bluuebunny/crossref_metadata_2025 huggingface dataset:
Restricted T cell receptor BV gene usage in the lungs and muscles of patients with idiopathic inflammatory myopathies
Authors: Englund Pernilla , Wahlström Jan , Fathi Maryam , Rasmussen Elsbeth , Grunewald Johan , Tornling Göran , Lundberg Ingrid E.
Published: December 2006

Objective

To investigate T cell receptor (TCR) expression in 3 different compartments that could be involved in patients with myositis: muscle, lung, and peripheral blood.

Methods

Nine patients with polymyositis (PM), dermatomyositis, or inclusion body myositis underwent bronchoscopy and bronchoalveolar lavage (BAL) as well as muscle biopsy and blood sampling. A panel of 19 monoclonal antibodies specific for TCR Vβ (BV) and Vα (AV) were used to characterize the TCR profile in CD4+ and CD8+ T cell populations in BAL fluid and peripheral blood by flow cytometry. Muscle biopsy tissues were analyzed by immunohistochemistry. Patients were also typed for HLA–DRB1 and DRB3 alleles.

Results

A total of 17 T cell expansions were detected in BAL fluid, 6 in the CD4+ T cell population and 11 in the CD8+ T cell population. Four T cell expansions were detected in peripheral blood. A selective TCR V usage was found in muscle. Two PM patients, both of whom had BAL fluid BV3+ T cell expansions in the CD4 population and in whom BV3 was also a prominent TCR V segment in muscle tissue, shared the HLA–DRB1*03 allele. These 2 patients were the only ones who were positive for anti–Jo‐1 antibody.

Conclusion

We found a restricted accumulation of T lymphocytes expressing selected TCR V‐gene segments in the target organ compartments (i.e., lung and muscle). The occurrence of shared TCR gene segment usage in muscle and lungs could suggest common target antigens in these organs.
Fracture risk with intermittent high‐dose oral glucocorticoid therapy
Authors: De Vries Frank , Bracke Madelon , Leufkens Hubert G. M. , Lammers Jan‐Willem J. , Cooper Cyrus , Van Staa Tjeerd P.
Published: December 2006

Objective

To evaluate the risk of fracture in patients receiving intermittent therapy with high‐dose oral glucocorticoids (GCs).

Methods

The study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of “current” and “no exposure.” The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation.

Results

Patients who intermittently received high‐dose GCs (daily dose ≥15 mg) and had no or little previous exposure to GCs (cumulative exposure ≤1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who received a daily dose ≥30 mg and whose cumulative exposure was >5 gm, the relative risk (RR) of osteoporotic fracture was 3.63 (95% confidence interval [95% CI] 2.54–5.20), the RR of fracture of the hip/femur was 3.13 (95% CI 1.49–6.59), and the RR of vertebral fracture was 14.42 (95% CI 8.29–25.08).

Conclusion

Intermittent use of high‐dose oral GCs (daily dose ≥15 mg and cumulative exposure ≤1 gm) may result in a small increased risk of osteoporotic fracture. Conversely, patients who receive several courses of high‐dose GCs (daily dose ≥15 mg and cumulative exposure >1 gm) have a substantially increased risk of fracture.
HLA–B27 up‐regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis‐like disease
Authors: Turner Matthew J. , DeLay Monica L. , Bai Shuzhen , Klenk Erin , Colbert Robert A.
Published: December 2006

Objective

HLA–B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA–B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA–B27/human β2‐microglobulin–transgenic (B27‐transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA–B27–induced UPR and to determine whether splenocytes respond in a similar manner.

Methods

Splenocytes were isolated and bone marrow macrophages were derived from B27‐transgenic and wild‐type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA–B27 expression and misfolding were assessed by real‐time reverse transcription–polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X‐box binding protein 1 messenger RNA (mRNA) splicing.

Results

HLA–B27 mRNA up‐regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA–B27 up‐regulation. In contrast, B27‐transgenic splenocytes exhibited only low‐level differences in the expression of UPR target genes after exposure to interferon‐γ or concanavalin A, which resulted in minimal HLA–B27 up‐regulation.

Conclusion

These results suggest that HLA–B27–associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA–B27 misfolding. Strategies that eliminate HLA–B27 up‐regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA.
Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: An in vitro study
Authors: Jansen Nathalie W. D. , Roosendaal Goris , Bijlsma Johannes W. J. , DeGroot Jeroen , Lafeber Floris P. J. G.
Published: December 2006

Objective

Joint bleeding, or hemarthrosis, leads in time to severe joint damage. This study was carried out to test the in vitro thresholds of exposure time and concentration that lead to irreversible joint damage, to add to the discussion on the usefulness of aspiration of the joint after a hemorrhage.

Methods

Explants of healthy human articular cartilage tissue were cultured in the presence or absence of 50% (volume/volume) blood for 1, 2, 3, or 4 days or in the presence of 0%, 5%, 10%, 20%, 30%, or 50% (v/v) blood for 4 days, followed by a 12‐day period of recovery after withdrawal of blood. The effect of blood exposure on cartilage was determined by measuring the rate of proteoglycan synthesis as well as the release and content of cartilage matrix proteoglycans and the activity of matrix metalloproteinases.

