bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Aspect of Magnesium Bromide‐Promoted Enantioselective Aryl Additions of Triaryl(tetrahydrofuran)aluminum to Ketones Catalyzed by a Titanium(IV) Catalyst of trans‐1,2‐Bis(hydroxycamphorsulfonylamino)cyclohexane
Authors: Chen Chien‐An , Wu Kuo‐Hui , Gau Han‐Mou
Published: June 2008

A novel aspect of MgBr2‐promoted asymmetric triarylaluminum‐tetrahydrofuran [AlAr3(THF)] additions to ketones catalyzed by a titanium catalyst of 20 mol% trans‐1,2‐bis(hydroxycamphorsulfonylamino)cyclohexane (2) is reported. The catalytic system works excellently for aromatic ketones with either an electron‐withdrawing or an electron‐donating substituent on the aromatic ring at the 2′‐, 3′‐, or 4′‐positions, affording tertiary alcohols in excellent enantioselectivities of ≥90% ee, except for the cases of phenyl addition to 2′‐methoxyacetophenone and 4‐trimethylsilylphenyl (4‐TMSC6H4) addition to acetopheneone.
Zeolite NaY‐Promoted Monocyclization of Epoxy Polyene Terpenes: A Unique Route for the Direct Synthesis of Incompletely Cyclized Naturally Occurring Terpenols
Authors: Tsangarakis Constantinos , Raptis Christos , Arkoudis Elias , Stratakis Manolis
Published: June 2008

A variety of epoxy polyene terpenes cyclize readily by confinement within zeolite NaY to form primarily products of monocyclization. The monocyclization pathway is highly predominant, irrespectively of the side chain of the epoxy terpene, while the monocyclic products possess regioselectively an exomethylenic double bond. The selective monocyclization in the case of epoxyfarnesyl acetate, epoxyfarnesylacetone or 2,3‐epoxysqualene, provides a direct route to the synthesis of a variety of natural products, such as elengasidiol, farnesiferols B–D, achilleol A, camelliol C and to four farnesylacetone‐derived metabolites isolated from the brown algae Cystophora monoliformis. The optical rotation of achilleol A derived from the cyclization of (S)‐2,3‐epoxysqualene matches with that of the natural product, thus the absolute configuration of achilleol A was established as 1S,3R. From the mechanistic point of view, the NaY‐promoted cyclization of 9,10‐epoxygeranylacetone, selectively deuterium labelled at the C‐10 methyl group, is >97% stereoselective with respect to the topicity of the gem‐dimethyl group. This result is in agreement with a concerted mechanism. Finally, we have proved through labelling experiments, for the first time, that the biomimetic transformation of epoxy polyene terpenes to 2,3,4‐trimethylcyclohexanones upon acid catalysis is a highly stereoselective process. Thus, the less hindered gem‐methyl group on the epoxide functionality becomes α‐ to the carbonyl in the final isomerized product.
Impact of Carbon Dioxide Pressurization on Liquid Phase Organic Reactions: A Case Study on Heck and Diels–Alder Reactions
Authors: Fujita S. , Tanaka T. , Akiyama Y. , Asai K. , Hao J. , Zhao F. , Arai M.
Published: June 2008

Heck coupling reactions of methyl acrylate with various aryl bromides have been investigated using a Pd/TPP catalyst in toluene under pressurized CO2 conditions up to 13 MPa. Although CO2 is not a reactant, the pressurization of the reaction liquid phase with CO2 has positive and negative impacts on the rate of Heck coupling depending on the structures of the substrates examined. In the case of either 2‐bromoacetophenone or 2‐bromocinnamate, the conversion has a maximum at a CO2 pressure of about 3 MPa; for the former, it is much larger by a factor of 3 compared with that under ambient pressure. For 2‐bromobenzene, in contrast, the conversion is minimized at a similar CO2 pressure, being half compared with that at ambient pressure. In the other substrates, including the other isomers of these three aryl bromides, the conversion simply decreases or does not change so much with the CO2 pressure. To examine the factors responsible for the effects of CO2 pressurization, the phase behavior and the molecular interactions with dense phase CO2 have also been studied by visual observation and in situ high pressure FT‐IR spectroscopy. In addition, impact of CO2 pressurization was also studied for the Diels–Alder reactions of isoprene with a few dienophiles like methyl acrylate, methyl vinyl ketone, and acrolein in the same solvent, toluene, but a heterogeneous silica‐alumina catalyst was used (the reaction system was liquid‐solid biphasic). When the CO2 pressure is raised, the conversion monotonously decreases for the three dienophiles; however, the product selectivity changes with the pressure, in particular for acrolein. The FT‐IR spectroscopic measurements suggest that its reactivity is altered by interactions with CO2 molecules under pressurized conditions.
Chiral Brønsted Acid‐Mediated Enantioselective Organocatalytic Three‐Component Reaction for the Construction of Trifluoromethyl‐Containing Molecules
Authors: Zhang Guang‐Wu , Wang Lian , Nie Jing , Ma Jun‐An
Published: June 2008

In combination with the advantages of organocatalysis, we have developed a highly enantioselective Friedel–Crafts aminoalkylation of indoles with imines generated in situ from trifluoroacetaldehyde methyl hemiacetal and aniline. Novel chiral trifluoromethyl‐containing compounds were obtained in high yields with excellent enantioselectivities. This methodology was further extended to difluoroacetaldehyde methyl hemiacetal to demonstrate the broad scope of substrates.
An Efficient Approach for Immobilizing the Oxo‐Vanadium Schiff Base onto Polymer Supports using Staudinger Ligation
Authors: Jain Suman L. , Sain Bir
Published: June 2008

