bluuebunny/crossref_metadata_2025 huggingface dataset:
A qualitative study of stakeholder views regarding participation in locally commissioned enhanced optometric services
Authors: Konstantakopoulou E , Harper R A , Edgar D F , Lawrenson J G
Published: May 2014

Objectives

To explore the views of optometrists, general practitioners (GPs) and ophthalmologists regarding the development and organisation of community-based enhanced optometric services.

Design

Qualitative study using free-text questionnaires and telephone interviews.

Setting

A minor eye conditions scheme (MECS) and a glaucoma referral refinement scheme (GRRS) are based on accredited community optometry practices.

Participants

41 optometrists, 6 ophthalmologists and 25 GPs.

Results

The most common reason given by optometrists for participation in enhanced schemes was to further their professional development; however, as providers of ‘for-profit’ healthcare, it was clear that participants had also considered the impact of the schemes on their business. Lack of fit with the ‘retail’ business model of optometry was a frequently given reason for non-participation. The methods used for training and accreditation were generally thought to be appropriate, and participating optometrists welcomed the opportunities for ongoing training. The ophthalmologists involved in the MECS and GRRS expressed very positive views regarding the schemes and widely acknowledged that the new care pathways would reduce unnecessary referrals and shorten patient waiting times. GPs involved in the MECS were also very supportive. They felt that the scheme provided an ‘expert’ local opinion that could potentially reduce the number of secondary care referrals.

Conclusions

The results of this study demonstrated strong stakeholder support for the development of community-based enhanced optometric services. Although optometrists welcomed the opportunity to develop their professional skills and knowledge, enhanced schemes must also provide a sufficient financial incentive so as not to compromise the profitability of their business.
The population genetic structure and diversification ofAristolochia delavayi(Aristolochiaceae), an endangered species of the dry hot valleys of the Jinsha River, southwestern China
Authors: Yang Zhi-Yun , Yi Ting-Shuang , Zeng Liang-Qin , Gong Xun
Published: May 2014

Aristolochia delavayi Franch. is an endangered species of the dry hot valleys of the Jinsha River, southwestern China. The genetic diversity and structure of the species and the occurrence of gene flow were investigated with eight inter-simple sequence repeat (ISSR) markers and four plastid loci (matK, trnL-trnT, rps4-trnT, and trnC-rpoB). The analysis of ISSR markers indicated that the genetic diversity of the species is relatively high (PPB = 84.71%). Similarly, a high gene diversity of HT= 0.833 was found based on the four plastid loci. It is possible that this species previously maintained a large effective population size and that the current relict distribution of the species is a result of large-scale fragmentation and habitat destruction. The origin of the species at approximately 3.407 million years ago and the ensuing intraspecific divergence are generally consistent with the history of two major glaciations in this region. Conservation measures are urgently needed to increase the genetic diversity and population size of this species through both in- and ex-situ action.
Unpredictability of the coefficients of m-fold symmetric bi-starlike functions
Authors: Hamidi Samaneh G. , Jahangiri Jay M.
Published: May 2014

In 1984, Libera and Zlotkiewicz proved that the inverse of the square-root transform of the Koebe function is the extremal function for the inverses of odd univalent functions. The purpose of this paper is to point out that this is not the case for the m-fold symmetric bi-starlike functions by demonstrating the unpredictability of the coefficients of such functions.
Semi-automated scar detection in delayed enhanced cardiac magnetic resonance images
Authors: Morisi Rita , Donini Bruno , Lanconelli Nico , Rosengarden James , Morgan John , Harden Stephen , Curzen Nick
Published: May 2014

Late enhancement cardiac magnetic resonance images (MRI) has the ability to precisely delineate myocardial scars. We present a semi-automated method for detecting scars in cardiac MRI. This model has the potential to improve routine clinical practice since quantification is not currently offered due to time constraints. A first segmentation step was developed for extracting the target regions for potential scar and determining pre-candidate objects. Pattern recognition methods are then applied to the segmented images in order to detect the position of the myocardial scar. The database of late gadolinium enhancement (LE) cardiac MR images consists of 111 blocks of images acquired from 63 patients at the University Hospital Southampton NHS Foundation Trust (UK). At least one scar was present for each patient, and all the scars were manually annotated by an expert. A group of images (around one third of the entire set) was used for training the system which was subsequently tested on all the remaining images. Four different classifiers were trained (Support Vector Machine (SVM), k-nearest neighbor (KNN), Bayesian and feed-forward neural network) and their performance was evaluated by using Free response Receiver Operating Characteristic (FROC) analysis. Feature selection was implemented for analyzing the importance of the various features. The segmentation method proposed allowed the region affected by the scar to be extracted correctly in 96% of the blocks of images. The SVM was shown to be the best classifier for our task, and our system reached an overall sensitivity of 80% with less than 7 false positives per patient. The method we present provides an effective tool for detection of scars on cardiac MRI. This may be of value in clinical practice by permitting routine reporting of scar quantification.
Improved community model for social networks based on social mobility
Authors: Lu Zhe-Ming , Wu Zhen , Luo Hao , Wang Hao-Xian
Published: May 2014

