bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of apoptosis in peripheral blood and synovial tissue very early after initiation of infliximab treatment in rheumatoid arthritis patients
Authors: Wijbrandts Carla A. , Remans Philip H. , Klarenbeek Paul L. , Wouters Diana , van den Bergh Weerman Marius A. , Smeets Tom J. , Vervoordeldonk Margriet J. , Baeten Dominique , Tak Paul P.
Published: October 2008

Objective

Infliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion.

Methods

The percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, 1 hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, 1 hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured.

Results

There were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P < 0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation.

Conclusion

Our findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti–tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium.
Treatment of rheumatoid arthritis with a syk kinase inhibitor: A twelve‐week, randomized, placebo‐controlled trial
Authors: Weinblatt Michael E. , Kavanaugh Arthur , Burgos‐Vargas Ruben , Dikranian Ara H. , Medrano‐Ramirez Gabriel , Morales‐Torres Jorge L. , Murphy Frederick T. , Musser Theresa Kane , Straniero Nicholas , Vicente‐Gonzales Angela V. , Grossbard Elliott
Published: October 2008

Objective

Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcγ‐activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA).

Methods

We enrolled 189 patients with active RA despite methotrexate therapy in a 3‐month, multicenter, ascending‐dose, double‐blind, placebo‐controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.

Results

Twice‐daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice‐daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin‐6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related.

Conclusion

These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.
Erosive arthritis in a patient with pycnodysostosis: An experiment of nature
Authors: Ainola Mari , Valleala Heikki , Nykänen Pekka , Risteli Juha , Hanemaaijer Roeland , Konttinen Yrjö T.
Published: October 2008

Objective

The excellent poster painter Henri de Toulouse‐Lautrec is the most famous patient with cathepsin K–deficient pycnodysostosis. Cathepsin K is believed to play a major role in osteoclast‐driven bone resorption. In this study we explored the role of cathepsin K in bone resorption in a patient with a cathepsin K mutation causing pycnodysostosis in whom psoriatic arthritis also developed. We hypothesized that the patient would develop only inflammatory synovitis but would not develop bone erosions or other osteolytic changes.

Methods

Monocytes from the patient with pycnodysostosis and normal control monocytes were isolated and stimulated to fuse and form multinuclear osteoclast‐like cells, which were identified by evaluating messenger RNA expression of osteoclast markers. The ability to resorb bone was assessed by determining the extent of pit formation and levels of collagen degradation products generated by cathepsin K (C‐terminal crosslinking telopeptide of type I collagen [CTX]) and matrix metalloproteinases (pyridinoline crosslinked C‐terminal telopeptide of type I collagen). These experiments were also done in normal control cells after incubation with the cathepsin K inhibitor E64 during bone resorption.

Results

In contrast to our a priori hypothesis, the patient developed a mutilating disease with extensive bony erosions associated with lysis of some of the distal phalanges of her hands and feet. After stimulation of monocytes from this patient, the cells formed multinuclear tartrate‐resistant acid phosphatase–positive and calcitonin receptor–positive multikaryons, which, however, totally lacked cathepsin K. These multinuclear cells were able to resorb bone but, in contrast to normal control osteoclasts, did not produce CTX. The resorption pattern was abnormal in that, unlike normal control osteoclasts, both osteoclasts from the patient and E64‐inhibited osteoclasts did not leave extensive osteoclast trails, but were relatively sessile.

Conclusion

In this “experiment of nature” we observed that cathepsin K is not necessary for bone degradation. These findings may be pertinent to our understanding of the functions of cathepsin K inhibitors, which are currently being developed as drugs to treat metabolic bone diseases.
Human muscle cells express the costimulatory molecule B7‐H3, which modulates muscle–immune interactions
Authors: Waschbisch Anne , Wintterle Sabine , Lochmüller Hanns , Walter Maggie C. , Wischhusen Jörg , Kieseier Bernd C. , Wiendl Heinz
Published: October 2008

Objective

Interactions between the family of B7 ligands and their receptors are increasingly recognized as crucial for stimulation and/or inhibition of immune responses. The present study was undertaken to examine the expression and functional relevance of B7 homolog 3 (B7‐H3), a novel B7 homolog attributed significant immunoregulatory functions, in human muscle cells in vivo and in vitro.

Methods

Thirty‐five muscle biopsy specimens obtained from patients with polymyositis, dermatomyositis, inclusion body myositis, or noninflammatory myopathies and normal controls were analyzed by immunohistochemistry for B7‐H3 expression. The expression of B7‐H3 protein on primary human myoblasts and TE671 muscle rhabdomyosarcoma cells was studied by flow cytometry and Western blot analysis. B7‐H3 small interfering RNA (siRNA) was used to study the impact of knockdown of B7‐H3 on CD8+ cell–mediated lysis in skeletal muscle cells.

Results

B7‐H3 was not detectable on normal muscle fibers. In contrast, its expression was markedly increased on muscle fibers from patients with inflammatory myopathies. Cell‐surface staining was most prominent in the contact areas between muscle fibers and inflammatory cells. B7‐H3 protein was detected on myoblasts cultured from control and myositis patient muscle tissue as well as in TE671 muscle rhabdomyosarcoma cells. Knockdown of B7‐H3 by siRNA in TE671 cells enhanced CD8+ T cell–specific lysis, indicating a functional role of B7‐H3 in the protection of skeletal muscle from immune‐mediated lysis.

