bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma
Authors: Roller Devin G. , Axelrod Mark , Capaldo Brian J. , Jensen Karin , Mackey Aaron , Weber Michael J. , Gioeli Daniel
Published: September 2012

Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP–ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving extracellular signal–regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype. Mol Cancer Ther; 11(11); 2505–15. ©2012 AACR.
Intratumoral Molecular Heterogeneity in a BRAF-Mutant, BRAF Inhibitor-Resistant Melanoma: A Case Illustrating the Challenges for Personalized Medicine
Authors: Wilmott James S. , Tembe Varsha , Howle Julie R. , Sharma Raghwa , Thompson John F. , Rizos Helen , Lo Roger S. , Kefford Richard F. , Scolyer Richard A. , Long Georgina V.
Published: September 2012

Targeted therapies are increasingly being used to treat a variety of cancers. Their efficacy depends upon the accurate detection and targeting of a specific mutation or aberration in the tumor. All cancers, such as melanoma, are molecularly heterogeneous, with drug-resistant subclones present before the treatment or emerging as a result of targeted therapies. Here, we show intralesional molecular heterogeneity in a progressing V600E BRAF-mutant melanoma metastasis from a patient treated for 7 months with the BRAF inhibitor vemurafenib. In the single metastasis, two distinct subclones were observed, both V600E BRAF-mutant and only one with an additional G13R NRAS mutation. Molecular heterogeneity even at the intralesional level shows that personalizing or adjusting therapies based on genotyping of a portion of a single lesion may not accurately depict the molecular profile or drivers of oncogenesis across the entire patient's melanoma. Mol Cancer Ther; 11(12); 2704–8. ©2012 AACR.
Ceramide–Antiestrogen Nanoliposomal Combinations—Novel Impact of Hormonal Therapy in Hormone-Insensitive Breast Cancer
Authors: Morad Samy A.F. , Levin Jonathan C. , Shanmugavelandy Sriram S. , Kester Mark , Fabrias Gemma , Bedia Carmen , Cabot Myles C.
Published: September 2012

Although the sphingolipid ceramide exhibits potent tumor suppressor effects, efforts to harness this have been hampered by poor solubility, uptake, bioavailability, and metabolic conversion. Therefore, identification of avenues to improve efficacy is necessary for development of ceramide-based therapies. In this study, we used mutant p53, triple-negative breast cancer (TNBC) cells, a type of breast cancer highly refractory to treatment, and cell-permeable nanoliposomal C6-ceramide in conjunction with the antiestrogen tamoxifen, which has been shown to be an effective modulator of ceramide metabolism. We show for the first time that nanoliposomal tamoxifen enhances nanoliposomal C6-ceramide cytotoxicity in cultured TNBC cells, a response that was accompanied by induction of cell-cycle arrest at G1 and G2, caspase-dependent induction of DNA fragmentation, and enhanced mitochondrial and lysosomal membrane permeability at 18 and 2 hours, respectively. Tamoxifen metabolites were also effective. Only tamoxifen promoted lysosomal membrane permeability. In addition, we show for the first time that tamoxifen inhibits acid ceramidase, as measured in intact cell assays; this effect was irreversible. Together, our findings show that tamoxifen magnifies the antiproliferative effects of C6-ceramide via combined targeting of cell-cycle traverse and lysosomal and mitochondrial integrity. We adduce that C6-ceramide–induced apoptosis is amplified by tamoxifen's impact on lysosomes and perhaps accompanying inhibition of acid ceramidase, which could result in decreased levels of sphingosine 1-phosphate. This drug regimen could serve as a promising therapy for chemoresistant and triple-negative types of breast cancer, and thus represents an indication for tamoxifen, irrespective of estrogen receptor status. Mol Cancer Ther; 11(11); 2352–61. ©2012 AACR.
Aberrant Methylation of RASGRF1 Is Associated with an Epigenetic Field Defect and Increased Risk of Gastric Cancer
Authors: Takamaru Hiroyuki , Yamamoto Eiichiro , Suzuki Hiromu , Nojima Masanori , Maruyama Reo , Yamano Hiro-o , Yoshikawa Kenjiro , Kimura Tomoaki , Harada Taku , Ashida Masami , Suzuki Ryo , Yamamoto Hiroyuki , Kai Masahiro , Tokino Takashi , Sugai Tamotsu , Imai Kohzoh , Toyota Minoru , Shinomura Yasuhisa
Published: September 2012