This paper proposes an improved community model for social networks based on social mobility. The relationship between the group distribution and the community size is investigated in terms of communication rate and turnover rate. The degree distributions, clustering coefficients, average distances and diameters of networks are analyzed. Experimental results demonstrate that the proposed model possesses the small-world property and can reproduce social networks effectively and efficiently.
THE REAL EXCHANGE RATE DETERMINATION: EMPIRICAL EVIDENCE FROM MALAYSIA
Authors: TSEN WONG HOCK
Published: May 2014

This study examines the real exchange rate determination in Malaysia. The result of the autoregressive distributed lag approach shows that an increase in the real interest rate differential, productivity differential, the real oil price or reserve differential will lead to an appreciation of the real exchange rate in the long run. The real oil price and reserve differential are important in the real exchange rate determination. The dynamic ordinary least squares (DOLS) estimator shows about the same conclusion of the autoregressive distributed lag approach. The result of the generalized forecast error variance decomposition shows that the real interest rate differential, productivity differential, the real oil price and reserve differential are generally important to the real exchange rate determination.
The Borexino scintillator and solvent procurement
Authors: Giammarchi Marco
Published: May 2014

The Borexino experiment for solar neutrino physics and other rare phenomena requires an extremely low radioactive background to disentangle the very few events due to neutrino interactions. Therefore, the Borexino scintillator has to satisfy the most stringent radiopurity requirements, being about eight orders of magnitude less radioactive than an ordinary material. This was achieved by means of scintillator purification techniques and of a special care during all the production, handling and procurement of the scintillator solvent. This paper describes the methodology and the quality control procedures that were employed during the production, handling and shipping of the solvent.
Generic model for Cooper pair splitting
Authors: Soller Henning
Published: May 2014

A superconductor connected to normal leads allows to generate Einstein–Podolsky–Rosen pairs by Cooper pair splitting (CPS). It has been realized with quantum dots either defined in carbon nanotubes or InAs nanowires. After establishing the presence of CPS in such devices new works have investigated the effects of a finite potential difference between the quantum dots to improve and characterize the efficiency of CPS. In this paper, we present a generic model for CPS and develop two minimal models specifically for the two experimental realizations and compare them to the experimental data. In addition, we also explore the relation of nonlocal charge transfer to positive current cross-correlation of currents and discuss the temperature dependence of CPS.
A study on the microstructural and magnetic properties of the Sr0.70-xBaxLa0.30Fe11.78Cu0.22O19 hexagonal ferrites
Authors: Yang Yujie , Liu Xiansong
Published: May 2014

Hexagonal ferrite Sr 0.70-x Ba x La 0.30 Fe 11.78 Cu 0.22 O 19 (0 ≤ x ≤0.7) magnetic powders and magnets were synthesized by the ceramic process. The phase compositions of the magnetic powders were investigated by X-ray diffraction. There is a single magnetoplumbite phase in the magnetic powders with barium content (x) from 0 to 0.70. The micrographs of the magnets were observed by a field emission scanning electron microscopy. All magnets have formed hexagonal structures and the particles are distributed evenly. Magnetic properties of the magnets were measured by a magnetic properties test instrument. The remanence, intrinsic coercivity, magnetic induction coercivity and maximum energy product of the magnets continuously decrease with the increase of barium content (x).
A wide-angle dual-band polarization-sensitive absorber with a multilayer grating
Authors: Liao Yan-Lin , Zhao Yan
Published: May 2014

In this paper, a wide-angle polarization-sensitive dual-band absorber at infrared wavelengths with a multilayer grating is reported. The simulation results show that the absorber has two absorption peaks at wavelengths λ = 1.365 μ m and λ = 3.035 μ m with the absorption magnitudes more than 0.97 and 0.99 for TM polarization (electric field perpendicular to the strips), respectively. And this absorber reflects almost all TE polarization (electric field parallel to the strips) light. The dual-band absorption peaks can be tuned by varying the width of the strips, and the absorption magnitudes are more than 0.9 for the dual-band absorption peaks for angles up to 70°.
Realizing exterior Cromwell moves on rectangular diagrams by Reidemeister moves
Authors: Ando Tatsuo , Hayashi Chuichiro , Nishikawa Yuki
Published: May 2014

