bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of DRB1 shared epitope genotypes with early mortality in rheumatoid arthritis: Results of eighteen years of followup from the early rheumatoid arthritis study
Authors: Mattey D. L. , Thomson W. , Ollier W. E. R. , Batley M. , Davies P. G. , Gough A. K. , Devlin J. , Prouse P. , James D. W. , Williams P. L. , Dixey J. , Winfield J. , Cox N. L. , Koduri G. , Young A.
Published: April 2007

Objective

To determine whether the HLA–DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA).

Methods

HLA–DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n = 186) were obtained from the Office of National Statistics. The association of HLA–DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA–DRB1 genotypes compared with other potential baseline risk factors.

Results

The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04–3.94], P = 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17–4.08], P = 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA–DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes.

Conclusion

The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA–DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.
CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis
Authors: Prasse Antje , Pechkovsky Dmitri V. , Toews Galen B. , Schäfer Markus , Eggeling Stephan , Ludwig Corinna , Germann Martin , Kollert Florian , Zissel Gernot , Müller‐Quernheim Joachim
Published: April 2007

Objective

In diffuse parenchymal lung diseases, the evolution of pulmonary fibrosis is often devastating and may result in death. In this study the role of CCL18 as a biomarker of disease activity in idiopathic interstitial pneumonias (IIPs) and systemic sclerosis (SSc) with lung involvement was evaluated.

Methods

CCL18 was assessed in supernatants of cultured bronchoalveolar lavage (BAL) cells as well as BAL fluid and serum samples from 43 patients with IIPs, 12 patients with SSc, and 23 healthy control subjects. Concentrations of CCL18 were measured by enzyme‐linked immunosorbent assay, and expression of CCL18 was assessed by flow cytometry.

Results

CCL18 concentrations were statistically significantly increased in all patients with fibrotic lung diseases. Spontaneous CCL18 production by BAL cells was negatively correlated with total lung capacity and the diffusion capacity for carbon monoxide, whereas there was a positive correlation of CCL18 concentrations with BAL neutrophil and eosinophil cell counts. Flow cytometry revealed an increase in the percentage of CCL18‐positive alveolar macrophages and an increase in the CCL18 fluorescence intensity per cell in patients with fibrotic lung diseases. In a cohort of patients who were followed up for at least 6 months (n = 40), a close negative correlation was observed between changes in the predicted total lung capacity and changes in CCL18 serum concentrations.

Conclusion

These findings suggest that CCL18 production by BAL cells and serum CCL18 concentrations reflect pulmonary fibrotic activity in patients with IIPs and those with SSc. Monitoring changes in CCL18 production might be an extraordinarily useful tool in clinical practice and in studies aimed at evaluating new approaches for treatment of fibrotic lung diseases.
Mycobacterial Hsp65‐IgG–expressing tolerogenic B cells confer protection against adjuvant‐induced arthritis in Lewis rats
Authors: Satpute Shailesh R. , Soukhareva Nadejda , Scott David W. , Moudgil Kamal D.
Published: April 2007

Objective

Tolerization of T cells directed against a target autoantigen is a desired goal of experimental approaches for the treatment of autoimmune diseases, and novel and improved methods of tolerance induction are continuously being sought. Because most traditional methods of tolerance induction using soluble antigen are effective in the prevention of autoimmunity but fail to control established disease, this study was carried out to explore an innovative tolerogenic approach for the treatment of ongoing disease, using the rat adjuvant‐induced arthritis (AIA) model of human rheumatoid arthritis.

Methods

Lewis (RT.1l) rats were injected subcutaneously with heat‐killed Mycobacterium tuberculosis H37Ra to induce AIA. Before or after AIA induction, Lewis rats were treated intraperitoneally (IP) with tolerogenic B cells expressing a fusion construct of mycobacterial 65‐kd heat‐shock protein (Hsp65) and IgG heavy‐chain. For comparison, control rats were treated IP with ovalbumin (OVA)–IgG–expressing B cells or soluble mycobacterial Hsp65, and the effects on AIA were observed. We also tested the immune response to mycobacterial Hsp65 in B cell–tolerized rats.

Results

Administration of tolerogenic mycobacterial Hsp65–expressing B cells as well as soluble mycobacterial Hsp65, but not OVA‐expressing B cells, resulted in a significant decrease in the severity of subsequent AIA. However, in rats with established disease, only the B cell regimen of mycobacterial Hsp65, but not the soluble antigen, suppressed ongoing AIA.

Conclusion

Mycobacterial Hsp65‐IgG–expressing B cells can successfully attenuate the progression of AIA. This study introduces a promising approach for the treatment of arthritis that should be further explored.
Association of Anti–Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis
Authors: Cha Seongwon , Choi Chan‐Bum , Han Tae‐Un , Kang Changsoo Paul , Kang Changwon , Bae Sang‐Cheol
Published: April 2007

Objective

Anti–cyclic citrullinated peptide (anti‐CCP) antibodies are rheumatoid arthritis (RA)–specific serologic markers. RA susceptibility has been associated with HLA–DRB1 shared epitope (SE) alleles and single‐nucleotide polymorphism (SNP) haplotypes in the peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti‐CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA.

Methods

Three nonsynonymous SNPs in PADI4 (padi4_89, padi4_90, and padi4_92) and SE alleles were genotyped, and serum anti‐CCP levels were measured, in 311 patients with nonerosive or erosive RA. The relationships between anti‐CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically.