Conclusion

Our results demonstrate that human muscle cells express B7‐H3, a functional coinhibitory molecule of the B7 family. B7‐H3 may play an important role in muscle–immune interactions, providing further evidence of the active role of muscle cells in local immunoregulatory processes.
Identification of interleukin‐7 as a candidate disease mediator in spondylarthritis
Authors: Rihl Markus , Kellner Herbert , Kellner Wolfgang , Barthel Christian , Yu David T. Y. , Tak Paul P. , Zeidler Henning , Baeten Dominique
Published: October 2008

Objective

Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA.

Methods

Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase–polymerase chain reaction and enzyme‐linked immunosorbent assay.

Results

Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor β2. Of the novel candidate genes selected for confirmation, interleukin‐7 (IL‐7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL‐7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor α and IL‐1β.

Conclusion

In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL‐7. The specific overexpression of IL‐7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted.
Severity of baseline magnetic resonance imaging–evident sacroiliitis and HLA–B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years
Authors: Bennett A. N. , McGonagle D. , O'Connor P. , Hensor E. M. A. , Sivera F. , Coates L. C. , Emery P. , Marzo‐Ortega H.
Published: October 2008

Objective

Magnetic resonance imaging (MRI) is increasingly used to detect sacroiliitis earlier. This study was undertaken to investigate what proportion of patients with MRI‐evident sacroiliitis develop ankylosing spondylitis (AS) in the long term and whether there are predictors of outcome.

Methods

Consecutive undiagnosed patients with early inflammatory back pain (IBP) (of <2 years' duration) were assessed clinically and radiologically. Baseline imaging assessments included fat‐suppressed MRI sequences of the sacroiliac joints and lumbar spine that were scored for active bone marrow edema representative of acute inflammation, and anteroposterior radiographs of the pelvis and lateral radiographs of the lumbar spine, which were scored using the Stoke Ankylosing Spondylitis Spine Score. Patients were reassessed clinically and radiographically after 8 years. The primary outcome was the modified New York criteria for AS at followup.

Results

Fifty patients were assessed at the beginning of the study, and 40 patients were followed up after a mean of 7.7 years. Of these 40 patients, 58% were HLA–B27 positive, and 98% met the European Spondylarthropathy Study Group criteria. At baseline, 33 (83%) of the 40 patients followed up had MRI‐evident sacroiliitis, and 6 (12%) had unequivocal AS according to the modified New York criteria. At followup, despite significant improvements in clinical outcomes, 13 of 39 patients (33.3%) had AS according to the modified New York criteria. The combination of severe sacroiliitis seen on MRI with HLA–B27 positivity was an excellent predictor of future AS (likelihood ratio [LR] 8.0, specificity 92%), while mild or no sacroiliitis, regardless of HLA–B27 status, was a predictor of not having AS (LR 0.4, specificity 38%).

Conclusion

Our findings indicate that in patients with early IBP, a combination of severe sacroiliitis and HLA–B27 positivity has a high specificity for development of AS, compared with mild or no sacroiliitis, regardless of HLA–B27 status, which confers a low likelihood of developing AS. This has implications for the diagnosis of “early” AS and possibly for selection of more aggressive therapies.
Neuronally released sympathetic neurotransmitters stimulate splenic interferon‐γ secretion from T cells in early type II collagen–induced arthritis
Authors: Straub Rainer H. , Rauch Luise , Fassold Alexander , Lowin Torsten , Pongratz Georg
Published: October 2008

Objective

The sympathetic nervous system confers a proinflammatory effect during the early phase of type II collagen–induced arthritis (CIA). These effects might be mediated by up‐regulation of cytokines such as interferon‐γ (IFNγ) or chemokines such as CXCL1 (cytokine‐induced neutrophil chemoattractant, or KC). This study aimed to identify the role of sympathetic neurotransmitters in splenic secretion of IFNγ and KC shortly after the onset of CIA.

Methods

At different time points during CIA, we determined the density of sympathetic nerve fibers in the spleens of mice. Spleens were removed when the mouse joints were assessed an arthritis score of 3 (at approximately day 32). Spleen slices (0.35 mm thick) were transferred to superfusion microchambers to allow observation of the effects of physiologically released sympathetic neurotransmitters on secretion of IFNγ and KC.

Results

Compared with control mice, mice with CIA demonstrated a decrease in sympathetic nerve fiber density in the spleens, which reached a minimum density shortly after the start of symptomatic arthritis (day 32). T cell depletion markedly reduced splenic secretion of IFNγ and KC. Electrical‐field stimulation of the spleen slices reduced the secretion of IFNγ, which was attenuated by an α1‐adrenergic antagonist. In addition, splenic IFNγ secretion was stimulated by norepinephrine, via β‐adrenergic receptors, and adenosine, via A1 adenosine receptors. Similarly, splenic KC secretion was stimulated by norepinephrine, via β‐adrenergic receptors.

