bluuebunny/crossref_metadata_2025 huggingface dataset:
Process scheduling under uncertainty using multiparametric programming
Authors: Li Zukui , Ierapetritou Marianthi G.
Published: October 2007

In this article, the problem of process scheduling under uncertainty was studied using multiparametric programming method. Based on the uncertainty type (prices, demands, and processing times), the scheduling formulation results in different parametric problems including multiparametric mixed integer linear (mpMILP), quadratic (mpMIQP), and general nonlinear programming (mpMINLP) problem. This article analyzes the solution characteristics and proposes a novel solution framework for specific mpMILP/mpMIQP problems addressing a wide variety of scheduling problems under different types of uncertainty, which are modeled as coefficient in objective function, as coefficient of integer variable and right hand side vector of the constraints. The main idea of the proposed framework is to decompose the problem into a series of smaller subproblems, each of them producing the parametric information around a given parameter value. The parametric solution of every subproblem is retrieved by solving a series of multiparametric linear programming (mpLP) and mixed integer linear/nonlinear programming problems (MILP/MINLP). Several examples were solved to analyze the complexity and the effectiveness of the proposed method. © 2007 American Institute of Chemical Engineers AIChE J, 2007
Toward the development of rational therapies in multiple sclerosis: what is on the horizon?
Authors: Hemmer Bernhard , Hartung Hans‐Peter
Published: October 2007

Although the cause of multiple sclerosis (MS) has remained obscure, many findings support an autoimmune pathogenesis on the background of a complex interaction between multiple genes and environmental factors. Accordingly, targeting the immune system has been a rational approach for the treatment of MS. The development of disease‐modifying immunomodulatory drugs with partial efficacy, coupled with advances in understanding the pathophysiology and pathology of MS, has provided momentum to explore more specific and hopefully more effective immune‐based therapeutic strategies. With increased knowledge and appreciation of the contribution of neurodegenerative processes to disease pathology, the therapeutic challenges, however, have become even more formidable. Future treatments will likely need both to target inflammation and to focus on promotion of neuroprotection and repair. In this review, we discuss the most promising therapeutic approaches for MS currently in the pipeline. Ann Neurol 2007
Metal‐Catalyzed Enantioselective Allylation in Asymmetric Synthesis
Authors: Lu Zhan , Ma Shengming
Published: October 2007

Metal‐catalyzed enantioselective allylation, which involves the substitution of allylic metal intermediates with a diverse range of different nucleophiles or SN2′‐type allylic substitution, leads to the formation of CH, C, O, N, S, and other bonds with very high levels of asymmetric induction. The reaction may tolerate a broad range of functional groups and has been applied successfully to the synthesis of many natural products and new chiral compounds.
Preparation of an organomontmorillonite master batch and its application to high‐temperature‐vulcanized silicone‐rubber systems
Authors: Wang Jincheng , Chen Yuehui
Published: October 2007

N,N‐Di(2‐hydroxyethyl)‐N‐dodecyl‐N‐methyl ammonium chloride was used as an intercalation agent to treat Na+‐montmorillonite and form a novel type of organic montmorillonite (OMMT). An OMMT master batch (OMMT‐MB) was prepared by solution intercalation and was used in the preparation of high‐temperature‐vulcanized silicone rubber (HTV‐SR)/OMMT‐MB nanocomposites. The properties, such as the tensile and thermal stability, were researched and compared with those of composites directly incorporated with OMMT or aerosilica. A combination of Fourier transform infrared spectroscopy, wide‐angle X‐ray diffraction, and transmission electron microscopy studies showed that HTV‐SR/OMMT‐MB composites were on the nanometer scale, and their structure was somewhat hindered by the presence of OMMT. The results showed that the tensile properties of HTV‐SR/OMMT‐MB and HTV‐SR/OMMT systems were better than those of pure HTV‐SR. Compared with those of HTV‐SR/OMMT‐20%, the tensile strength and elongation at break of HTV‐SR/OMMT‐MB‐20% were improved about 1.5 and 0.9 times, respectively. This was probably due to the nanoeffect of the exfoliated silicate layers. Moreover, the tensile strength of HTV‐SR/OMMT‐MB‐20% was nearly equal to that of HTV‐SR/aerosilica‐20%, and the elongation at break even showed much improvement. Additionally, the thermal degradation center temperature of the HTV‐SR/OMMT‐MB‐20% nanocomposite was increased by 30°C compared with that of the HTV‐SR/OMMT‐20% composite. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
Comparative proteomic characterization of articular cartilage tissue from normal donors and patients with osteoarthritis
Authors: Wu Jiang , Liu Wei , Bemis Amanda , Wang Eunice , Qiu Yongchang , Morris Elisabeth A. , Flannery Carl R. , Yang Zhiyong
Published: October 2007

Objective

To identify potential molecular mediators and biomarkers for osteoarthritis (OA), through comparative proteomic analysis of articular cartilage tissue obtained from normal donors without OA (n = 7) and patients with OA (n = 7).

Methods

The proteomic analyses comprised extraction of soluble proteins from cartilage, separation of the protein mixtures by sodium dodecyl sulfate–polyacrylamide gel electrophoresis followed by in‐gel digestion, and subsequent nano‐liquid chromatography–tandem mass spectrometry analysis in conjunction with a database search for protein identification and semiquantitation.

Results

A total of 814 distinct proteins were identified with high confidence from 14 samples; 420 of these proteins were detected with ≥3 unique peptides in at least 4 samples from the same group. Using stringent criteria, 59 proteins were found to be differentially expressed in OA cartilage. Gene Ontology and Ingenuity pathway analysis tools were used to characterize these proteins into functional categories. One of the up‐regulated proteins, HtrA1, a serine protease, was detected at high levels in cartilage.