Results

Anti‐CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti‐CCP–positive patients with RA with a disease duration of ≤34 months (P = 0.041), but not among patients with a longer disease duration or among those who had erosive RA versus nonerosive RA. In contrast, the levels were significantly higher in SE carriers than in noncarriers among patients with RA with a disease duration of ≥141 months (P = 0.0037) and among those who had erosive RA (P = 0.000098), but not among patients who had a shorter disease duration or those who had nonerosive RA.

Conclusion

The PADI4 RA risk haplotype is associated with increased anti‐CCP levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti‐CCP levels in RA patients with very longstanding disease and in patients with erosive RA, suggesting that SE alleles play a role in very late RA.
Protection against autoimmune nephritis in MyD88‐deficient MRL/lpr mice
Authors: Sadanaga Atsushi , Nakashima Hitoshi , Akahoshi Mitsuteru , Masutani Kohsuke , Miyake Katsuhisa , Igawa Takashi , Sugiyama Naonobu , Niiro Hiroaki , Harada Mine
Published: April 2007

Objective

To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis.

Methods

MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll‐like receptors (TLRs) except TLR‐3. We therefore generated MyD88‐knockout (MyD88‐KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88‐independent pathway in autoimmune nephritis, we injected MyD88‐KO MRL/lpr mice intraperitoneally with either poly(I‐C) (50 or 100 μg per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters.

Results

In comparison with wild‐type mice, MyD88‐KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti–double‐stranded DNA (anti‐dsDNA) and production of cytokines, including interferon‐α (IFNα), interleukin‐12 (IL‐12), IL‐6, and IFNγ, in splenocytes were significantly reduced in MyD88‐KO MRL/lpr mice. Interestingly, MyD88‐KO MRL/lpr mice that had been treated with the MyD88‐independent TLR‐3 ligand poly(I‐C) showed an almost complete reversion to the features of wild‐type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti‐dsDNA titers and increased cytokine production in splenocytes.

Conclusion

The findings indicate that both MyD88‐dependent and MyD88‐independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/lpr mice.
The effects of glucosamine hydrochloride on subchondral bone changes in an animal model of osteoarthritis
Authors: Wang Susanne X. , Laverty Sheila , Dumitriu Mircea , Plaas Anna , Grynpas Marc D.
Published: April 2007

Objective

To quantify periarticular subchondral bone changes in a rabbit model of experimental osteoarthritis (OA), and to determine the effects of continuous administration of a clinically relevant dose of glucosamine HCl on subchondral bone changes in this model.

Methods

Anterior cruciate ligament transection (ACLT) was performed on the left femorotibial joints of 16 rabbits to induce OA. Ten rabbits that did not undergo ACLT served as unoperated controls. Eight rabbits that underwent ACLT and 6 control rabbits were treated with 100 mg of glucosamine daily, and the others were given a placebo. The articular cartilage was evaluated macroscopically and graded at the time of necropsy, 8 weeks after ACLT. Bone mineral density (BMD) was measured using dual‐energy x‐ray absorptiometry on the dissected distal femur and proximal tibia. Subchondral trabecular bone turnover, architecture, and connectivity, as well as subchondral plate thickness and mineralization were studied on the undecalcified tibia sections from each animal.

Results

Eight weeks after ACLT, most of the operated joints had various degrees of cartilage damage and fibrillation. Compared with the control group, the ACLT group had significantly increased subchondral bone turnover and lower BMD, bone volume, connectivity, and bone mineralization. The high bone turnover was significantly reduced in glucosamine‐treated animals that underwent ACLT. In fact, there were no significant differences between the ACLT/glucosamine group and the control/glucosamine group in most of the bone parameters studied.

Conclusion

This study shows that subchondral bone turnover, structure, and mineralization are significantly altered in the early stages of experimental OA, and that these changes are attenuated by glucosamine treatment.
The effect of methotrexate and anti–tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 PERSON‐YEARS of observation
Authors: Wolfe Frederick , Michaud Kaleb
Published: April 2007

Objective

To ascertain the relationship between anti–tumor necrosis factor (anti‐TNF) therapy, methotrexate (MTX), and the risk of lymphoma in patients with rheumatoid arthritis (RA). This report updates our previous report during 29,314 person‐years of followup.

Methods

Participants in the National Data Bank for Rheumatic Diseases (NDB) longitudinal study of long‐term outcomes of RA completed semiannual questionnaires from 1998 through 2005, during 89,710 person‐years of followup. Lymphoma reports were validated by medical records. The association between lymphoma and treatment was investigated using conditional logistic regression, adjusted for severity and demographic covariates.

Results

Of the 19,591 participants, 55.3% received biologic agents and 68.0% received MTX while enrolled in the NDB. The lymphoma incidence rate was 105.9 (95% confidence interval [95% CI] 86.6–129.5) per 100,000 person‐years of exposure. Compared with the SEER (Surveillance, Epidemiology, and End‐Results) lymphoma database, the standardized incidence ratio was 1.8 (95% CI 1.5–2.2). The odds ratio (OR) for lymphoma in patients who received anti‐TNF therapy compared with patients who did not receive anti‐TNF therapy was 1.0 (95% CI 0.6–1.8 [P = 0.875]). The OR for lymphoma in patients who received anti‐TNF plus MTX therapy compared with patients who received MTX treatment alone was 1.1 (95% CI 0.6–2.0 [P = 0.710]). Infliximab and etanercept considered individually also were not associated with a risk of lymphoma.

