact stiffness was close to that of healthy hyaline cartilage. Unstimulated periosteal cells and cells activated by liposomal gene transfer formed only fibrocartilaginous repair tissue with minor contact stiffness. However, within 6 months following transplantation, the AAV/Ad‐stimulated cells in the superficial zone tended to dedifferentiate, as indicated by a switch from type II to type I collagen synthesis and reduced contact stiffness. In deeper zones, these cells retained their chondrocytic phenotype, coinciding with positive staining for type II collagen in the matrix.

Conclusion

Large partial‐thickness cartilage defects can be resurfaced efficiently with hyaline‐like cartilage formed by transgene‐activated periosteal cells. The long‐term stability of the cartilage seems to depend on physicobiochemical factors that are active only in deeper zones of the cartilaginous tissue.
Heparan sulfate–dependent ERK activation contributes to the overexpression of fibrotic proteins and enhanced contraction by scleroderma fibroblasts
Authors: Chen Yunliang , Leask Andrew , Abraham David J. , Pala Daphne , Shiwen Xu , Khan Korsa , Liu Shangxi , Carter David E. , Wilcox‐Adelman Sarah , Goetinck Paul , Denton Christopher P. , Black Carol M. , Pitsillides Andrew A. , Sarraf Catherine E. , Eastwood Mark
Published: January 2008

Objective

To investigate the contribution of heparan sulfate proteoglycan and Ras/MEK/ERK to the overexpression of profibrotic proteins and the enhanced contractile ability of dermal fibroblasts from patients with systemic sclerosis (SSc; scleroderma).

Methods

The effects of the MEK/ERK inhibitor U0126, the heparan sulfate side chain formation inhibitor β‐xyloside, and soluble heparin on the overexpression of profibrotic genes were compared in fibroblasts from lesional skin of patients with diffuse SSc and fibroblasts from healthy control subjects. Identified protein expressions were compared with the contractile abilities of fibroblasts while they resided within a collagen lattice. Forces generated were measured using a culture force monitor.

Results

Inhibiting MEK/ERK with U0126 significantly reduced expression of a cohort of proadhesive and procontractile proteins that normally are overexpressed by scleroderma fibroblasts, including integrin α4 and integrin β1. Antagonizing heparan sulfate side chain formation with β‐xyloside or the addition of soluble heparin prevented ERK activation, in addition to reducing the expression of these proadhesive/contractile proteins. Treatment with either U0126, β‐xyloside, or heparin resulted in a reduction in the overall peak contractile force generated by dermal fibroblasts. Blocking platelet‐derived growth factor receptor with Gleevec (imatinib mesylate) reduced overall contractile ability and the elevated syndecan 4 expression and ERK activation in SSc fibroblasts.

Conclusion

The results of this study suggest that heparan sulfate–dependent ERK activation contributes to the enhanced contractile ability demonstrated by dermal fibroblasts from lesional skin of patients with scleroderma. These results are consistent with the notion that the MEK/ERK procontractile pathway is dysregulated in scleroderma dermal fibroblasts. Additionally, the results suggest that antagonizing the MEK/ERK pathway is likely to modulate heparan sulfate proteoglycan activity, which in turn may have a profound effect on the fibrotic response in SSc.
Effective treatment with oral administration of rebamipide in a mouse model of Sjögren's syndrome
Authors: Kohashi Masayuki , Ishimaru Naozumi , Arakaki Rieko , Hayashi Yoshio
Published: January 2008

Objective

To determine whether oral administration of rebamipide, a mucosal protective agent, is effective in the treatment of Sjögren's syndrome (SS) in the NFS/sld mouse model of the disease.

Methods

NFS/sld mice were given daily oral doses of rebamipide (0.3 mg/kg of body weight or 3 mg/kg) or vehicle alone starting from the age of 4 weeks to the age of 8 weeks. The volume of saliva and tears was monitored during and after treatment. After the final dose, histologic features of the tissues, TUNEL+ apoptotic duct cells in affected glands, T cell and cytokine function, and levels of immunoglobulin isotypes and serum autoantibodies were examined.