The present paper describes the use of Staudinger ligation as an efficient and high‐yielding approach for the immobilization of oxo‐vanadium Schiff base on polymeric supports via covalent attachment under mild conditions. The described strategy is simple in use, versatile, highly efficient with respect to better catalyst loading and proceeds under mild, metal‐free conditions. The catalytic potential of the prepared polymer immobilized oxo‐vanadium Schiff bases was tested for the oxidation of sulfides using aqueous tert‐butyl hydroperoxide (TBHP) as oxidant. The polymer‐supported catalysts could easily be recovered from the reaction mixture and reused for four runs without loss in activity and no metal leaching was observed during this course.
One‐Pot Oxidative Heteroannulations of N‐Sulfonylanilines with Styrenes for the Construction of 5‐Aminocoumaran Derivatives
Authors: Fan Renhua , Li Weixun , Ye Yang , Wang Linfei
Published: June 2008

An efficient one‐pot oxidative heteroannulation of N‐sulfonylaniline derivatives with styrene derivatives for the rapid construction of 5‐aminocoumaran derivatives is reported. Copper trifluoromethanesulfonate was found to be an excellent catalyst for the oxidative heteroannulation reactions with low reactive styrenes.
Chemisches Design von leistungsfähigen Nanosonden für die Kernspintomographie
Authors: Jun Young‐wook , Lee Jae‐Hyun , Cheon Jinwoo
Published: June 2008

Synthetische magnetische Nanopartikel (MNP) werden in der Biomedizin immer häufiger als Sonden eingesetzt. Dies gilt besonders für die Anwendung in der Kernspintomographie (Magnetic Resonance Imaging, MRI). Diese Nanopartikel sind von ähnlicher Größe wie biologische Funktionseinheiten. Deshalb und wegen ihrer einzigartigen magnetischen Eigenschaften eignen sie sich zur molekularen Bildgebung. Dieser Aufsatz gibt einen Überblick zu neuartigen MNP‐Sonden, mit denen biologische Ereignisse auf molekularer und zellulärer Ebene empfindlich und spezifisch nachgewiesen werden können.
Synthesis and Antimicrobial Study of Novel 1‐Aryl‐2‐oxo‐indano[3,2‐d]pyrido/pyrimido[1,2‐b]pyrimidines
Authors: Sarvesh Pandey K. , Nizamuddin Khan
Published: June 2008

A series of 2‐(arylidene)‐indan‐1, 3‐diones1were prepared by Knoevenagel reaction between indane‐1,3‐dione and the appropriate araldehydes. The α,β‐enones1have been used as a component of Michael addition with equimolar amounts of 2‐aminopyridine/2‐aminopyrimidine to give novel heterocyclic systems4and5, respectively. They are reported here for the first time. The structures of the newly synthesized compounds were confirmed by IR,1H‐NMR,13C‐NMR, and elemental analysis. All compounds were screened for their antibacterial and antifungal activities. Some of them showed promising activities.
The Discovery of Taranabant, a Selective Cannabinoid‐1 Receptor Inverse Agonist for the Treatment of Obesity
Authors: Hagmann William K.
Published: June 2008

The cannabinoid‐1 receptor (CB1R) has emerged as one of the most important targets for the treatment of obesity. Pioneering studies with rimonabant helped to validate animal models of food intake reduction and weight loss and made the connection to weight loss in the clinic. A novel, acyclic amide was identified from a high throughput screen (HTS) of the Merck sample collection and found to be a potent and selective CB1R inhibitor. Further optimization led to more potent compounds that were orally active in reducing food intake and weight loss in diet‐induced obese (DIO) rats. However, many of these analogues exhibited a high potential for bioactivation and the formation of reactive intermediates and covalent protein binding. Identification of the products of oxidative metabolism guided medicinal chemistry efforts to minimize the formation of these unwanted products. These efforts resulted in the identification of the CB1R inverse agonist, taranabant, which is currently in Phase‐III clinical studies for the treatment of obesity. This mini‐review will describe some of the medicinal chemistry strategies that were followed from the original high throughput screen hit to the discovery of taranabant.
Induction of interferon‐α by scleroderma sera containing autoantibodies to topoisomerase I: Association of higher interferon‐α activity with lung fibrosis
Authors: Kim Daniel , Peck Anders , Santer Deanna , Patole Prashant , Schwartz Stephen M. , Molitor Jerry A. , Arnett Frank C. , Elkon Keith B.
Published: June 2008

Objective

Peripheral blood cells (PBMCs) from some patients with systemic sclerosis (SSc) express an interferon‐α (IFNα) signature. The aim of this study was to determine whether SSc patient sera could induce IFNα and whether IFNα induction was associated with specific autoantibodies and/or clinical features of the disease.

Methods

SSc sera containing autoantibodies against either topoisomerase I (anti–topo I; n = 12), nucleolar protein (ANoA; n = 12), or centromeric protein (ACA; n = 13) were cultured with a HeLa nuclear extract and normal PBMCs. In some experiments, different cell extracts or inhibitors of plasmacytoid dendritic cell (DC) activation, Fcγ receptor II (FcγRII), endocytosis, or nucleases were used. IFNα was measured by enzyme‐linked immunosorbent assay.

Results

Topo I–containing sera induced significantly higher levels of IFNα as compared with all other groups. IFNα induction was inhibited by anti–blood dendritic cell antigen 2 (90%), anti‐CD32 (76%), bafilomycin (99%), and RNase (82%). In contrast, ACAs induced low levels of IFNα even when necrotic, apoptotic, or demethylated extracts were used, despite the fact that CENP‐B–binding oligonucleotide containing 2 CpG motifs effectively stimulated IFNα. IFNα production was significantly higher in patients with diffuse SSc (mean ± SEM 641 ± 174 pg/ml) than in those with limited SSc (215 ± 66 pg/ml) as well as in patients with lung fibrosis than in those without.

