bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE EFFECTS OF UPHILL TREADMILL RUNNING AND COLLAGENASE ON RODENT ACHILLES TENDONS
Authors: Dirks R C , Fearon A M , Scott A , Galley M R , Koch L G , Britton S L , Warden S J 
Published: May 2013

IntroductionOveruse conditions of the Achilles tendon likely develop due to a combination of extrinsic and intrinsic risk factors. The purpose of this study was to investigate the individual and combined effects of uphill treadmill running (extrinsic risk factor) and collagenase injection (intrinsic risk factor) on the histological appearance of rodent Achilles tendons. Previous studies have shown that collagenase injection leads to inflammation of the tendon,1 while exercise can lead to adaptation and tendon hypertrophy.2 Our hypothesis was that collagenase injection would result in initial tendon inflammation which would become degenerative when combined with mechanical loading.MethodsTwenty-four mature high-capacity running rats were studied. All rats received a collagenase injection into one Achilles tendon at baseline. After 1 week, animals were randomly divided into either a run or cage-control group. The run group ran on a treadmill at a 15° incline, 5 days/week at increasing duration and speed. Tendons were harvested at either 4 or 10 weeks after the start of the running regimen. Specimens were fixed in formalin and embedded in paraffin. H&E stained sections were evaluated using a modified Bonar scale by two blinded and independent assessors, with a third to resolve disputes.ResultsAt 4 weeks, higher levels of pathology were seen in the injected tendons than in the non-injected tendons (ANOVA: p=0.007). No side to side difference was seen at 10 weeks (ANOVA: p=0.309). There was no difference between running and non-running groups at 4 weeks (ANOVA: p=0.579) or 10 weeks (ANOVA: p=0.429). No interaction effects were seen between injection and running at 4 weeks (ANOVA: p=0.934) or 10 weeks (ANOVA: p=0.847).DiscussionIn high capacity running rats, uphill treadmill running using these experimental parameters did not independently create histopathology of the Achilles tendon. Furthermore, the effect of collagenase did not have a long-term effect and was not influenced by running. Therefore, the combination of collagenase injection and uphill treadmill running does not seem to create a histological presentation similar to the degeneration seen in human Achilles tendinopathy.
BILATERAL CHANGES IN UNILATERAL ACHILLES TENDINOPATHY QUANTIFIED USING ULTRASOUND TISSUE CHARACTERISATION
Authors: Docking S I , van Schie J T M , Daffy J , Rosengarten S , Cook J L 
Published: May 2013

IntroductionAchilles tendinopathy is a prevalent musculoskeletal injury in the young athletic population as well as older individuals. A high proportion of individuals develop symptoms within both Achilles tendons as well as an increased incidence of tendon rupture in the contralateral tendon post Achilles tendon rupture. Bilateral pathological changes have been reported in the literature in a number of animal studies,1 as well as pathological changes observed histologically and ultrasonographically in the asymptomatic tendon.2 3 Recent studies have suggested that these changes may be centrally mediated rather than alterations in gait, and may predispose the tendon to further degeneration and the development of symptoms. The current study examined changes in tendon structure in patients suffering from unilateral Achilles tendinopathy using ultrasound tissue characterisation (UTC) in both the symptomatic and asymptomatic tendon. UTC allows semi quantitative analysis of tendon structure by assessing the stability of the echopattern, which is closely related to the 3-D structure of the tendon.Methods13 unilateral Achilles tendinopathy patients were recruited with various times of symptoms. Both Achilles tendons were scanned using UTC. UTC captures 600 contiguous transverse images over a distance of 12 cm and renders a three-dimensional image of the tendon. Tendon structure was quantified from the insertion to the musculotendinous junction using customised software that quantifies the stability of the echopattern and allows semi-quantification of tendon structure, which has previously been matched with pathological specimens. Tendon structure was compared between the symptomatic and asymptomatic tendon using a related-samples Wilcoxon signed rank test.ResultsNo significant difference was observed for any of the four echo-types between the symptomatic and asymptomatic tendon (p=0.388, p=0.158, 0.624, p=0.824, respectively). Despite no differences being observed in the echopatterns, disorganisation within the asymptomatic group was diffusely scattered throughout the length of the tendon. Disorganisation in the symptomatic tendon was confined to focal lesions predominately characterised by echo-types representing extensive fibrillar disorganisation.DiscussionDespite the overall echopattern of the tendon not differing between the two groups, the distribution of disorganisation within the tendon differed. However, as changes in tendon structure were not confined to the symptomatic tendon, treatments should aim to improve tendon structure in both limbs to minimise the risk of developing symptoms and potential tendon rupture.
THE LINK BETWEEN DYSLIPIDEMIA AND TENDON PATHOLOGY
Authors: Grewal N , Granville D , Reid D , Scott A 
Published: May 2013