If a rectangular diagram represents the trivial knot, then it can be deformed into the trivial rectangular diagram with only four edges by a finite sequence of merge operations and exchange operations, without increasing the number of edges, which was shown by Dynnikov in [Arc-presentations of links: Monotone simplification, Fund. Math. 190 (2006) 29–76; Recognition algorithms in knot theory, Uspekhi Mat. Nauk 58 (2003) 45–92. Translation in Russian Math. Surveys 58 (2003) 1093–1139]. Using this, Henrich and Kauffman gave in [Unknotting unknots, preprint (2011), arXiv:1006.4176v4 [math.GT]] an upper bound for the number of Reidemeister moves needed for unknotting a knot diagram of the trivial knot. However, exchange or merge moves on the top and bottom pairs of edges of rectangular diagrams are not considered in [Unknotting unknots, preprint (2011), arXiv:1006.4176v4 [math.GT]]. In this paper, we show that there is a rectangular diagram of the trivial knot which needs such an exchange move for being unknotted, and study upper bound of the number of Reidemeister moves needed for realizing such an exchange or merge move.
Recursion formulas for HOMFLY and Kauffman invariants
Authors: Chen Qingtao , Reshetikhin Nicolai
Published: May 2014

In this paper, we describe the recursion relations between two parameter HOMFLY and Kauffman polynomials of framed links. These relations correspond to embeddings of quantized universal enveloping algebras. The relation corresponding to embeddings gn ⊃ gk × sln-k where gn is either so2n+1, so2n or sp2n is new.
WRIST ARTHROPLASTY: WHERE DO WE STAND TODAY? A REVIEW OF HISTORIC AND CONTEMPORARY DESIGNS
Authors: Reigstad Ole , Røkkum Magne
Published: May 2014

Earlier generations of wrist arthroplasty were limited to low demand patients. Bone fixation problems, excessive wear, and adverse designs resulting in loosening, imbalance, and dislocation led to the withdrawal of a number of models. Contemporary wrist prostheses aim at replacing wrist arthrodesis in the majority of patients with radiocarpal destruction, including high demand cases. Contraindications are wrist imbalance, insufficient soft tissue, or bone stock and infection. Various designs, fixation principles, bearing materials, and articulations have been employed. Some of the devises (RE-MOTIONTM, Motec®) demonstrate promising short- to midterm results, and calls for cautious optimism.
RESOURCE UTILISATION ASSOCIATED WITH SINGLE DIGIT DUPUYTREN'S CONTRACTURE TREATED WITH EITHER SURGERY OR INJECTION OF COLLAGENASE CLOSTRIDIUM HISTOLYTICUM
Authors: Povlsen Bo , Shields Adrian M. , Bhabra Gev S.
Published: May 2014

The gold standard treatment for Dupuytren's contracture is surgical excision of the cord. A non-surgical treatment with collagenase clostridium histolyticum injection is available but appears costly.

Objectives: To provide data on resource consumption related to surgical and non-surgical treatment for Dupuytren's contracture.

Design and Participants: Twenty patients with a single digit Dupuytren's contracture, 10 treated with surgical excision, and 10 treated with a single injection of collagenase.

Measurements: Minutes spent in theatre, number of follow-up appointments, time to skin healing, and patients return to normal activities of daily living.

Results: The injection group was significantly better regarding theatre time (p < 0.0001), follow-up appointments (p = 0.048), skin healing time (p < 0.001), and return to normal activities of daily living (p = 0.02) than the operated group.

Conclusions: There are significant personal and health economic differences between the two methods of treatment which may influence local choice.
A 20-YEAR ANALYSIS OF HAND AND WRIST RESEARCH PRODUCTIVITY IN ASIA
Authors: Bae Gordon H. , Daly Michael C. , Li Richard , Park David J. , Day Charles S.
Published: May 2014

Bibliometric analyses of the hand and wrist research have previously shown a significant increase in research productivity in Asia. We examined the key contributors to this change by performing bibliometric analyses regarding hand and wrist research in all Asian countries producing significant research. Original research articles from 1988 to 2007 were collected from seven English language journals based on the impact factor. Trends in research productivity were determined by country using linear regression analysis. Compared to the rest of the world, Asia produced fewer level I and basic studies, but more level IV studies. Significant increase in both research volume and productivity in Asia was observed, with Japan, Korea, and Taiwan having the highest aggregate productivity in hand and wrist research. From 1988 to 2007, the relative research production among Asian countries showed significant change, in contrary to that of Europe, Latin American, and the United States.
SAUVÉ-KAPANDJI PROCEDURE IN A PATIENT WITH WRIST DISARTICULATION: CASE REPORT
Authors: Gong Hyun Sik , Chung Myung Ki , Baek Goo Hyun
Published: May 2014