Conclusion

Autoantibody subsets in SSc sera differentially induce IFNα and may explain the IFNα signature observed in SSc. IFNα is induced by plasmacytoid DCs and required uptake of immune complexes through FcγRII, endosomal transport, and the presence of RNA, presumably for interaction with Toll‐like receptor 7. The higher IFNα induction in sera from patients with diffuse SSc than in those with limited SSc as well as in sera from patients with lung fibrosis suggests that IFNα may contribute to tissue injury.
Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast‐enhanced magnetic resonance imaging
Authors: Proulx Steven T. , Kwok Edmund , You Zhigang , Papuga M. Owen , Beck Christopher A. , Shealy David J. , Calvi Laura M. , Ritchlin Christopher T. , Awad Hani A. , Boyce Brendan F. , Xing Lianping , Schwarz Edward M.
Published: June 2008

Objective

While bone marrow edema (BME) detected by magnetic resonance imaging (MRI) is a biomarker of arthritis, its nature remains poorly understood due to the limitations of clinical studies. In this study, MRI of murine arthritis was used to elucidate its cellular composition and vascular involvement.

Methods

BME was quantified using normalized bone marrow intensity (NBMI) from precontrast MRI and normalized marrow contrast enhancement (NMCE) following intravenous administration of gadopentate dimeglumine. Wild‐type (WT) and tumor necrosis factor (TNF)–transgenic mice were scanned from 2 to 5 months of age, followed by histologic or fluorescence‐activated cell sorting (FACS) analysis of marrow. In efficacy studies, TNF‐transgenic mice were treated with anti‐TNF or placebo for 8 weeks, and then were studied using bimonthly MRI and histologic analysis.

Results

NBMI values were similar in WT and TNF‐transgenic mice at 2 months. The values in WT mice steadily decreased thereafter, with mean values becoming significantly different from those of TNF‐transgenic mice at 3.5 months (mean ± SD 0.29 ± 0.08 versus 0.46 ± 0.13; P < 0.05). Red to yellow marrow transformation occurred in WT but not TNF‐transgenic mice, as observed histologically at 5 months. The marrow of TNF‐transgenic mice that received anti‐TNF therapy converted to yellow marrow, with lower NBMI values versus placebo at 6 weeks (mean ± SD 0.26 ± 0.07 versus 0.61 ± 0.22; P < 0.05). FACS analysis of bone marrow revealed a significant correlation between NBMI values and CD11b+ monocytes (R2 = 0.91, P = 0.0028). Thresholds for “normal” red marrow versus pathologic BME were established, and it was also found that inflammatory marrow is highly permeable to contrast agent.

Conclusion

BME signals in TNF‐transgenic mice are caused by yellow to red marrow conversion, with increased myelopoiesis and increased marrow permeability. The factors that mediate these changes warrant further investigation.
Biomechanics of cartilage articulation: Effects of lubrication and degeneration on shear deformation
Authors: Wong Benjamin L. , Bae Won C. , Chun June , Gratz Kenneth R. , Lotz Martin , Robert L. Sah
Published: June 2008

Objective

To characterize cartilage shear strain during articulation, and the effects of lubrication and degeneration.

Methods

Human osteochondral cores from lateral femoral condyles, characterized as normal or mildly degenerated based on surface structure, were selected. Under video microscopy, pairs of osteochondral blocks from each core were apposed, compressed 15%, and subjected to relative lateral motion with synovial fluid (SF) or phosphate buffered saline (PBS) as lubricant. When cartilage surfaces began to slide steadily, shear strain (Exz) and modulus (G) overall in the full tissue thickness and also as a function of depth from the surface were determined.

Results

In normal tissue with SF as lubricant, Exz was highest (0.056) near the articular surface and diminished monotonically with depth, with an overall average Exz of 0.028. In degenerated cartilage with SF as lubricant, Exz near the surface (0.28) was 5‐fold that of normal cartilage and localized there, with an overall Exz of 0.041. With PBS as lubricant, Exz values near the articular surface were ∼50% higher than those observed with SF, and overall Exz was 0.045 and 0.062 in normal and degenerated tissue, respectively. Near the articular surface, G was lower with degeneration (0.06 MPa, versus 0.18 MPa in normal cartilage). In both normal and degenerated cartilage, G increased with tissue depth to 3–4 MPa, with an overall G of 0.26–0.32 MPa.

Conclusion

During articulation, peak cartilage shear is highest near the articular surface and decreases markedly with depth. With degeneration and diminished lubrication, the markedly increased cartilage shear near the articular surface may contribute to progressive cartilage deterioration and osteoarthritis.
Cartilage oligomeric matrix protein induction of chronic arthritis in mice
Authors: Carlsen Stefan , Nandakumar Kutty Selva , Bäcklund Johan , Holmberg Jens , Hultqvist Malin , Vestberg Mikael , Holmdahl Rikard
Published: June 2008

Objective

To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP‐induced arthritis (COMPIA).

Methods

Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q × DBA/1)F1, (BALB/c × B10.Q)F1, Ncf1 mutated, H‐2Aq, H‐2Ap, and human DR4+‐transgenic mice were used. Anti‐COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested.

Results

Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H‐2q and H‐2p MHC haplotypes allowed the initiation of COMPIA. Using H‐2Aq–transgenic and H‐2Ap–transgenic mice, we demonstrated a role of both the Aq and Ep class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA‐resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti‐COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)–associated DR4 molecule were found to be highly susceptible to COMPIA.