Conclusion

Altered protein expression in the disease state is associated with many aspects of the pathogenesis of OA, such as increased proteolysis, lipid metabolism, immune response, and decreased signal transduction. To our knowledge, this is the first time that a large portion of these proteins and their expression patterns were identified in cartilage, thus providing new insights for finding novel pathologic mediators and biomarkers of OA.
Protease‐activated receptor 2 mediates the proinflammatory effects of synovial mast cells
Authors: Palmer H. S. , Kelso E. B. , Lockhart J. C. , Sommerhoff C. P. , Plevin R. , Goh F. G. , Ferrell W. R.
Published: October 2007

Objective

Mast cells are hypothesized to play a role in the pathogenesis of rheumatoid arthritis (RA) by mechanisms requiring elucidation. Tryptase released from these cells can activate protease‐activated receptor 2 (PAR‐2), which was recently shown to have proinflammatory actions. The purpose of this study was to examine the relationship between synovial mast cells and PAR‐2. Mast cell proximity to PAR‐2–expressing cells was investigated in RA synovium. In murine studies, we assessed the capacity of mast cell tryptase to mediate synovial proinflammatory responses via PAR‐2 and whether degranulating mast cells induced synovial hyperemia by PAR‐2 activation.

Methods

RA synovial tissue was examined by immunohistochemistry. PAR‐2+/+and PAR‐2−/−C57BL/6J mice were used to investigate the PAR‐2 dependence of compound 48/80–induced synovial hyperemia, as measured by laser Doppler imaging, and joint swelling and hyperemic responses to recombinant human β‐tryptase.

Results

Mast cells and synovial lining cells staining for PAR‐2 were colocalized in RA articular tissue. Compound 48/80 administration resulted in vasodilatation in PAR‐2+/+mice but not in PAR‐2−/−mice, which showed a vasoconstrictor response. Eliminating the 5‐hydroxytryptamine–mediated component of this response with methysergide unveiled an enhanced PAR‐2–mediated vasodilatation to compound 48/80 in PAR‐2+/+mice and ablated the vasoconstrictor response in PAR‐2−/−mice. Treatment with β‐tryptase resulted in dose‐dependent knee joint swelling and synovial vasodilatation in PAR‐2+/+mice but not PAR‐2−/−mice.

Conclusion

This in vivo study is the first to explore the relationship between synovial mast cells and PAR‐2. Our results support the hypothesis that mast cells contribute to the pathogenesis of inflammatory arthritis through PAR‐2 activation via release of mast cell tryptase.
Soft tissue, joint, and bone manifestations of AL amyloidosis: Clinical presentation, molecular features, and survival
Authors: Prokaeva Tatiana , Spencer Brian , Kaut Maurya , Ozonoff Al , Doros Gheorghe , Connors Lawreen H. , Skinner Martha , Seldin David C.
Published: October 2007

Objective

To characterize symptoms and signs of AL amyloidosis that may bring patients to the attention of rheumatologists, evaluate Ig VL gene usage in this subgroup of patients, and assess the impact of soft tissue and bone involvement and VL gene usage on survival.

Methods

Clinical features of soft tissue and bone involvement were assessed in 191 patients with AL amyloidosis. VL gene sequencing was carried out to determine light‐chain family, rate of somatic mutation, and evidence of antigen selection. The association of soft tissue and bone involvement with VL gene usage was assessed by logistic regression analysis, and survival time was analyzed using log rank tests and Cox regression models.

Results

Soft tissue and bone involvement occurred in 42.9% of the patients, and 9.4% had dominant soft tissue and bone involvement. The most common manifestations were submandibular gland enlargement, macroglossia, and carpal tunnel syndrome. Dominant soft tissue and bone involvement was significantly associated with VLκI gene usage. Mutation rate and evidence of antigen selection in the VL genes were not found to be confounding factors, providing evidence against a contribution of autoimmunity in this type of AL amyloidosis. Survival time was initially longer in patients with dominant soft tissue and bone involvement than in patients with other dominant organ involvement; however, this difference diminished over time.

Conclusion

Amyloid infiltration into soft tissue, joints, periarticular structures, and bones can bring patients with AL amyloidosis to the attention of rheumatologists. Recognition of the presenting symptoms is essential for accurate diagnosis and appropriate treatment, since the long‐term outlook for untreated patients with dominant soft tissue and bone involvement is not better than that for patients with other dominant features of AL amyloidosis.
Morphologic changes in the vastus medialis muscle in patients with osteoarthritis of the knee
Authors: Fink Bernd , Egl Monika , Singer Joachim , Fuerst Martin , Bubenheim Michael , Neuen‐Jacob Eva
Published: October 2007

Objective

To investigate the frequency of structural changes in the vastus medialis muscle in patients with osteoarthritis (OA) of the knee.

Methods

Specimens of vastus medialis muscle from 78 patients with end‐stage OA of the knee undergoing total joint arthroplasty were examined histopathologically. Morphologic changes were assessed in relation to clinical features that might have contributed to muscle injury.

Results

All muscle specimens exhibited atrophy of type 2 fibers. In 32% of the patients, atrophy of type 1 fibers was also noted. Fiber type grouping of type 1 fiber in 15% of the patients and type 2 fiber in 37%, indicating reinnervation, led to the diagnosis of neurogenic muscular atrophy in 32% of the patients; selective atrophy of type 2 fiber in 68% of the specimens was interpreted as possibly resulting from pain‐associated disuse. Signs of muscle degeneration and regeneration were found in 65% and 96% of the samples, respectively. Soft tissue changes indicating long‐term disease, such as calcification, fibrosis, and lipomatosis, were frequently observed (in 69%, 71%, and 94% of the patients, respectively). Statistical analysis of clinical and morphologic parameters revealed a significant association between degenerative muscle changes and the presence of a varus deviation of the leg axis.