Conclusion

In a study of lymphoma in 19,591 RA patients over 89,710 person‐years of followup, which included exposure to anti‐TNF therapy in 10,815 patients, we did not observe evidence for an increase in the incidence of lymphoma among patients who received anti‐TNF therapy.
Are common symptoms in childhood associated with chronic widespread body pain in adulthood?: Results from the 1958 british birth cohort study
Authors: Jones Gareth T. , Silman Alan J. , Power Chris , Macfarlane Gary J.
Published: April 2007

Objective

Studies have shown that common symptoms in childhood predict the onset of chronic widespread pain in the short term. However, it is unknown whether this association persists into adulthood. The aim of the current study was to examine, prospectively, whether children with common symptoms experience an increased risk of chronic widespread pain as adults.

Methods

Information on vomiting/bilious attacks, abdominal pain, and headaches/migraine was collected on 10,453 7‐year‐old children, by maternal report. Similar data were gathered when the children were ages 11 years and 16 years. Body pain at age 45 years was assessed by postal questionnaire. Poisson regression was used to examine chronic widespread pain in relation to childhood symptom reporting.

Results

Of the 10,453 subjects on whom data were obtained when they were children, 7,470 participated at age 45 years (71.5%). Children with multiple symptoms at age 7 years experienced a 50% increased risk of chronic widespread pain (relative risk 1.5 [95% confidence interval 1.03, 2.3]). This relationship persisted after adjustment for sex, recent psychological distress, and childhood and current socioeconomic status, and after excluding children with major illnesses that might have explained early symptom reporting. A similar relationship with symptoms at ages 11 and 16 years was observed, although this was not associated with additional risk compared with that found with the presence of symptoms at age 7 years. However, despite a modest increase in risk, the presence of multiple symptoms at early ages was uncommon (<1.5%), and therefore, the associated population attributable risk was low (<1%).

Conclusion

Multiple common symptoms in childhood are associated with an increased risk of chronic widespread pain in adulthood. However, the magnitude of this increased risk is modest, and reports of multiple symptoms in childhood are uncommon. Thus the “early pain pathway” phenomenon is applicable only to a small proportion of individuals with chronic widespread pain.
Smoking interacts with family history with regard to change in knee cartilage volume and cartilage defect development
Authors: Ding Changhai , Cicuttini Flavia , Blizzard Leigh , Jones Graeme
Published: April 2007

Objective

To describe the effects of smoking on change in knee cartilage volume and increases in knee cartilage defects, and to test for interaction between smoking and family history of osteoarthritis (OA).

Methods

Subjects with at least 1 parent having severe primary knee OA (offspring) and randomly selected controls without this history (a total of 325 subjects with a mean age of 45 years) were measured at baseline and 2.3 years later. Knee cartilage volume and defect score (on a 0–4 scale) were determined using T1‐weighted fat‐saturated magnetic resonance imaging. Smoking status and duration and number of cigarettes were recorded by questionnaire.

Results

In offspring, smoking was associated with annual change in medial and lateral tibial cartilage volume (β = −2.20% and β = −1.45%, respectively, for current smokers versus former smokers and those who had never smoked; β = −0.07%/pack‐year at both tibial sites, for smoking severity) in multivariate analysis. Smoking was also associated with increases (change ≥1) in medial and lateral tibiofemoral cartilage defect scores (odds ratio [OR] 4.91 and OR 2.98, respectively, for current smokers versus those who had never smoked; OR 9.90 and OR 12.98, respectively, for heavy smoking [total of >20 pack‐years] versus never smoking) (all P < 0.05). In contrast, smoking was not associated with any of the above in controls except for change in lateral tibial cartilage volume. There was significant interaction between smoking and offspring–control status for change in medial tibial cartilage volume (P = 0.047) and increases in medial (P = 0.03) and lateral (P = 0.049) tibiofemoral cartilage defects.

Conclusion

Smoking leads to knee cartilage loss and defect development primarily in individuals with a family history of knee OA. This provides evidence for a gene–environment interaction in the etiology of knee OA.
Delayed gadolinium‐enhanced magnetic resonance imaging of the meniscus: An index of meniscal tissue degeneration?
Authors: Krishnan Nitya , Shetty Sanjay K. , Williams Ashley , Mikulis Brandon , McKenzie Charles , Burstein Deborah
Published: April 2007

Objective

Much attention has been focused recently on the need for a better understanding of the mechanisms and natural progression of knee osteoarthritis (OA), particularly in its early stages. One technique that has been used to investigate early OA is delayed gadolinium‐enhanced magnetic resonance imaging of cartilage (dGEMRIC), where T1(Gd) (T1 value after penetration of the MRI contrast agent gadopentate dimeglumine [Gd‐DTPA2−]) is used as an index of the molecular status of articular cartilage. The goal of this study was to explore T1(Gd) in the meniscus and its relationship with articular cartilage T1(Gd) in knee dGEMRIC image data sets.

Methods

T1(Gd) maps of the meniscus and articular cartilage were made from knee dGEMRIC images obtained from prior studies of dGEMRIC of the knee in 21 asymptomatic subjects and 9 patients with self‐reported OA.