Conclusion

The results of this study demonstrate a reduction of sympathetic nerve fibers in the spleens of arthritic animals. Nevertheless, sympathetic nerves help to increase secretion of IFNγ and KC, which, at the early stages shortly after the onset of CIA, can contribute to the proinflammatory effect of the sympathetic nervous system.
Cognitive and neurologic status in patients with systemic lupus erythematosus without major neuropsychiatric syndromes
Authors: Kozora Elizabeth , Arciniegas David B. , Filley Christopher M. , West Sterling G. , Brown Mark , Miller David , Grimm Alex , Devore Maria D. , Wingrove Christy , Zhang Lening
Published: October 2008

Objective

To examine neuropsychological and neurologic functioning in systemic lupus erythematosus (SLE) patients without histories of overt neuropsychiatric disorders (non‐NPSLE patients).

Methods

Sixty‐seven non‐NPSLE patients and 29 healthy controls were administered a standardized neurologic examination and measures of cognition, depression, and self‐reported cognitive functioning.

Results

Non‐NPSLE patients scored lower than controls on the total score of the neurologic examination (P < 0.0001). Item analysis indicated that the physician's description of mentation and mood was the only item that differed significantly between patients with SLE and controls (P = 0.004). Compared with controls, non‐NPSLE patients had significantly higher rates of impairment on logical reasoning (P = 0.012) and verbal memory (P = 0.03), and trends toward greater impairment on visual attention (P = 0.06) and working memory (P = 0.098). There were no significant differences between non‐NPSLE patients and controls on a cognitive impairment index (CII): 20.9% of non‐NPSLE patients and 13.8% of controls were impaired. Patients with SLE scored higher on depressive symptoms (P < 0.0001) and perceived cognitive difficulties (P = 0.001) compared with controls.

Conclusion

The utility of a standardized neurologic examination in SLE for excluding overt neurologic dysfunction and assuring a non‐NPSLE group selection was demonstrated. In contrast to our earlier study, we did not find differences between non‐NPSLE patients and controls on the CII. Slightly lower CII scores in non‐NPSLE patients and higher CII scores in controls may have reduced cognitive differences between these groups. Non‐NPSLE patients demonstrate specific decline in the areas of attention, memory, and reasoning; continued studies of associated brain regions are warranted.
Optimal treatment of knee monarthritis in juvenile idiopathic arthritis: A decision analysis
Authors: Beukelman Timothy , Guevara James P. , Albert Daniel A.
Published: October 2008

Objective

To identify the optimal initial treatment strategy for knee monarthritis in juvenile idiopathic arthritis (JIA) using a decision model and parents' preferences.

Methods

We utilized a decision analysis model with Markov states and a 6‐month multi‐attribute outcome with 7 dimensions pertinent to the treatment decision. The 3 most common treatment strategies for knee monarthritis were compared: nonsteroidal antiinflammatory drugs (NSAIDs) only, NSAID trial followed by intraarticular corticosteroid injection (IACI) if arthritis was not resolved after 2 months, and initial IACI. Probability estimates for the efficacy and adverse effects of NSAIDs and IACIs were derived from a systematic review of the literature. Parents' preferences for the 7 dimensions of the multi‐attribute outcome were elicited by a unique hybrid of the time tradeoff and magnitude estimation techniques. These preferences were then combined with the outcomes of the decision analysis to determine an individual's preferred treatment.

Results

The NSAID trial strategy may avert IACIs in some patients, but at a cost of continued active arthritis. The number of patients that need to be treated with the NSAID trial strategy to avoid a single IACI compared with the initial IACI strategy is 3.8 with an expected additional cost of 6.7 months of active arthritis. Of the 12 parent subjects, 11 (92%) preferred the initial IACI strategy and 1 preferred the NSAID‐only strategy. These preferences were not sensitive to model assumptions or probability estimates.

Conclusion

Initial IACI appears to be the optimal treatment strategy for knee monarthritis in JIA.
Assessment of reproductive history in systemic sclerosis
Authors: Bernatsky Sasha , Hudson Marie , Pope Janet , Vinet Evelyne , Markland Janet , Robinson David , Jones Niall , Docherty Peter , Abu‐Hakima Maysan , LeClercq Sharon , Dunne James , Smith Douglas , Mathieu Jean‐Pierre , Khalidi Nader , Sutton Evelyn , Baron Murray ,   Canadian Scleroderma Research Group
Published: October 2008

Objective

To assess the number of live births in women whose systemic sclerosis (SSc) onset occurred during their reproductive years, and to compare this with general population rates.

Methods

Within the Canadian Scleroderma Research Group cohort, we identified 320 women whose SSc symptoms began prior to age 50 years. We determined the number of children born in the years following first onset of symptoms. We summed the years of followup from the time of first symptoms in subjects up to age 50 years (or oldest age attained, if the subject was age <49 years). We applied age‐specific birth rates for Canadian women to these years of followup in order to determine the expected number of live births for the period. We then calculated the standardized incidence ratio (SIR) of observed to expected live births.

Results

In the 320 women studied, the number of live births over the interval since symptom onset was below the expected number (111 live births observed versus 140 expected; SIR 0.79, 95% confidence interval [95% CI] 0.65–0.95). This finding was more prominent in women with diffuse cutaneous disease versus limited cutaneous disease. The mean and median numbers of live births were similar across SSc subgroups based on organ involvement or cyclophosphamide exposure. In repeat analyses, including the reproductive period before SSc symptom onset, the ratio of observed to expected births was 1.23 (95% CI 1.13–1.33).