Conclusion

Patients with OA of the knee frequently exhibit muscle changes, with probable multifactorial etiology. Selective atrophy of type 2 fibers might reflect pain‐related immobilization of a limb. Changes such as neurogenic muscular atrophy, muscle fiber degeneration, and regeneration might contribute as cofactors in the development or progression of OA.
Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: A multicenter, randomized, double‐blind, placebo‐controlled trial of the angiotensin‐converting enzyme inhibitor quinapril
Authors: Gliddon A. E. , Doré C. J. , Black C. M. , McHugh N. , Moots R. , Denton C. P. , Herrick A. , Barnes T. , Camilleri J. , Chakravarty K. , Emery P. , Griffiths B. , Hopkinson N. D. , Hickling P. , Lanyon P. , Laversuch C. , Lawson T. , Mallya R. , Nisar M. , Rhys‐Dillon C. , Sheeran T. , Maddison P. J.
Published: October 2007

Objective

To evaluate the efficacy and tolerability of prolonged administration of quinapril, a long‐acting angiotensin‐converting enzyme inhibitor, in the management of the peripheral vascular manifestations of limited cutaneous systemic sclerosis (lcSSc) and in the prevention of the progression of visceral organ involvement in the disease.

Methods

This was a multicenter, randomized, double‐blind, placebo‐controlled study evaluating quinapril 80 mg/day, or the maximum tolerated dosage, in 210 patients with lcSSc or with Raynaud's phenomenon (RP) and the presence of SSc‐specific antinuclear antibodies. Treatment was for 2–3 years. The primary outcome measure was the number of new ischemic ulcers appearing on the hands; secondary measures were the frequency and severity of RP attacks, skin score, treatments for ischemia, health status (measured by the Short Form 36 instrument), measures of kidney and lung function, and echocardiographic estimates of pulmonary artery pressure. An intent‐to‐treat analysis was used.

Results

Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. It did not alter the treatments that were prescribed for either infected ulcers or severe RP symptoms. There was no apparent effect on the estimated tricuspid gradient. Health status was not affected by quinapril, and one‐half of the patients who believed they had benefited from the trial treatment were in the placebo arm. Quinapril was not tolerated by one‐fifth of the patients, with dry cough being the most frequent side effect.

Conclusion

Administration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcSSc in this patient population.
NOD2 gene–associated pediatric granulomatous arthritis: Clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin‐1 blockade in a Spanish cohort
Authors: Aróstegui Juan I. , Arnal Cristina , Merino Rosa , Modesto Consuelo , Antonia Carballo María , Moreno Purificación , García‐Consuegra Julia , Naranjo Antonio , Ramos Eduardo , de Paz Pilar , Rius Josefa , Plaza Susana , Yagüe Jordi
Published: October 2007

Objective

Blau syndrome and early‐onset sarcoidosis are NOD2 gene–associated chronic autoinflammatory diseases characterized by skin rash, arthritis, and/or eye involvement, with noncaseating granulomata as their pathologic hallmark. This study was undertaken to describe the expanded clinical phenotype, treatment outcomes, and NOD2 gene mutation analysis in a Spanish cohort with pediatric granulomatous arthritis, a chronic disease resembling Blau syndrome/early‐onset sarcoidosis.

Methods

Clinical, laboratory, and treatment data on the 12 patients in the cohort were obtained through direct interviews. NOD2 gene analysis was performed in a central laboratory, by bidirectional sequencing. Cytokine levels were measured using the human Flex‐Set cytokine bead array.

Results

The classic Blau syndrome/early‐onset sarcoidosis triad of skin rash, arthritis, and recurrent uveitis was identified in 5 patients (41.7%), whereas 7 patients (58.3%) presented with fewer than 3 of the classic features. Novel atypical manifestations such as persistent fever and myocardiopathy were also observed. NOD2 analysis revealed 1 heterozygous mutation in each patient, and familial studies confirmed its full penetrance. Of the 12 cases, 58.3% were sporadic, due to de novo mutations. Four different missense mutations on exon 4 were detected. Two of them (R334W and R334Q) were recurrent mutations and were found in 77.8% of the Spanish families, whereas the other 2 (C495Y and R587C) were novel. In the patient who received anakinra treatment, all clinical inflammatory symptoms improved and plasma cytokine levels normalized.

Conclusion

These findings indicate that the expanding clinical heterogeneity of the disease (that is, the presentation of incomplete forms of the classic triad and atypical manifestations) and the high prevalence of sporadic cases should alert clinicians to the possible genetic basis of the condition and support the inclusion of DNA analysis as a diagnostic test. The positive response to anakinra observed in 1 patient suggests a new potential therapeutic approach that merits further investigation, and suggests that the pathogenesis of pediatric granulomatous arthritis may involve interleukin‐1–mediated events.
Transforming growth factor α suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis
Authors: Appleton C. Thomas G. , Usmani Shirine E. , Bernier Suzanne M. , Aigner Thomas , Beier Frank
Published: October 2007

Objective

To define the roles of transforming growth factor α (TGFα) in cartilage degradation.

Methods

Primary rat articular chondrocytes and articular osteochondral explants were cultured with TGFα to assess the effects of TGFα on chondrocyte physiology and phenotype.

