bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractObjectiveTo define the roles of transforming growth factor α (TGFα) in cartilage degradation.MethodsPrimary rat articular chondrocytes and articular osteochondral explants were cultured with TGFα to assess the effects of TGFα on chondrocyte physiology and phenotype.ResultsTGFα 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.ConclusionThis 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

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

AbstractObjectiveOverall 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.MethodsA 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.ResultsA 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.ConclusionOur 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

AbstractObjectiveAutoantibodies 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.MethodsExpression 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.ResultsIn 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.ConclusionPAD‐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

AbstractObjectiveTo 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.MethodsThe 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.ResultsThe 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).ConclusionHigh 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

AbstractObjectiveTo 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.MethodsMice 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.ResultsThere 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.ConclusionDual 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

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

AbstractHuman 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

Abstract

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

AbstractBackgroundSurgical 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.MethodsA 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.ResultsAfter 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.ConclusionOne-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

AbstractThe 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

AbstractThe 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.