Aberrant DNA methylation is implicated in the epigenetic field defect seen in gastric cancer. Our aim in this study was to identify predictive biomarkers by screening for DNA methylation in noncancerous background gastric mucosa from patients with gastric cancer. Using methylated-CpG island amplification coupled with CpG island microarray (MCAM) analysis, we identified 224 genes that were methylated in the noncancerous gastric mucosa of patients with gastric cancer. Among them, RASGRF1 methylation was significantly elevated in gastric mucosa from patients with either intestinal or diffuse type gastric cancer, as compared with mucosa from healthy individuals (8.3% vs. 22.4%, P < 0.001; 8.3% vs. 19.4%, P < 0.001). RASGRF1 methylation was independent of mucosal atrophy and could be used to distinguish both serum pepsinogen test-positive [sensitivity, 70.0%; specificity, 86.7%; area under the receiver operator characteristic (ROC) curve, AUC, 0.763] and -negative patients with gastric cancer (sensitivity, 72.2%; specificity, 87.0%; AUC, 0.844) from healthy individuals. Ectopic expression of RASGRF1 suppressed colony formation and Matrigel invasion by gastric cancer cells, suggesting it may be involved in gastric tumorigenesis. Collectively, our data suggest that RASGRF1 methylation is significantly involved in an epigenetic field defect in the stomach, and that it could be a useful biomarker to identify individuals at high risk for gastric cancer. Cancer Prev Res; 5(10); 1203–12. ©2012 AACR.
Intervening to Reduce the Future Burden of Occupational Cancer in Britain: What Could Work?
Authors: Hutchings Sally , Cherrie John W. , Van Tongeren Martie , Rushton Lesley
Published: September 2012

In Britain, 14 carcinogenic agents and occupational circumstances currently account for 86% of estimated occupation attributable cancer. The future burden associated with these carcinogens has been forecast, using attributable fractions for forecast scenarios representing patterns of past and predicted future exposure, and exposure levels representing the introduction of new occupational exposure limits, increased levels of compliance with these limits and other reductions in worker exposure. Without intervention, occupational attributable cancers are forecast to remain at more than 10,000 by 2060. With modest intervention over 2,600, or with stricter interventions more than 8,200 cancers could be avoided by 2060 although because of long latency no impact will be seen until at least 10 years after intervention. Effective interventions assessed in this study include reducing workplace exposure limits and improving compliance with these limits. Cancers associated with asbestos, diesel engine exhaust, polycyclic aromatic hydrocarbons, work as a painter, radon, and solar radiation are forecast to continue, with construction remaining the prime industry of concern. Although exposure levels to the established carcinogens are falling, workers are remaining exposed at low levels at which there is still a cancer risk, although the aging population also contributes to rising cancer numbers, These forecasts can be used to assess the relative costs to society of different occupational carcinogenic agents, and the relative merits and savings associated with alternative intervention strategies. The methods are adaptable for different data circumstances, other types of interventions and could be extended to environmental carcinogens and other chronic diseases. Cancer Prev Res; 5(10); 1213–22. ©2012 AACR.
Metabolic Profiling, a Noninvasive Approach for the Detection of Experimental Colorectal Neoplasia
Authors: Montrose David C. , Zhou Xi Kathy , Kopelovich Levy , Yantiss Rhonda K. , Karoly Edward D. , Subbaramaiah Kotha , Dannenberg Andrew J.
Published: September 2012

