bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progression rates and sample size estimates for PPMS based on the CLIMB study population
Authors: Raghavan Kesav , Healy Brian C , Carruthers Robert L , Chitnis Tanuja 
Published: July 2014

Background: The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts. Objective: The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression. Methods: We studied PPMS ( n = 73) and relapsing-onset MS (ROMS) patients ( n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women’s Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression. Results: The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS ( p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS ( p < 0.001). PPMS patients progressed faster to EDSS 3 ( p < 0.001) and from EDSS 3 to 6 ( p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83–8.35), significantly faster than the RO group ( p < 0.001). Conclusions: Our modern PPMS cohort is demographically similar to previously studied cohorts. PPMS is associated with faster disability accrual than ROMS. Current real-world observations of time to sustained progression will inform design of new clinical trials for PPMS.
Aliskiren inhibits prorenin-induced human aortic smooth muscle cell migration
Authors: Ferri Nicola , Panariti Federica , Ricci Chiara , Maiocchi Giuseppe , Corsini Alberto 
Published: July 2014

Background: In the present study, we investigated the potential effect of aliskiren on smooth muscle cell (SMC) migration in response to prorenin. Methods: Cultured human SMCs were incubated with angiotensinogen (ANG) (1.5 × 10−7M) and increasing concentrations of aliskiren (10−6−10−5M). After 24 h, SMC migration was assessed by Boyden’s chamber chemotactic assay using prorenin as chemotactic factor (10−8M). The effect of aliskiren on RhoA and Rac activity was also determined by G-LISA assay and the lamellipodia formation by rhodamine–phalloidin staining. Changes in cell morphology were recorded in real-time using the iCelligence system. Results: Aliskiren determined, at 10−5M, a significant inhibition of SMC migration induced by prorenin (−66.4±18.1%; p < 0.05), while no significant effect was observed when PDGF-BB was utilized as chemotactic agent. Aliskiren also reduced Rac-GTP levels in response to prorenin (−54.2±5.4%) without affecting the RhoA-GTP levels. Finally, aliskiren inhibited both the lamellipodia formation and morphological changes induced by prorenin with no significant effect on PDGF-BB activity. Conclusions: Taken together, we provide the first evidence of the inhibitory action of aliskiren on SMC migration induced by prorenin.
Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes
Authors: Færch Louise H , Thorsteinsson Birger , Tarnow Lise , Holst Jens Juul , Kjær Troels , Kanters Jørgen , Larroude Charlotte , Dela Flemming , Pedersen-Bjergaard Ulrik 
Published: July 2014

Introduction: High spontaneous activity of the renin–angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function during hypoglycaemia. Methods: Nine patients with type 1 diabetes and high spontaneous RAS activity were included in a double-blind, randomised, cross-over study on the effect of angiotensin II receptor antagonist (candesartan 32 mg) or placebo for one week on cognitive function, cardiovascular parameters, hormonal counter-regulatory response, substrate mobilisation, and symptoms during hypoglycaemia induced by two hyperinsulinaemic, hypoglycaemic clamps. Results: Compared to placebo, candesartan did neither change performance of the cognitive tests nor the EEG at a plasma glucose concentration of 2.6±0.2 mmol/l. During candesartan treatment, the QT interval in the ECG was not affected. No effect of candesartan was observed in the hormonal counter-regulatory responses, in substrate concentrations, or in symptom scores. A 36% reduced glucose infusion rate during hypoglycaemia with candesartan was observed. Conclusion: In conclusion candesartan has no effect on cerebral function during mild experimental hypoglycaemia in subjects with type 1 diabetes and high RAS activity. Candesartan may reduce glucose utilisation or increase endogenous glucose production during hypoglycaemia.
Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and pancreatitis risk: A meta-analysis
Authors: Fang Fang , Pan Jian , Xu Lixiao , Su Guanghao , Li Gang , Wang Jian 
Published: July 2014

Objective: Many studies have focused on the relationship between the angiotensin-converting enzyme gene ( ACE) insertion/deletion (I/D) polymorphism and pancreatitis risk, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between ACE I/D polymorphism and pancreatitis risk. Methods: Relevant publications were searched in several widely used databases and seven studies from six eligible articles were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between ACE I/D polymorphism and pancreatitis risk. Results: Significant associations between ACE I/D polymorphism and pancreatitis risk were observed in both overall meta-analysis for DI versus II (OR=0.80, 95% CI=0.67–0.96) and DD + DI versus II (OR=0.83, 95% CI=0.70–0.98), and acute pancreatitis subgroup for DI versus II (OR=0.65, 95% CI=0.44–0.95). However, no significant pancreatitis risk variation was detected for all genetic models in the subgroup meta-analysis based on ethnicity. Conclusions: According to the results of our meta-analysis, the ACE I/D polymorphism probably associates with pancreatitis risk, especially acute pancreatitis risk, with the I allele acting as a risk factor.
Criticality in Practice
Authors: Collins Joshua C. , Chlup Dominique T. 
Published: July 2014