The advantage of preserving the distal radioulnar joint in wrist disarticulation is that full forearm rotation is possible if the joint is intact, which improves the capability of the amputee. The Sauvé-Kapandji procedure has been performed to treat rheumatoid or post-traumatic chronic instability and/or arthritis of the distal radioulnar joint. We report a patient with wrist disarticulation that presented to us with limited supination of the wrist due to an injured distal radioulnar joint. We performed the Sauvé-Kapandji procedure, and the patient could regain functional supination of the forearm without losing the ulnar styloid flare that improved prosthetic suspension. This case suggests that the Sauvé-Kapandji procedure can be performed to maintain the advantage of wrist disarticulation even when the initial trauma involves an irreparable injury of the distal radioulnar joint.
A CASE REPORT OF TRIGGER WRIST ASSOCIATED WITH CARPAL TUNNEL SYNDROME CAUSED BY AN INTRAMUSCULAR LIPOMA
Authors: Berlund Paul , Kalamaras Michael
Published: May 2014

Triggering at the wrist with finger movement is an uncommon presentation. We present the case of a 46 year old male with painful wrist triggering with associated carpal tunnel syndrome caused by an intramuscular lipoma of the lumbrical muscle. As far as we are aware this is only the second documented case of wrist triggering caused by an intramuscular limpoma. Surgical removal of the tumour led to a resolution of the patients symptoms. We review the literature and discuss other published cases of this rare presentation.
A CASE OF RECURRING MULTIFOCAL GIANT CELL TUMOUR OF THE TENDON SHEATH IN A CHILD
Authors: Byrne Miriam , Chan Jeffrey C. Y. , Kelly John L.
Published: May 2014

Giant cell tumour of the tendon sheath is rare in children. We present an unusual case of a recurring multifocal giant cell tumour of the tendon sheath in the hand and wrist of an 11-year-old boy. We are not aware of any similar report in the literature.
MYCOBACTERIUM KANASIIFLEXOR TENOSYNOVITIS OF THE FINGER
Authors: Jing S. S. , Teare L. , Iwuagwu F.
Published: May 2014

We report an extreme case of Mycobacterium kanasii flexor tenosynovitis with flexor tendon rupture in a healthy 65-year-old left-hand dominant Caucasian housewife.

This case highlights the diagnostic conundrum of atypical mycobacteria infections due to their insidious presentation, the need for a high index of suspicion to prevent worsening or delaying the diagnosis from inappropriate steroid use and that these infections can occur in otherwise healthy individuals.
A NEW BUILDING BLOCK: COSTO-OSTEOCHONDRAL GRAFT FOR INTRA-ARTICULAR INCONGRUITY AFTER DISTAL RADIUS FRACTURE
Authors: Tang Chris Yuk Kwan , Fung Boris , Poon T. L. , Fok Margaret
Published: May 2014

Even with the invention of locking plates, intra-articular fractures of distal radius with extreme comminution remain a challenge for orthopaedic surgeons. Osteochondral graft is a potential choice to reconstruct the articular defect. We report a patient who had a fracture of distal radius with costo-osteochondral graft for articular reconstruction which has not yet been described in the English literature. At nine-year follow-up, he was pain free and had full range of movement of the wrist. The authors suggest that costo-osteochondral graft could be an option with satisfactory result.
SURGICAL TIPS TO OPTIMIZE DIGITAL FLEXOR SHEATH WASHOUT
Authors: Nikkhah Dariush , Barabas Tony
Published: May 2014

Flexor sheath infection is a hand surgery emergency, and emergent washout is the accepted practice to prevent digital amputation. The authors describe surgical steps to optimize flexor sheath irrigation.
The Age Specific Incidence Anomaly Suggests that Cancers Originate During Development
Authors: Brody James P.
Published: May 2014

The accumulation of genetic alterations causes cancers. Since this accumulation takes time, the incidence of most cancers is thought to increase exponentially with age. However, careful measurements of the age-specific incidence show that the specific incidence for many forms of cancer rises with age to a maximum, and then decreases. This decrease in the age-specific incidence with age is an anomaly. Understanding this anomaly should lead to a better understanding of how tumors develop and grow. Here we derive the shape of the age-specific incidence, showing that it should follow the shape of a Weibull distribution. Measurements indicate that the age-specific incidence for colon cancer does indeed follow a Weibull distribution. This analysis leads to the interpretation that for colon cancer two subpopulations exist in the general population: a susceptible population and an immune population. Colon tumors will only occur in the susceptible population. This analysis is consistent with the developmental origins of disease hypothesis and generalizable to many other common forms of cancer.
Interaction between Record Matching and Data Repairing
Authors: Fan Wenfei , Ma Shuai , Tang Nan , Yu Wenyuan
Published: May 2014