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Although noninvasive stool-based screening tests are used for the early detection of colorectal neoplasia, concerns have been raised about their sensitivity and specificity. A metabolomics-based approach provides a potential noninvasive strategy to identify biomarkers of colorectal carcinogenesis including premalignant adenomas. Our primary objective was to determine whether a distinct metabolic profile could be found in both feces and plasma during experimental colorectal carcinogenesis. Feces, plasma as well as tumor tissue and normal colorectal mucosa were obtained from A/J mice at several time points following administration of azoxymethane or saline. Ultra-performance liquid chromatography tandem mass spectroscopy and gas chromatography mass spectroscopy were used to quantify metabolites in each of these matrices. Here, we show that colorectal carcinogenesis was associated with significant metabolic alterations in both the feces and plasma, some of which overlap with metabolic changes in the tumor tissue. These consisted of 33 shared changes between feces and tumor, 14 shared changes between plasma and tumor, and 3 shared changes across all 3 matrices. For example, elevated levels of sarcosine were found in both tumor and feces whereas increased levels of 2-hydroxyglutarate were found in both tumor and plasma. Collectively, these results provide evidence that metabolomics can be used to detect changes in feces and plasma during azoxymethane-induced colorectal carcinogenesis and thus provide a strong rationale for future studies in humans. Cancer Prev Res; 5(12); 1358–67. ©2012 AACR.
Aspirin Use after a Prostate Cancer Diagnosis and Cancer Survival in a Prospective Cohort
Authors: Dhillon Preet K. , Kenfield Stacey A. , Stampfer Meir J. , Giovannucci Edward L. , Chan June M.
Published: September 2012

Experimental and clinical data suggest that aspirin and other nonsteroidal inflammatory drugs may delay the progression of prostate cancer through inhibition of the COX pathway and its effects on cellular proliferation, apoptosis, and angiogenesis. Epidemiologic data support a reduced risk of prostate cancer incidence with aspirin use, yet no evidence exists about whether aspirin after diagnosis influences progression or survival. We conducted a prospective study of 3,986 participants of the Health Professionals Follow-up Study, with a prostate cancer diagnosis between January 1, 1990, and December 31, 2005. We used Cox proportional hazards regression to evaluate the association between aspirin use after diagnosis and the development of metastases or fatal prostate cancer through January 31, 2008, adjusting for risk factors associated with incidence and mortality in this cohort, prediagnostic aspirin use, Gleason score, tumor–node–metastasis (TNM) stage, and primary treatment. In total, 265 men developed bony or other organ metastases or fatal prostate cancer during the 18 years of follow-up. We observed no association between updated aspirin use after diagnosis and lethal prostate cancer [tablets/week: <2: HR, 1.12; 95% confidence interval (CI), 0.72–1.72; 2–5: HR, 1.05; 95% CI, 0.62–1.80; ≥ 6: HR, 1.08; 95% CI, 0.76–1.54; Ptrend = 0.99]. The results remained unchanged when we examined aspirin use at baseline only (Ptrend = 0.70) or frequency of use (d/wk; Ptrend = 0.35) or limited the outcome to fatal prostate cancer (Ptrend = 0.63). There was no association between aspirin use after a prostate cancer diagnosis and lethal disease in this cohort of prostate cancer survivors. Cancer Prev Res; 5(10); 1223–8. ©2012 AACR.
Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
Authors: Ercan Dalia , Xu Chunxiao , Yanagita Masahiko , Monast Calixte S. , Pratilas Christine A. , Montero Joan , Butaney Mohit , Shimamura Takeshi , Sholl Lynette , Ivanova Elena V. , Tadi Madhavi , Rogers Andrew , Repellin Claire , Capelletti Marzia , Maertens Ophélia , Goetz Eva M. , Letai Anthony , Garraway Levi A. , Lazzara Matthew J. , Rosen Neal , Gray Nathanael S. , Wong Kwok-Kin , Jänne Pasi A.
Published: September 2012

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP–ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non–small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.

Significance: Our study identifies activated ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. Cancer Discov; 2(10); 934–47. ©2012 AACR.

Read the Commentary on this article by Blakely and Bivona, p. 872.

This article is highlighted in the In This Issue feature, p. 857.
Acceleration of Collateral Development by Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Expression on CD11b
+
/Gr-1
+
Myeloid Cells—Brief Report
Authors: Bickert Thomas , Marshall Robert Percy , Zhang Ziyang , Ludewig Peter , Binder Mascha , Klinke Anna , Rottbauer Wolfgang , Amling Michael , Wagener Christoph , Ito Wulf D. , Horst Andrea Kristina
Published: September 2012

Objective—

Previously, we demonstrated the relevance for endothelial carcinoembryonic antigen−related cell adhesion molecule 1 (CEACAM1) expression in collateral formation. However, a proarteriogenic role for CEACAM1
+
myeloid cells is unknown. Here, we investigated the contribution of CEACAM1
+
myeloid cells on collateral formation.