The Problem The connection between human resource development (HRD) and the practice of being an ally of social justice in the workplace seems worthy of meaningful dialogue, yet few publications have addressed this vital workplace need. The Solution The purpose of this article is to explore the importance of social justice allies’ critical perspectives regarding climates of inclusion in the workplace, and HRD’s role in facilitating the development of social justice allies. We envision the ally development process as cyclical, and we offer suggestions for HRD practitioners and organizations on how to foster environments of inclusion by allowing allies to grow and openly vocalize their convictions. The Stakeholders Viewing HRD as a mechanism for advancing and understanding the development of social justice allies in the workplace has the potential to impact both research and practice, for those deemed to possess privilege and for those deemed to be oppressed, and across many levels of hierarchy in organizations—from investors, to executives, to managers, to employees, and even to consumers/customers.
Synovial Fluid Lubricant Properties Are Transiently Deficient After Arthroscopic Articular Cartilage Defect Repair With Platelet-Enriched Fibrin Alone and With Mesenchymal Stem Cells
Authors: Grissom Murray J. , Temple-Wong Michele M. , Adams Matthew S. , Tom Matthew , Schumacher Barbara L. , McIlwraith C. Wayne , Goodrich Laurie R. , Chu Constance R. , Sah Robert L. 
Published: July 2014

Background: Following various types of naturally occurring traumatic injury to an articular joint, the lubricating ability of synovial fluid is impaired, with a correlated alteration in the concentration and/or structure of lubricant molecules, hyaluronan, and proteoglycan-4 (PRG4). However, the effect of arthroscopic cartilage repair surgery on synovial fluid lubricant function and composition is unknown. Hypothesis: Arthroscopic treatment of full-thickness chondral defects in horses with (1) platelet-enriched fibrin or (2) platelet-enriched fibrin + mesenchymal stem cells leads to equine synovial fluid with impaired lubricant function and hyaluronan and PRG4 composition. Study Design: Controlled laboratory study. Methods: Equine synovial fluid was aspirated from normal joints at a preinjury state (0 days) and at 10 days and 3 months following fibrin or fibrin + mesenchymal stem cell repair of full-thickness chondral defects. Equine synovial fluid samples were analyzed for friction-lowering boundary lubrication of normal articular cartilage (static and kinetic friction coefficients) and concentrations of hyaluronan and PRG4, as well as molecular weight distribution of hyaluronan. Experimental groups deficient in lubrication function were also tested for the ability of exogenous high–molecular weight hyaluronan to restore lubrication function. Results: Lubrication and biochemical data varied with time after surgery but generally not between repair groups. Relative to preinjury, kinetic friction was higher (+94%) at 10 days but returned to baseline levels at 3 months, while static friction was not altered. Correspondingly, hyaluronan concentration was transiently lower (−64%) and shifted toward lower molecular weight forms, while PRG4 concentration was increased (+210%) in 10-day samples relative to preinjury levels. Regression analysis revealed that kinetic friction decreased with increasing total and high–molecular weight hyaluronan. Addition of high–molecular weight hyaluronan to bring 10-day hyaluronan levels to 2.0 mg/mL restored kinetic friction to preinjury levels. Conclusion: Following arthroscopic surgery for cartilage defect repair, synovial fluid lubrication function is transiently impaired, in association with decreased hyaluronan concentration. This functional deficiency in synovial fluid lubrication can be counteracted in vitro by addition of high–molecular weight hyaluronan. Clinical Relevance: Synovial fluid lubrication is deficient shortly after arthroscopic cartilage repair surgery, and supplementation with high–molecular weight hyaluronan may be beneficial.
Injuries in Elite Men’s Lacrosse
Authors: Webb Mark , Davis Caroline , Westacott Daniel , Webb Robin , Price Jessica 
Published: July 2014