Central to a data cleaning system are record matching and data repairing. Matching aims to identify tuples that refer to the same real-world object, and repairing is to make a database consistent by fixing errors in the data by using integrity constraints. These are typically treated as separate processes in current data cleaning systems, based on heuristic solutions. This article studies a new problem in connection with data cleaning, namely the interaction between record matching and data repairing. We show that repairing can effectively help us identify matches, and vice versa. To capture the interaction, we provide a uniform framework that seamlessly unifies repairing and matching operations to clean a database based on integrity constraints, matching rules, and master data. We give a full treatment of fundamental problems associated with data cleaning via matching and repairing, including the static analyses of constraints and rules taken together, and the complexity, termination, and determinism analyses of data cleaning. We show that these problems are hard, ranging from NP-complete or coNP-complete, to PSPACE-complete. Nevertheless, we propose efficient algorithms to clean data via both matching and repairing. The algorithms find
deterministic
fixes
and
reliable
fixes
based on confidence and entropy analyses, respectively, which are more accurate than fixes generated by heuristics. Heuristic fixes are produced only when deterministic or reliable fixes are unavailable. We experimentally verify that our techniques can significantly improve the accuracy of record matching and data repairing that are taken as separate processes, using real-life and synthetic data.
Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration
Authors: Grijalva James L. , Huizenga Megan , Mueller Kaly , Rodriguez Steven , Brazzo Joseph , Camargo Fernando , Sadri-Vakili Ghazaleh , Vakili Khashayar
Published: May 2014

The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liver-to-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.
CD8+ T lymphocyte response against extrahepatic biliary epithelium is activated by epitopes within NSP4 in experimental biliary atresia
Authors: Zheng Shuaiyu , Zhang Hongyi , Zhang Xiaojin , Peng Fei , Chen Xuyong , Yang Jixin , Brigstock David , Feng Jiexiong
Published: May 2014

Interferon (IFN)-γ-driven and CD8+ T cell-dependent inflammatory injury to extrahepatic biliary epithelium (EHBE) is likely to be involved in the development of biliary atresia (BA). We previously showed that viral protein NSP4 is the pathogenic immunogen that causes biliary injury in BA. In this study, NSP4 or four synthetic NSP4 (NSP4157–170, NSP4144–152, NSP493–110, NSP424–32) identified by computer analysis as candidate CD8+ T cell epitopes were injected into neonatal mice. The pathogenic NSP4 epitopes were confirmed by studying extrahepatic bile duct injury, IFN-γ release and CD8+ T cell response against EHBE. The results revealed, at 7 days postinjection, inoculation of glutathione S-transferase (GST)-NSP4 caused EHBE injury and BA in neonatal mice. At 7 or 14 days postinject, inoculation of GST-NSP4, NSP4144–152, or NSP4157–170 increased IFN-γ release by CD8+ T cells, elevated the population of hepatic memory CD8+ T cells, and augmented cytotoxicity of CD8+ T cells to rhesus rotavirus (RRV)-infected or naive EHBE cells. Furthermore, depletion of CD8+ T cells in mice abrogated the elevation of GST-NSP4-induced serum IFN-γ. Lastly, parenteral immunization of mouse dams with GST-NSP4, NSP4144–152, or NSP4157–170 decreased the incidence of RRV-induced BA in their offspring. Overall, this study reports the CD8+ T cell response against EHBE is activated by epitopes within rotavirus NSP4 in experimental BA. Neonatal passive immunization by maternal vaccination against NSP4144–152 or NSP4157–170 is effective in protecting neonates from developing RRV-related BA.
Timing and magnitude of systolic stretch affect myofilament activation and mechanical work
Authors: Tangney Jared R. , Campbell Stuart G. , McCulloch Andrew D. , Omens Jeffrey H.
Published: May 2014

Dyssynchronous activation of the heart leads to abnormal regional systolic stretch. In vivo studies have suggested that the timing of systolic stretch can affect regional tension and external work development. In the present study, we measured the direct effects of systolic stretch timing on the magnitude of tension and external work development in isolated murine right ventricular papillary muscles. A servomotor was used to impose precisely timed stretches relative to electrical activation while a force transducer measured force output and strain was monitored using a charge-couple device camera and topical markers. Stretches taking place during peak intracellular Ca2+ statistically increased peak tension up to 270%, whereas external work due to stretches in this interval reached values of 500 J/m. An experimental analysis showed that time-varying elastance overestimated peak tension by 100% for stretches occurring after peak isometric tension. The addition of the force-velocity relation explained some effects of stretches occurring before the peak of the Ca2+ transient but had no effect in later stretches. An estimate of transient deactivation was measured by performing quick stretches to dissociate cross-bridges. The timing of transient deactivation explained the remaining differences between the model and experiment. These results suggest that stretch near the start of cardiac tension development substantially increases twitch tension and mechanical work production, whereas late stretches decrease external work. While the increased work can mostly be explained by the time-varying elastance of cardiac muscle, the decreased work in muscles stretched after the peak of the Ca2+ transient is largely due to myofilament deactivation.
Direct measurement of cell-free DNA from serially collected capillary plasma during incremental exercise
Authors: Breitbach Sarah , Sterzing Björn , Magallanes Carlos , Tug Suzan , Simon Perikles
Published: May 2014