Conclusion

Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.
Skewed distribution of Th17 lymphocytes in patients with Wegener's granulomatosis in remission
Authors: Abdulahad Wayel H. , Stegeman Coen A. , Limburg Pieter C. , Kallenberg Cees G. M.
Published: June 2008

Objective

The recently characterized interleukin‐17 (IL‐17)–producing T helper cell lineage (Th17), rather than the Th1 lineage, is involved in several autoimmune diseases. The possible role of Th17 cells in Wegener's granulomatosis (WG) has not yet been elucidated. We undertook this study to assess the distribution of Th1/Th2/Th17 cells and to investigate the presence of Th17 cells specific for the WG autoantigen proteinase 3 (PR3) in WG.

Methods

Peripheral blood from patients with WG in remission (n = 26) and healthy controls (n = 10) was stimulated in vitro with PR3 or with the control stimuli staphylococcal enterotoxin B (SEB), tetanus toxoid (TT), or phorbol myristate acetate/calcium ionophore, together with anti‐CD28 and anti‐CD49d. The frequencies of the various CD4+ T cell phenotypes responsive to stimuli were determined by 7‐color flow cytometric detection of CD3, CD8, an early activation marker (CD69), and intracellular cytokines (IL‐2, interferon‐γ [IFNγ], IL‐17, and IL‐4).

Results

The percentage of CD69+,CD4+ T cells in patients with WG in remission was significantly decreased in response to PR3 and tended to be lower in response to other stimuli compared with the percentage in healthy controls. The percentages of Th17 cells (IL‐4−,IL‐17+,IFNγ−) and Th2 cells (IL‐4+,IL‐17−,IFNγ–) within the activated CD69+,CD4+ T cell population were significantly increased in patients with WG in remission, while no difference was found in Th1 cells (IL‐4−,IL‐17−,IFNγ+) compared with the percentage in healthy controls. Increased percentages of Th17 cells in response to TT and SEB were found both in antineutrophil cytoplasmic antibody (ANCA)–positive and in ANCA‐negative patients, while an increased frequency of PR3‐specific Th17 cells was restricted to ANCA‐positive patients.

Conclusion

A skewed Th17 response found in ANCA‐positive WG patients following stimulation with the autoantigen PR3 suggests that IL‐17 is involved in disease pathogenesis and could constitute a new therapeutic target.
(−)‐Epigallocatechin‐3‐gallate suppresses osteoclast differentiation and ameliorates experimental arthritis in mice
Authors: Morinobu Akio , Biao Wang , Tanaka Shino , Horiuchi Marika , Jun Liu , Tsuji Goh , Sakai Yoshitada , Kurosaka Masahiro , Kumagai Shunichi
Published: June 2008

Objective

To verify the effects of (−)‐epigallocatechin‐3‐gallate (EGCG) on osteoclast differentiation and on experimental arthritis in mice.

Methods

Human osteoclasts were differentiated from peripheral blood monocytes. The effects of EGCG were examined by tartrate‐resistant acid phosphatase (TRAP) staining, bone resorption assay, Western blotting, and quantitative real‐time polymerase chain reaction. Arthritis was induced in mice by injecting a cocktail of monoclonal antibodies against collagen. EGCG (20 μg/gm body weight) was administered intraperitoneally every day from day 0 through the end of the experiments (day 15). The effects of EGCG were determined by assessments of joint swelling, histologic changes, and TRAP staining on day 15.

Results

EGCG reduced the generation of TRAP‐positive multinucleated cells, bone resorption activity, and osteoclast‐specific gene expression without affecting cell viability. EGCG down‐regulated expression of nuclear factor of activated T cells c1 (NF‐ATc1), but not of NF‐κB, c‐Fos, and c‐Jun, suggesting that down‐regulation of NF‐ATc1 is one of the molecular bases of EGCG action. Additionally, EGCG treatment ameliorated clinical symptoms and reduced histologic scores in arthritic mice (P < 0.05). The in vivo effect of EGCG on osteoclast differentiation was not clear in this model, probably because EGCG suppressed the inflammation itself.

Conclusion

EGCG suppressed osteoclast differentiation and ameliorated experimental arthritis in mice over the short term. It remains to be established whether EGCG is useful for the prevention and treatment of osteoporosis and rheumatoid arthritis.
Association of autoimmunity to peptidyl arginine deiminase type 4 with genotype and disease severity in rheumatoid arthritis
Authors: Harris Michelle L. , Darrah Erika , Lam Gordon K. , Bartlett Susan J. , Giles Jon T. , Grant Audrey V. , Gao Peisong , Scott William W. , El‐Gabalawy Hani , Casciola‐Rosen Livia , Barnes Kathleen C. , Bathon Joan M. , Rosen Antony
Published: June 2008

Objective

Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)–specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD‐4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti–PAD‐4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti–PAD‐4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD‐4 polymorphisms influence the anti–PAD‐4 autoantibody response.

Methods

Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti–PAD‐4 autoantibodies by immunoprecipitation of in vitro–translated PAD‐4. The epitope(s) recognized by PAD‐4 autoantibodies were mapped using various PAD‐4 truncations. PAD‐4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method.

Results

PAD‐4 autoantibodies were found in 36–42% of RA patients, and were very infrequent in controls. Recognition by anti–PAD‐4 autoantibodies required the 119 N‐terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti–PAD‐4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti–PAD‐4 antibodies were associated with more severe joint destruction in RA.