Results

Exposure of cartilage to 50% (v/v) blood led to adverse changes that were largely independent of the exposure time. The adverse effects persisted after an initial exposure of up to or exceeding 2 days. Exposure of cartilage to increasing concentrations of blood for 4 days led to concentration‐dependent adverse changes. These effects persisted when the concentration equaled or exceeded 10% (v/v) blood. Moreover, after 2 days of exposure to a blood load of 10% (v/v), the adverse effects on cartilage were not reversible.

Conclusion

A 2‐day exposure of cartilage in vitro to 10% (v/v) blood leads to prolonged impairment of joint cartilage. This suggests that aspiration of blood from the joint within 2 days after hemarthrosis should be considered to prevent blood‐induced joint damage in the long term.
Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: An international inception cohort study
Authors: Hanly J. G. , Urowitz M. B. , Sanchez‐Guerrero J. , Bae S. C. , Gordon C. , Wallace D. J. , Isenberg D. , Alarcón G. S. , Clarke A. , Bernatsky S. , Merrill J. T. , Petri M. , Dooley M. A. , Gladman D. , Fortin P. R. , Steinsson K. , Bruce I. , Manzi S. , Khamashta M. , Zoma A. , Aranow C. , Ginzler E. , Van Vollenhoven R. , Font J. , Sturfelt G. , Nived O. , Ramsey‐Goldman R. , Kalunian K. , Douglas J. , Thompson K. , Farewell V. ,   Systemic Lupus International Collaborating Clinics
Published: December 2006

Objective

To describe the prevalence, characteristics, attribution, and clinical significance of neuropsychiatric (NP) events in an international inception cohort of systemic lupus erythematosus (SLE) patients.

Methods

The study was conducted by the Systemic Lupus International Collaborating Clinics (SLICC). Patients were enrolled within 15 months of fulfilling the American College of Rheumatology (ACR) SLE classification criteria. All NP events within a predefined enrollment window were identified using the ACR case definitions of 19 NP syndromes. Decision rules were derived to determine the proportion of NP disease attributable to SLE. Clinical significance was determined using the Short Form 36 (SF‐36) Health Survey and the SLICC/ACR Damage Index (SDI).

Results

A total of 572 patients (88% female) were recruited, with a mean ± SD age of 35 ± 14 years. The mean ± SD disease duration was 5.2 ± 4.2 months. Within the enrollment window, 158 of 572 patients (28%) had at least 1 NP event. In total, there were 242 NP events that encompassed 15 of 19 NP syndromes. The proportion of NP events attributed to SLE varied from 19% to 38% using alternate attribution models and occurred in 6.1–11.7% of patients. Those with NP events, regardless of attribution, had lower scores on the SF‐36 and higher SDI scores compared with patients with no NP events.

Conclusion

Twenty‐eight percent of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE. Regardless of attribution, the occurrence of NP events was associated with reduced quality of life and increased organ damage.
Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human β2‐glycoprotein I: Mutation studies including residues R39 to R43
Authors: Ioannou Yiannis , Pericleous Charis , Giles Ian , Latchman David S. , Isenberg David A. , Rahman Anisur
Published: December 2006

Objective

Pathogenic antiphospholipid antibodies (aPL) bind the self antigen N‐terminal domain (domain I) of β2‐glycoprotein I (β2GPI), with residues G40–R43 being important. However, peptides homologous to other regions of domain I have also been shown to bind aPL. Furthermore, there are no published reports of the effects of altering R39, which has greater surface exposure than the G40–R43 residues.

Methods

We used a novel, efficient method of production and purification of human domain I by Escherichia coli to create multiple mutants of domain I. These domain I mutants were then screened for binding to a range of polyclonal IgG purified from patients with antiphospholipid syndrome, using both solid‐phase and fluid‐phase assays.

Results

E coli–expressed purified domain I selectively bound IgG derived from patients with antiphospholipid syndrome. In region R39–R43, the R39S mutation had the greatest effect in terms of reducing binding to a panel of aPL in the fluid phase (mean ± SD inhibition 14 ± 18.5% versus 44.1 ± 31.7% for G40E and 62.9 ± 25.7% for wild‐type domain I). Conversely, altering both D8 and D9 to S8 and G9, respectively, had the effect of enhancing binding to aPL in the fluid phase. Adding the remainder of the domain I–II interlinker resulted in enhanced binding over wild‐type in the solid phase but not the fluid phase.

Conclusion

The binding of aPL to β2GPI domain I is complex and likely to involve discontinuous epitopes that include R39 in addition to G40–R43, the domain I–II interlinker, and possibly D8 and D9. Domain I variants with enhanced binding to aPL compared with wild‐type domain I may aid in the development of novel therapies.
Association of a TNAP haplotype with ankylosing spondylitis
Authors: Tsui Hing Wo , Inman Robert D. , Reveille John D. , Tsui Florence W. L.
Published: December 2006

Objective

To use a candidate gene approach to the identification of genetic markers that are significantly associated with ankylosing spondylitis (AS).

Methods

We genotyped 201 multiplex AS families with 1 exonic and 5 intronic single‐nucleotide polymorphisms (SNPs) in TNAP, the gene that encodes tissue‐nonspecific alkaline phosphatase, and performed family‐based association analyses.