Results

TGFα altered chondrocyte morphology through reorganization of the actin cytoskeleton and formation of stress fibers. Expression of anabolic genes, including aggrecan, type II collagen, and cartilage link protein, was reduced in response to TGFα. Proliferation of chondrocytes and formation of articular chondrocyte clusters was stimulated by TGFα. Expression of matrix metalloproteinase 13 and cathepsin C was increased by TGFα. We demonstrated the down‐regulation of Sox9 messenger RNA and protein levels by TGFα. This was associated with reduced levels of phosphorylated and total SOX9 in cartilage explants upon TGFα treatment. In contrast, another growth factor identified in our microarrays, Kitl, had no effects on the chondrocyte parameters tested. To examine correlations between the increased levels of TGFα in experimental knee osteoarthritis (OA) with the levels of TGFα in humans with knee OA, a microarray analysis of mRNA from 13 normal and 12 late‐stage OA cartilage samples was performed. Seven OA samples showed TGFA mRNA levels similar to those in the normal controls, but expression was markedly increased in the other 5 OA samples. These data confirm that TGFA transcript levels are increased in a subset of patients with OA.

Conclusion

This study adds TGFα to the list of dysregulated cytokines present in degrading cartilage in OA. Since TGFα inhibits articular chondrocyte anabolic capacity, increases catabolic factors, and contributes to the development of chondrocyte clusters, TGFα may be a potential target for therapeutic strategies in the treatment of OA.
Increased expression of discoidin domain receptor 2 is linked to the degree of cartilage damage in human knee joints: A potential role in osteoarthritis pathogenesis
Authors: Sunk Ilse‐Gerlinde , Bobacz Klaus , Hofstaetter Jochen G. , Amoyo Love , Soleiman Afschin , Smolen Josef , Xu Lin , Li Yefu
Published: October 2007

Objective

To investigate the relationship between increased discoidin domain receptor 2 (DDR‐2) expression and cartilage damage in osteoarthritis (OA).

Methods

Full‐thickness cartilage tissue samples from 16 human knee joints were obtained and the grade of cartilage damage was evaluated according to the Mankin scale. Expression of DDR‐2, matrix metalloproteinase 13 (MMP‐13), and MMP‐derived type II collagen fragments was visualized immunohistochemically. Moreover, upon stimulation with either type II collagen or gelatin, levels of DDR‐2 and MMP‐13 messenger RNA (mRNA) in primary human articular chondrocytes were assessed by real‐time polymerase chain reaction.

Results

Immunohistochemical analysis showed an increase in DDR‐2 expression in human articular cartilage, which was correlated with the degree of tissue damage. In parallel, the extent of MMP‐13 and type II collagen breakdown products was elevated as a function of increased DDR‐2 expression and cartilage damage. Furthermore, in vitro experiments revealed an up‐regulation of both DDR‐2 and MMP‐13 mRNA in human articular chondrocytes after stimulation with type II collagen.

Conclusion

Our data indicate that 3 factors, DDR‐2 expression, MMP‐13 expression, and the degree of cartilage damage, are linked, such that DDR‐2 promotes tissue catabolism, and tissue degradation promotes DDR‐2 up‐regulation and activation. Thus, the perpetuation of DDR‐2 expression and activation can be seen as a vicious circle that ultimately leads to cartilage destruction in OA.
The widening mortality gap between rheumatoid arthritis patients and the general population
Authors: Gonzalez Angel , Maradit Kremers Hilal , Crowson Cynthia S. , Nicola Paulo J. , Davis John M. , Therneau Terry M. , Roger Veronique L. , Gabriel Sherine E.
Published: October 2007

Objective

Overall mortality rates in the general US population have declined substantially over the last 4–5 decades, but it is unclear whether patients with rheumatoid arthritis (RA) have experienced the same improvements in survival. The purpose of this study was to determine the mortality trends among RA patients compared with those in the general population.

Methods

A population‐based incidence cohort of RA patients was assembled, comprising all residents of Rochester, Minnesota ages ≥18 years in whom RA was first diagnosed (according to the American College of Rheumatology [formerly, the American Rheumatism Association] 1987 criteria) between 1955 and 1995 and all residents of Olmsted County, Minnesota in whom RA was first diagnosed between 1995 and 2000. The patients were followed up longitudinally through their complete (inpatient and outpatient) medical records until death or January 1, 2007. Expected mortality was estimated from the National Center for Health Statistics life tables on the white population in Minnesota, using person‐year methods. Poisson regression was used to model the observed mortality rates, adjusting for age, sex, and disease duration.

Results

A cohort of 822 RA patients (72% women, mean age at RA incidence 58 years) was followed up for a median of 11.7 years, during which 445 of the RA patients died. Between 1965 and 2005, the mortality rates across the calendar years for female and male RA patients were relatively constant at 2.4 and 2.5 per 100 person‐years, respectively. In contrast, the expected mortality rate in the Minnesota white population decreased substantially over the same time period in both sexes. Mortality in the female general population declined from 1.0 per 100 person‐years in 1965 to 0.2 per 100 person‐years in 2000. Mortality in the male general population decreased from 1.2 per 100 person‐years in 1965 to 0.3 per 100 person‐years in 2000. Therefore, the difference between the observed and expected mortality rates increased in more recent years, resulting in a widening of the mortality gap.