Conclusion

Compared with the general population, fewer live births were noted in women with SSc, but this phenomenon was only apparent in the period after symptom onset.
Quality appraisal of clinical practice guidelines and consensus statements on the use of biologic agents in rheumatoid arthritis: A systematic review
Authors: Lopez‐Olivo Maria A. , Kallen Michael A. , Ortiz Zulma , Skidmore Becky , Suarez‐Almazor Maria E.
Published: October 2008

Objective

To evaluate the quality of clinical practice guidelines (CPGs) and consensus statements (CS) for the treatment of rheumatoid arthritis with tumor necrosis factor α (TNFα) antagonists.

Methods

We searched for CPGs and CS on the use of infliximab, etanercept, and/or adalimumab for the treatment of rheumatoid arthritis, published through October 10, 2006. Sources included electronic databases (Medline, EMBase, BIOSIS, etc.), guideline registries, and pertinent Web sites. Review of 4,915 citations revealed 16 CPGs and 20 CS. Two independent reviewers evaluated development methods of selected studies using the 23‐item Appraisal of Guidelines for Research and Evaluation (AGREE) instrument and compared recommendations between guidelines.

Results

Of the 16 guidelines, only 5 (31%) were based on a systematic review of relevant research evidence. Only 4 (25%) of the guidelines fulfilled ≥60% of the AGREE criteria. AGREE scores were lower for guidelines from rheumatology societies than government agencies when reporting scope and purposes (P= 0.03), stakeholder involvement (P= 0.03), and clarity and presentation (P= 0.01). Guidelines scored higher than CS in most domains. Overall, guideline recommendations were consistent with respect to the use of biologic agents after failure of disease‐modifying antirheumatic drugs, but differed or did not provide specific guidance on tests for screening.

Conclusion

Guidelines for introducing TNFα antagonists in rheumatoid arthritis often fail to meet expected methodologic criteria and therefore vary significantly in quality and with respect to some recommendations for patient assessment and management.
Perceived technology clusters and ownership of related technologies: The case of consumer electronics
Authors: Van Rijnsoever Frank J. , Castaldi Carolina
Published: October 2008

We contribute to the understanding of how technologies may be perceived to be part of technology clusters. The value added of the paper is both at a theoretical and an empirical level. We add to the theoretical understanding of technology clusters by distinguishing between clusters in perceptions and clusters in ownership, and by proposing a mechanism to explain the existence of clusters. Our empirical analysis combines qualitative and quantitative methods to investigate clusters of consumer electronics for a sample of Dutch consumers. We find that perceived clusters in consumer electronics are mostly determined by functional linkages, and that perceived technology clusters are good predictors of ownership clusters, but only for less widely diffused products.
Observational analysis of the wind‐evaporation‐SST feedback over the tropical Pacific Ocean
Authors: Lin Jia‐Lin , Han Weiqing , Lin Xin
Published: October 2008

Theoretical studies suggested that the wind‐evaporation‐sea surface temperature (SST) (WES) feedback plays an important role in maintaining the latitudinal asymmetry of the intertropical convergence zone (ITCZ) in the tropical Pacific Ocean. This study examines the geographical distribution of the strength of WES feedback over the tropical Pacific Ocean using multiple long‐term observational datasets. The results show that the WES feedback is very weak over the eastern Pacific warm pool and stratocumulus regions, where the strongest latitudinal asymmetry of the ITCZ exists, suggesting that some other mechanisms are responsible for the asymmetry. To the west of 120W, the WES feedback has larger magnitude but is often statistically insignificant. This is because the effect of the air–sea humidity difference tends to offset the wind effect, which is a factor not considered in the original WES feedback theory. Copyright © 2008 Royal Meteorological Society
Randnahe Vierfachbefestigungen unter Querlast
Authors: Unterweger Andreas , Spyridis Panagiotis , Mihala Ronald , Bergmeister Konrad
Published: October 2008

Ankergruppen in Beton kommen als Befestigungsmittel häufig am Rand zur Anwendung. Bei der Verbindung der Stahlanker mit der Montageplatte kommt es wegen des Lochspiels zu einer zufälligen Ankerstellung in den Durchgangslöchern der Montageplatte. Dadurch werden bei einer Querbelastung nicht alle Anker gleichzeitig aktiviert, was die Tragfähigkeit der Gruppenbefestigung beeinflusst. Bei randnahen Vierfachbefestigungen unter Querlast ist die für die Bruchlast ungünstigste Ankerstellung dann erreicht, wenn die randnäheren Anker zuerst belastet werden. Ausgehend davon berücksichtigt die derzeitige Bemessung nach ETAG 001 für den Grenzzustand der Tragfähigkeit (ULS) ausschließlich die randnähere Ankerreihe. Unter anderem wird hier gezeigt, dass Versuche gängiger Geometrien mit ungünstigster Ankerstellung im Vergleich dazu wesentlich höhere Bruchlasten aufweisen.