IntroductionDyslipidemia, abnormal amounts of lipid in the blood, has been associated with chronic Achilles tendinopathy. Tendinopathy is a major cause of morbidity in athletic populations and in the work force,1 traditionally thought to occur as a consequence of an imbalance between damage (resulting from mechanical loading) and repair.2 However, one third of the cases for midportion Achilles tendinopathy occur in sedentary individuals, and recent data suggests an association between dyslipidemia and the occurrence of tendon rupture or tendinopathy.3 The goal of this study is to examine the missing biological link between elevated lipids and the development of tendinopathy, and establish a suitable model to examine the potential reversibility of tendinopathy associated with dyslipidemia. The study will use the ApoE-knockout mouse model, in which deficiency of ApoE leads to development of hypercholesterolemia. We hypothesise that ApoE-KO mice fed on a high fat diet, in comparison to those fed a normal diet and the wild type (non-atherosclerotic) mice, will demonstrate reduced collagen density and organisation, increased intracellular and extracellular lipid deposition, increased tendon cross-sectional area, and reduced tendon biomechanical function.MethodsThe ApoE-KO mice are fed a high fat or regular diet at 7 weeks of age, and sacrificed at 0, 15, and 30 weeks. For collagen density and organisation, tendon tissue will be viewed using second harmonic generation microscopy to determine collagen density and organisation. Tendons will be systematically scanned, and collagen density will be determined and compared among different study groups. Lipid deposition in Achilles tendon will be observed with oil red O and filipin staining. Tissue sections will be viewed and photographed with brightfield, polarisation, and fluorescence microscopy. Filipin dye will be excited with epiillumination and viewed through a 510-nm barrier filter. Ultrasound imaging will be used to analyse patellar tendon cross-sectional area (ie, tendon thickening, an indicator of tendon pathology). The effect of dyslipidemia on tendon biomechanics will be determined by testing the tendon to failure at 0.003 mm/s in a Bose ElectroForce BioDynamic test instrument. Local strain will be measured and tendon stiffness calculated.Anticipated results and significanceTendinopathy tendon in an H&E stained tissue section is expected to show disorganised collagen architecture with high cellularity of rounded tenocytes (as compared to parallel, longitudinal architecture with scattered elongated tenocytes of normal tendons).4 Tissue sections of Achilles tendon is expected to have wavy, discrete, band-like deposits of green filipin staining. Oil red O staining is to be observed intracellularly and extracellularly.5 If significant, these results will provide the first insights into the biology underlying dyslipidemia-induced tendinopathy, and could have direct impact on clinical care and preventive strategies.
HISTOCHEMICAL ANALYSIS OF GAGS IN ALTERED TENDON: A MEANS TO EVALUATE THE DEGREE OF PATHOLOGY
Authors: Attia M , Carpentier G , Etienne S , Thierart S , Scott A , Oystein L , Papy-Garcia D , Tassoni M C , Martelly I 
Published: May 2013