Background: There are limited data on injuries sustained during men’s lacrosse. As the sport gains popularity, practitioners will be more likely to treat lacrosse players. Purpose: To analyze data from the 2010 World Lacrosse Championships. Study Design: Descriptive epidemiology study. Methods: This was a prospective observational study of injuries reported during the 2010 World Lacrosse Championships. An injury surveillance questionnaire was completed, and data were categorized into body part injured, diagnosis, mechanism, and time of injury. Results: Over 9 days, 667 players from 29 countries competed in 105 games. A total of 150 injuries were sustained by 129 individuals aged 16 to 46 years. Five times more injuries occurred during games than in training (69.3% [n = 104] vs 13.3% [n = 20]; rate ratio [95% CI] = 5.2 [4.9-5.5]), resulting in 39.5 injuries per 1000 hours played. The most frequent mechanism was contact (53.3%; n = 80), including direct impact with another player (30%; n = 45), with a stick (16.7%; n = 25), or with a ball (5.3%; n = 8). Change of direction and/or speed were the most common noncontact mechanisms (27.3%; n = 41). The most frequently reported injuries were contusions (32.0%; n = 48), sprains (22.7%; n = 34), and strains (22.7%; n = 34). The lower limb was the most injured body part (50.7%; n = 76) compared with the upper limb (23.3%; n = 35; rate ratio [95% CI] = 2.2 [2.1-2.3]). The ankle was the most injured joint (14.0%; n = 21), followed by the shoulder (10.0%; n = 15). Conclusion: As participation expands, health professionals may become more responsible for treating lacrosse players. Players are susceptible to a range of injuries. Familiarity with the common injury patterns could help treatment and prevention. Despite differences in rules during international competition, this study corroborates reports from North America. Clinical Relevance: The epidemiology of men’s lacrosse injuries needs to be documented and understood to effectively prevent injuries. The 2014 World Championships are to be held in Denver, Colorado (July 10-19, 2014), and it is important that practitioners treating players are aware of the differences in the international game. Publication of these data will allow for those planning lacrosse tournaments to do so more effectively.
Mutational Analysis of PI3K/AKT Signaling Pathway in Tamoxifen Exemestane Adjuvant Multinational Pathology Study
Authors: Sabine Vicky S. , Crozier Cheryl , Brookes Cassandra L. , Drake Camilla , Piper Tammy , van de Velde Cornelis J.H. , Hasenburg Annette , Kieback Dirk G. , Markopoulos Christos , Dirix Luc , Seynaeve Caroline , Rea Daniel W. , Bartlett John M.S. 
Published: July 2014

Purpose Deregulation of key PI3K/AKT pathway genes may contribute to endocrine resistance in breast cancer (BC). PIK3CA is the most frequently mutated gene in luminal BC (∼ 35%); however, the effect of mutations in helical versus kinase domains remains controversial. We hypothesize that improved outcomes occur in patients with estrogen receptor–positive (ER positive) BC receiving endocrine therapy and possessing PIK3CA mutations. Materials and Methods DNA was extracted from 4,540 formalin-fixed paraffin-embedded BC samples from the Exemestane Versus Tamoxifen-Exemestane pathology study. Mutational analyses were performed for 25 mutations (PIK3CAx10, AKT1x1, KRASx5, HRASx3, NRASx2 and BRAFx4). Results PIK3CA mutations were frequent (39.8%), whereas RAS/RAF mutations were rare (< 1%). In univariable analyses PIK3CA mutations were associated with significantly improved 5-year distant relapse-free survival (DRFS; HR, 0.76; 95% CI, 0.63 to 0.91; P = .003). However, a multivariable analysis correcting for known clinical and biologic prognostic factors failed to demonstrate that PIK3CA mutation status is an independent prognostic marker for DRFS (HR, 0.92; 95% CI, 0.75 to 1.12; P = .4012). PIK3CA mutations were more frequent in low-risk luminal BCs (eg, grade 1 node v 3, node-negative v -positive), confounding the relationship between mutations and outcome. Conclusion PIK3CA mutations are present in approximately 40% of luminal BCs but are not an independent predictor of outcome in the context of endocrine therapy, whereas RAS/RAF mutations are rare in luminal BC. A complex relationship between low-risk cancers and PIK3CA mutations was identified. Although the PI3K/AKT pathway remains a viable therapeutic target as the result of a high mutation frequency, PIK3CA mutations do not seem to affect residual risk following treatment with endocrine therapy.
Prevalence and Clinical Outcomes for Patients With ALK-Positive Resected Stage I to III Adenocarcinoma: Results From the European Thoracic Oncology Platform Lungscape Project
Authors: Blackhall Fiona H. , Peters Solange , Bubendorf Lukas , Dafni Urania , Kerr Keith M. , Hager Henrik , Soltermann Alex , O'Byrne Kenneth J. , Dooms Christoph , Sejda Aleksandra , Hernández-Losa Javier , Marchetti Antonio , Savic Spasenija , Tan Qiang , Thunnissen Erik , Speel Ernst-Jan M. , Cheney Richard , Nonaka Daisuke , de Jong Jeroen , Martorell Miguel , Letovanec Igor , Rosell Rafael , Stahel Rolf A. 
Published: July 2014