Results

T1(Gd) of the meniscus covered a range of values (247–515 msec) and patterns (homogeneous and focal variations). In addition, T1(Gd) of the meniscus correlated with that of articular cartilage (R = 0.38, P = 0.037; R = 0.57, P = 0.001 for correlations of the medial posterior meniscus with the medial femoral and tibial cartilage, respectively; T1[Gd] of the anterior meniscus and lateral compartments also correlated, with R > 0.38 and P < 0.037), potentially demonstrating parallel degradative processes in the knee.

Conclusion

While the biophysical basis for the T1(Gd) results relative to meniscus molecular structure needs investigation, these findings introduce a potential means of examining the time course of meniscal tissue change in the development and progression of arthritis.
Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark
Authors: Pedersen Merete , Jacobsen Søren , Garred Peter , Madsen Hans O. , Klarlund Mette , Svejgaard Arne , Pedersen Bo V. , Wohlfahrt Jan , Frisch Morten
Published: April 2007

Objective

To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs).

Methods

To address these issues, a nationwide case–control study was conducted in Denmark during 2002–2004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex‐ and age‐matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk.

Results

Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti‐CCP–positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8–29.4) but not anti‐CCP–negative RA (OR 1.07, 95% CI 0.53–2.18). Strong combined gene–environment effects were observed, with markedly increased risks of anti‐CCP–positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0–154), heavy coffee drinkers (OR 53.3, 95% CI 15.5–183), or oral contraceptive users (OR 44.6, 95% CI 15.2–131) compared with SE noncarriers who were not exposed to these environmental risk factors.

Conclusion

Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti‐CCP–positive RA. A distinction between anti‐CCP–positive RA and anti‐CCP–negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.
Differential tissue targeting of autoimmunity manifestations by Autoantigen‐Associated Y RNAs
Authors: Greidinger Eric L. , Zang YunJuan , Martinez Laisel , Jaimes Kimberly , Nassiri Mehdi , Bejarano Pablo , Barber Glen N. , Hoffman Robert W.
Published: April 2007

Objective

To assess the Y RNAs, a family of homologous RNAs that bind to the Ro autoantigen, for the ability to contribute to autoimmune disease by activating RNA‐responsive Toll‐like receptors (TLRs).

Methods

Using cell lines expressing or stably transfected with TLR‐3, TLR‐7, or TLR‐8, we determined the patterns of RNA‐specific TLR activation by in vitro transcripts of all of the known murine and human Y RNAs. Next, 8–10‐week‐old female mice were exposed to a single 50‐μg subcutaneous injection of mouse Y1 or mouse Y3 RNA, and the effects were observed.

Results

Y RNA family members differed in their TLR reactivities. Both human and mouse Y3 RNAs, but not other human or mouse Y RNAs, prominently induced TLR‐3 activation. Although most human and mouse Y RNAs activated TLR‐7 efficiently, mouse Y3 RNA and human Y5 RNA did not. Single subcutaneous injections of mice with either mouse Y1 RNA or mouse Y3 RNA induced or inhibited lymphoid infiltrates in different target organs based on the Y RNA and TLR status of the mouse used. Mouse Y1 RNA induced kidney lesions in TLR‐3–intact mice but not in TLR‐3–knockout mice. In contrast, mouse Y3 RNA treatment was associated with nephritis in TLR‐3–knockout mice but not in TLR‐3–intact mice. Sialoadenitis developed in untreated TLR‐3−/− mice and in TLR‐3−/− mice treated with mouse Y3 RNA, but sialoadenitis was not present in TLR‐3−/− mice treated with mouse Y1 RNA.

Conclusion

Y RNAs can induce innate immune responses and influence clinical manifestations of autoimmunity, suggesting that they are relevant to syndromes of anti‐Ro autoimmunity. Distinct patterns of tissue targeting can be seen after exposure to different Y RNAs, in a pattern that correlates with the innate immune signals they induce. Thus, the balance of innate immune signals induced by exposure to endogenous Y RNAs may help determine the nature of the clinical syndrome in anti‐Ro autoimmunity.
The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto‐5′‐nucleotidase: Findings in a study of ecto‐5′‐nucleotidase gene–deficient mice
Authors: Montesinos M. Carmen , Takedachi Masahide , Thompson Linda F. , Wilder Tuere F. , Fernández Patricia , Cronstein Bruce N.
Published: April 2007

Objective

Evidence from in vitro, in vivo, and clinical studies indicates that adenosine mediates, at least in part, the antiinflammatory effects of methotrexate (MTX), although the biochemical events involved have not been fully elucidated. This study was undertaken to investigate whether MTX exerts antiinflammatory effects in mice that lack ecto‐5′‐nucleotidase (ecto‐5′‐NT) (CD73) and are unable to convert AMP to adenosine extracellularly, in order to determine whether adenosine is generated intracellularly and transported into the extracellular space or is generated from the extracellular dephosphorylation of AMP to adenosine.

Methods

Male CD73 gene–deficient mice and age‐matched wild‐type mice received intraperitoneal injections of saline or MTX (1 mg/kg/week) for 5 weeks. Air pouches were induced on the back by subcutaneous injection of air; 6 days later, inflammation was induced by injection of carrageenan.

Results

Fewer leukocytes, but higher levels of tumor necrosis factor α (TNFα), accumulated in the air pouches of vehicle‐treated CD73‐deficient mice compared with those of wild‐type mice. As expected, MTX treatment reduced the number of leukocytes and TNFα levels in the exudates and increased exudate adenosine concentrations in wild‐type mice. In contrast, MTX did not reduce exudate leukocyte counts or TNFα levels or increase exudate adenosine levels in CD73‐deficient mice.