Methods and Results—

Collateral growth and vascular remodeling were analyzed in CEACAM1-competent and CEACAM1 null mice after femoral artery ligation in hindlimb ischemia. Reperfusion of the adductor muscles was evaluated by Laser Doppler measurements and microcomputed tomography imaging. In CEACAM1 null mice, poor reperfusion and reduced collateral formation were observed, accompanied by reduction in arterial diameters. Using flow cytometry, we identified an increase of the muscle-resident CD11b
+
/granulocyte receptor-1+ (Gr-1+) population in CEACAM1 null mice only, pointing toward a CEACAM1-dependent functional deviation. Direct and reciprocal bone marrow transplantations between CEACAM1-competent and CEACAM1 null mice, and antibody-mediated depletion of the CD11b
+
/Gr-1
+
population, confirmed the requirement of CEACAM1 expression on the CD11b
+
/Gr-1
+
population for reestablishment of perfusion after arterial occlusion.

Conclusion—

CEACAM1 expression on CD11b
+
/Gr-1
+
myeloid cells is a prerequisite for adequate collateral formation.
Macrophages Regulate Smooth Muscle Differentiation of Mesenchymal Stem Cells via a Prostaglandin F
2α
−Mediated Paracrine Mechanism
Authors: Lee Mi Jeong , Kim Min Young , Heo Soon Chul , Kwon Yang Woo , Kim Young Mi , Do Eun Kyoung , Park Ji Hye , Lee Jung Sub , Han Jin , Kim Jae Ho
Published: September 2012

Objective—

Mesenchymal stem cells are useful for vascular regeneration of injured tissues. Macrophages are involved in acute or chronic inflammatory diseases, and interleukin-1β (IL-1β), a proinflammatory cytokine, plays a key role in the activation of macrophages within injured tissues. To explore the role of macrophages on mesenchymal stem cell–mediated vascular regeneration, we examined the effects of IL-1β–activated macrophages on differentiation of human adipose tissue–derived mesenchymal stem cells (hASCs) to smooth muscle cells (SMCs) and the vascular regenerative capacity of the differentiated SMCs in a hindlimb ischemia animal model.

Methods and Results—

We demonstrate that IL-1β–conditioned medium from RAW 264.7 macrophages induces differentiation of human adipose tissue–derived mesenchymal stem cells to α-smooth muscle actin–positive SMCs, and the differentiated SMCs exhibited increased contractility in response to KCl and carbachol treatment. Transplantation of the differentiated SMCs attenuated severe hindlimb ischemia and promoted vascular regeneration. IL-1β treatment stimulated secretion of prostaglandin F
2α
from RAW 264.7 cells. Small interfering RNA–mediated silencing of the prostaglandin F
2α
receptor completely abrogated IL-1β conditioned medium–stimulated α-smooth muscle actin expression. Moreover, prostaglandin F
2α
treatment stimulated expression of α-smooth muscle actin in human adipose tissue–derived mesenchymal stem cells.

Conclusion—

These results suggest that IL-1β–activated macrophages promote differentiation of human adipose tissue–derived mesenchymal stem cells to SMCs through a prostaglandin F
2α
–mediated paracrine mechanism.
Endocardial Cushion Morphogenesis and Coronary Vessel Development Require Chicken Ovalbumin Upstream Promoter-Transcription Factor II
Authors: Lin Fu-Jung , You Li-Ru , Yu Cheng-Tai , Hsu Wen-Hsin , Tsai Ming-Jer , Tsai Sophia Y.
Published: September 2012

Objective—

Septal defects and coronary vessel anomalies are common congenital heart defects, yet their ontogeny and the underlying genetic mechanisms are not well understood. Here, we investigated the role of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII, NR2F2) in cardiac organogenesis.