Results

The 3‐mg/kg dose of rebamipide prevented the development of autoimmune lesions. The average volume of saliva in rebamipide‐treated mice was significantly higher than that in control mice. We found decreased TUNEL+ apoptotic duct cells in the salivary and lacrimal glands of rebamipide‐treated mice as compared with control mice. Rebamipide treatment suppressed the activation of CD4+ T cells and Th1 cytokines (interleukin‐2, interferon‐γ) associated with impaired NF‐κB activity. Production of serum autoantibodies, IgM, and IgG1 was clearly inhibited.

Conclusion

Our findings demonstrate the efficacy of oral administration of rebamipide in the treatment of SS. Rebamipide represents a new therapeutic strategy for the treatment of patients with sicca symptoms caused by SS, as well as for patients with other diseases.
Folding of HLA–B27 subtypes is determined by the global effect of polymorphic residues and shows incomplete correspondence to ankylosing spondylitis
Authors: Galocha Begoña , de Castro José A. López
Published: January 2008

Objective

To investigate the maturation and folding of HLA–B27 subtypes and the relationship of these features to ankylosing spondylitis (AS).

Methods

Stable transfectants expressing B27 subtypes and site‐directed mutants were used. Maturation/export rates were measured by acquisition of endoglycosidase H resistance. Folding efficiency was estimated from the ratio of unfolded heavy chain to folded heavy chain, which was immunoprecipitated with specific antibodies, in pulse‐chase experiments. Association with calnexin was analyzed in coprecipitation experiments. Cytosolic dislocation was estimated by immunoprecipitation of deglycosylated heavy chain after proteasome inhibition. The level of heavy chain expression on unstimulated or interferon‐γ (IFNγ)–stimulated cells was quantified by Western blotting.

Results

There was no correlation between the export rate and the association of HLA–B27 subtypes with AS. Three of the 4 AS‐associated B27 subtypes showed inefficient folding, but B*2707 folded with the same high efficiency as the non–disease‐associated subtypes. Some individual mutations that mimicked subtype polymorphism profoundly influenced folding, but in a context‐dependent way. The differences in export and folding rates among B27 variants were unrelated to levels of heavy chain expression in the corresponding transfectants, as indicated by the lack of correlation between the two parameters and by heavy chain up‐regulation with IFNγ. Misfolded heavy chain was inefficiently cleared from the endoplasmic reticulum, based on the marginal increase in levels of deglycosylated heavy chain, which resulted from loss of the glycan moiety after cytosolic dislocation, following proteasome inhibition.

Conclusion

HLA–B27 subtype folding is determined by the overall heavy‐chain structure, since the effect of a given polymorphism depends on its structural context. Heavy chain misfolding does not explain the association of B*2707 with AS.
Stress activation of cellular markers of inflammation in rheumatoid arthritis: Protective effects of tumor necrosis factor α antagonists
Authors: Motivala Sarosh J. , Khanna Dinesh , FitzGerald John , Irwin Michael R.
Published: January 2008

Objective

Psychological stress is thought to aggravate disease activity in rheumatoid arthritis (RA), although the physiologic mechanisms are unclear. Tumor necrosis factor α (TNFα) is an inflammatory cytokine involved in the exacerbation of RA, and TNFα antagonists have emerged as efficacious treatments. The purpose of this study was to determine whether RA patients show increased monocyte production of TNFα following acute psychological stress and whether such responses are abrogated in RA patients taking TNFα antagonists.

Methods

A standardized stress task was administered to 3 groups of subjects: RA patients taking TNFα antagonists, RA patients not taking such medications, and healthy controls. Lipopolysaccharide‐stimulated monocyte production of inflammatory cytokines was repeatedly measured using intracellular staining and flow cytometry. Subjective stress, cardiovascular responses, adrenocorticotropic hormone (ACTH) levels, and cortisol levels were also measured.

Results

The stress task induced increases in subjective stress, cardiovascular activity, and levels of ACTH and cortisol, with similar responses in the 3 groups. In addition, the stress task induced a significant increase (P < 0.001) in monocyte production of TNFα among RA patients who were not taking TNFα antagonists. However, monocyte production of TNFα did not change following psychological stress in RA patients taking TNFα antagonists or in healthy controls.