Conclusion

These results demonstrate that the antiinflammatory actions of MTX are mediated, at least in part, by increased release of adenine nucleotides that are hydrolyzed extracellularly to adenosine via an ecto‐5′‐NT–dependent pathway.
What do we know about the h index?
Authors: Bornmann Lutz , Daniel Hans‐Dieter
Published: April 2007

Jorge Hirsch (2005a, 2005b) recently proposed the h index to quantify the research output of individual scientists. The new index has attracted a lot of attention in the scientific community. The claim that the h index in a single number provides a good representation of the scientific lifetime achievement of a scientist as well as the (supposed) simple calculation of the h index using common literature databases lead to the danger of improper use of the index. We describe the advantages and disadvantages of the h index and summarize the studies on the convergent validity of this index. We also introduce corrections and complements as well as single‐number alternatives to the h index.
Die Michaeliskirche in Hildesheim – Erhaltung des Weltkulturerbes
Authors: Eilhardt‐Braune Eva‐Maria , Götz Jürgen , Steffens Klaus
Published: April 2007

Die Kirche des ehemaligen Benediktinerklosters St. Michael in Hildesheim gilt als herausragendes Bauwerk der ottonischen Baukunst und wurde 1985 in die Liste der UNESCO zum Schutz des Kultur‐ und Naturerbes der Welt eingetragen.

Das Gotteshaus, das Bischof Bernward (993–1022) errichten ließ und dessen Grundstein mit dem Jahr 1010 datiert ist und im Jahre 1022 – kurz vor seinem Tod – von ihm eingeweiht wurde, hat eine bewegte bauliche Vergangenheit.

Baugrundprobleme mit der Folge von Teil einstürzen sowie mangelnde Bauunterhaltung über Jahrhunderte erfordern derzeit eine grundlegende Anamnese, Bewertung des Ist‐Zustands und die Planung einer nachhaltigen Sanierung dieser bedeutenden romanischen Kirche.
Zur Traglastermittlung von Druckstäben im Holzbau
Authors: Möller Gunnar
Published: April 2007

Bei der Bemessung von druckbeanspruchten Bauteilen im Holzbau ist die Zunahme der Beanspruchungen infolge der sich einstellenden Verformungen zu berücksichtigen. Die Zusatzbeanspruchungen aus dem nichtlinearen Anwachsen der Verformungen müssen rechnerisch immer dann berücksichtigt werden, wenn sich die Schnittgrößen infolge des geometrischen nichtlinearen Tragverhaltens (Theorie II. Ordnung) um mehr als 10% vergrößern. Zur Erfassung der Zusatzbeanspruchungen nach Theorie II. Ordnung sieht die DIN 1052 [1] zwei Verfahren vor. Der Nachweis kann mit einer Ermittlung der Schnittgrößen am unverformten System mit einer anschließenden Bemessung nach dem Ersatzstabverfahren erfolgen.

Alternativ zum Nachweis nach dem Ersatzstabverfahren können die Schnittgrößen nach Theorie II. Ordnung ermittelt und anschließend eine Bemessung des Querschnitts für Biegung mit Druck durchgeführt werden.

In diesem Beitrag werden die Unterschiede der beiden alternativen Nachweise aufgezeigt, und es wird eine Vorgehensweise vorgeschlagen, bei der beide Verfahren unter Berücksichtigung des Modifikationsbeiwertes für einfache Fälle gleiche Traglasten ergeben.
Platten aus Stahlbeton unter zweiaxialer Biegebeanspruchung
Authors: Keuser Manfred , Rüdiger Lars , Hallermann Norman
Published: April 2007

Stahlbetonflächentragwerke erfahren i. d. R. zweiaxiale Beanspruchungszustände, beispielsweise in Hohlkästen im Brückenbau, bei zweiachsig gespannten Deckenplatten oder auch im Bereich der Lasteinleitung über und unter Stützen. Die Bemessung solcher Bereiche erfolgt derzeit mit Hilfe vereinfachender Annahmen, die auf der sicheren Seite liegend nicht immer zur wirtschaftlichsten Lösung führen. Durch die Superposition einzelner Lastfälle oder die Aufaddierung der daraus ermittelten Bewehrungsmengen kann es zu einer Überbemessung von Bauteilen kommen. Interaktionen, wie z. B. die Auswirkungen von Änderungen der Bauteilsteifigkeiten, werden gar nicht oder nicht vollständig berücksichtigt. Inhomogenitäten im Material, insbesondere der Einfluss der Bewehrung, sind eine wesentliche Ursache für nichtlineares Materialverhalten, das i. d. R. zu Schnittgrößenumlagerungen führt. Im Rahmen eines Forschungsprojektes am Institut für Konstruktiven Ingenieurbau der Universität der Bundeswehr München wurden aufbauend auf Untersuchungen an Stahlbetonscheiben Versuche an Stahlbetonplatten mit variabler Bewehrungsrichtung und verschiedenen Biegemomentenverhältnissen durchgeführt. Die daraus gewonnenen Versuchsergebnisse sollen als Grundlage zur Entwicklung eines Ingenieurmodells zur vereinfachten Beschreibung der Zusammenhänge dienen.
Zum statischen System von Kellerwänden aus unbewehrtem Beton unter Erddruck
Authors: Hegger Josef , Niewels Jörg , Dreßen Tobias , Will Norbert
Published: April 2007