Conclusion

Our findings show that RA patients have not experienced improvements in survival over the past 4 decades, despite dramatic improvements in the overall rates of mortality in the general US population. Further research into the causes of the widening gap in mortality between RA patients and the general population, and the influence of current therapeutic strategies on mortality, is needed in order to develop strategies to reduce the excess mortality observed in RA patients.
Peptidyl arginine deiminase type 2 (PAD‐2) and PAD‐4 but not PAD‐1, PAD‐3, and PAD‐6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation
Authors: Foulquier Céline , Sebbag Mireille , Clavel Cyril , Chapuy‐Regaud Sabine , Al Badine Roula , Méchin Marie‐Claire , Vincent Christian , Nachat Rachida , Yamada Michiyuki , Takahara Hidenari , Simon Michel , Guerrin Marina , Serre Guy
Published: October 2007

Objective

Autoantibodies to citrullinated proteins (ACPAs) are specific for rheumatoid arthritis (RA) and probably are involved in its pathophysiology. Citrullyl residues, posttranslationally generated by peptidyl arginine deiminase (PAD), are indispensable components of ACPA‐targeted epitopes. The aim of this study was to identify which PAD isotypes are expressed in the synovial tissue (ST) of patients with RA and are involved in the citrullination of fibrin, the major synovial target of ACPAs.

Methods

Expression of all PAD isotypes, including the recently described PAD type 6 (PAD‐6), was explored by reverse transcription–polymerase chain reaction and immunoblotting, first in blood‐derived mononuclear leukocytes from healthy donors, then in ST samples from 16 patients with RA and 11 control patients (4 with other arthritides and 7 with osteoarthritis [OA]). In ST samples from patients with RA, PADs were localized by immunohistochemistry.

Results

In lymphocytic and monocytic cells and, similarly, in ST samples from patients with RA, the PAD‐2, PAD‐4, and PAD‐6 genes were found to be transcribed, but only PAD‐2 and PAD‐4 enzymes were detected. PAD‐2 was also expressed in ST from control patients, including those with OA, while PAD‐4 was preferentially expressed in ST from patients with other arthritides. In RA, the expression levels of PAD‐2 and PAD‐4 were correlated with the intensity of inflammation (cell infiltration, hypervascularization, and synovial lining hyperplasia), and both enzymes were demonstrable within or in the vicinity of citrullinated fibrin deposits.

Conclusion

PAD‐2 and PAD‐4 are the only PAD isotypes expressed in the ST of patients with RA and those with other arthritides. Inflammatory cells are a major source, but PAD‐4 also comes from hyperplastic synoviocytes. Both isotypes are probably involved in the citrullination of fibrin.
Urinary TIINE concentrations in a randomized controlled trial of doxycycline in knee osteoarthritis: Implications of the lack of association between TIINE levels and joint space narrowing
Authors: Otterness Ivan G. , Brandt Kenneth D. , Graverand Marie‐Pierre Hellio Le , Mazzuca Steven A.
Published: October 2007

Objective

To use the collagenase cleavage site neoepitope, TIINE, a marker of type II collagen breakdown in cartilage, to analyze the mechanism underlying the slowing of joint space narrowing (JSN) in patients with knee osteoarthritis treated with doxycycline.

Methods

The creatinine‐adjusted urinary TIINE concentration was determined at baseline and every 6 months thereafter in a subset of patients who completed a 30‐month randomized, placebo‐controlled study of the effect of doxycycline on radiographic progression of JSN. The subset was selected a priori to permit comparison of 60 radiographic progressors with 60 radiographic nonprogressors. JSN was determined in highly standardized, semiflexed anteroposterior images.

Results

The coefficient of variation of TIINE concentrations over the 5 study visits was 30%. At the 5 semiannual followup visits, the mean TIINE concentration for doxycycline‐treated patients was higher than that for the placebo group. In both treatment groups, the correlation between TIINE levels and JSN in the index knee was weak (for doxycycline, r2 = 0.06, P = 0.08; for placebo, r2 = 0.06, P = 0.05).

Conclusion

High variability from visit to visit limits the sensitivity of the TIINE assay for detecting changes in individual patients and restricts its utility to group comparisons. The increase in TIINE concentration with treatment indicates that inhibition of collagenase‐mediated breakdown of type II collagen in articular cartilage is unlikely to have accounted for the observed reduction of JSN in the index knees of patients in the doxycycline treatment group.
Double‐knockout of ADAMTS‐4 and ADAMTS‐5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis
Authors: Majumdar Manas K. , Askew Roger , Schelling Scott , Stedman Nancy , Blanchet Tracey , Hopkins Bei , Morris Elisabeth A. , Glasson Sonya S.
Published: October 2007

Objective

To phenotypically characterize ADAMTS‐4– and ADAMTS‐5–double‐knockout mice, and to determine the effect of deletion of ADAMTS‐4 and ADAMTS‐5 on the progression of osteoarthritis (OA) in mice.

Methods

Mice lacking the catalytic domain of ADAMTS‐4 and ADAMTS‐5 were crossed to generate ADAMTS‐4/5–double‐knockout animals. Twelve‐week‐old and 1‐year‐old male and female ADAMTS‐4/5–double‐knockout mice were compared with age‐ and sex‐matched wild‐type (WT) mice by evaluating terminal body weights, organ weights, clinical pathology parameters, PIXImus mouse densitometry findings, and macroscopic and microscopic observations. ADAMTS‐4/5–double‐knockout mice were challenged by surgical induction of joint instability to determine the importance of these genes in the progression of OA. Articular and nonarticular cartilage explants from WT and ADAMTS‐4/5–double‐knockout mice were treated with interleukin‐1 (IL‐1) plus retinoic acid ex vivo, to examine proteoglycan degradation.