Conclusion

Our findings indicate that anti–PAD‐4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti–PAD‐4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD‐4 protein, potentially contributing to disease propagation.
Application of inflammation‐responsive promoter for an in vitro arthritis model
Authors: Rachakonda P. Sivaramakrishna , Rai Muhammad Farooq , Schmidt Michael F. G.
Published: June 2008

Objective

The application of inflammation‐regulated therapeutic gene expression in arthritis conditions increases the efficiency of gene therapy by self‐limiting the transgene. Incidentally, constitutive overexpression of transgenes typically leads to detrimental effects in disease conditions; therefore, regulation of expression is warranted. We undertook this study to validate a new gene therapy approach using a cell culture–based inflammation model and a novel self‐limiting, inflammation‐responsive promoter construct.

Methods

We designed a self‐limiting promoter construct that expresses an antiinflammatory gene (interleukin‐4 [IL‐4]) only in the presence of inflammation. Our construct featured a truncated promoter sequence of cyclooxygenase 2 (COX‐2) upstream of the IL‐4 gene. We triggered inflammation in vitro in articular chondrocytes by applying the inflammatory cytokines IL‐1β and tumor necrosis factor α (TNFα) together exogenously, and we studied the extent of IL‐4 expression and its effect on the inflammatory cascade.

Results

Using articular chondrocytes, we showed that our COX‐2 promoter construct expressed IL‐4 only in the presence of IL‐1β and TNFα. IL‐4 expressed in the presence of IL‐1β and TNFα down‐regulated a series of inflammation mediators, prostaglandins, and matrix metalloproteinases.

Conclusion

The use of this construct for the expression of antiinflammatory genes allows production of a therapeutic gene product that is controlled by the severity of the disease. The effectiveness of this promoter construct for combating inflammation makes it a suitable candidate for the development of a new local gene therapy strategy for the treatment of osteoarthritis, in which IL‐1β and TNFα trigger a signal cascade that elevates COX‐2 levels.
Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritis
Authors: Day T. G. , Ramanan A. V. , Hinks A. , Lamb R. , Packham J. , Wise C. , Punaro M. , Donn R. P.
Published: June 2008

Objective

To investigate the association of NLRP3, NOD2, MEFV, and PSTPIP1, genes that cause 4 of the autoinflammatory hereditary periodic fever syndromes (HPFS), with juvenile idiopathic arthritis (JIA).

Methods

Fifty‐one single‐nucleotide polymorphisms (SNPs) across the 4 loci were investigated using MassArray genotyping in 950 Caucasian patients with JIA living in the UK and 728 ethnically matched healthy controls.

Results

Prior to Bonferroni correction for multiple testing, significant genotype associations between 6 SNPs in MEFV and JIA were observed and, in subgroup analysis, associations between 12 SNPs across all 4 loci and the subgroup of patients with psoriatic JIA were found. After Bonferroni correction for multiple testing, 2 genotype associations remained significant in the subgroup of patients with psoriatic JIA (MEFV SNP rs224204 [corrected P = 0.025] and NLRP3 SNP rs3806265 [corrected P = 0.04]).

Conclusion

These findings support the use of monogenic loci as candidates for investigating the genetic component of complex disease and provide preliminary evidence of association between SNPs in autoinflammatory genes and psoriatic JIA. Our findings raise the interesting possibility of a shared disease mechanism between the HPFS and psoriatic JIA, potentially involving abnormal production of interleukin‐1β.
Functional outcome after stroke in patients with rheumatoid arthritis and systemic lupus erythematosus
Authors: Nguyen‐Oghalai Tracy U. , Wu Helen , McNearney Terry A. , Granger Carl V. , Ottenbacher Kenneth J.
Published: June 2008

Objective

To compare outcomes following stroke rehabilitation among patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) versus patients with neither RA nor SLE (non‐RA/SLE).

Methods

We conducted a retrospective analysis using a national database of patients with stroke admitted to inpatient rehabilitation between 1994 and 2001. Primary outcomes were discharge disposition and functional status, rated by the Functional Independence Measure (FIM) Instrument, at discharge and at followup. The independent variable was RA or SLE. Covariates were age, sex, race/ethnicity, admission FIM ratings, additional comorbidities (none, 1–3, and >3), type of stroke, and length of stay.

Results

We studied 47,853 patients with stroke, 368 with RA, and 119 with SLE. Discharge dispositions were similar for patients with RA and non‐RA/SLE (81% discharged home). At discharge, the average FIM rating for patients with RA was 85.8, compared with 87.8 for non‐RA/SLE patients. At followup, the average FIM rating for patients with RA was 95.9, compared with 99.6 for non‐RA/SLE patients. RA was associated with lower FIM ratings at discharge and followup in multivariate analyses. SLE was associated with younger age (17.5 years). However, patients with SLE had similar discharge dispositions and FIM ratings to non‐RA/SLE patients.

Conclusion

RA was associated with lower functional status ratings at discharge and followup. Outpatient therapy for patients with RA may reduce long‐term assistance. Patients with SLE were younger, but had similar functional outcomes to patients without RA/SLE, suggesting early morbidity from stroke among patients with SLE.
The internet‐based arthritis self‐management program: A one‐year randomized trial for patients with arthritis or fibromyalgia
Authors: Lorig Kate R. , Ritter Philip L. , Laurent Diana D. , Plant Kathryn
Published: June 2008

Objective

To determine the efficacy of an Internet‐based Arthritis Self‐Management Program (ASMP) as a resource for arthritis patients unable or unwilling to attend small‐group ASMPs, which have proven effective in changing health‐related behaviors and improving health status measures.

Methods

Randomized intervention participants were compared with usual care controls at 6 months and 1 year using repeated‐measures analyses of variance. Patients with rheumatoid arthritis, osteoarthritis, or fibromyalgia and Internet and e‐mail access (n = 855) were randomized to an intervention (n = 433) or usual care control (n = 422) group. Measures included 6 health status variables (pain, fatigue, activity limitation, health distress, disability, and self‐reported global health), 4 health behaviors (aerobic exercise, stretching and strengthening exercise, practice of stress management, and communication with physicians), 5 utilization variables (physician visits, emergency room visits, chiropractic visits, physical therapist visits, and nights in hospital), and self‐efficacy.