Die üblichen Baustoffe für Kellerwände im Wohnungsbau sind Mauerwerk oder bewehrter Beton. Beide Bauarten sind zeit‐ und kostenintensiver als eine Ausführung der Kelleraußenwände in unbewehrtem Beton. Der Hauptgrund für die allgemeine Zurückhaltung gegenüber Wänden aus unbewehrtem Beton ist die erforderliche Wanddicke. So ergeben sich nach DIN 1045‐1 z. T. deutlich größere Wanddicken als bei einer Bemessung für Mauerwerk nach DIN 1053. Nachfolgend werden, neben den Gründen für die bisher ungünstigere Bemessung, über die Regelungen von DIN 1045‐1 hinausgehende Systemannahmen erläutert, die deutlich geringere Wanddicken für durch Erddruck beanspruchte unbewehrte Kelleraußenwände durch Ausnutzung ihrer Verformungsfähigkeit ergeben.
Anpassung des Verkehrslastmodells des DIN FB 101 für kommunale Brücken
Authors: Novák Balthasar , Brosge Sven , Barthel Klaus , Pfisterer Werner
Published: April 2007

Für den Verantwortungsbereich des BMVBS ist das kürzlich eingeführte Lastmodell LM1 für die Verkehrslasten auf Brücken ohne weitere Reduktionen für alle neuen Brückenbauwerke anzusetzen. Dies führt jedoch leider gerade im Bereich der Kommunen zu teilweise konservativen Ergebnissen, da die geometrischen Abmessungen von kommunalen Brücken deutlich von den “üblichen” Abmessungen von Autobahnen und Bundesstraßen abweichen können und die Belastung aus dem LM1 durch den realen Verkehr nicht erzeugt werden kann. Es werden Vorschläge präsentiert, wie bei bestimmten geometrischen Randbedingungen und abhängig vom statischen System eine weitere Abminderung des LM1 möglich ist, ohne das Sicherheitsniveau zu verlassen. Die Arbeit entstand in enger Zusammenarbeit mit den Städten Frankfurt/Main, Leipzig und Stuttgart.
Zuschrift zu Kaldenhoff, M.; Schütte, J.; Hauser, A.: Anwendungserfahrungen mit der neuen DIN 1055 Teil 6 bei der Sanierung zweier Rohmehlsilos
Authors: Lippold Dieter
Published: April 2007

Zuschrift zu

Beton‐und Stahlbetonbau 102 (2007), Heft 2, S. 107–113,

Erwiderung der Autoren
Remarks upon Empirical Regression Belt
Authors: Schmerling S. , Peil J.
Published: April 2007

In the presented paper the method of the empirical regression belt is demonstrated. An empirical regression curve r(x), which is determined by the realizations (measured points) (x1, y1), i = 1,…., n of a continuous two‐dimensional random variable (X, Y), is enclosed by a belt, the local width of which varies dependent on local frequency and variance of the measured points. This empirical regression belt yields certain information for evaluating the empirical regression curve, providing a useful basis for the biomathematical forming of a model. By giving three examples derived from morphometrics the authors discuss important qualities of the empirical regression belt.
Relative Efficiency of Estimators of the Mean of a Normal Distribution when Coefficient of Variation is Known
Authors: Sen A. R.
Published: April 2007

A biased but simple and consistent estimator of the parameter ϑ has been obtained for the normal distribution N(ϑ, aϑ2), ϑ>0 where a is a known constant. It is shown that the estimator is more efficient than the sample mean or any suitably chosen constant multiple of the sample standard deviation. It is also proved to be more efficient than the mimumum variance unbiased estimator among a typical class of unbiased estimators derived by RASUL KHAN (1968).
Some Theorems Concerning Characterization of the WEIBULL Distribution
Authors: Janardan K. G. , Taneja V. S.
Published: April 2007

This paper presents a number of characterizations of the WEIBULL distribution. Some of these results are generalizations of the corresponding results for the exponential distribution. Some characterizing properties lead to a functional equation f(x) · f(y) = f((xc+yc)i/c) which is analogous to the CAUCHY functional equation. While the first two characterizations assume somewhat less accessible information concerning the probability distribution, the third and fourth require more readily available information regarding the expected values.
Discriminant Variables
Authors: Krzyśko M.
Published: April 2007

Several fundamental properties of discriminant variables are developed. In addition, the proportionality of the discriminant variables, canonical variables and RAO principal components is demonstrated.
In vitro scavenging activity for reactive oxygen species by N‐substituted indole‐2‐carboxylic acid esters
Authors: Kruk Irena , Aboul‐Enein Hassan Y. , Michalska Teresa , Lichszteld Krzysztof , Kubasik‐Kladna Katarzyna , Ölgen Sureyya
Published: April 2007