Purpose The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non–small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. Methods Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. Results Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). Conclusion In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.
Basis for Classification, Typologization, and Identification of Factors that Create Working Conditions (general principles and approaches)
Authors: Файнбург  , Faynburg Grigoriy 
Published: July 2014

This paper presents a comprehensive approach to system description of dangerous and harmful factors, deals with the
problems of its classification, typologization and identification. A new principle is suggested to classify workplace factors
considering all aspects of harmful impact. Advocated approach to classification of harmful workplace factors promotes a
more precise identification, analysis and assessment of professional risks.
Genome‐wide identification of miR‐200 targets reveals a regulatory network controlling cell invasion
Authors: Bracken Cameron P , Li Xiaochun , Wright Josephine A , Lawrence David M , Pillman Katherine A , Salmanidis Marika , Anderson Matthew A , Dredge B Kate , Gregory Philip A , Tsykin Anna , Neilsen Corine , Thomson Daniel W , Bert Andrew G , Leerberg Joanne M , Yap Alpha S , Jensen Kirk B , Khew‐Goodall Yeesim , Goodall Gregory J 
Published: July 2014

AbstractThe microRNAs of the miR‐200 family maintain the central characteristics of epithelia and inhibit tumor cell motility and invasiveness. Using the Ago‐HITS‐CLIP technology for transcriptome‐wide identification of direct microRNA targets in living cells, along with extensive validation to verify the reliability of the approach, we have identified hundreds of miR‐200a and miR‐200b targets, providing insights into general features of miRNA target site selection. Gene ontology analysis revealed a predominant effect of miR‐200 targets in widespread coordinate control of actin cytoskeleton dynamics. Functional characterization of the miR‐200 targets indicates that they constitute subnetworks that underlie the ability of cancer cells to migrate and invade, including coordinate effects on Rho‐ROCK signaling, invadopodia formation, MMP activity, and focal adhesions. Thus, the miR‐200 family maintains the central characteristics of the epithelial phenotype by acting on numerous targets at multiple levels, encompassing both cytoskeletal effectors that control actin filament organization and dynamics, and upstream signals that locally regulate the cytoskeleton to maintain cell morphology and prevent cell migration.
Effects of species' similarity and dominance on the functional and phylogenetic structure of a plant meta‐community
Authors: Chalmandrier L. , Münkemüller T. , Lavergne S. , Thuiller W. 
Published: July 2014

Different assembly processes drive the spatial structure of meta‐communities (β‐diversity). Recently, functional and phylogenetic diversities have been suggested as indicators of these assembly processes. Assuming that diversity is a good proxy for niche overlap, high β‐diversity along environmental gradients should be the result of environmental filtering while low β‐diversity should stem from competitive interactions. So far, studies trying to disentangle the relative importance of these assembly processes have provided mixed results. One reason for this may be that these studies often rely on a single measure of diversity and thus implicitly make a choice on how they account for species relative abundances and how species similarities are captured by functional traits or phylogeny.Here, we tested the effect of gradually scaling the importance of dominance (the weight given to dominant vs. rare species) and species similarity (the weight given to small vs. large similarities) on resulting β‐diversity patterns of an alpine plant meta‐community. To this end, we combined recent extensions of the Hill numbers framework with Pagel's phylogenetic tree transformation approach. We included functional (based on the leaf–height–seed spectrum) and phylogenetic facets of β‐diversity in our analysis and explicitly accounted for effects of environmental and spatial covariates.We found that functional β‐diversity was high when the same weight was given to dominant vs. rare species and to large vs. small species' similarities. In contrast, phylogenetic β‐diversity was low when greater weight was given to dominant species and small species' similarities. Those results suggested that different environments along the gradients filtered different species according to their functional traits, while, the same competitive lineages dominated communities across the gradients.Our results highlight that functional vs. phylogenetic facets, presence‐absence vs. abundance structure and different weights of species' dissimilarity provide complementary and important information on the drivers of meta‐community structure. By utilizing the full extent of information provided by the flexible frameworks of Hill numbers and Pagel's tree transformation, we propose a new approach to disentangle the patterns resulting from different assembly processes.