Methods and Results—

We analyzed embryos deficient in
COUP-TFII
and observed a spectrum of cardiac defects, including atrioventricular septal defect, thin-walled myocardium, and abnormal coronary morphogenesis. We show by expression analysis that COUP-TFII is expressed in the endocardium and the epicardium but not in the myocardium of the ventricle. Using endothelial-specific
COUP-TFII
mutants and molecular approaches, we show that
COUP-TFII
deficiency resulted in endocardial cushion hypoplasia. This was attributed to the reduced growth and survival of atrioventricular cushion mesenchymal cells and defective epithelial-mesenchymal transformation (EMT) in the underlying endocardium. In addition, the endocardial EMT defect was accompanied by downregulation of
Snai1
, one of the master regulators of EMT, and upregulation of vascular endothelial-cadherin. Furthermore, we show that although COUP-TFII does not play a major role in the formation of epicardial cell cysts, it is critically important for the formation of epicardium. Ablation of COUP-TFII impairs epicardial EMT and coronary plexus formation.

Conclusion—

Our results reveal that COUP-TFII plays cell-autonomous roles in the endocardium and the epicardium for endocardial and epicardial EMT, which are required for proper valve and coronary vessel formation during heart development.
Translational Success Stories
Authors: Coppens Michiel , Eikelboom John W. , Gustafsson David , Weitz Jeffrey I. , Hirsh Jack
Published: September 2012

Anticoagulants are the cornerstone of therapy for conditions associated with arterial and venous thrombosis. Direct thrombin inhibitors (DTIs) are anticoagulants that bind to thrombin and block its enzymatic activity. The bivalent parenteral DTIs hirudin and bivalirudin were based on the observation that the salivary extracts of medicinal leeches prevented blood from clotting. Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.
Serious Cardiac Arrhythmias After Stroke
Authors: Kallmünzer Bernd , Breuer Lorenz , Kahl Nicolas , Bobinger Tobias , Raaz-Schrauder Dorette , Huttner Hagen Bernhard , Schwab Stefan , Köhrmann Martin
Published: September 2012

Background and Purpose—

Patients with acute cerebrovascular events are susceptible to serious cardiac arrhythmias, but data on the time course and the determinants of their onset are scarce.

Methods—

The prospective Stroke-Arrhythmia-Monitoring-Database (SAMBA) assessed cardiac arrhythmias with need for urgent evaluation and treatment in 501 acute neurovascular patients during the first 72 hours after admission to a monitored stroke unit. Arrhythmias were systematically detected by structured processing of telemetric data. Time of arrhythmia onset and predisposing factors were investigated.

Results—

Significant cardiac arrhythmias occurred in 25.1% of all patients. Incidence was highest during the first 24 hours after admission. Serious arrhythmic tachycardia (ventricular or supraventricular >130 beats/min) was more frequent than bradycardic arrhythmia (sinus-node dysfunction, bradyarrhythmia, or atrioventricular block °II and °III). Arrhythmias were independently associated with higher age and severer neurological deficits as measured by the National Institutes of Health Stroke Scale on admission.

Conclusions—

The risk for significant cardiac arrhythmia after an acute cerebrovascular event is highest during the first 24 hours of care and declines with time during the first 3 days. Along with established vascular risk factors, the National Institutes of Health Stroke Scale may be considered for a stratified allocation of monitoring capabilities.

Clinical Trial Registration—

URL:
www.clinicaltrials.gov
. Unique identifier: NCT01177748.
Antegrade Flow Across Incomplete Vessel Occlusions Can Be Distinguished From Retrograde Collateral Flow Using 4-Dimensional Computed Tomographic Angiography
Authors: Frölich Andreas M.J. , Psychogios Marios N. , Klotz Ernst , Schramm Ramona , Knauth Michael , Schramm Peter
Published: September 2012

Background and Purpose—

In acute stroke patients with intracranial vessel occlusion, angiographic demonstration of antegrade contrast opacification distal to the occlusion site (termed the “clot outline sign”) has been associated with higher rates of vessel recanalization. We sought to determine whether antegrade flow can be demonstrated on timeresolved 4-dimensional computed tomographic angiography (4-dimensional CTA), whether it can be distinguished from retrograde collateral flow, and if it can be used to predict early recanalization.