The hydroxyl radical (HO•)‐ and superoxide anion radical (O)‐scavenging activity, as well as the singlet oxygen (1O2)‐quenching property of N‐substituted indole‐2‐carboxylic acid esters (INDs) were investigated by deoxyribose degradation assay, a chemiluminescence method and the electron spin resonance (ESR) spin‐trapping technique. This novel group of compounds was developed as a search for cyclooxygenase‐2 (COX‐2)‐selective enzyme inhibitors. The results obtained demonstrated that of the 16 compounds examined, five inhibited light emission from the superoxide anion radical (O)–DMSO system by at least 60% at a concentration of 1 mmol/L, nine prevented the degradation of deoxyribose induced by the Fenton reaction system (range 3–78%) or scavenged hydroxyl radicals (HO•) directly (range 8–93%) and 14 showed the 1O2‐quenching effect (range 10–74%). These results indicate that majority of the indole esters tested possess the ability to scavenge O−2 and HO radicals and to quench 1O2 directly, and consequently may be considered effective antioxidative agents. Copyright © 2007 John Wiley & Sons, Ltd.
Plasmid adsorption to anion‐exchange matrices: Comments on plasmid recovery
Authors: Tiainen Peter , Galaev Igor , Larsson Per‐Olof
Published: April 2007

A number of anion‐exchange adsorbents were constructed, employing nonporous silica fibers, and examined with the aim of describing factors that influence desorption and recovery of plasmid DNA (pDNA). The fibers were provided with ligands via adsorption of the polymeric amines poly(ethyleneimine) or chitosan, or via graft‐polymerization of primary, tertiary, or quaternary amine monomers to vinyl‐silanized fibers. Several adsorbents showed an almost irreversible plasmid binding. It was suggested that important factors affecting the DNA releasing ability are (i) type of amine ligand used (primary amines bind plasmids the strongest), (ii) the structure of the nucleic acid (supercoiled pDNA may bind stronger than linear genomic DNA), (iii) shift of ligand pKa (due to the proximity of highly charged pDNA), and (iv) the solid support itself (steric factors may lead to kinetically stable complexes). The last factor was derived from several comparisons between support‐bound ligand and free soluble ligand. It was thus observed that polyelectrolyte complexes associated with a surface were much more difficult to dissociate than the equivalent soluble complexes.
Influence of microbial growth kinetics on steady state multiplicity and stability of a two‐step nitrification (SHARON) model
Authors: Volcke Eveline I.P. , Sbarciog Mihaela , Loccufier Mia , Vanrolleghem Peter A. , Noldus Erik J.L.
Published: April 2007

In this paper, the influence of microbial growth kinetics on the number and the stability of steady states for a nitrogen removal process is addressed. A two‐step nitrification model is studied, in which the maximum growth rate of ammonium oxidizers is larger than the one of nitrite oxidizers. This model describes the behavior of a SHARON reactor for the treatment of wastewater streams with high ammonium concentrations. Steady states are identified through direct calculation using a canonical state space model representation, for several types of microbial kinetics. The stability of the steady states is assessed and the corresponding phase portraits are analyzed. Practical operation of a SHARON reactor aims at reaching ammonium conversion to nitrite while suppressing further conversion to nitrate. Regions in the input space are identified that result in this desired behavior, with only nitrite formation. It is demonstrated that not only the dilution rate plays a role, as is commonly known, but also the influent ammonium concentration. Besides, the type of microbial (inhibition) kinetics has a nonnegligible influence. While the results indicate that product inhibition does not affect the number of steady states of a (bio)reactor model, it is shown that substrate inhibition clearly yields additional steady states. Particular attention is devoted to the physical interpretation of these phenomena. Biotechnol. Bioeng. 2007;98: 882–893. © 2007 Wiley Periodicals, Inc.
Production of lentiviral vectors by large‐scale transient transfection of suspension cultures and affinity chromatography purification
Authors: Segura María Mercedes , Garnier Alain , Durocher Yves , Coelho Helene , Kamen Amine
Published: April 2007

The use of lentiviral vectors as gene delivery vehicles has become increasingly popular in recent years. The growing interest in these vectors has created a strong demand for large volumes of vector stocks, which entails the need for scaleable vector manufacturing procedures. In this work, we present a simple and robust process for the production of lentiviral vectors using scaleable production and purification methodologies. Lentivirus particles were produced by transient transfection of serum‐free suspension‐growing 293 EBNA‐1 cells with four plasmids encoding the vector components using linear polyethylenimine (PEI) as transfection reagent. This process was successfully scaled‐up from shake flaks to a 3‐L bioreactor from which 1010 IVP were recovered. In addition, an affinity chromatography protocol designed for purification of bioactive oncoretroviral vectors has been adapted in this work for the purification of VSV‐G pseudotyped lentiviral vectors. Using heparin affinity chromatography, lentiviral particles were concentrated and purified directly from the clarified supernatants. During this step, a recovery of 53% of infective lentiviral particles was achieved while removing 94% of the impurities contained in the supernatant. Biotechnol. Bioeng. 2007; 98: 789–799. © 2007 Wiley Periodicals, Inc.
Iron‐Catalyzed C2C3 Bond Cleavage of Phenylpyruvate with O2: Insight into Aliphatic CC Bond‐Cleaving Dioxygenases
Authors: Paine Tapan Kanti , England Jason , Que Lawrence
Published: April 2007