Results

In our cohort of 201 multiplex AS families, the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) was significantly associated with AS (P = 0.032 by additive model). Haplotype‐Based Association Testing (HBAT) analyses of AS families in which both men and women were affected showed that the same TNAP haplotype was significantly associated with AS (P = 0.002 by additive model). Using setafftrait code 1 0 0 in the HBAT program, testing specifically for affected men in AS families containing affected individuals of both sexes, this TNAP haplotype was also significantly associated with AS (P = 0.001 by additive model). The HBAT –p option (haplotype permutation test) was used to compute the “exact” P value via a Monte Carlo method for each haplotype (haplotype permutation test) and for the minimum observed P value among the haplotypes (whole marker permutation using the minimal P test), and both P values were statistically significant (2‐sided P value for haplotype rs3767155 [G]/rs3738099 [G]/rs1780329 [T] = 0.00059, the smallest observed P value among all the individual haplotype scores = 0.003). Interestingly, this haplotype was not associated with AS in affected women from the same families.

Conclusion

Our results indicate that the TNAP haplotype rs3767155 (G)/rs3738099 (G)/rs1780329 (T) is a novel genetic marker in men that is significantly associated with AS in multiplex families containing affected individuals of both sexes.
Effect of glutathione S‐TRANSFERASE polymorphisms and proximity to hazardous waste sites on time to systemic lupus erythematosus diagnosis: Results from the roxbury lupus project
Authors: Karlson Elizabeth W. , Watts Julie , Signorovitch James , Bonetti Marco , Wright Elizabeth , Cooper Glinda S. , McAlindon Timothy E. , Costenbader Karen H. , Massarotti Elena M. , Fitzgerald Lisa M. , Jajoo Ramina , Husni M. Elaine , Fossel Anne H. , Pankey Helen , Ding Wei‐Zi , Knorr Robert , Condon Suzanne , Fraser Patricia A.
Published: December 2006

Objective

The high prevalence of systemic lupus erythematosus (SLE) among African American women may be due to environmental exposures, genetic factors, or a combination of factors. Our goal was to assess association of residential proximity to hazardous waste sites and genetic variation in 3 glutathione Stransferase (GST) genes (GSTM1, GSTT1, and GSTP1) with age at diagnosis of SLE.

Methods

Residential histories were obtained by interviewing 93 SLE patients from 3 predominantly African American neighborhoods in Boston. Residential addresses and locations of 416 hazardous waste sites in the study area were geocoded using ArcView software. Time‐varying Cox models were used to study the effect of residential proximity to hazardous sites, GST genotype, and interaction between genotype and exposure in determining age at diagnosis.

Results

The prevalence of SLE among African American women in these neighborhoods was 3.56 SLE cases per 1,000. Homozygosity for GSTM1‐null and GSTP1 Ile105Val in combination was associated with earlier SLE diagnosis (P= 0.03), but there was no association with proximity to 416 hazardous sites. Available data on specific site contaminants suggested that, at a subset of 67 sites, there was higher potential risk for exposure to volatile organic compounds (P< 0.05 with Bonferroni correction). GST genotypes had a significant interaction with proximity (P= 0.03) in analyses limited to these sites.

Conclusion

There was no independent association between residential proximity to hazardous waste sites and the risk of earlier SLE diagnosis in this urban population. However, analysis of a limited number of sites indicated that the risk of earlier SLE associated with proximity to hazardous sites might be modulated by GST polymorphisms.
Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus
Authors: Flores‐Borja Fabian , Kabouridis Panagiotis S. , Jury Elizabeth C. , Isenberg David A. , Mageed Rizgar A.
Published: December 2006

Objective

B lymphocytes from patients with systemic lupus erythematosus (SLE) exhibit defective intracellular signaling, hyperactivity, and autoantibody production. Recent evidence indicates a reduced expression of Lyn kinase, a negative regulator of B cell signaling, and reduced translocation of Lyn into membrane signaling domains in SLE. The present study was undertaken to investigate the causes of this altered regulation of Lyn by assessing the expression levels of regulatory molecules and their translocation into the signaling domains of SLE B lymphocytes.

Methods

Blood was obtained from 48 patients with SLE and 28 healthy controls for the assessment of B lymphocytes. Levels and intracellular distribution of Lyn, CD45, COOH‐terminal Src kinase (Csk), and c‐Cbl were studied by Western blotting, confocal microscopy, and flow cytometry. The kinetics of signaling molecule translocation to the B cell receptor (BCR)–antigen synapse were investigated by confocal microscopy.

Results

A profound alteration in the expression and translocation of regulatory signaling molecules in membrane domains of B cells from patients with SLE was observed. B lymphocytes from SLE patients, but not those from healthy controls, expressed a low molecular weight isoform of CD45 in lipid raft signaling microdomains. Kinetic studies revealed that translocation of Lyn, CD45, Csk, and c‐Cbl led to increased recruitment and retention of Lyn and CD45 in the BCR–antigen synapse in SLE B cells.

Conclusion

The results provide evidence of altered expression and translocation/interaction of kinases and phosphatases in membrane signaling microdomains of B cells from patients with SLE. Altered translocation of CD45 correlated with reduced expression of Lyn, indicating that Lyn is a key molecule in the regulation of BCR‐mediated signaling.
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis
Authors: Distler Jörg H. W. , Jüngel Astrid , Huber Lars C. , Schulze‐Horsel Ursula , Zwerina Jochen , Gay Renate E. , Michel Beat A. , Hauser Thomas , Schett Georg , Gay Steffen , Distler Oliver
Published: December 2006

Objective

Imatinib mesylate is a clinically well‐tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor β (TGFβ) and platelet‐derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).