To investigate the kinetics of cell-free DNA (cfDNA) due to exercise, we established a direct real-time PCR for the quantification of cfDNA from unpurified capillary plasma by amplification of a 90- and a 222-bp multilocus L1PA2 sequence. Twenty-six male athletes performed an incremental treadmill test. For cfDNA measurement, capillary samples were collected serially from the fingertip preexercise, during, and several times postexercise. Venous blood was drawn before and immediately after exercise to compare capillary and venous cfDNA values. To elucidate the strongest association of cfDNA accumulations with either cardiorespiratory or metabolic function during exercise, capillary cfDNA values were correlated with standard measures like heart rate, oxygen consumption, or lactate concentrations. The venous cfDNA concentrations were significantly higher compared with the capillary plasma, but in both fractions cfDNA increased 9.8-fold and the values correlated significantly ( r = 0.796). During incremental treadmill running, the capillary cfDNA concentrations increased nearly parallel to the lactate values. The values correlated best with heart rate and energy expenditure, followed by oxygen consumption, Borg values, and lactate levels (0.710 ≤ r ≥ 0.808). With this article, we present a sensitive procedure for the direct quantification of cfDNA in unpurified capillary plasma instead of purified venous plasma. Further studies should investigate the differences between capillary and venous cfDNA that might mirror different physiological mechanisms. Enhanced cardiorespiratory function during exercise might lead to the accumulation of cfDNA via the release of stress hormones that already increase at intensities below the anaerobic threshold. Furthermore, cfDNA might be released by neutrophil extracellular traps.
Loss of LRIG1 Locus Increases Risk of Early and Late Relapse of Stage I/II Breast Cancer
Authors: Thompson Patricia A. , Ljuslinder Ingrid , Tsavachidis Spyros , Brewster Abenaa , Sahin Aysegul , Hedman Håkan , Henriksson Roger , Bondy Melissa L. , Melin Beatrice S.
Published: May 2014

Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32–2.73), relapse ≥ 5 years (HR, 2.39; 95% CI, 1.31–4.36), and death (HR, 1.55; 95% CI, 1.11–2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients. Cancer Res; 74(11); 2928–35. ©2014 AACR.
CBP-93872 Inhibits NBS1-Mediated ATR Activation, Abrogating Maintenance of the DNA Double-Strand Break–Specific G2 Checkpoint
Authors: Hirokawa Takahisa , Shiotani Bunsyo , Shimada Midori , Murata Kazuhiro , Johmura Yoshikazu , Haruta Mayumi , Tahara Hidetoshi , Takeyama Hiromitsu , Nakanishi Makoto
Published: May 2014

CBP-93872 was previously identified as a G2 checkpoint inhibitor using a cell-based high-throughput screening system. However, its molecular actions as well as cellular targets are largely unknown. Here, we uncovered the molecular mechanisms underlying abrogation of the G2 checkpoint by CBP-93872. CBP-93872 specifically abrogates the DNA double-stranded break (DSB)–induced G2 checkpoint through inhibiting maintenance but not initiation of G2 arrest because of specific inhibition of DSB-dependent ATR activation. Hence, ATR-dependent phosphorylation of Nbs1 and replication protein A 2 upon DSB was strongly suppressed in the presence of CBP-93872. CBP-93872 did not seem to inhibit DNA-end resection, but did inhibit Nbs1-dependent and ssDNA-induced ATR activation in vitro in a dose-dependent manner. Taken together, our results suggest that CBP-93872 is an inhibitor of maintenance of the DSB-specific G2 checkpoint and thus might be a strong candidate as the basis for a drug that specifically sensitizes p53-mutated cancer cells to DSB-inducing DNA damage therapy. Cancer Res; 74(14); 3880–9. ©2014 AACR.
Hyperpolarized [1-13C] Glutamate: A Metabolic Imaging Biomarker of IDH1 Mutational Status in Glioma
Authors: Chaumeil Myriam M. , Larson Peder E.Z. , Woods Sarah M. , Cai Larry , Eriksson Pia , Robinson Aaron E. , Lupo Janine M. , Vigneron Daniel B. , Nelson Sarah J. , Pieper Russell O. , Phillips Joanna J. , Ronen Sabrina M.
Published: May 2014

Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use 13C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-13C] α-KG to hyperpolarized [1-13C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-13C] α-KG, hyperpolarized [1-13C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-13C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-13C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-13C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production. Cancer Res; 74(16); 4247–57. ©2014 AACR.
Squamous Cell Carcinoma of the Oral Tongue in Young Non-Smokers Is Genomically Similar to Tumors in Older Smokers
Authors: Pickering Curtis R. , Zhang Jiexin , Neskey David M. , Zhao Mei , Jasser Samar A. , Wang Jiping , Ward Alexandra , Tsai C. Jillian , Ortega Alves Marcus V. , Zhou Jane H. , Drummond Jennifer , El-Naggar Adel K. , Gibbs Richard , Weinstein John N. , Wheeler David A. , Wang Jing , Frederick Mitchell J. , Myers Jeffrey N.
Published: May 2014

Purpose: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.