Zu Beginn dieser Arbeit werden randnahe Vierfachversuche ungünstigster Ankerstellung mit der derzeitigen Bemessung verglichen. Anschließend werden Einzelversuche durchgeführt, um mittels elektronischer Speckle‐Interferometrie (ESPI) die Beeinflussung des einzelnen Ankers auf die umgebende Betonoberfläche zu untersuchen. Abschließend zeigen Kraftflussüberlegungen einer finiten Elemente Simulation die Auswirkungen auf den inneren Spannungszustand.
Montageplanung und Herstellung der Seitenfelder der Stonecutters Bridge
Authors: Morgenthal Guido , Sham Robin , Yamane Kaoru
Published: October 2008

Eine der größten Herausforderungen beim Bau von Stonecutters Bridge war die Herstellung der Beton‐Seitenfelder mit einem geometrisch anspruchsvollen Überbau in Form eines Gitterrosts in 70 m Höhe. Dieser kann sein Eigengewicht nur mit Hilfe der Schrägkabel tragen und wurde daher auf einem Lehrgerüst hergestellt, das bis zum Einbau der Kabel aktiviert bleibt. Eine sorgfältige und auf die Herstellung des Überbaus abgestimmte Planung des Lehrgerüsts war nötig. Dieser Beitrag beschreibt, wie der Bau des Betontragwerks geplant und umgesetzt wurde. Die Modellierung aller wesentlichen Herstellungsschritte für Tragfähigkeitsnachweise sowie zur Kontrolle der Geometrie wird ebenso erläutert wie die Planung der Baubehelfe. Die Bearbeitung erfolgte in hohem Maße interaktiv mit der Baufirma, was zu einer erfolgreichen Umsetzung des Projekts beigetragen hat.
Robust deformation capture from temporal range data for surface rendering
Authors: Castellani Umberto , Gay‐Bellile Vincent , Bartoli Adrien
Published: October 2008

Imagine an object such as a paper sheet being waved in front of some sensor. Reconstructing the time‐varying 3D shape of the object finds direct applications in computer animation. The goal of this paper is to provide such a deformation capture system for surfaces. It uses temporal range data obtained by sensors such as those based on structured light or stereo. So as to deal with many different kinds of material, we do not make the usual assumption that the object surface has textural information. This rules out those techniques based on detecting and matching keypoints or directly minimizing color discrepancy. The proposed method is based on a planar mesh that is deformed so as to fit each of the range images. We show how to achieve this by minimizing a compound cost function combining several data and regularization terms, needed to make the overall system robust so that it can deal with low quality datasets. Carefully examining the parameter to residual relationship shows that this cost function can be minimized very efficiently by coupling nonlinear least squares methods with sparse matrix operators. Experimental results for challenging datasets coming from different kinds of range sensors are reported. The algorithm is reasonably fast and is shown to be robust to missing and erroneous data points. Copyright © 2008 John Wiley & Sons, Ltd.
Hydrogen‐Bond Detection, Configuration Assignment and Rotamer Correction of Side‐Chain Amides in Large Proteins by NMR Spectroscopy through Protium/Deuterium Isotope Effects
Authors: Liu Aizhuo , Wang Jifeng , Lu Zhenwei , Yao Lishan , Li Yue , Yan Honggao
Published: October 2008

The configuration and hydrogen‐bonding network of side‐chain amides in a 35 kDa protein were determined by measuring differential and trans‐hydrogen‐bond H/D isotope effects by using the isotopomer‐selective (IS)‐TROSY technique, which leads to a reliable recognition and correction of erroneous rotamers that are frequently found in protein structures. First, the differential two‐bond isotope effects on carbonyl 13C′ shifts, which are defined as Δ2Δ13C′(ND)=2Δ13C′(NDE)‐2Δ13C′(NDZ), provide a reliable means for the configuration assignment for side‐chain amides, because environmental effects (hydrogen bonds and charges, etc.) are greatly attenuated over the two bonds that separate the carbon and hydrogen atoms, and the isotope effects fall into a narrow range of positive values. Second and more importantly, the significant variations in the differential one‐bond isotope effects on 15N chemical shifts, which are defined as Δ1Δ15N(D)=1Δ15N(DE)‐1Δ15N(DZ) can be correlated with hydrogen‐bonding interactions, particularly those involving charged acceptors. The differential one‐bond isotope effects are additive, with major contributions from intrinsic differential conjugative interactions between the E and Z configurations, H‐bonding interactions, and charge effects. Furthermore, the pattern of trans‐H‐bond H/D isotope effects can be mapped onto more complicated hydrogen‐bonding networks that involve bifurcated hydrogen‐bonds. Third, the correlations between Δ1Δ15N(D) and hydrogen‐bonding interactions afford an effective means for the correction of erroneous rotamer assignments of side‐chain amides. Rotamer correction by differential isotope effects is not only robust, but also simple and can be applied to large proteins.
N,N‐Dimethylaminopropylsilane: A Case Study on the Nature of Weak Intramolecular Si⋅⋅⋅N Interactions
Authors: Hagemann Michael , Berger Raphael J. F. , Hayes Stuart A. , Stammler Hans‐Georg , Mitzel Norbert W.
Published: October 2008