Iron(II)‐phenylpyruvate complexes of tetradentate tris(6‐methyl‐2‐pyridylmethyl)amine (6‐Me3‐TPA) and tridentate benzyl bis(2‐quinolinylmethyl)amine (Bn‐BQA) were prepared to gain insight into CC bond cleavage catalyzed by dioxygenase enzymes. The complexes we have prepared and characterized are [Fe(6‐Me3‐tpa)(prv)][BPh4] (1), [Fe2(6‐Me3‐tpa)2(pp)][(BPh4)2] (2), and [Fe2(6‐Me3‐tpa)2(2′‐NO2‐pp)][(BPh4)2] (3), [Fe(6‐Me3‐tpa)(pp‐Me)][BPh4] (4), [Fe(6‐Me3‐tpa)(CN‐pp‐Et)][BPh4] (5), and [Fe(Bn‐bqa)(pp)] (8), in which PRV is pyruvate, PP is the enolate form of phenylpyruvate, 2′‐NO2‐PP is the enolate form of 2′‐nitrophenylpyruvate, PP‐Me is the enolate form of methyl phenylpyruvate, and CN‐PP‐Et is the enolate form of ethyl‐3‐cyanophenylpyruvate. The structures of mononuclear complexes 1 and 5 were determined by single‐crystal X‐ray diffraction. Both the PRV ligand in 1 and the CN‐PP‐Et ligand in 5 bind to the iron(II) center in a bidentate manner and form 5‐membered chelate rings, but the α‐keto moiety is in the enolate form in 5 with concomitant loss of a CHβ proton. The PP ligands of 2, 3, 4, and 8 react with dioxygen to form benzaldehyde and oxalate products, which indicates that the C2C3 PP bond is cleaved, in contrast to cleavage of the C1C2 bond previously observed for complexes that do not contain α‐ketocarboxylate ligands in the enolate form. These reactions serve as models for metal‐containing dioxygenase enzymes that catalyze the cleavage of aliphatic CC bonds.
Efficacy and safety of bortezomib in patients with plasma cell leukemia
Authors: Musto Pellegrino , Rossini Fausto , Gay Francesca , Pitini Vincenzo , Guglielmelli Tommasina , D'Arena Giovanni , Ferrara Felicetto , Filardi Nunzio , Guariglia Roberto , Palumbo Antonio ,   for the GISMM, GISL, and GIMEMA Cooperative Groups, Italy
Published: April 2007

BACKGROUND.

The prognosis of patients with plasma cell leukemia (PCL), an aggressive variant of multiple myeloma (MM), is usually poor. Bortezomib is the first proteasome inhibitor approved for the treatment of advanced MM. Currently available information regarding the role of bortezomib in PCL is scanty and derives from anecdotal, single–case reports.

METHODS.

The authors conducted a retrospective survey of unselected Italian patients with primary or secondary PCL who were treated with bortezomib outside of clinical trials. Twelve evaluable patients were recorded who had received bortezomib for 1 to 6 cycles as either a single agent or variously combined with other drugs. Three patients were treated with bortezomib as frontline therapy, and 9 patients received bortezomib after 1 to 4 lines of chemotherapy, including autologous stem cell transplantation and thalidomide.

RESULTS.

According to the International uniform response criteria of the International Myeloma Working Group, 5 partial responses (defined as a reduction in M‐protein of >50%), 4 very good partial responses (defined as a reduction of >90% in M‐protein), and 2 complete responses (defined as negative immunofixation) were achieved, for a response rate of 92%. Responses did not appear to be influenced by previous treatments or by other clinical or biologic parameters, including chromosome 13 deletion or the combination of bortezomib with other drugs. The median progression‐free and overall survivals after bortezomib were 8 months and 12 months, respectively. At the time of last follow–up, 8 patients were alive 6 to 21 months after treatment with bortezomib, 4 of whom were in very good partial or complete responses. Grade 3/4 hematologic or neurologic toxicities (graded according to the Common Terminology Criteria for Adverse Events [CTCAE; version 3]) were reported to occur in 9 patients and 1 patient, respectively, whereas 6 patients experienced possible or documented infections.

CONCLUSIONS.

Bortezomib appears to be an effective drug for PCL that could significantly improve the usually adverse clinical outcome of these patients. Cancer 2007. © 2007 American Cancer Society.
Achievement of long‐term local control in patients with craniopharyngiomas using high precision stereotactic radiotherapy
Authors: Combs Stephanie E. , Thilmann Christoph , Huber Peter E. , Hoess Angelika , Debus Jürgen , Schulz‐Ertner Daniela
Published: April 2007

BACKGROUND.

The long‐term outcome in patients with craniopharyngiomas treated with fractionated stereotactic radiotherapy (FSRT) was evaluated.

METHODS.

A total of 40 patients with craniopharyngiomas were treated between May 1989 and July 2006 with FSRT. Most patients were treated for tumor progression after surgery. A median target dose of 52.2 grays (Gy) (range, 50.4–56 Gy) was applied in a median conventional fractionation of 5 × 1.8 Gy per week. Follow‐up examinations included thorough clinical assessment as well as contrast‐enhanced magnetic resonance imaging scans.

RESULTS.

After a median follow‐up of 98 months (range, 3–326 months), local control was 100% at both 5 years and 10 years. Overall survival rates at 5 years and 10 years were 97% and 89%, respectively. A complete response was observed in 4 patients and partial responses were noted in 25 patients. Eleven patients presented with stable disease during follow‐up. Acute toxicity was mild in all patients. Long‐term toxicity included enlargement of cysts requiring drainage 3 months after FSRT. No visual impairment, radionecrosis, or development of secondary malignancies were observed.

CONCLUSIONS.

The long‐term outcome of FSRT for craniopharyngiomas is excellent with regard to local control as well as treatment‐related side effects. Cancer 2007. © 2007 American Cancer Society.