Conclusion

Brief psychological stress can trigger increased stimulated monocyte production of TNFα in RA patients. The use of TNFα antagonists protects against stress activation of cellular markers of inflammation in RA patients.
Mutations of the hemophagocytic lymphohistiocytosis–associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis
Authors: Hazen Melissa M. , Woodward Amy L. , Hofmann Inga , Degar Barbara A. , Grom Alexei , Filipovich Alexandra H. , Binstadt Bryce A.
Published: January 2008

The clinical syndromes of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are both characterized by dysregulated inflammation with prolonged fever, hepatosplenomegaly, coagulopathy, hematologic cytopenias, and evidence of hemophagocytosis in the bone marrow or liver. While HLH is either inherited or acquired, children with severe rheumatic diseases, most notably systemic juvenile idiopathic arthritis, are at risk for MAS. The phenotypic similarity between HLH and MAS raises the possibility that they share common pathogenetic mechanisms. Familial forms of HLH have been attributed to mutations in the genes encoding perforin (PRF1) and Munc13‐4 (UNC13D), among others, and are characterized by defective cytotoxic lymphocyte function. While some patients with systemic JIA have decreased levels of perforin protein expression and natural killer (NK) cell function, mutations of HLH‐associated genes in patients with systemic JIA have not been reported. We report the case of an 8‐year‐old girl with systemic JIA without MAS who was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function. This case broadens the range of clinical phenotypes attributable to UNC13D mutations and offers new insights into the etiology and pathogenesis of systemic JIA.
Infliximab treatment shifts the balance between stimulatory and inhibitory Fcγ receptor type II isoforms on neutrophils in patients with rheumatoid arthritis
Authors: Belostocki Kristina , Pricop Luminita , Redecha Patricia B. , Aydin Ani , Leff Linda , Harrison Melanie J. , Salmon Jane E.
Published: January 2008

Objective

Human neutrophils express both activating and inhibitory Fcγ receptors (FcγR), and their relative expression determines the inflammatory response to immune complexes. Tumor necrosis factor α (TNFα) up‐regulates the expression of stimulatory FcγRIIa on neutrophils in vitro, and amplifies immune complex–induced activation of neutrophils in vivo. This study was undertaken to determine whether TNFα blockade in patients with rheumatoid arthritis (RA) alters the balance of activating FcγR and inhibitory FcγR and thereby decreases inflammation.

Methods

We used fluorescence‐activated cell sorting and Western blotting to examine FcγR expression on neutrophils in 24 patients with RA, preceding their first infusion of infliximab and immediately prior to ≥3 subsequent infusions.

Results

In 13 of 24 patients (54.2%), there was a decrease in the expression of the predominant activating FcγR, FcγRIIa, after treatment with infliximab, an effect that persisted over ≥3 months of treatment. Although prior to initiation of infliximab therapy the inhibitory FcγR, FcγRIIb, was undetectable in neutrophils from 23 of 24 patients with RA, FcγRIIb protein was detected by Western blotting in 9 patients (37.5%) at the time of the third infliximab infusion. The induction of inhibitory FcγRIIb was always associated with decreased levels of FcγRIIa, and improvement following infliximab therapy, measured using the Health Assessment Questionnaire, was significantly associated with down‐regulation of FcγRIIa.

Conclusion

Our findings indicate that TNFα inhibition may reduce inflammation in patients with RA by restoring the balance of activating and inhibitory FcγR and thereby raising the threshold for immune complex–mediated activation of neutrophils.
Genetic variation including nonsynonymous polymorphisms of a major aggrecanase, ADAMTS‐5, in susceptibility to osteoarthritis
Authors: Rodriguez‐Lopez Julio , Mustafa Zehra , Pombo‐Suarez Manuel , Malizos Konstantinos N. , Rego Ignacio , Blanco Francisco J. , Tsezou Aspasia , Loughlin John , Gomez‐Reino Juan J. , Gonzalez Antonio
Published: January 2008

Objective

Given the recent characterization of ADAMTS‐5 as the main aggrecanase of cartilage destruction in mouse models, we explored whether genetic variation and, in particular, putative damaging polymorphisms in the ADAMTS‐5 gene modify susceptibility to osteoarthritis (OA).