Results

There were no genotype‐related phenotype differences between ADAMTS‐4/5–double‐knockout and WT mice through 1 year of age, with the exception that female ADAMTS‐4/5–double‐knockout mice had a lower mean terminal body weight at the 12‐week time point. Eight weeks after surgical induction of joint instability, OA was significantly less severe in ADAMTS‐4/5–double‐knockout mice compared with WT mice. Following stimulation of cartilage explants with IL‐1 plus retinoic acid, aggrecanase‐mediated degradation in ADAMTS‐4/5–double‐knockout mice was ablated, to a level comparable with that in ADAMTS‐5–knockout mice.

Conclusion

Dual deletion of ADAMTS‐4 and ADAMTS‐5 generated mice that were phenotypically indistinguishable from WT mice. Deletion of ADAMTS‐4/5 provided significant protection against proteoglycan degradation ex vivo and decreased the severity of murine OA. These effects in the ADAMTS‐4/5–double‐knockout mice were comparable with those observed with deletion of ADAMTS‐5 alone.
Radiographic joint damage in early rheumatoid arthritis is highly dependent on body mass index
Authors: Westhoff Gisela , Rau Rolf , Zink Angela
Published: October 2007

Objective

To investigate the association between body mass index (BMI) and radiographic joint damage (using the Ratingen Score [RS]) in early rheumatoid arthritis (RA).

Methods

The study was carried out in 767 patients with early RA. Standard clinical data, RS, and BMI were evaluated at baseline and after 3 years. Multivariate logistic regression analyses were performed in rheumatoid factor (RF)–positive and RF‐negative patients to determine the influence of BMI (<25 versus ≥30 kg/m2) on considerable joint damage (RS ≥7) after 3 years, adjusting for sex, age, disease duration, and disease activity (using the Disease Activity Scale in 28 joints [DAS28]).

Results

Patients of normal weight already had significantly more joint damage at study entry than obese patients (mean RS 4.5 versus 2.4; P = 0.004) and experienced significantly more progression than obese patients (RS 3.4 versus 1.3; P = 0.011). At 3 years, their RS score was twice as high as that of the obese patients (7.5 versus 3.7; P < 0.001). Multivariate regression analyses in both serologic groups revealed significantly higher odds of RS ≥7 in RF‐positive patients of normal weight than in RF‐positive obese patients (odds ratio [OR] 3.3), but not in RF‐negative patients. Male sex (OR 1.6), osteoporosis (OR 2.0), C‐reactive protein levels >15 mg/liter versus <5 mg/liter (OR 2.6), and disease activity (DAS28 ≥5.1 versus <3.2; OR 1.9) were independently associated with RS ≥7.

Conclusion

BMI provides a risk estimate of joint damage in RA patients. Further studies are needed to elucidate the association between BMI, RF, and joint damage in RA and the possible role of adipose tissue.
Total Synthesis of Sialylated Glycans Related to Avian and Human Influenza Virus Infection
Authors: Hanashima Shinya , Seeberger Peter H.
Published: October 2007

Human and avian influenza type A viruses bind sialylated pentasaccharides. Herein, the total synthesis of four of these glycans is reported. Efficient sialylations relied on two N‐Troc‐protected (Troc=2,2,2‐trichloroethoxycarbonyl) sialic acid building blocks. The first, a thiophenyl glycoside, readily produced the sialyl‐α(2‐6)galactose disaccharide. Combination of the second building block, a novel glycosyl phosphite, and a benzylidene‐protected galactoside produced the best results for the formation of the sialyl‐α(2‐3)galactose. Two common trisaccharides were assembled by the introduction of glucose, galactose, and glucosamine building blocks followed by selective deprotection. Two sets of pentasaccharides were obtained by the union of two sialylgalactose N‐phenyl trifluoroacetimidate building blocks with the two trisaccharides above. Global deprotection furnished the desired pentasaccharides. The products of these total syntheses are currently employed on the surface of carbohydrate microarrays to detect and type different strains of the influenza virus.
Management of acute gallbladder disease in England
Authors: David G G , Al-Sarira A A , Willmott S , Deakin M , Corless D J , Slavin J P
Published: October 2007

Background

Recent literature suggests that early laparoscopic cholecystectomy for acute gallbladder disease is safe and efficacious, but few data are available on the management of acute gallbladder disease in England.

Methods

Hospital Episode Statistics data for the years 2003–2005 were obtained from the Department of Health. All patients admitted as an emergency with acute gallbladder disease during the period from April 2003 to March 2004 were included as a cohort. Repeat emergency admissions for acute gallbladder disease, and cholecystectomies performed during the first admission, an emergency readmission or an elective admission were followed up until March 2005.

Results

Some 25 743 patients were admitted as an emergency with acute gallbladder disease, of whom 3791 had an emergency cholecystectomy during the first admission (open cholecystectomy (OC) 29·8 per cent, laparoscopic conversion rate (LCR) 10·7 per cent) and 9806 patients had an elective cholecystectomy (OC 11·3 per cent, LCR 8·3 per cent) during the study period.

Conclusion

Early cholecystectomy for acute gallbladder disease is not widely practised by surgeons in England. Open cholecystectomy is more commonly used in the emergency than in the elective setting. Early laparoscopic cholecystectomy following an emergency admission carries a higher conversion rate than elective cholecystectomy.
Systematic evaluation of surgical strategies for acute malignant left-sided colonic obstruction
Authors: Breitenstein S , Rickenbacher A , Berdajs D , Puhan M , Clavien P-A , Demartines N
Published: October 2007

Background

Surgical strategy for acute colorectal obstruction due to colorectal cancer remains controversial. One-, two- and three-stage surgical procedures, and preoperative stenting of the stenosis as a bridge to surgery, are available.