N,N‐Dimethylaminopropylsilane H3Si(CH2)3NMe2was synthesised by the reaction of (MeO)3Si(CH2)3NMe2with lithium aluminium hydride. Its solid‐state structure was determined by X‐ray diffraction, which revealed a five‐membered ring with an Si⋅⋅⋅N distance of 2.712(2) Å. Investigation of the structure by gas‐phase electron diffraction (GED), ab initio and density functional calculations and IR spectroscopy revealed that the situation in the gas phase is more complicated, with at least four conformers present in appreciable quantities. Infrared spectra indicated a possible Si⋅⋅⋅N interaction in the SiH stretching region (2000–2200 cm−1), as the approach of the nitrogen atom in the five‐membered ring weakens the bond to the hydrogen atom in thetransposition. Simulated gas‐phase IR spectra generated from ab initio calculations (MP2/TZVPP) exhibited good agreement with the experimental spectrum. A method is proposed by which the fraction of the conformer with a five‐membered ring can be determined by a least‐squares fit of the calculated to experimental absorption intensities. The abundance of this conformer was determined as 23.7(6) %, in good agreement with the GED value of 24(6) %. The equilibrium Si⋅⋅⋅N distance predicted by theory for the gas‐phase structure was highly variable, ranging from 2.73 (MP2) to 3.15 Å (HF). The value obtained by GED is 2.91(4) Å, which could be confirmed by a scan of the potential‐energy surface at the DF‐LCCSD[T] level of theory. The nature of the weak dative bond in H3Si(CH2)3NMe2can be described in terms of attractive inter‐electronic correlation forces (dispersion) and is also interpreted in terms of the topology of the electron density.
Total Synthesis of Discodermolide: Optimization of the Effective Synthetic Route
Authors: de Lemos Elsa , Porée François‐Hugues , Bourin Arnaud , Barbion Julien , Agouridas Evangelos , Lannou Marie‐Isabelle , Commerçon Alain , Betzer Jean‐François , Pancrazi Ange , Ardisson Janick
Published: October 2008

An efficient and modulable total synthesis of discodermolide (DDM), a unique marine anticancer polyketide is described including related alternative synthetic approaches. Particularly notable is the repeated application of a crotyltitanation reaction to yield homoallylic (Z)‐O‐ene‐carbamate alcohols with excellent selectivity. Advantage was taken of this reaction not only for the stereocontrolled building of the syn–anti methyl–hydroxy–methyl triads of DDM, but also for the direct construction of the terminal (Z)‐diene. Of particular interest is also the installation of the C13C14 (Z)‐double bond through a highly selective dyotropic rearrangement. The preparation of the middle C8–C14 fragment in two sequential stages and its coupling to the C1–C7 moiety was a real challenge and required careful optimization. Several synthetic routes were explored to allow high and reliable yields. Due to the flexibility and robust character of this approach, it might enable a systematic structural variation of DDM and, therefore, the elaboration and exploration of novel discodermolide structural analogues.
Enantioselective determination of mexiletine and its metabolites p‐hydroxymexiletine and hydroxymethylmexiletine in rat plasma by normal‐phase liquid chromatography‐tandem mass spectrometry: Application to pharmacokinetics
Authors: Godoy Ana Leonor Pardo Campos , Parisi Caio Cesar , Marques Maria Paula , Coelho Eduardo Barbosa , Lanchote Vera Lucia
Published: October 2008

Mexiletine (MEX), hydroxymethylmexiletine (HMM) and p‐hydroxymexiletine (PHM) were analyzed in rat plasma by LC‐MS/MS. The plasma samples were prepared by liquid‐liquid extraction using methyl‐tert‐butyl ether as extracting solvent. MEX, HMM, and PHM enantiomers were resolved on a Chiralpak® AD column. Validation of the method showed a relative standard deviation (precision) and relative errors (accuracy) of less than 15% for all analytes studied. Quantification limits were 0.5 ng ml−1 for the MEX and 0.2 ng ml−1 for the HMM and PHM enantiomers. The validated method was successfully applied to quantify the enantiomers of MEX and its metabolites in plasma samples of rats (n = 6) treated with a single oral dose of racemic MEX. Chirality, 2009. © 2008 Wiley‐Liss, Inc.
Preparation of enantiopure (R)‐hydroxy metabolite of denbufylline using immobilized Lactobacillus kefiri DSM 20587 as a catalyst
Authors: Pȩkala Elżbieta , Burbiel Joachim C. , Müller Christa E.
Published: October 2008

Lactobacillus kefiri DSM 20587 cells were immobilized in calcium alginate and carrageenan. The immobilized cells were used as biocatalysts for the enantioselective reduction of the methyl ketone group of denbufylline to synthesize the enantiopure (R)‐hydroxy metabolite: (−)‐1,3‐dibutyl‐7‐((2′R)‐hydroxypropyl)‐1H‐purine‐2,6(3H,7H)‐dione (1). The experimental conditions for the biotransformation were optimized. As denbufylline is insoluble in aqueous media, the influence of cosolvents (dimethylsulfoxide (DMSO), acetonitrile) and different concentrations of each solvent in the reaction mixture on the yield and enantiomeric excess of the final biotransformation product was studied. The maximum biotransformation yield (96–98%) and highest enantioselectivity (96% ee) for the obtained metabolite were reached using DMSO as a cosolvent at a concentration of 7.5% (v/v) in the presence of L. kefiri immobilized either in calcium alginate or in carrageenan. The absolute configuration of the stereogenic center of 1 was determined by applying Mosher's method. Chirality 2009. © 2008 Wiley‐Liss, Inc.
Stereoselective pharmacokinetics of diniconazole enantiomers in rabbits
Authors: Wang Qiuxia , Qiu Jing , Zhou Zhiqiang , Cao Aocheng , Wang Xinquan , Zhu Wentao , Dang Ziheng
Published: October 2008