Methods

Two likely deleterious nonsynonymous single‐nucleotide polymorphisms (SNPs) were identified in ADAMTS‐5 by bioinformatics analysis, rs2830585 in exon 5 affecting a thrombospondin 1 motif, and rs226794 in exon 7. Exploration of their role was carried out in 3 steps, discovery, extension, and replication, on samples obtained from 4 European Caucasian collections, comprising a total of 2,715 patients with knee, hip, or hand OA and 1,185 OA‐free controls. In addition, 6 tagSNPs were studied to fully evaluate genetic variation in the ADAMTS‐5 locus.

Results

Initial analyses of 2 sample collections (n = 277 and n = 159) showed a trend toward decreased frequency of the putative deleterious allele of rs226794 among patients with severe knee OA (P = 0.047 versus controls). However, results in patients with knee OA from 2 additional sample collections (n = 360 and n = 265) did not confirm this trend. No association was found with hip OA or hand OA. None of the other SNPs or haplotypes constructed with these SNPs showed a significant association with OA susceptibility.

Conclusion

Use of several collections of OA samples allowed us to obtain sound evidence against the participation of genetic variation in ADAMTS‐5 in OA susceptibility. These results indicate the need to further explore the function of this aggrecanase in human OA to determine whether it is as critical as has been observed in mouse models.
Difference in disease features between childhood‐onset and adult‐onset systemic lupus erythematosus
Authors: Brunner Hermine I. , Gladman Dafna D. , Ibañez Dominique , Urowitz Murray D. , Silverman Earl D.
Published: January 2008

Objective

To investigate potential differences between childhood‐onset and adult‐onset systemic lupus erythematosus (SLE).

Methods

An inception cohort with childhood‐onset SLE (n = 67) was compared with an inception cohort with adult‐onset SLE (n = 131), each of whom was diagnosed between 1990 and 1998 and followed up until February 1999. Prospective information included data on medications, laboratory markers, and disease activity and damage as measured by the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), respectively.

Results

Eighty‐five percent of patients with childhood‐onset SLE and 88% of patients with adult‐onset SLE were female; the mean duration of followup was 3.2 and 3.5 years, respectively. On average, the children had more‐active disease than did the adults at the time of diagnosis and during followup. There was a higher incidence of renal disease in those with childhood‐onset SLE (78% versus 52% in adults; P = 0.0005), and the adjusted mean SLEDAI renal score was higher in the children than in the adults (2.37 versus 0.82; P < 0.0001). Treatment with steroids (97% versus 72%; P < 0.0001) and immunosuppressive drugs (66% versus 37%; P = 0.0001) was used significantly more often in children with SLE. Four adult patients with SLE, but none of the children, died during the followup. At the end of the followup, the mean SDI scores in those with childhood‐onset SLE were higher than those with adult‐onset SLE (1.70 versus 0.76; P = 0.008).

Conclusion

Children with childhood‐onset SLE have more active disease at presentation and over time than do adults with SLE, especially active renal disease. Compared with adults with SLE, children receive more intensive drug therapy and accrue more damage, often related to steroid toxicity.
Suppressive role of leukocyte cell–derived chemotaxin 2 in mouse anti–type II collagen antibody–induced arthritis
Authors: Okumura Akinori , Saito Takeshi , Otani Isao , Kojima Kazuo , Yamada Yasunori , Ishida‐Okawara Akiko , Nakazato Katsuyoshi , Asano Masahide , Kanayama Kiichi , Iwakura Yoichiro , Suzuki Kazuo , Yamagoe Satoshi
Published: January 2008

Objective

We previously reported that the Val58Ile polymorphism of the leukocyte cell–derived chemotaxin 2 gene (LECT2) is associated with the severity of rheumatoid arthritis (RA). To define the role of LECT2 in inflammatory arthritides, we investigated the development of collagen antibody–induced arthritis (CAIA) in LECT2‐deficient (LECT2−/−) mice.

Methods

CAIA was induced in mice by administering anti–type II collagen antibodies followed by lipopolysaccharide. Daily assessment of hind paw swelling was used to monitor the development of arthritis. The histopathologic features and expression of inflammatory cytokines were also analyzed. We confirmed the role of LECT2 by introducing a LECT2 expression vector into LECT2−/− mice, using a hydrodynamic gene transfer method.