IntroductionThe social and economic consequences of injured tendons have long been recognised. In particular, patellar tendinopathy is often recalcitrant to standard treatment, highlighting the need for prevention and therapeutic strategies that aim at minimising tissue alteration and protecting tendon structure and function. This relies on a pertinent diagnostic of the degree of pathology. A means to correlate anatomical and biochemical properties of injured tendon to the extent of the pathology is thus important to acquire. Sulfated glycosaminoglycans (GAGs), along with the proteoglycan aggrecan, are known to increase with tendon pathology, indicating a shift of tenocytes towards a chondroïd phenotype. It could be postulated that the amount of GAGs correlates with the degree of pathology of patellar tendon assessed by the VISA Score.MethodsAnalysis of total and specific GAGs using a DiMethyl Methylene Blue histochemical technique and immuno-histological technique with antibodies against Dermatan Sulfate, Chondroitin Sulfate, Heparan Sulfate and proteoglycans (PG) (decorin, versican and aggrecan) respectively were performed on normal and pathological tendon sections from rat supraspinatus and human patellar tendons.ResultsAs observed in rat overused supraspinatus tendon, total GAGs as well as Dermatan and Chondroitin sulfate were increased in human pathological patellar tendon. Correlatively, PGs such as decorin, and above all versican and aggrecan were also enhanced. Amounts of GAGs and aggrecan found in tendons changed with the Visa score of patellar tendons. A correlation was established between VISA score and the amount of GAGs. This correlation allowed us to verify the correct sampling of patient tendons and was predictive for the extent of pathology of unclassified tendon samples.ConclusionThis study underscores the importance of excessive GAGs in relation to tendon pain and function. Accurate GAG assessment would represent a help in establishing a reliable diagnostic of patellar tendinopathy as a complement of the Visa score. This knowledge may be useful in stimulating the development of more sensitive imaging modalities capable of detecting early changes in the composition of tendon extracellular matrix.
IDENTIFICATION OF BIOMARKERS FOR EARLY TENDON DEGENERATION USING AN IN-VIVO RABBIT MODEL
Authors: Huisman E , Thornton G , Roberts C , Scott A 
Published: May 2013

IntroductionTendinopathy is a common and costly diagnosis in workers with Activity-related Soft Tissue Disorder (ASTD), and in recreational and professional athletes. The associated pain results in reduced physical activity, reduced productivity, missed work days, and substantial costs to the government. Workers whose tendons are exposed to prolonged repetitive activity (eg, manual workers like fish processors) and/or high mechanical loads (eg, construction workers) are at high risk for the development of ASTD-associated tendinopathy. Pain is usually one of the first symptoms of tendinopathy; however imaging studies have demonstrated that significant degenerative tendon alterations can develop in response to mechanical loading, months before there are any overt symptoms.Goal: To identify circulation markers of early tendon degeneration.Research questions: (1) Will fatigue damage in tendons, caused by different loading regimes, correlate with changes in expression of genes involved in tendon degeneration? (2) Can we track the development of early phase tendon degeneration in vivo using ultrasound and measure indicators of tendon degradative activity in the circulation? It is hypothesised that different loading regimes will lead to characteristic, degradative differences in gene expression. Ultrasound will be able to visualise and follow early onset, degradative changes in the strained tendons.MethodsRabbit Achilles tendons will be subjected to varying loading regimens using the in-vivo Backman model. After set periods of exercise, microdialysis and blood samples will be taken and analysed for genes involved in degradation of tendons. At the same intervals, ultrasound images will be taken to track changes in the cross sectional area of the tendon. After the end of the full exercise period, the tendon tissue will be examined for characteristic degradative changes using microscopy.ResultsIt is expected that the exercise regimen will lead to significant changes in gene expression in the tendon.1 Blood and microdialysis samples are expected to show significant changes in for example, collagen type I and III, matrix metalloproteinases (MMPs), tissue inhibitors for MMPs (TIMPs), and other genes involved.2 It is expected that the tissue will exhibit characteristic morphological changes seen in degradative tendon tissue, for example, rounded nuclei of tenocytes and a looser, kinked pattern of the collagen fibrils.3DiscussionTreatment for tendinopathies in workers can be a long and costly process which is not always successful, due to the degenerative nature of chronic tendinopathy. Detecting the early stages of tendinopathy could allow for the possibility of interventions to decrease or prevent tendon pain and/or rupture, and reduce healthcare and insurance costs.
SYMPOSIUM SPONSORS AND COMMITTEE MEMBERS
Authors: Scott A 
Published: May 2013

ISTS2012 was sponsored by the Department of Physical Therapy, the Canadian Institutes of CIHR (meeting planning and dissemination grant), the Vancouver Coastal Health Research Centre, BJSM, Sonosite, The Orthopaedic Biologic Institute, and ASTYM corporation.Thanks to the scientific committee and organising committee.Scientific committee: Alex Scott, Jill Cook, Patrick Danielson, Malcolm Collins, Craig Purdam, Henning Langberg, Nele Mahieu, Paul Ackermann, Roger Smith, Tomas Fernando Fernandez Jaén.Organising committee: Angela Fearon, Callista Haggis, Jacqueline Alexander, Aishwariya Sharma.
A Multicenter, First-in-Pediatrics, Phase 1, Pharmacokinetic and Pharmacodynamic Study of Ridaforolimus in Patients with Refractory Solid Tumors
Authors: Gore Lia , Trippett Tanya M. , Katzenstein Howard M. , Boklan Jessica , Narendran Aru , Smith Amy , Macy Margaret E. , Rolla Katherine ,   for the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC), Narashimhan Narayana , Squillace Rachel M. , Turner Christopher D. , Haluska Frank G. , Nieder Michael 
Published: May 2013

AbstractPurpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies.Experimental Design: Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 + 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized.Results: Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas.Conclusions: This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies. Clin Cancer Res; 19(13); 3649–58. ©2013 AACR.
Identifying the Ubiquitin Ligase Complex That Regulates the NF1 Tumor Suppressor and Ras
Authors: Hollstein Pablo E. , Cichowski Karen 
Published: May 2013

Abstract
The NF1 tumor suppressor protein neurofibromin is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome, and its degradation and reexpression are essential for maintaining appropriate levels of Ras-GTP. Like p53, NF1/neurofibromin can be inactivated in cancer by both mutations and excessive proteasomal destruction; however, little is known about the mechanisms that underlie this latter process. Here, we show that a Cullin 3 (Cul3)/kelch repeat and BTB domain-containing 7 complex controls both the regulated proteasomal degradation of neurofibromin and the pathogenic destabilization of neurofibromin in glioblastomas. Importantly, RNAi-mediated Cul3 ablation and a dominant-negative Cul3 directly stabilize neurofibromin, suppress Ras and extracellular signal-regulated kinase, and inhibit proliferation in an NF1-dependent manner. Moreover, in glioblastomas where neurofibromin is chronically destabilized, Cul3 inhibition restabilizes the protein and suppresses tumor development. Collectively, these studies show a previously unrecognized role for Cul3 in regulating Ras and provide a molecular framework that can be exploited to develop potential cancer therapies.
Significance: This study identifies the ubiquitin ligase complex that controls the regulated and pathogenic destruction of the NF1 tumor suppressor protein. These observations provide a molecular framework for developing potential therapies for glioblastoma, where neurofibromin is chronically destabilized, and reveal a new strategy to attenuate Ras that has broader therapeutic implications. Cancer Discov; 3(8); 880–93. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 826
Mineralocorticoid Receptor Agonists Induce Mouse Aortic Aneurysm Formation and Rupture in the Presence of High Salt
Authors: Liu Shu , Xie Zhongwen , Daugherty Alan , Cassis Lisa A. , Pearson Kevin J. , Gong Ming C. , Guo Zhenheng 
Published: May 2013

Objective—
Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown.

Approach and Results—
We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm.

Conclusions—
The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.
Basilar Artery Diameter Is an Independent Predictor of Incident Cardiovascular Events
Authors: Tanaka Makiko , Sakaguchi Manabu , Miwa Kaori , Okazaki Shuhei , Furukado Shigetaka , Yagita Yoshiki , Mochizuki Hideki , Kitagawa Kazuo 
Published: May 2013

Objective—
Basilar arterial (BA) dolichoectasia is associated with cerebral small-vessel disease and stroke. However, the association between moderate dilation of the BA and cerebral small-vessel disease or subsequent cardiovascular events remains unclear. This study aims to clarify the factors related to BA diameter and to clarify whether the BA diameter is an independent predictor of cardiovascular events.

Approach and Results—

The study subjects comprised 493 outpatients with atherosclerotic risk factors. BA diameter, lacunar infarct, severity of deep white matter hyperintensities, and intracranial steno-occlusive lesions were assessed with MRI and magnetic resonance angiography. Then, we prospectively evaluated the association between BA diameter and cardiovascular events. The BA diameter ranged from 1.1 to 5.2 mm, and only 0.8% of the patients had dolichoectasia. Male sex, the presence of lacunar infarcts, the severity of deep white matter hyperintensities, the fetal-type variation of the circle of Willis, and intracranial steno-occlusive lesions were independently associated with BA diameter. In the mean follow-up of 6.0 years, 91 patients developed cardiovascular events. BA diameter was independently associated with total cardiovascular events after adjusting for age, sex, and conventional risk factors (hazard ratio, 1.55 per 1 mm increase in BA diameter;
P
=0.009).

Conclusions—
Increased BA diameter within the normal range is related to both large-vessel disease and cerebral small-vessel disease, and it could be a new predictor of cardiovascular events.