Methods

The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real‐time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin‐induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.

Results

Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose‐dependent manner. The induction of ECM proteins after stimulation with TGFβ and PDGF was also strongly and dose‐dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects.

Conclusion

These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.
Association between reduced levels of MEFV messenger RNA in peripheral blood leukocytes and acute inflammation
Authors: Üstek Duran , Ekmekci Cumhur Gökhan , Selçukbiricik Fatih , Cakiris Aris , Oku Basar , Vural Burcak , Yanar Hakan , Taviloglu Korhan , Özbek Ugur , Gül Ahmet
Published: December 2006

Objective

Familial Mediterranean fever (FMF) is associated with more than 70 missense mutations in the MEFV gene. The purpose of this study was to investigate the relative expression of messenger RNA (mRNA) for the MEFV gene in peripheral blood leukocytes (PBLs) obtained from patients with FMF during attacks of acute abdominal inflammation as well as during asymptomatic periods.

Methods

We studied 16 patients with FMF during an attack of acute peritonitis and 17 otherwise healthy individuals who were undergoing surgery because of acute appendicitis. Blood samples were collected from both groups of patients during both acute inflammatory and asymptomatic periods. Relative levels of MEFV mRNA in PBLs were detected with real‐time reverse transcriptase–polymerase chain reaction using LightCycler, with 2 sets of primers for the MEFV gene (exons 7–10 and exons 2–3) and with primers for CIAS1 and PSTPIP1 genes. Expression levels were compared with β2‐microglobulin as an internal control.

Results

MEFV expression was reduced in FMF patients during asymptomatic periods as compared with the non‐FMF controls (P < 0.001). We observed a further decrease in MEFV expression in FMF patients during periods of inflammation (P = 0.01). Reduced levels of MEFV mRNA were also noted during the preoperative period as compared with asymptomatic periods in control patients with acute appendicitis (P = 0.01). CIAS1 expression in PBLs from patients with FMF was also found to be lower than that in the control patients. However, CIAS1 expression did not change with acute inflammation.

Conclusion

This study confirmed that reduced expression of the MEFV gene is associated with inflammation and that it may be one of the pathogenic mechanisms of the attacks of inflammation in FMF patients, along with disease‐associated variations in pyrin.
Effects of short‐term infliximab therapy on autoantibodies in systemic lupus erythematosus
Authors: Aringer Martin , Steiner Günter , Graninger Winfried B. , Höfler Elisabeth , Steiner Carl W. , Smolen Josef S.
Published: December 2006

Objective

To analyze changes in autoantibodies occurring in patients with systemic lupus erythematosus (SLE) treated with 4 infusions of the chimeric anti–tumor necrosis factor α (TNFα) antibody infliximab.

Methods

In an open‐label safety study, 7 patients with SLE were treated with infliximab at weeks 0, 2, 6, and 10 in combination with azathioprine or methotrexate. Antibodies to double‐stranded DNA (dsDNA) were determined by radioimmunoassay and the Crithidia luciliae indirect immunofluorescence assay; anticardiolipin antibodies (aCL) and antibodies to histone and chromatin were measured by enzyme‐linked immunosorbent assay. Antihistone antibodies were also analyzed by immunoblotting. Peripheral blood mononuclear cells from healthy individuals and SLE patients were incubated for 2 weeks with or without TNFα. TNFα was removed by washing and by the addition of infliximab. Apoptotic cells were stained with annexin V and analyzed by flow cytometry.

Results

Autoantibodies to dsDNA increased in 5 of 7 patients. Histone, chromatin, and IgM aCL levels were increased in 4 of 7, 6 of 7, and 4 of 7 patients, respectively, peaking 4–10 weeks after the last infliximab infusion, but falling to baseline levels or lower thereafter. In the in vitro experiments, TNF withdrawal after long‐term incubation with recombinant human TNF led to increased percentages of apoptotic cells.

Conclusion

While TNF blockade was clinically effective, the majority of SLE patients treated with infliximab showed an increase in autoantibodies to nuclear antigens and phospholipids. These increases were transient and were not associated with disease flares. Increased availability of apoptotic antigens after TNF blockade may play a role in the autoantibody formation induced by TNF blockade.
Moderation of psychosocial risk factors through dysfunction of the hypothalamic–pituitary–adrenal stress axis in the onset of chronic widespread musculoskeletal pain : Findings of a population‐based prospective cohort study
Authors: McBeth J. , Silman A. J. , Gupta A. , Chiu Y. H. , Ray D. , Morriss R. , Dickens C. , King Y. , Macfarlane G. J.
Published: December 2006

Objective

To test the hypothesis that abnormalities in the hypothalamic–pituitary–adrenal (HPA) stress‐response system would act as an effect moderator between HPA function and the onset of chronic widespread pain (CWP).