Results

Arthritis in LECT2−/− mice was significantly exacerbated compared with that in wild‐type (WT) controls. Histopathologic assessment of the tarsal joints showed that inflammation and erosion of cartilage and bone in LECT2−/− mice were more severe than that in controls. Interleukin‐1β (IL‐1β), IL‐6, and certain chemokines were present at significantly higher levels in the arthritic hind paws of LECT2−/− mice. In contrast, the amount of LECT2 in the serum and locally in the hind paws was higher in arthritic WT mice. Finally, hydrodynamic gene transfer experiments revealed that the severity of arthritis was reduced by the systemic expression of exogenous mouse LECT2 protein in LECT2−/− mice.

Conclusion

These results strongly suggest that LECT2 directly suppresses the development of CAIA. Manipulation of LECT2 might provide a rationale for novel therapeutic approaches to the treatment of inflammatory arthritides such as RA.
Primary central nervous system vasculitis with prominent leptomeningeal enhancement: A subset with a benign outcome
Authors: Salvarani Carlo , Brown Robert D. , Calamia Kenneth T. , Christianson Teresa J. H. , Huston John , Meschia James F. , Giannini Caterina , Miller Dylan V. , Hunder Gene G.
Published: January 2008

Objective

Primary central nervous system vasculitis (PCNSV) is an uncommon condition that affects the brain and spinal cord. This study was undertaken to evaluate the clinical features and outcomes among patients with PCNSV who presented with prominent gadolinium meningeal enhancement on magnetic resonance imaging (MRI).

Methods

Through retrospective review using the Mayo Clinic medical records linkage system, we identified 101 consecutive patients with PCNSV based on brain biopsy or conventional angiography (or both) between January 1, 1983, and December 31, 2003. We evaluated data on demographics, clinical findings, laboratory studies, imaging, biopsy of brain or spinal cord (or both), treatment, and neurologic outcome.

Results

MRIs showed prominent leptomeningeal enhancement in 8 of 101 patients with PCNSV. In 6 of those 8, cerebral angiography or magnetic resonance angiography results were normal, but biopsy of the brain or spinal cord showed vasculitis in all 8. Granulomatous vascular inflammation was found in 6 specimens and was associated in 4 cases with vascular deposits of β‐amyloid peptide. All 8 patients had a prompt response to therapy, with resolution of the MRI meningeal enhancement. Although 3 of the 8 patients had relapses during followup, the overall outcome was favorable. Patients with meningeal enhancement, compared with patients without enhancement, more commonly had substantial abnormalities of cerebrospinal fluid (100% versus 58%; P = 0.02) and amyloid angiopathy (50% versus 12%; P = 0.03).

Conclusion

Prominent gadolinium leptomeningeal enhancement on MRI may point to a distinct subtype of PCNSV with small leptomeningeal artery vasculitis and rapid response to therapy.
Secretion of matrix metalloproteinase 3 by expanded articular chondrocytes as a predictor of ectopic cartilage formation capacity in vivo
Authors: Pelttari Karoliina , Lorenz Helga , Boeuf Stephane , Templin Markus F. , Bischel Oliver , Goetzke Katrin , Hsu Hsin‐Yun , Steck Eric , Richter Wiltrud
Published: January 2008

Objective

Monolayer expansion of human articular chondrocytes (HACs) is known to result in progressive dedifferentiation of the chondrocytes and loss of their stable cartilage formation capacity in vivo. For an optimal outcome of chondrocyte‐based repair strategies, HACs capable of ectopic cartilage formation may be required. This study was undertaken to identify secreted candidate molecules, in supernatants of cultured HACs, that could serve as predictors of the ectopic cartilage formation capacity of cells.

Methods

Standardized medium supernatants (n = 5 knee cartilage samples) of freshly isolated HACs (PD0) and of HACs expanded for 2 or 6 population doublings (PD2 and PD6, respectively) were screened by a multiplexed immunoassay for 15 distinct interleukins, 8 matrix metalloproteinases (MMPs), and 11 miscellaneous soluble factors. Cartilage differentiation markers such as cartilage oligomeric matrix protein and YKL‐40 were determined by enzyme‐linked immunosorbent assay. HACs from each culture were subcutaneously transplanted into SCID mice, and the capacity of the chondrocytes to form stable cartilage was examined histologically 4 weeks later.