Results

At 1 year, the intervention group significantly improved in 4 of 6 health status measures and self‐efficacy. No significant differences in health behaviors or health care utilization were found.

Conclusion

The Internet‐based ASMP proved effective in improving health status measures at 1 year and is a viable alternative to the small‐group ASMP.
Varus malalignment and its association with impairments and functional limitations in medial knee osteoarthritis
Authors: Lim Boon‐Whatt , Hinman Rana S. , Wrigley Tim V. , Bennell Kim L.
Published: June 2008

Objective

To examine the association of varus malalignment with impairments and functional limitations in people with medial knee osteoarthritis (OA).

Methods

Anatomic radiographic knee alignment was assessed in 107 community volunteers with medial tibiofemoral knee OA. Impairments assessed included pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), quadriceps and hamstring isometric strength, and knee varus‐valgus laxity. WOMAC, walking speed, step test, and stair climb test were used to assess functional limitations. Participants were categorized into tertiles according to knee alignment (least, moderate, and most varus). Impairments and functional limitations between groups were compared using analyses of variance with and without adjustment for age, sex, and disease severity. Regression analyses were also performed in the entire cohort to further determine the relationship of varus malalignment to impairments and functional limitations.

Results

The most varus group (mean varus 7.7 degrees) did not demonstrate greater impairments or worse functional limitations compared with the moderate varus (4.2 degrees) and least varus (5.0 degrees) groups. In fact, the most varus participants performed significantly better on the step test compared with moderate (P = 0.006) and least varus (P = 0.004) participants. Knee alignment accounted for a significant but small proportion of the variance in step test performance (7%) and quadriceps strength (4%), but did not contribute significantly to the variance in any other parameter measured.

Conclusion

Greater varus malalignment was associated with increased quadriceps strength and improved step test performance, but did not influence the severity of other measured impairments and functional limitations.
Synthetic Molecular Machine Based on Reversible End‐to‐Interior and End‐to‐End Loop Formation Triggered by Electrochemical Stimuli
Authors: Lee Jae Wook , Hwang Ilha , Jeon Woo Sung , Ko Young Ho , Sakamoto Shigeru , Yamaguchi Kentaro , Kim Kimoon
Published: June 2008

We have designed and synthesized a novel [2]pseudorotaxane‐based molecular machine in which the interconversion between end‐to‐interior and end‐to‐end loop structures is reversibly controlled by electrochemical stimuli. Cucurbit[8]uril (CB[8]) and the thread molecule 34+ with an electron‐rich hydroxynaphthalene unit and two electron‐deficient viologen units form the 1:1 complex 44+ with an end‐to‐interior loop structure, which is reversibly converted into an end‐to‐end structure upon reduction. Large changes in shape and size of the molecule accompany the reversible redox process. The key feature of the machine‐like behavior is the reversible interconversion between an intramolecular charge‐transfer complex and viologen cation radical dimer inside CB[8] triggered by electrochemical stimuli.
Aerobic Oxidation of Alcohols with Bifunctional Transition‐Metal Catalysts Bearing C–N Chelate Ligands
Authors: Arita Sachiko , Koike Takashi , Kayaki Yoshihito , Ikariya Takao
Published: June 2008

The aerobic oxidation of alcohols with a family of bifunctional Ir, Rh, and Ru complexes bearing C–N chelating ligands derived from primary benzylic amines was investigated. The isolable amido–Ir complexes [Cp*Ir{κ2(N,C)‐(NHCR2‐2‐C6H4)}] (R=C6H5, CH3; Cp*=1,2,3,4,5‐pentamethylcyclopentadienyl) effected the oxidation of secondary alcohols smoothly under atmospheric pressure of air at 30 °C in THF to give the corresponding ketones in good yields. The hydrido(amine)–Ir complexes [Cp*IrH{κ2(N,C)‐(NH2CR2‐2‐C6H4)}] and the combined catalyst system involving the chloro(amine)–Ir complex [Cp*IrCl{κ2(N,C)‐(NH2CR2‐2‐C6H4)}] and KOC(CH3)3 were also found to be effective catalysts, whereas the tertiary amine complex [Cp*IrCl{κ2(N,C)‐(N(CH3)2CH2‐2‐C6H4)}], which does not have a metal/NH moiety, did not show catalytic activity. The employment of primary alcohols in the aerobic reaction with the Cp*IrCl complex and KOC(CH3)3 resulted in the formation of esters through oxidative dimerization.
Impact of preoperative thyroid ultrasonography on the surgical management of primary hyperparathyroidism
Authors: Monroe D P , Edeiken-Monroe B S , Lee J E , Evans D B , Perrier N D
Published: June 2008

Background

Primary hyperparathyroidism (PHPT) with coexisting thyroid disease has been considered a contraindication to minimally invasive parathyroidectomy (MIP). This study assessed the impact of thyroid ultrasonography and guided fine-needle aspiration (FNA) biopsy with cytological review of the aspiration in distinguishing patients eligible for MIP from those requiring open parathyroidectomy with thyroid surgery.

Methods

The records of 194 consecutive patients who had minimally invasive or open parathyroidectomy for sporadic PHPT were reviewed retrospectively. Thyroid ultrasonographic findings and FNA results were compared with surgical and pathology records.