Methods

We conducted a population‐based prospective cohort study. Current pain and psychosocial status were ascertained in 11,000 subjects. Of the 768 eligible subjects free of CWP but at future risk based on their psychosocial profile, 463 were randomly selected, and 267 (57.7%) consented to assessment of their HPA axis function. Diurnal function was measured by assessing levels of salivary cortisol in the morning (9:00 AM) and evening (10:00 PM). Serum cortisol levels were measured after an overnight low‐dose (0.25 mg) dexamethasone suppression test and a potentially stressful clinical examination. All subjects were followed up 15 months later to identify cases of new‐onset CWP.

Results

A total of 241 subjects (94.9%) completed the followup study, and 28 (11.6%) reported the new onset of CWP. High levels of cortisol post‐dexamethasone (odds ratio [OR] 3.53, 95% confidence interval [95% CI] 1.17–10.65), low levels in morning saliva (OR 1.43, 95% CI 0.52–3.94), and high levels in evening saliva (OR 2.32, 95% CI 0.64–8.42) were all associated with CWP. These 3 factors were found to be independent and additive predictors of CWP (OR for all 3 factors 8.5, 95% CI 1.5–47.9) in analyses controlling for age, sex, depression, sleep disturbance, recent traumatic life events, and pain status. One or more of these 3 HPA factors identified 26 (92.9%) cases of new‐onset CWP.

Conclusion

Among a group of psychologically at‐risk subjects, dysfunction of the HPA axis helps to distinguish those who will and will not develop new‐onset CWP.
Conceptions of information science
Authors: Zins Chaim
Published: December 2006

The field of information science is constantly changing. Therefore, information scientists are required to regularly review—and if necessary—redefine its fundamental building blocks. This article is one of four articles that documents the results of the Critical Delphi study conducted in 2003–2005. The study, “Knowledge Map of Information Science,” was aimed at exploring the foundations of information science. The international panel was composed of 57 leading scholars from 16 countries who represent nearly all the major subfields and important aspects of the field. In this study, the author documents 50 definitions of information science, maps the major theoretical issues relevant to the formulation of a systematic conception, formulates six different conceptions of the field, and discusses their implications.
Cover Picture: Columnar Mesophase Formation of Cyclohexa‐m‐phenylene‐Based Macrocycles (Chem. Asian J. 1/2007)
Authors: Pisula Wojciech , Kastler Marcel , Yang Changduk , Enkelmann Volker , Müllen Klaus
Published: December 2006

Towering columns can be formed by macrocycles with rigid, unsaturated hydrocarbon backbones through π‐stacking interactions. However, little is known about the correlation of the molecular structure of these macrocycles with supramolecular packing and phase behavior. In their Full Paper on page 51 ff., K. Müllen and co‐workers investigate the long‐range solid‐state self‐assembly of alkyl‐substituted phenylene‐based macrocycles and discover the factors affecting the formation of columnar superstructures.
Analysis of oxygen transport in a diffusion‐limited model of engineered heart tissue
Authors: Brown David A. , MacLellan W. Robb , Laks Hillel , C.Y. Dunn James , M. Wu Benjamin , Beygui Ramin E.
Published: December 2006

Cardiac tissue engineering has made notable progress in recent years with the advent of an experimental model based on neonatal cardiomyocytes entrapped in collage gels and purified basement membrane extract, known as “engineered heart tissues” (EHTs). EHTs are a formidable display of tissue‐level contractile function and cellular‐level differentiation, although they suffer greatly from mass transport limitations due to the high density of metabolically active cells and the diffusion‐limited nature of the hydrogel. In this report, a mathematical model was developed to predict oxygen levels inside a one‐dimensional, diffusion‐limited model of EHT. These predictions were then compared to values measured in corresponding experiments with a hypoxia‐sensitive stain (pimonidazole). EHTs were cast between two plastic discs, which allowed for mass transfer with the culture medium to occur in only the radial direction. EHTs were cultured for up to 36 h in the presence of pimonidazole, after which time they were snap‐frozen, histologically sectioned, and stained for bound pimonidazole. Quantitative image analysis was performed to measure the distance from the culture medium at which hypoxia first occurs under various conditions. As tested by variation of simple design parameters, the trends in oxygen profiles predicted by the model are in reasonable agreement with those obtained experimentally, although a number of ambiguities related to the specific model parameters led to a general overprediction of oxygen concentrations. Based on the sensitivity analysis in the present study, it is concluded that diffusion‐reaction models may offer relatively precise predictions of oxygen concentrations in diffusion‐limited tissue constructs. Biotechnol. Bioeng. 2007;97: 962–975. © 2006 Wiley Periodicals, Inc.
Influence of cultivation conditions on mechanical and morphological properties of bacterial cellulose tubes
Authors: Bodin Aase , Bäckdahl Henrik , Fink Helen , Gustafsson Lena , Risberg Bo , Gatenholm Paul
Published: December 2006