Results

Whereas freshly isolated (PD0) HACs generated stable ectopic cartilage that was positive for type II collagen, none of the cell transplants at PD6 formed cartilaginous matrix. Loss of the ectopic cartilage formation capacity between PD0 and PD6 correlated with a drop in the secretion of MMP‐3 to <10% of initial levels, whereas changes in the other investigated molecules were not predictive. Chondrocytes with MMP‐3 levels of ≥20% of initial levels synthesized cartilaginous matrix, whereas those with low MMP‐3 levels (<10% of initial levels) at PD2 failed to regenerate ectopic cartilage.

Conclusion

Loss of the capacity for stable ectopic cartilage formation in the course of HAC dedifferentiation can be predicted by determining the relative levels of MMP‐3, demonstrating that standardized culture supernatants can be used for quality control of chondrocytes dedicated for cell therapeutic approaches.
Quality of life over time in patients with systemic lupus erythematosus
Authors: Kuriya Bindee , Gladman Dafna D. , Ibañez Dominque , Urowitz Murray B.
Published: January 2008

Objective

To determine whether quality of life in patients with systemic lupus erythematosus (SLE) measured by the Short Form 36 (SF‐36) changes over time and which patient‐ and disease‐related factors influence such change.

Methods

SLE patients who had ≥6 SF‐36 evaluations during followup were identified from a database. Outcomes were slopes of scores of the 8 SF‐36 domains as well as the physical and mental component scores. Based on the direction of the slope, patients were designated as unchanged, improved, or worsened. Linear regression models were used to test the contribution of risk factors to slopes. Nonparametric tests were used to evaluate risk factors between patterns of clinical change.

Results

A total of 146 patients had ≥6 SF‐36 evaluations in 1,047 visits over a mean ± SD period of 8.2 ± 1.1 years. During the interval, the majority of patients showed no change in the SF‐36 domains and only a small minority demonstrated improvement. Physical and mental component scores were unchanged in 84.3% and 87.7% of patients whereas 4.1% and 7.5% improved, respectively. According to slopes of the domains and summary scores, only physical functioning demonstrated a significant decrease over time. There were no lupus disease features associated with decline in physical functioning except for the presence of fibromyalgia.

Conclusion

The SF‐36 in SLE patients with established disease changed little over an 8‐year period. Changes in the SF‐36 were not affected by disease activity, steroids, or damage accumulation during the interval, but were affected by the presence of fibromyalgia.
Pharmacokinetic study of oral prednisolone compared with intravenous methylprednisolone in patients with juvenile dermatomyositis
Authors: Rouster‐Stevens Kelly A. , Gursahaney Aneel , Ngai Ka‐leung , Daru Jennifer A. , Pachman Lauren M.
Published: January 2008

Objective

To determine areas under the curve (AUCs) of oral prednisolone (OP) and intravenous methylprednisolone (IVMP) in patients with juvenile dermatomyositis (DM) and assess the association with nailfold end‐row loops (ERLs). Patients with active disease have fewer ERLs that possibly occur in the gastrointestinal tract, impairing absorption of oral medications.

Methods

Six patients with juvenile DM received 50 mg/m2 of OP (day 1) and IVMP (day 2). Blood was drawn at baseline and at 5, 15, 30, 45, 60, and 90 minutes, and hourly (hours 2–8) after each dose. Samples were analyzed by reverse‐phase high‐performance liquid chromatography for levels of prednisolone and methylprednisolone. AUCs of OP and IVMP were determined by the trapezoid method; pharmacokinetic parameters were obtained using noncompartmental and compartmental analysis. ERLs were determined from freeze‐frame video microscopy and nailfold capillaroscopy.

Results

There was a trend toward significance in difference in mean AUC of IVMP (116.72 μg × ml/hour) compared with OP (65.16 μg × ml/hour; P = 0.059). Mean peak concentration was higher for IVMP (34.49 μg/ml) than OP (7.08 μg/ml); mean half‐life was shorter for IVMP (1.90 hours) than OP (2.36 hours). There was an inverse association between ΔAUCs (IVMP AUC − OP AUC) and ERLs (R = −0.68, P = 0.044).