Experimental Design: DNA isolated from tongue tumors of young (<45 years, non-smokers) and old (>45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.

Results: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site–specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.

Conclusions: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood. Clin Cancer Res; 20(14); 3842–8. ©2014 AACR.
Skin Autofluorescence Associates With Vascular Calcification in Chronic Kidney Disease
Authors: Wang Angela Yee-Moon , Wong Chun-Kwok , Yau Yat-Yin , Wong Sharon , Chan Iris Hiu-Shuen , Lam Christopher Wai-Kei
Published: May 2014

Objective—

This study aims to evaluate the relationship between tissue advanced glycation end products, as reflected by skin autofluorescence, and vascular calcification in chronic kidney disease.

Approach and Results—

Three hundred patients with stage 3 to 5 chronic kidney disease underwent multislice computed tomography to estimate total coronary artery calcium score (CACS) and had tissue advanced glycation end product assessed using a skin autofluorescence reader. Intact parathyroid hormone (
P
<0.001) displaced estimated glomerular filtration rate as third most significant factor associated with skin autofluorescence after age (
P
<0.001) and diabetes mellitus (
P
<0.001) in multiple regression analysis. On univariate multinomial logistic regression analysis, every 1-U increase in skin autofluorescence was associated with a 7.43-fold (95% confidence intervals, 3.59–15.37;
P
<0.001) increased odds of having CACS ≥400 compared with those with zero CACS. Skin autofluorescence retained significance in predicting CACS ≥400 (odds ratio, 3.63; 95% confidence intervals, 1.44–9.18;
P
=0.006) when adjusting for age, sex, serum calcium, phosphate, albumin, C-reactive protein, lipids, blood pressure, estimated glomerular filtration rate, and intact parathyroid hormone but marginally lost significance when additionally adjusting for diabetes mellitus (odds ratio, 2.23; 95% confidence intervals, 0.81–6.14;
P
=0.1). Combination of diabetes mellitus and higher intact parathyroid hormone was associated with greater skin autofluorescence and CACS versus those without diabetes mellitus and having lower intact parathyroid hormone.

Conclusions—

Tissue advanced glycation end product, as reflected by skin autofluorescence, showed a significant novel association with vascular calcification in chronic kidney disease. These data suggest that increased tissue advanced glycation end product may contribute to vascular calcification in chronic kidney disease and diabetes mellitus and warrant further experimental investigation.
Genome-Scale Methods Converge on Key Mitochondrial Genes for the Survival of Human Cardiomyocytes in Hypoxia
Authors: Edwards Lindsay M. , Sigurdsson Martin I. , Robbins Peter A. , Weale Michael E. , Cavalleri Gianpiero L. , Montgomery Hugh E. , Thiele Ines
Published: May 2014

Background—

Any reduction in myocardial oxygen delivery relative to its demands can impair cardiac contractile performance. Understanding the mitochondrial metabolic response to hypoxia is key to understanding ischemia tolerance in the myocardium. We used a novel combination of 2 genome-scale methods to study key processes underlying human myocardial hypoxia tolerance. In particular, we hypothesized that computational modeling and evolution would identify similar genes as critical to human myocardial hypoxia tolerance.

Methods and Results—

We analyzed a reconstruction of the cardiac mitochondrial metabolic network using constraint-based methods, under conditions of simulated hypoxia. We used flux balance analysis, random sampling, and principal component analysis to explore feasible steady-state solutions. Hypoxia blunted maximal ATP (−17%) and heme (−75%) synthesis and shrank the feasible solution space. Tricarboxylic acid and urea cycle fluxes were also reduced in hypoxia, but phospholipid synthesis was increased. Using mathematical optimization methods, we identified reactions that would be critical to hypoxia tolerance in the human heart. We used data regarding single-nucleotide polymorphism frequency and distribution in the genomes of Tibetans (whose ancestors have resided in persistent high-altitude hypoxia for several millennia). Six reactions were identified by both methods as being critical to mitochondrial ATP production in hypoxia: phosphofructokinase, phosphoglucokinase, complex II, complex IV, aconitase, and fumarase.

Conclusions—

Mathematical optimization and evolution converged on similar genes as critical to human myocardial hypoxia tolerance. Our approach is unique and completely novel and demonstrates that genome-scale modeling and genomics can be used in tandem to provide new insights into cardiovascular genetics.
Ranolazine Effectively Suppresses Atrial Fibrillation in the Setting of Heart Failure
Authors: Burashnikov Alexander , Di Diego José M. , Barajas-Martínez Hector , Hu Dan , Cordeiro Jonathan M. , Moise N. Sydney , Kornreich Bruce G. , Belardinelli Luiz , Antzelevitch Charles
Published: May 2014

Background—

There is a critical need for safer and more effective pharmacological management of atrial fibrillation (AF) in the setting of heart failure (HF).