Bacterial cellulose (BC) was deposited in tubular form by fermenting Acetobacter xylinum on top of silicone tubes as an oxygenated support and by blowing different concentrations of oxygen, that is, 21% (air), 35%, 50%, and 100%. Mechanical properties such as burst pressure and tensile properties were evaluated for all tubes. The burst pressure of the tubes increased with an increase in oxygen ratio and reached a top value of 880 mmHg at 100% oxygen. The Young's modulus was approximately 5 MPa for all tubes, irrespective of the oxygen ratio. The elongation to break decreased from 30% to 10–20% when the oxygen ratio was increased. The morphology of the tubes was characterized by Scanning Electron Microscopy (SEM). All tubes had an even inner side and a more porous outer side. The cross section indicated that the tubes are composed of layers and that the amount of layers and the yield of cellulose increased with an increase in oxygen ratio. We propose that an internal vessel wall with high density is required for the tube to sustain a certain pressure. An increase in wall thickness by an increase in oxygen ratio might explain the increasing burst pressure with increasing oxygen ratio. The fermentation method used renders it possible to produce branched tubes, tubes with unlimited length and inner diameters. Endothelial cells (ECs) were grown onto the lumen of the tubes. The cells formed a confluent layer after 7 days. The tubes potential as a vascular graft is currently under investigation in a large animal model at the Centre of Vascular Engineering, Sahlgrenska University Hospital, Gothenburg. Biotechnol. Bioeng. 2007;97: 425–434. © 2006 Wiley Periodicals, Inc.
Erythrocyte sodium pump stimulation by ouabain and an endogenous ouabain‐like factor
Authors: Balzan Silvana , D'Urso Giuseppina , Nicolini Giuseppina , Forini Francesca , Pellegrino Mario , Montali Umberto
Published: December 2006

Cardiac glycosides inhibit the sodium pump. However, some studies suggest that nanomolar ouabain concentrations can stimulate the activity of the sodium pump.

In this study, using the Na+/K+‐ATPase of human erythrocytes, we compared the effect of digoxin, ouabain and an ouabain like‐factor (OLF), on 86Rb uptake.

Ouabain concentrations below 10−9 M significantly stimulate Rb+ uptake, and the maximal increase above base‐line values is 18 ± 5% at 10−10 M ouabain. No stimulation is observed in the same conditions by digoxin. OLF behaved like ouabain, producing an activation of Rb+ flux at concentrations lower than 10−9 M ouabain equivalents (14 ± 3% at 10−10 M).

Western blot analysis revealed the presence of both α1 and α3 pump isoforms in human erythrocytes. Our data confirm the analogies between OLF and ouabain and suggest that Na+/K+‐ATPase activation may be related to the α3 isoform.

In addition, we investigated whether ouabain at different concentrations was effective in altering the intracellular calcium concentration of erythrocytes. We found that ouabain at concentration lower than 10−9 M did not affect this homeostasis. Copyright © 2006 John Wiley & Sons, Ltd.
Regulation of human lymphocyte proliferation by fatty acids
Authors: Gorjão Renata , Cury‐Boaventura Maria Fernanda , de Lima Thaís Martins , Curi Rui
Published: December 2006

In the present study, the effect of increasing concentrations of palmitic (PA, C16:0), stearic (SA, C18:0), oleic (OA, C18:1, n‐9), linoleic (LA, C18:2n‐6), docosahexaenoic (DHA, C22:6 n‐3) and eicosapentaenoic (EPA, C20:5 n‐3) acids on lymphocyte proliferation was investigated. The maximal non‐toxic concentrations of these fatty acids for human lymphocytes in vitro were determined. It was also evaluated whether these fatty acids at non‐toxic concentrations affect IL‐2 induced lymphocyte proliferation and cell cycle progression. OA and LA at 25 µM increased lymphocyte proliferation and at higher concentrations (75 µM and 100 µM) inhibited it. Both fatty acids promoted cell death at 200 µM concentration. PA and SA decreased lymphocyte proliferation at 50 µM and promoted cell death at concentrations of 100 µM and above. EPA and DHA decreased lymphocyte proliferation at 25 and 50 µM being toxic at 50 and 100 µM, respectively. PA, SA, DHA and EPA decreased the stimulatory effect of IL‐2 on lymphocyte proliferation, increasing the percentage of cells in G1 phase and decreasing the proportion of cells in S and G2/M phases. OA and LA caused an even greater pronounced effect. The treatment with all fatty acids increased neutral lipid accumulation in the cells but the effect was more pronounced with PA and DHA. In conclusion, PA, SA, DHA and EPA decreased lymphocyte proliferation, whereas OA and LA stimulated it at non‐toxic concentrations. Copyright © 2006 John Wiley & Sons, Ltd.
Redox regulation of proliferation of lens epithelial cells in culture
Authors: Wilhelm J. , Smištík Z. , Mahelková G. , Vytášek R.
Published: December 2006

Both oxidants and antioxidants have been shown to modulate cell proliferation. We studied the effects of hydrogen peroxide and two antioxidants on the rate of proliferation of lens epithelial cells in culture. Hydrogen peroxide at concentrations higher than 32 µM caused a significant inhibition of proliferation. However, in the concentration range of 0.01–0.5 µM, hydrogen peroxide stimulated the rate of proliferation. The effect of hydrogen peroxide was dependent on the amount of cells in an individual culture well, indicating decomposition of hydrogen peroxide by cellular enzymes. In order to eliminate the possibility of decomposition of the dose of hydrogen peroxide given as a bolus, we induced continual production of hydrogen peroxide by adding glucose oxidase to the incubation medium. We found that hydrogen peroxide, generated by 1–50 µU · ml−1 of glucose oxidase significantly increased the rate of cell proliferation. This effect was most apparent at the beginning of the exponential phase of cellular growth. Glucose oxidase alone (100–500 µU · ml−1) did not produce any effect. The effects of pro‐oxidative hydrogen peroxide were compared with the effects of two biologically important antioxidants, α‐tocopherol and retinol. Both antioxidants completely inhibited proliferation at concentrations of 30 µM and higher. In contrast to retinol, the effect of α‐tocopherol was dependent on the amount of cells, indicating cellular decomposition of α‐tocopherol. The results document the possibility of redox regulation of cellular proliferation at physiologically relevant reactant concentrations. Copyright © 2006 John Wiley & Sons, Ltd.
Reversible Inactivation of the CG Specific SssI DNA (Cytosine‐C5)‐Methyltransferase with a Photocleavable Protecting Group
Authors: Rathert Philipp , Raskó Tamás , Roth Markus , Ślaska‐Kiss Krystyna , Pingoud Alfred , Kiss Antal , Jeltsch Albert
Published: December 2006