Results

A total of 163 patients (84·0 per cent) were eligible for MIP based on ultrasonographic findings with or without FNA results. Ultrasonography detected concurrent thyroid disease in 163 patients (84·0 per cent). Thirty-nine (23·9 per cent) underwent FNA, of whom 16 had benign findings and were eligible for MIP; the remaining 23 had suspicious FNA results and had open parathyroidectomy combined with thyroid surgery. Postoperative thyroid histopathology confirmed malignancy in nine patients, eight of whom had disease detected ultrasonographically. Micronodular thyroid disease (less than 1 cm) accounted for four of nine malignancies.

Conclusion

Most patients with PHPT are eligible for MIP. Experienced ultrasonographers can diagnose coexisting micronodular and macronodular thyroid disease, and identify patients eligible for MIP.
Clinical and cost effectiveness of sacral nerve stimulation for faecal incontinence
Authors: Muñoz-Duyos A , Navarro-Luna A , Brosa M , Pando J A , Sitges-Serra A , Marco-Molina C
Published: June 2008

Background

Sacral nerve stimulation (SNS) has better results and safety than other surgical procedures for faecal incontinence. This prospective study assessed the clinical effectiveness and costs of SNS at a single centre.

Methods

Patients who had experienced one or more episodes of faecal incontinence were studied for up to 5 years by continence diary, anorectal manometry and quality of life questionnaires. Direct medical costs were calculated and the cost-effectiveness of the treatment was analysed.

Results

Fifty-seven percutaneous nerve evaluations were performed in 47 patients between June 1999 and February 2006; 29 patients underwent permanent implantation. After a median follow-up of 34·7 (range 2·3–81·2) months, 25 of the 29 patients had a significant reduction in incontinence episodes; 14 patients were in complete remission. At 3-year follow-up, the mean reduction in incontinence episodes was 89 per cent. No change was observed in anal manometric values. Patients reported a significant improvement in quality of life. The introduction of SNS has an incremental cost-effectiveness ratio, below the accepted Spanish threshold.

Conclusion

The introduction of SNS to the management of faecal incontinence within the Spanish setting is both effective and efficient.
Zn2+ Complexes of Di‐ and Tri‐nucleating Azacrown Ligands as Base‐Moiety‐Selective Cleaving Agents of RNA 3′,5′‐Phosphodiester Bonds: Binding to Guanine Base
Authors: Wang Qi , Leino Ewelina , Jancsó Attila , Szilágyi István , Gajda Tamás , Hietamäki Emilia , Lönnberg Harri
Published: June 2008

The ability of the dinuclear Zn2+ complex of 1,4‐bis[(1,5,9‐triazacyclododecan‐3‐yloxy)methyl]benzene (L1) to promote the cleavage of the phosphodiester bond of dinucleoside‐3′,5′‐monophosphates that contain a guanine base has been studied over a narrow pH range from pH 5.8 to 7.2 at 90 °C. Comparative measurements have been carried out by using the trinuclear Zn2+ complex of 1,3,5‐tris[(1,5,9‐triazacyclododecan‐3‐yloxy)methyl]benzene (L2) as a cleaving agent and guanylyl‐3′,5′‐guanosine (5′‐GpG‐3′) as a substrate. The strength of the interaction between the cleaving agent and the starting material has been elucidated by UV spectrophotometric titrations. The speciation and binding mode have been clarified by potentiometric titrations with hydrolytically stable 2′‐O‐methylguanylyl‐3′,5′‐guanosine and 1H NMR spectroscopic measurements with guanylyl‐3′,5′‐guanosine. The results show that the guanine base is able to serve as a site for anchoring for the Zn2+–azacrown moieties of the cleaving agents L1 and L2, analogously to uracil base. The interaction is, however, weaker than with the uracil base and, hence, only the 5′‐GpG‐3′ site (in addition to 5′‐GpU‐3′ and 5′‐UpG‐3′ sites) is able to markedly modulate the phosphodiester cleavage by the Zn2+ complexes of di‐ and trinucleating azacrown ligands containing an ether oxygen as a potential H‐bond‐acceptor site.
Benzene Polyphosphates as Tools for Cell Signalling: Inhibition of Inositol 1,4,5‐Trisphosphate 5‐Phosphatase and Interaction with the PH Domain of Protein Kinase Bα
Authors: Mills Stephen J. , Vandeput Fabrice , Trusselle Melanie N. , Safrany Stephen T. , Erneux Christophe , Potter Barry V. L.
Published: June 2008

Novel benzene polyphosphates were synthesised as inositol polyphosphate mimics and evaluated against type‐I inositol 1,4,5‐trisphosphate 5‐phosphatase, which only binds soluble inositol polyphosphates, and against the PH domain of protein kinase Bα (PKBα), which can bind both soluble inositol polyphosphates and inositol phospholipids. The most potent trisphosphate 5‐phosphatase inhibitor is benzene 1,2,4‐trisphosphate (2, IC50 of 14 μM), a potential mimic of D‐myo‐inositol 1,4,5‐trisphosphate, whereas the most potent tetrakisphosphate Ins(1,4,5)P3 5‐phosphatase inhibitor is benzene 1,2,4,5‐tetrakisphosphate, with an IC50 of 4 μM. Biphenyl 2,3′,4,5′,6‐pentakisphosphate (4) was the most potent inhibitor evaluated against type I Ins(1,4,5)P3 5‐phosphatase (IC50 of 1 μM). All new benzene polyphosphates are resistant to dephosphorylation by type I Ins(1,4,5)P3 5‐phosphatase. Unexpectedly, all benzene polyphosphates studied bind to the PH domain of PKBα with apparent higher affinity than to type I Ins(1,4,5)P3 5‐phosphatase. The most potent ligand for the PKBα PH domain, measured by inhibition of biotinylated diC8‐PtdIns(3,4)P2 binding, is biphenyl 2,3′,4,5′,6‐pentakisphosphate (4, Ki=27 nm). The approximately 80‐fold enhancement of binding relative to parent benzene trisphosphate is explained by the involvement of a cation–π interaction. These new molecular tools will be of potential use in structural and cell signalling studies.
Rhizobium rubiT: A Gram‐Negative Phytopathogenic Bacterium Expressing the Lewis B Epitope on the Outer Core of its Lipooligosaccharide Fraction
Authors: Gargiulo Valentina , Garozzo Domenico , Lanzetta Rosa , Molinaro Antonio , Sturiale Luisa , De Castro Cristina , Parrilli Michelangelo
Published: June 2008