Diniconazole [(E)‐(RS)‐1‐(2,4,‐dichlorophenyl)‐4,4‐dimethyl‐2‐(1H‐1,2,4‐triazole‐1‐yl)pent‐1‐en‐3‐ol)] is a potent triazole fungicide. The enantioselective pharmacokinetics of diniconazole enantiomers in rabbits was studied via intravenous (i.v.) injection. The pharmacokinetics and the enantiomer fraction (EF) were determined using normal high‐performance liquid chromatography with diode array detection and a cellulose‐tris‐(3,5‐dimethylphenylcarbamate)‐based chiral stationary phase (CDMPC‐CSP). The time–concentration curves in plasma were fitted by a two‐compartment open mode. The results showed that the concentration of S‐diniconazole in plasma decreased faster than that of R‐diniconazole, and EFs increased with time after administration of racemic diniconazole (rac‐diniconazole). The R‐/S‐enantiomer ratio of the area under the time–plasma concentration curve (AUC0–∞) after administration was 1.52. The total plasma clearance value of S‐enantiomer was 1.57‐fold higher than that of the R‐diniconazole. These results indicate substantial stereoselectivity in the kinetics of diniconazole enantiomers in rabbit. Chirality, 2009. © 2008 Wiley‐Liss, Inc.
Design and Synthesis of Potent and Selective Azaindole‐Based Rho Kinase (ROCK) Inhibitors
Authors: Schirok Hartmut , Kast Raimund , Figueroa‐Pérez Santiago , Bennabi Samir , Gnoth Mark J. , Feurer Achim , Heckroth Heike , Thutewohl Michael , Paulsen Holger , Knorr Andreas , Hütter Joachim , Lobell Mario , Münter Klaus , Geiß Volker , Ehmke Heimo , Lang Dieter , Radtke Martin , Mittendorf Joachim , Stasch Johannes‐Peter
Published: October 2008

Rho kinase plays a pivotal role in several cellular processes such as vasoregulation, making it a suitable target for the treatment of hypertension and related disorders. We discovered a new compound class of Rho kinase (ROCK) inhibitors containing a 7‐azaindole hinge‐binding scaffold tethered to an aminopyrimidine core. Herein we describe the structure–activity relationships elucidated through biochemical and functional assays. The introduction of suitable substituents at the 3‐position of the bicyclic moiety led to an increase in activity, which was required to design compounds with favorable pharmacokinetic profile. Azaindole32was identified as a highly selective and orally available ROCK inhibitor able to cause a sustained blood pressure reduction in vivo.
Improved fluorescence of indocyanine green in vitro and in vivo after simple cooling procedures
Authors: Boddington Sophie , Sutton Elizabeth J. , Jones Ella , Purcell Derk D. , Henning Tobias D. , Tavri Sidhartha , Meier Reinhard , Sista Akhilesh , Fu Yanjun , Daldrup‐Link Heike
Published: October 2008

Indocyanine green (ICG) is a contrast agent used for detecting angiogenesis with optical imaging (OI). The purpose of this study was to investigate whether cooling procedures increase the signal yield of ICG with OI. Test samples of 0.05 and 0.02 mM ICG in 40% DMSO and 60% DMEM underwent OI at four different temperatures (5, 37, 55 and 75°C). In addition, six athymic rats with an antigen‐induced arthritis of the knee and ankle joints underwent OI before and after injection of ICG (10 mg/ml, dose 15 mg/kg) on two separate days with and without cooling of the joints. The fluorescent signals of the test samples and arthritic joints were measured and evaluated for significant differences before and after cooling with a t‐test. In vitro studies showed a strong negative correlation between ICG temperature and fluorescent signal. The mean fluorescent signal of arthritic joints (measured in efficiency) was 0.345 before ICG‐injection, 4.55 after ICG‐injection and before cooling and 9.71 after ICG‐injection and after cooling. The fluorescent signal enhancement of arthritic joints with ICG‐enhanced OI images increased significantly after cooling (p = 0.02). The signal yield of ICG can be significantly increased by cooling the target pathology. The primary underlying cause of the temperature dependence of ICG is enhanced collisional quenching with increasing temperature. This simple cooling method may be immediately helpful to increase the fluorescence signal yield in current ICG‐enhanced OI‐studies in patients. Copyright © 2008 John Wiley & Sons, Ltd.
Phase 2 trial of rituximab plus hyper‐CVAD alternating with rituximab plus methotrexate‐cytarabine for relapsed or refractory aggressive mantle cell lymphoma
Authors: Wang Michael , Fayad Luis , Cabanillas Fernando , Hagemeister Fredrick , McLaughlin Peter , Rodriguez Maria A , Kwak Larry W. , Zhou Yuhong , Kantarjian Hagop , Romaguera Jorge
Published: October 2008

BACKGROUND.