Methods

A systematic review was conducted, searching MEDLINE, EMBASE and CENTRAL, as well as bibliographies of included studies, to identify randomized and non-randomized controlled trials that compared two or more surgical procedures in acute colonic obstruction.

Results

After screening 1748 titles and abstracts, 209 were selected for full text assessment; 29 studies with 2286 patients were finally included. In general, the quality of the studies was limited, with only three randomized trials. Eight non-randomized studies comparing one-stage with two- or three-stage surgery consistently favoured a one-stage procedure in terms of mortality (relative risk difference from − 2 to − 27 per cent), but reported morbidity rates were not different. Trials of different one-stage procedures (segmental and total/subtotal colectomy) showed none to be clearly superior. Stenting procedures were superior to non-stenting treatments.

Conclusion

One-stage surgery appears to be superior to two- or three-stage procedures. Stenting is a promising option, allowing the resection to be carried out in an elective setting.
Tropomyosin 4 defines novel filaments in skeletal muscle associated with muscle remodelling/regeneration in normal and diseased muscle
Authors: Vlahovich Nicole , Schevzov Galina , Nair‐Shaliker Visalini , Ilkovski Biljana , Artap Stanley T. , Joya Josephine E. , Kee Anthony J. , North Kathryn N. , Gunning Peter W. , Hardeman Edna C.
Published: October 2007

The organisation of structural proteins in muscle into highly ordered sarcomeres occurs during development, regeneration and focal repair of skeletal muscle fibers. The involvement of cytoskeletal proteins in this process has been documented, with nonmuscle γ‐actin found to play a role in sarcomere assembly during muscle differentiation and also shown to be up‐regulated in dystrophic muscles which undergo regeneration and repair [Lloyd et al.,2004; Hanft et al.,2006]. Here, we show that a cytoskeletal tropomyosin (Tm), Tm4, defines actin filaments in two novel compartments in muscle fibers: a Z‐line associated cytoskeleton (Z‐LAC), similar to a structure we have reported previously [Kee et al.,2004], and longitudinal filaments that are orientated parallel to the sarcomeric apparatus, present during myofiber growth and repair/regeneration. Tm4 is upregulated in paradigms of muscle repair including induced regeneration and focal repair and in muscle diseases with repair/regeneration features, muscular dystrophy and nemaline myopathy. Longitudinal Tm4‐defined filaments also are present in diseased muscle. Transition of the Tm4‐defined filaments from a longitudinal to a Z‐LAC orientation is observed during the course of muscle regeneration. This Tm4‐defined cytoskeleton is a marker of growth and repair/regeneration in response to injury, disease state and stress in skeletal muscle. Cell Motil. Cytoskeleton 2008. © 2007 Wiley‐Liss, Inc.
Why insulin sensitizers but not secretagogues should be retained when initiating insulin in type 2 diabetes
Authors: Raskin Philip
Published: October 2007

The stringent targets set for HbA1c levels in type 2 diabetes are currently achieved by fewer than half the patients in the United States. Failure to manage hyperglycaemia in the early stages of disease results in progressive loss of β‐cell function, which ultimately necessitates the initiation of insulin therapy. At this point, choices have to be made on whether to continue oral anti‐diabetic drug therapy and, if so, with which agent(s). Historically, sulfonylureas have been the mainstay of oral anti‐diabetic drug therapy; however, their long‐term efficacy in patients with depleted β‐cell capacity is doubtful, and other classes of oral anti‐diabetic drugs, notably the insulin sensitizers, may prove more reliable. These agents (metformin and thiazolidinediones) appear to provide various benefits over and above sustained glycaemic control, which may variably include reduced loss of β‐cell function as well as improvements to cardiovascular risk factors, morbidity, and mortality. Metformin also limits weight gain associated with insulin therapy. This manuscript presents the case that when insulin therapy is initiated it should be tailored to individual needs through combination with one or more insulin sensitizers rather than a secretagogue. Copyright © 2007 John Wiley & Sons, Ltd.
Early infant feeding and risk of type 1 diabetes mellitus—a nationwide population‐based case–control study in pre‐school children
Authors: Rosenbauer J. , Herzig P. , Giani G.
Published: October 2007

Background

The evidence on the role of environmental factors in the development of type 1 diabetes is conflicting. Reducing potential bias and the variety of exposures, we investigated the association between type 1 diabetes risk and nutritional and environmental exposures in pre‐school children.

Methods

This nationwide population‐based case–control study included 760 cases under 5 years of age newly diagnosed with type 1 diabetes during 1992–1995. From the general population, 1871 controls were randomly selected and individually matched on age ( ± 1 year), sex, and residence. Information on infant diet, foetal, perinatal and socio‐economic factors, and familial diabetes was obtained by a parent‐administered questionnaire. Data were analysed by multiple conditional logistic regression.

Results

Duration of breastfeeding and age at introduction of bottle‐feeding were inversely associated with type 1 diabetes risk according to a dose‐response relationship (trend test p < 0.05). Adjusted odd ratios (95% CI) for a long breastfeeding period and a late introduction of bottle‐feeding (≥5 month versus < 2 weeks) were 0.71 (0.54–0.93) and 0.80 (0.62–1.04), respectively. Familial type 1 diabetes, maternal age > 40 years, and low birth weight were found more frequently among diabetic than among control children. Current cow's milk consumption, higher social status, and a larger family were associated with a reduced diabetes risk. Up to one half of the diabetic cases in the population could be attributed to modifiable exposures.