Conclusion

Patients with juvenile DM and ERL loss may have decreased bioavailability of OP compared with IVMP. This can provide the rationale for greater efficacy of IVMP in patients with active vasculopathy of juvenile DM. Further studies investigating the pharmacokinetics and pharmacodynamics of high‐dose IVMP need to be performed in patients with juvenile DM.
Quality of life in systemic sclerosis: Psychometric properties of the World Health Organization Disability Assessment Schedule II
Authors: Hudson Marie , Steele Russell , Taillefer Suzanne , Baron Murray ,   Canadian Scleroderma Research Group
Published: January 2008

Objective

To determine the validity of the World Health Organization Disability Assessment Schedule II (WHODAS II) in systemic sclerosis (SSc).

Methods

Patients enrolled in the Canadian Scleroderma Research Group registry participated in a standardized evaluation and completed the WHODAS II. Criterion validity was assessed by comparing the WHODAS II with the Medical Outcomes Study Short Form 36 (SF‐36), construct validity was assessed by examining how it relates to common measures of outcome in SSc, and discriminative validity was assessed by examining how it distinguishes patients with more severe disease from those with less severe disease.

Results

A total of 402 patients with SSc were included (mean ± SD age 55 ± 13 years, 87% women, mean ± SD disease duration 11 ± 9 years). The mean ± SD WHODAS II score was 24.6 ± 17.4, and the greatest impairments were in life activities and mobility. There were moderate to good correlations between the WHODAS II and the SF‐36 Physical Component Summary score (r = −0.44), the SF‐36 Mental Component Summary score (r = −0.41), and measures of function (r = 0.54), depression (r = 0.44), pain (r = 0.40), and fatigue (r = −0.49, P < 0.0001 for all). The WHODAS II was able to consistently distinguish patients with milder disease from those with more severe disease.

Conclusion

The WHODAS II had good psychometric properties in patients with SSc and should be considered a valid measure of health‐related quality of life in SSc.
Avoidable hospitalizations in patients with systemic lupus erythematosus
Authors: Ward Michael M.
Published: January 2008

Objective

Avoidable hospitalizations are hospitalizations for indications that could have been prevented by prompt and appropriate outpatient treatment. Avoidable hospitalizations thus serve as an indicator of poor access to, or underutilization of, medical care. This study examined risk factors for avoidable hospitalizations among patients with systemic lupus erythematosus (SLE).

Methods

Data were obtained on acute‐care hospitalizations in a population‐based sample of 8,670 patients with SLE age ≥18 years hospitalized in New York state in 2000, 2001, and 2002. Hospitalizations were classified as avoidable based on the principal indication for hospitalization. Patient demographic and hospital characteristics were examined as risk factors.

Results

Of 16,751 hospitalizations, 2,123 (12.7%) were for avoidable conditions, most commonly pneumonia, congestive heart failure, and cellulitis. The likelihood of avoidable hospitalizations increased progressively with age, was higher among patients with Medicare than among those with other types of medical insurance, and was higher among those of lower socioeconomic status. Hospitalizations for avoidable conditions were less likely at hospitals that admitted larger numbers of patients with SLE than at hospitals that admitted fewer patients with SLE.

Conclusion

Avoidable hospitalizations occur more commonly among older and poorer patients, suggesting that these patients have more difficulty accessing care. The lower risk of avoidable hospitalizations at centers that admit large numbers of patients with SLE may be due to patient selection or may represent better outpatient care by physicians at these centers.
Accumulation of coronary artery disease risk factors over three years: Data from an international inception cohort
Authors: Urowitz M. B. , Gladman D. , Ibañez D. , Fortin P. , Sanchez‐Guerrero J. , Bae S. , Clarke A. , Bernatsky S. , Gordon C. , Hanly J. , Wallace D. , Isenberg D. , Ginzler E. , Merrill J. , Alarcón G. S. , Steinsson K. , Petri M. , Dooley M. A. , Bruce I. , Manzi S. , Khamashta M. , Ramsey‐Goldman R. , Zoma A. , Sturfelt G. , Nived O. , Maddison P. , Font J. , van Vollenhoven R. , Aranow C. , Kalunian K. , Stoll T. ,   Systemic lupus international collaborating clinics
Published: January 2008

Objective

To examine the accumulation of risk factors over 3 years in a multicenter, international inception cohort of patients with systemic lupus erythematosus (SLE).