The structure of the core oligosaccharide from the phytopathogenic bacterium Rhizobium rubi was deduced by combining information from complementary chemical approaches (alkaline and acid hydrolysis), similar to the “overlap peptide” strategy. This structure is new and it contains two main oligosaccharide backbones that differ in the substitution degree of the external Kdo unit. The relevant feature shared by both oligosaccharides is the presence of a tetrasaccharide motif that is similar to the blood group Lewis B antigen (LeB). This epitope differs from LeB in the glycosidic configuration of the glucosamine unit (α and not β) and in the occurrence of acetyls substituents at O3 and/or O4 of the galactose moiety. Other notable structural features are the location of the Dha residue, the presence of a α‐glucose unit that is linked to the inner Kdo unit, the high number of acid sugars and the highly branched core structure.
Ultrasonic measurement of the reaction kinetics of the setting of calcium sulfate cements using implicit calibration
Authors: Carlson Johan E. , Taavitsainen Veli‐Matti
Published: June 2008

Injectable bone cements based on calcium sulfate and calcium phosphates are being developed for use as bone defect filling and reinforcement of osteoporotic bones. For developers and end‐users, kinetic properties of the setting reaction of such cements are of great interest. Existing standards for setting time measurement are based on visual examination of the cement surface and thus suffer from poor repeatability and subjectivity. Implicit calibration provides the means of determining parameters of a physical model at the same time as a calibration based on regression. This enables the use of indirect observations for the determination of implicit model parameters. In this paper, we study the hydration of calcium sulfate hemihydrate into calcium sulfate dihydrate, by combining multivariate calibration with a physical model of the reaction kinetics. The physical model contains three parameters, the reaction rate, the reaction order and a time delay. These parameters are estimated from ultrasound amplitude spectra. The resulting model fit has an R2 value of 99.9%. Copyright © 2008 John Wiley & Sons, Ltd.
“Click Chemistry” in Zeolites: Copper(I) Zeolites as New Heterogeneous and Ligand‐Free Catalysts for the Huisgen [3+2] Cycloaddition
Authors: Chassaing Stefan , Sani Souna Sido Abdelkarim , Alix Aurélien , Kumarraja Mayilvasagam , Pale Patrick , Sommer Jean
Published: June 2008

For the first time, copper(I)‐exchanged zeolites were developed as catalysts in organic synthesis. These solid materials proved to be versatile and efficient heterogeneous, ligand‐free catalytic systems for the Huisgen [3+2] cycloaddition. These cheap and easy‐to‐prepare catalysts exhibited a wide scope and compatibility with functional groups. They are very simple to use, easy to remove (by filtration), and are recyclable (up to three times without loss of activity). Investigations with deuterated alkynes and deuterated zeolites proved that this CuI‐zeolite‐catalyzed “click” reaction exhibited a mechanism different from that reported for the Meldal–Sharpless version.
Visible‐Light Photochromism of Triarylamine‐ or Ferrocene‐Bound Diethynylethenes that Switches Electronic Communication between Redox Sites and Luminescence
Authors: Sakamoto Ryota , Kume Shoko , Nishihara Hiroshi
Published: June 2008

Redox‐active ferrocene‐ and triarylamine‐terminated diethynylethene derivatives have been synthesized and their photochromic properties and switching behavior based on through‐bond electronic communication between the two redox sites, as well as their emissions, have been examined. Both bis(ferrocenylethynyl)ethene 1 and bis(triarylaminoethynyl)ethene 2 show visible‐light photochromism induced by donor–acceptor charge‐transfer (CT) transitions from the ferrocene or triarylamine to the diethynylethene moieties. The reversibility and quantum yields of the photochromism of 2 (ΦE→Z=6.1×10−2, ΦZ→E=1.4×10−2) are far higher than those of 1 (ΦE→Z=8.6×10−6, ΦZ→E=2.5×10−6). The higher efficiency in 2 may be attributed to the absence of the heavy atom effect and of a low‐lying 3LF state, which are characteristic of ferrocenyl compounds. This proposition is further supported by the fact that bis(ferrocenylbuta‐1,3‐diynyl)ethene 3, which, unlike 1, is free from steric interference between the two ferrocenyl groups in the Z form, does not show a significant improvement in its photoisomerization quantum yields (ΦE→Z=6.2×10−5, ΦZ→E=3.4×10−5). The visible‐light photochromism of 1 and 2 is accompanied by a switch in the strength of the electronic communication between the two redox sites in their mixed‐valence states (ΔE0′ values are 70 and 48 mV for (E)‐1 and (Z)‐1, and 74 and 63 mV for (E)‐2 and (Z)‐2). In the case of 2, further evaluations were carried out through intervalence charge‐transfer (IVCT) band analyses and DFT calculations. We have also demonstrated that steric repulsion between the methyl ester moieties in the Z form is implicated in the reduction in the through‐bond electronic communication. Compound 2 exhibits photoluminescence, which is more efficient in the E form than in the Z form, whereas 1 and 3 show no photoluminescence.