Conclusions

Our findings indicate that infant feeding is associated with type 1 diabetes risk and that a considerable part of new type 1 diabetic cases is potentially preventable. Copyright © 2007 John Wiley & Sons, Ltd.
Synthesis and Magnetic Study of μ1,1‐Azido‐Bridged Dinuclear Manganese(II) Complexes Based on Tripyridyl Ligands
Authors: Yu Ming‐Ming , Ni Zhong‐Hai , Zhao Chong‐Chao , Cui Ai‐Li , Kou Hui‐Zhong
Published: October 2007

Three azido‐bridged MnII complexes of formulas [Mn2(N3)4(ttp)2] (1), [Mn2(N3)4(ttp‐N3)2] (2) and [Mn2(N3)4(ttp‐N3)2]3[MnIII(ttp‐N3)(N3)3]2 (3), where ttp and ttp‐N3 represent 4′‐p‐tolyl‐2,2′:6′,2″‐terpyridine and 4′‐p‐azidomethylphenyl‐2,2′:6′,2″‐terpyridine, were synthesized and characterized by single‐crystal X‐ray diffraction analysis and magnetic studies. The Mn ions in complexes 1 and 2 are coordinated by three N atoms of the ttp or ttp‐N3 ligands, and they are connected by double end‐on (EO) azide ligands; this forms a dinuclear MnII system with Mn–N–Mn bridging angles of 103.5 and 103.1°. The Br atoms of the –CH2Br ligands were replaced by azido groups during the formation of complexes 2 and 3. The structure of complex 3 comprises two structurally similar MnII dimers with double end‐on bridging azide groups and one mononuclear MnIII structure. The bridging Mn–N–Mn angles in 3 are 104.2, 105.1, and 106.73°. Magnetic studies indicate the presence of intramolecular ferromagnetic superexchange. The strength of ferromagnetic coupling within the Mn2 cores in 1–3 is dependent on the Mn–N–Mn bridging angles. The magnetic coupling constants for intermolecular exchange are 2.46(4), 2.25(2), and 1.92(4) cm–1 for 1, 2, and 3, respectively, on the basis ofHamiltonian Ĥ = –2JŜ1Ŝ2.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)
Perceived collective continuity: seeing groups as entities that move through time
Authors: Sani Fabio , Bowe Mhairi , Herrera Marina , Manna Cristian , Cossa Tiziana , Miao Xiulou , Zhou Yuefang
Published: October 2007

This paper presents two studies, conducted in two different countries, investigating perceptions of ingroups as enduring, temporally persistent entities, and introduces a new instrument measuring ‘perceived collective continuity’ (PCC). In Study 1 we show that perceptions of ingroup continuity are based on two main dimensions: perceived cultural continuity (perceived continuity of norms and traditions) and perceived historical continuity (perceived interconnection between different historical ages and events). This study also allows the construction of an internally consistent PCC scale including two subscales tapping on these two dimensions. Study 2 replicates findings from the first study; it also reveals that PCC is positively correlated to a set of social identity‐related measures (e.g., group identification and collective self‐esteem), and that its effects on these measures are mediated by perceived group entitativity. Overall, these two studies confirm that PCC is an important theoretical construct, and that the PCC scale may become an important instrument in future research on group processes and social identity. Copyright © 2007 John Wiley & Sons, Ltd.
Hippocampal signaling cascades are modulated in voluntary and treadmill exercise rats
Authors: Chen Wei‐Qiang , Viidik Andrus , Skalicky Monika , Höger Harald , Lubec Gert
Published: October 2007

Systematic protein expression studies in the brain of exercising and sedentary animals have not been carried out for far. Signaling proteins are main structures regulating hippocampal function and we decided to determine differences in signaling protein levels in rat hippocampus by a proteomic approach. Aged, male Sprague–Dawley rats, 23 months old, were used for the study: the first group consisted of sedentary rats, the second of rats with voluntary exercise from 5 to 23 months and the third was performing involuntary exercise on a treadmill from 5 to 23 months. 2‐DE with subsequent mass spectrometrical identification of spots followed by quantification of spots was carried out. Annexin A5, A3, phosphatidylethanolamine‐binding protein, guanine nucleotide‐binding protein G(I)/G(S)/G(T), 14‐3‐3 protein gamma, 14‐3‐3 protein zeta/delta, prohibitin, visinin‐like 1, protein phosphatase 1, septin 8, phosphoprotein enriched in astrocytes 15, transcription factor Pur‐beta, EEA1 protein, SH3 domain‐binding glutamic acid‐rich‐like protein 2, and cell division cycle 42 showed differential protein levels in the three groups. These results form the basis for functional studies elucidating mechanisms and links between exercise and hippocampal signaling and function.
Analysing the Relationship Between Typhoon‐Triggered Landslides and Critical Rainfall Conditions
Authors: Chang Kang‐tsung , Chiang Shou‐Hao , Lei Feng
Published: October 2007

Many landslides are triggered by rainfall. Previous studies of the relationship between landslides and rainfall have concentrated on deriving minimum rainfall thresholds that are likely to trigger landslides. Though useful, these minimum thresholds derived from a log–log plot do not offer any measure of confidence in a landslide monitoring or warning system. This study presents a new and innovative method for incorporating rainfall into landslide modelling and prediction. The method involves three steps: compiling radar reflectivity data in a QPESUMS (quantitative precipitation estimation and segregation using multiple sensors) system during a typhoon (tropical hurricane) event, estimating rainfall from radar data and using rainfall intensity and rainfall duration as explanatory variables to develop a landslide logit model. Given the logit model, this paper discusses ways in which the model can be used for computing probabilities of landslide occurrence for a real‐time monitoring system or a warning system, and for delineating and mapping landslides. Copyright © 2007 John Wiley & Sons, Ltd.