Caging of proteins by conjugation with a photocleavable group is a powerful approach for reversibly blocking enzymatic activity. Here we describe the covalent modification of the bacterial SssI DNA methyltransferase (M.SssI) with the cysteine‐specific reagent 4,5‐dimethoxy‐2‐nitrobenzylbromide (DMNBB). M.SssI contains two cysteine residues; replacement of the active‐site Cys141 with Ser resulted in an approximately 100‐fold loss of enzymatic activity; this indicates an important role for this residue in catalysis. However, replacement of Cys368 with Ala did not affect methyltransferase activity. Treatment of the Cys368Ala mutant enzyme with DMNBB led to an almost complete loss of activity. Irradiation of the inactivated enzyme with near‐ultraviolet light (320–400 nm) restored 60 % of the catalytic activity. This indicates that caging by DMNBB can be used for the reversible inactivation of M.SssI.
Site‐Specific Functionalization of Proteins by Organopalladium Reactions
Authors: Kodama Koichiro , Fukuzawa Seketsu , Nakayama Hiroshi , Sakamoto Kensaku , Kigawa Takanori , Yabuki Takashi , Matsuda Natsuko , Shirouzu Mikako , Takio Koji , Yokoyama Shigeyuki , Tachibana Kazuo
Published: December 2006

A new carbon–carbon bond has been regioselectively introduced into a target position (position 32 or 174) of the Ras protein by two types of organopalladium reactions (Mizoroki–Heck and Sonogashira reactions). Reaction conditions were screened by using a model peptide, and the stability of the Ras protein under the reaction conditions was examined by using the wild‐type Ras protein. Finally, the iF–Ras proteins containing a 4‐iodo‐L‐phenylalanine residue were subjected to organopalladium reactions with vinylated or propargylated biotin. Site‐specific biotinylations of the Ras protein were confirmed by Western blot and LC‐MS/MS.
A Comparative Analysis of the Sugar Phosphate Cyclase Superfamily Involved in Primary and Secondary Metabolism
Authors: Wu Xiumei , Flatt Patricia M. , Schlörke Oliver , Zeeck Axel , Dairi Tohru , Mahmud Taifo
Published: December 2006

Sugar phosphate cyclases (SPCs) catalyze the cyclization of sugar phosphates to produce a variety of cyclitol intermediates that serve as the building blocks of many primary metabolites, for example, aromatic amino acids, and clinically relevant secondary metabolites, for example, aminocyclitol/aminoglycoside and ansamycin antibiotics. Feeding experiments with isotopically labeled cyclitols revealed that cetoniacytone A, a unique C7N‐aminocyclitol antibiotic isolated from an insect endophyticActinomycessp., is derived from 2‐epi‐5‐epi‐valiolone, a product of SPC. By using heterologous probes from the 2‐epi‐5‐epi‐valiolone synthase class of SPCs, an SPC homologue gene,cetA, was isolated from the cetoniacytone producer.cetAis closely related toBE‐orf9found in the BE‐40644 biosynthetic gene cluster fromActinoplanessp. strain A40644. Recombinant expression ofcetAandBE‐orf9and biochemical characterization of the gene products confirmed their function as 2‐epi‐5‐epi‐valiolone synthases. Further phylogenetic analysis of SPC sequences revealed a new clade of SPCs that might regulate the biosynthesis of a novel set of secondary metabolites.
Initial experience with the cardiva Boomerang™ vascular closure device in diagnostic catheterization
Authors: Doyle Brendan J. , Godfrey Michael J. , Lennon Ryan J. , Ryan James L. , Bresnahan John F. , Rihal Charanjit S. , Ting Henry H.
Published: December 2006