Methods

The Systemic Lupus International Collaborating Clinics registry for atherosclerosis comprises 27 centers from 11 countries. An inception cohort of 935 patients with SLE was assembled, according to a standardized protocol, from 2000 to 2006 to study risk factors for atherosclerosis. Both classic and other coronary artery disease (CAD) risk factors were collected at entry and through 3 years of followup. Therapy was documented over the 3 years. The Framingham 10‐year risk factor profile was calculated for each patient at year 1 and year 3.

Results

A total of 278 patients from the inception cohort were followed for 3 years and constituted the population for this study. At enrollment a substantial number of patients already demonstrated several risk factors for CAD, both classic and other. All risk factors increased from enrollment over the 3 years of followup. Treatment of hypertension and hypercholesterolemia also increased over 3 years, but less so for hypercholesterolemia. The Framingham 10‐year CAD risk profile was higher in men than in women both at entry and at 3 years, and remained unchanged over the 3 years. Corticosteroid use increased only slightly over 3 years, but use of antimalarials and immunosuppressive agents increased to a greater extent.

Conclusion

Patients with SLE should be monitored for CAD risk factors from the time of diagnosis and appropriate treatment should be instituted early.
Gluteal tendinopathy in refractory greater trochanter pain syndrome: Diagnostic value of two clinical tests
Authors: Lequesne M. , Mathieu P. , Vuillemin‐Bodaghi V. , Bard H. , Djian P.
Published: January 2008

Objective

To evaluate the value (sensitivity and specificity) of 2 modified physical tests for the diagnosis of gluteal tendinopathy in patients with refractory greater trochanter pain syndrome (GTPS).

Methods

The 2 tests were prospectively evaluated by a single physician in all consecutive patients with persistent (≥4 months) GTPS and no hip joint arthropathy seen on radiography between 2002 and 2006. The 2 tests evaluated the occurrence of pain similar to spontaneous pain during a single‐leg stance held for 30 seconds and resisted external derotation in a supine position (hip flexed 90°) then prone position (hip extended). A matched control population without hip pain was examined similarly. Tendinitis, tendon tear, and associated bursitis in the target group were documented by magnetic resonance imaging (MRI) in transverse, coronal, and sagittal planes, with MRI serving as the gold standard.

Results

Seventeen patients completed the study (mean ± SD age 68.1 ± 10.8 years, mean duration of symptoms 13 months). MRI revealed tendinopathy and/or bursitis of the gluteus medius and/or minimus tendons in all patients, with evidence of tearing in 15. Sensitivity and specificity were 100% and 97.3%, respectively, for the single‐leg stance test and 88% and 97.3%, respectively, for the resisted external derotation test in the supine position.

Conclusion

The 30‐second single‐leg stance and resisted external derotation tests had very good sensitivity and specificity for the diagnosis of tendinous lesion and bursitis in patients with MRI‐documented refractory GTPS.
The Effect of training on biologists acceptance of bioinformatics tools: A field experiment
Authors: Shachak Aviv , Fine Sara
Published: January 2008

A recent development in biological research is the emergence of bioinformatics, which employs novel informatics techniques to handle biological data. Although the importance of bioinformatics training is widely recognized, little attention has been paid to its effect on the acceptance of bioinformatics by biologists. In this study, the effect of training on biologists' acceptance of bioinformatics tools was tested using the technology acceptance model (TAM) as a theoretical framework. Ninety individuals participated in a field experiment during seven bioinformatics workshops. Pre‐ and post‐intervention tests were used to measure perceived usefulness, perceived ease of use, and intended use of bioinformatics tools for primer design and microarray analysis—a simple versus a complex tool that is used for a simple and a complex task, respectively. Perceived usefulness and ease of use were both significant predictors of intended use of bioinformatics tools. After hands‐on experience, intention to use both tools decreased. The perceived ease of use of the primer design tool increased but that of the microarray analysis tool decreased. It is suggested that hands‐on training helps researchers to form realistic perceptions of bioinformatics tools, thereby enabling them to make informed decisions about whether and how to use them.