Methods and Results—

This study investigates the electrophysiological, antiarrhythmic, and proarrhythmic effects of a clinically relevant concentration of ranolazine (5 μmol/L) in coronary-perfused right atrial and left ventricular preparations isolated from the hearts of HF dogs. HF was induced by ventricular tachypacing (2–6 weeks at 200–240 beats per minute; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but significantly depressed sodium channel current–dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to the development of postrepolarization refractoriness, and an increase in diastolic threshold of excitation and atrial conduction time. Ranolazine did not significantly alter these parameters or promote arrhythmias in the ventricles. Ranolazine produced greater inhibition of peak sodium channel current in atrial cells isolated from HF versus normal dogs. A single premature beat reproducibly induced self-terminating AF in 10 of 17 atria. Ranolazine (5 μmol/L) suppressed induction of AF in 7 of 10 (70%) atria. In the remaining 3 atria, ranolazine reduced frequency and duration of AF.

Conclusions—

Our results demonstrate more potent suppression of AF by ranolazine in the setting of HF than previously demonstrated in nonfailing hearts and absence of ventricular proarrhythmia. The data suggest that ranolazine may be of benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF.
Reference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal Circulation at Term by Phase-Contrast Magnetic Resonance Imaging
Authors: Prsa Milan , Sun Liqun , van Amerom Joshua , Yoo Shi-Joon , Grosse-Wortmann Lars , Jaeggi Edgar , Macgowan Christopher , Seed Mike
Published: May 2014

Background—

Phase-contrast MRI with metric-optimized gating is a promising new technique for studying the distribution of the fetal circulation. However, mean and reference ranges for blood flow measurements made in the major fetal vessels using this technique are yet to be established.

Methods and Results—

We measured flow in the major vessels of the fetal circulation in 40 late-gestation normal human fetuses using phase-contrast MRI (mean gestational age, 37 [SD=1.1] weeks). Flows were indexed to the fetal weight, which was estimated from the fetal volume calculated by MRI segmentation. The following mean flows (in mL/min per kilogram; ±2SD) were obtained: combined ventricular output, 465 (351, 579); main pulmonary artery, 261 (169, 353); ascending aorta, 191 (121, 261); superior vena cava, 137 (77, 197); ductus arteriosus, 187 (109, 265); descending aorta, 252 (160, 344); pulmonary blood flow, 77 (0, 160); umbilical vein, 134 (62, 206); and foramen ovale, 135 (37, 233). Expressed as percentages of the combined ventricular output, the mean flows±2 SD were as follows: main pulmonary artery, 56 (44, 68); ascending aorta, 41 (29, 53); superior vena cava, 29 (15, 43); ductus arteriosus, 41 (25, 57); descending aorta, 55 (35, 75); pulmonary blood flow, 16 (0, 34); umbilical vein, 29 (11, 47); and foramen ovale, 29 (7, 51). A strong inverse relationship between foramen ovale shunt and pulmonary blood flow was noted (
r
=−0.64;
P
<0.0001).

Conclusions—

Although too small a sample size to provide normal ranges, these results are in keeping with those predicted in humans based on measurements made in fetal lambs using radioactive microspheres and provide preliminary reference ranges for the late-gestation human fetuses. The wide range we found in foramen ovale shunting suggests a degree of variability in the way blood is streamed through the fetal circulation.
Endoglin Deficiency Impairs Stroke Recovery
Authors: Shen Fanxia , Degos Vincent , Chu Pei-Lun , Han Zhenying , Westbroek Erick M. , Choi Eun-Jung , Marchuk Douglas , Kim Helen , Lawton Michael T. , Maze Mervyn , Young William L. , Su Hua
Published: May 2014

Background and Purpose—

Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery.

Methods—

Eng
heterozygous (
Eng

+/–

) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between
ENG
207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients.

Results—

After pMCAO,
Eng

+/–

mice showed larger infarct/atrophic volumes at all time points (
P
<0.05) and showed worse behavior performance (
P
<0.05) at 15, 30, and 60 days when compared with wild-type mice.
Eng

+/–

mice had fewer macrophages on day 3 (
P
=0.009) and more macrophages on day 60 (
P
=0.02) in the peri-infarct region. Although
Eng

+/–

and wild-type mice had similar numbers of pial collateral vessels before pMCAO,
Eng

+/–

mice had lower vascular density in the peri-infarct region (
P
=0.05) on day 60 after pMCAO. In humans,
ENG
207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation.

Conclusions—

Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.