Objectives: The authors studied the safety and efficacy of the Cardiva Boomerang™ vascular closure device in patients undergoing diagnostic cardiac catheterization. Background: Conventional vascular closure devices (sutures, collagen plugs, or metal clips) have been associated with catastrophic complications including arterial occlusion and foreign body infections; furthermore, they cannot be utilized in patients with peripheral vascular disease or vascular access site in a vessel other than the common femoral artery. The Cardiva Boomerang™ device facilitates vascular hemostasis without leaving any foreign body behind at the access site, can be used in peripheral vascular disease, and can be used in vessels other than the common femoral artery Methods: A total of 96 patients undergoing transfemoral diagnostic cardiac catheterization were included in this study, including 25 (26%) patients with contraindications to conventional closure devices. Femoral angiography was performed prior to deployment of the Cardiva Boomerang™ closure device. Patients were ambulated at 1 hr after hemostasis was achieved. Results: The device was successfully deployed and hemostasis achieved with the device alone in 95 (99%) patients. The device failed to deploy in 1 (1%) patient and required conversion to standard manual compression. Minor complications were observed in 5 (5%) patients. No patients experienced major complications including femoral hematoma > 4 cm, red blood cell transfusion, retroperitoneal bleed, arteriovenous fistula, pseudoaneurysm, infection, arterial occlusion, or vascular surgery. Conclusions: The Cardiva Boomerang™ device is safe and effective in patients undergoing diagnostic cardiac catheterization using the transfemoral approach, facilitating early ambulation with low rates of vascular complications. © 2006 Wiley‐Liss, Inc.
The impact of renal insufficiency on patients outcomes in emergent angioplasty for acute myocardial infarction
Authors: Assali Abid R. , Brosh David , Ben‐Dor Itsik , Solodky Alejandro , Fuchs Shmuel , Teplitsky Igal , Kornowski Ran
Published: December 2006

Background: Renal insufficiency (RF) was shown to be associated with a worsened prognosis following acute myocardial infarction (AMI). Objectives: The authors analyzed the outcomes of AMI patients with impaired renal function tests treated using primary percutaneous coronary intervention (PCI), to determine factors associated with increased mortality risk. Methods: This study included 558 consecutive AMI patients treated using primary PCI between January 2001 and June 2005. The authors compared outcome results according to glomerular filtration rate (GFR). An abbreviated equation was used to calculate GFR. Patients were grouped as follow: normal (≥90 mL/min/1.73 m2), mildly impaired (60–89 mL/min/1.73 m2), moderately impaired (30–59 mL/min/1.73 m2), and severely impaired GFR (< 30 mL/min/1.73 m2). Results: There was a stepwise increase in 30‐day mortality among patients with normal, mildly, moderately, and severely impaired RF: 2.1%, 3.7%, 8.2%, and 22.2%, respectively (P = 0.004). Seventeen out of the 324 with any degree of RF died within 1 month [5.3%] of these nine patients [53%] died because of cardiac cause. Univariate correlation analysis, factors associated with an increased risk of 1 month mortality included: age > 75 years, left ventricular ejection fraction < 35%, lower GFR, killip class > 1, multivessel coronary artery disease, failure to achieve TIMI flow grade = 3, the occurrence of no‐reflow, IABP use, lack of administration of anti GP 2b/3a. The amount of contrast media used during the procedure [mL/Kg] as well as renal function deterioration were also associated with increased mortality. Conclusions: Clinical and angiographic parameters collected before and during PCI can be used to predict 30‐day mortality among AMI patients with RF. Findings indicate that in the setting of contemporary catheter‐based reperfusion strategy for AMI, the extent of coronary artery disease, measures of PCI complexity, and degree of renal impairment prior/following the procedure are altogether related to mortality. © 2006 Wiley‐Liss, Inc.
Solving multicomponent chiral separation challenges using a new SFC tandem column screening tool
Authors: Welch Christopher J. , Biba Mirlinda , Gouker Joseph R. , Kath Gary , Augustine Paul , Hosek Paul
Published: December 2006

A tool for improved tandem column chiral supercritical fluid chromatography (SFC) method development screening was prepared by modification of a commercial analytical SFC instrument with two different software‐controllable, six position high‐pressure column selection valves, each controlling a bank of five different columns and a pass through line. The resulting instrument, which has the ability to screen 10 different individual columns and 25 different tandem column arrangements, is a useful tool for facilitating the screening of tandem column SFC arrangements for separation of complex mixtures of stereoisomers or other multicomponent mixtures. Strategies for optimal use of the instrument are discussed, and several examples of the use of the instrument in developing tandem SFC methods for resolution of multicomponent mixtures are presented. Chirality, 2007. © 2006 Wiley‐Liss, Inc.
Synthesis and enantioselective rearrangement of (Z)‐4‐triphenylmethoxy‐2,3‐epoxybutan‐1‐ol enantiomers
Authors: Faigl Ferenc , Thurner Angelika , Farkas Ferenc , Battancs Melinda , Poppe László
Published: December 2006

Efficient enzyme catalyzed kinetic resolutions of a synthetically useful chiral building block, (Z)‐4‐triphenylmethoxy‐2,3‐epoxybutan‐1‐ol, are reported. The highest selectivities were achieved by Lipozyme TL IM and Amano Lipase PS enzymes in the presence of vinyl acetate. Enantiomeric enrichment of the optically active acetate isomer was accomplished by selective crystallization of the racemic part of the enantiomeric mixture. Enzyme catalyzed hydrolysis of the acetate also provided an optically pure epoxybutanol derivative. O‐Benzylation of (+)‐(Z)‐1‐hydroxy‐4‐triphenylmethoxy‐2,3‐epoxybutane followed by super base promoted diastereo‐ and enantio‐selective rearrangement resulted in (+)‐(2R,3R,1′R)‐3‐[1‐hydroxy‐2‐(triphenylmethoxy)ethyl]‐2‐phenyloxetane in >98% ee and de. Configurations of the new optically active products were determined by chemical correlation. Chirality, 2007. © 2006 Wiley‐Liss, Inc.