Relapsed or refractory mantle cell lymphoma has a very poor prognosis. The authors evaluated the response rates and survival times of patients treated with an intense regimen known to be effective against untreated aggressive mantle cell lymphoma: rituximab plus hyper‐CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab plus methotrexate‐cytarabine.

METHODS.

In this prospective, open‐label, phase 2 study, patients received this combination for 6 to 8 cycles. Twenty‐nine patients were evaluable for response.

RESULTS.

The median number of cycles received was 5 (range, 1‐7 cycles), and the overall response rate was 93% (45% complete response [CR] or CR unconfirmed [CRu] and 48% partial response [PR]). All 5 patients previously resistant to treatment had a response (1 CR, 4 PR), and both patients whose disease did not change in response to prior therapy had PRs. Toxic events occurring in response to the 104 cycles given included neutropenic fever (11%), grade 3 or 4 neutropenia (74%), and grade 3 or 4 thrombocytopenia (63%). There were no deaths from toxicity. At a median follow‐up of 40 months (range, 5‐48 months), the median failure‐free survival time was 11 months with no plateau in the survival curve.

CONCLUSIONS.

This combination chemotherapy was effective for refractory/relapsed mantle cell lymphoma. Cancer 2008. © 2008 American Cancer Society.
Pathomorphologic evaluation of pulmonary radiofrequency ablation
Authors: Clasen Stephan , Krober Stefan‐Martin , Kosan Bora , Aebert Hermann , Fend Falko , Bomches Andrea , Claussen Claus D. , Pereira Philippe L.
Published: October 2008

BACKGROUND.

Radiofrequency (RF) ablation is an increasingly applied technique. Promising results of hepatic RF ablation raised expectations of its capabilities for treatment of primary and secondary lung tumors. Because of different thermal and electrical properties of lung tissue, compared with liver tissue, a simple analogy of tissue response is not possible. The authors aimed to evaluate the effectiveness of image‐guided pulmonary RF ablation and to characterize pathomorphology of tissue response.

METHODS.

RF ablations of 11 pulmonary malignancies in 9 patients were performed under computed tomography (CT)‐guidance. Three days after RF ablation, surgical resection was performed followed by pathologic examination. Specimens were evaluated macroscopically, histologically by hematoxylin and eosin (H & E) staining, terminal deoxy‐nucleotidyl transferase‐mediated nick end‐labeling (TUNEL), and electron microscopy.

RESULTS.

Tumor tissues and adjacent lung tissues were characterized by double‐strand fragmentation as determined by TUNEL. Ultrastructurally apoptotic bodies were found, indicating apoptotic cells. Criteria for tissue necrosis were not fulfilled by standard histological staining (H & E), showing preserved tissue architecture and only few microscopic cellular details suggestive of tumor regression. Because of DNA fragmentation, as determined by TUNEL and results from electron microscopy, the authors confirmed the tumor tissue to be completely ablated in 10 (90.9%) cases. However, in 2 cases, a safety margin was absent.

CONCLUSIONS.

CT‐guided pulmonary RF ablation of pulmonary malignancies is a locally effective treatment. Three days after RF ablation, tumor tissue seemed to be thermally fixed still showing characteristics of vital tumor tissue in standard histological staining; however the tissue proved to be in regression toward coagulative necrosis verified ultrastructurally and by TUNEL. Cancer 2008. © 2008 American Cancer Society.
Breast cancer survivors' health‐related quality of life
Authors: Paskett Electra D. , Alfano Catherine M. , Davidson Mario A. , Andersen Barbara L. , Naughton Michelle J. , Sherman Aurora , McDonald Paige Green , Hays Jennifer
Published: October 2008

BACKGROUND.

Small samples with few minority women and/or the absence of comparisons to peers without cancer histories have limited previous research suggesting racial differences in breast cancer survivors' health‐related quality of life (HRQoL). This study not only compared HRQoL of African American and white breast cancer survivors, but also compared the HRQoL of these women to that of same‐race women with no cancer history.

METHODS.

Data from the Women's Health Initiative‐Observational Study were used, including 5021 cancer survivors and 88,532 women without a history of cancer. Multivariate regression analyses estimated differences in breast cancer survivors' baseline HRQoL (RAND36), depressive symptoms (CES‐D short‐form), and sleep quality (WHIIRS).

RESULTS.

African American breast cancer survivors reported worse physical functioning and general health compared with white survivors. Among African Americans, survivors reported worse role limitations due to physical health, pain, general health, and vitality than women without a history of cancer. This was most evident in those with more recent diagnoses. Most significant differences between groups were small in magnitude (Cohen d = .21‐.36).

CONCLUSIONS.

These results add to the increasing knowledge of cancer disparities by showing that African American women have small, but clinically meaningful, decrements in physical HRQoL compared with white survivors and with African American women without cancer. Because African American women also face diagnosis with higher grade tumors and higher breast cancer mortality, more research is needed to examine the physical and psychosocial experiences of African American breast cancer survivors to elucidate the mechanisms leading to poorer outcomes. Cancer 2008. © 2008 American Cancer Society.