Methods—

Fiftyseven acute stroke patients with intracranial anterior circulation vessel occlusion were retrospectively identified. All patients had received a multimodal computed tomography examination including thinsection 4-dimensional CTA and subsequent digital subtraction angiography as part of an endovascular procedure. Pretreatment 4-dimensional CTA and singlephase CTA were assessed for presence of antegrade contrast opacification distal to the occlusion site. Digital subtraction angiograms were reviewed for preintervention Thrombolysis in Cerebral Infarction grade, presence of the clot outline sign, as well as postintervention Thrombolysis in Cerebral Infarction grade.

Results—

On 4-dimensional CTA, evidence of antegrade flow was present in 11 of 57 cases (19.3%). Compared with angiography, 4-dimensional CTA predicted antegrade flow with 100% sensitivity and 97.9% specificity. Singlephase CTA offered 40% sensitivity and 87.2% specificity. Early recanalization occurred in 3 patients (6.5%) after intravenous thrombolysis (n=46); all demonstrated antegrade flow on 4-dimensional CTA.

Conclusions—

Using 4-dimensional CTA, it is possible to noninvasively distinguish antegrade flow across a cerebral artery occlusion from retrograde collateral flow. Presence of antegrade flow on 4-dimensional CTA is associated with an increased chance of early vessel recanalization.
Features of Acute Ischemic Stroke With Rheumatic Heart Disease in a Hospitalized Chinese Population
Authors: Wang Deren , Liu Ming , Hao Zilong , Tao Wendan , Lin Sen , Zhang Shihong , Wu Bo , Ma Zhenxing , Dong Wei
Published: September 2012

Background and Purpose—

Rheumatic heart disease (RHD) is an important risk factor for ischemic stroke in developing countries. Observational data on its characteristics and influence on outcome or recurrence of ischemic stroke are scarce. We aimed to investigate proportions, characteristics, functional outcome, and recurrence of acute ischemic stroke patients with RHD in a hospitalized Chinese population.

Methods—

We prospectively enrolled consecutive patients with acute ischemic stroke who were admitted within 1 month of stroke onset from January 2003 to February 2007, into the analysis. Clinical characteristics such as age, gender, risk factors, and National Institutes of Health Stroke Scale on admission were investigated. Basic characteristics, functional outcomes, and recurrence were compared between RHD group and nonRHD group.

Results—

Of the 1638 cases included, RHD was present in 130 patients (7.9%). RHD patients, compared with those without RHD, were younger, more frequently female, and more often had experienced atrial fibrillation and higher National Institutes of Health Stroke Scale score on admission (all
P
<0.006). After adjustment for age, sex, and National Institutes of Health Stroke Scale on admission, the death risk in patients with RHD was 2.0-fold higher at 3 months, 6 months, and 1 year compared with patients without RHD (all
P
<0.013). Compared with patients without RHD, those with RHD showed a significantly higher cumulative recurrence rate (13.6% vs 6.0%;
P
=0.001, log rank test) by 1-year cumulative recurrent curves.

Conclusions—

Stroke attributable to RHD is still common in the Chinese population. RHD was associated with 2-fold increased risk of death and 1-fold increased risk of recurrence in stroke patients.
Role of Uniforms in the Body Image of Female College Volleyball Players
Authors: Steinfeldt Jesse A. , Zakrajsek Rebecca A. , Bodey Kimberly J. , Middendorf Katharine G. , Martin Scott B.
Published: September 2012

Female student athletes often desire a muscular body to be successful in sport, but this body type does not conform to traditional cultural norms of femininity. In this study, the authors qualitatively examined the experiences of female intercollegiate volleyball players to better understand their beliefs about their bodies—both as athletes and as women outside of sport—in addition to whether perceptions about their revealing sports uniforms were related to body image. Results indicated that body image among female student athletes is a multidimensional construct. Participants reported conflicting messages about their bodies in regard to how they look on the court and how they are supposed to look off the court. In addition, results suggested that revealing uniforms contributed to decreased body esteem, and these uniforms also distracted players and impacted on-court performance. Results are interpreted within the framework of objectification theory, and implications for psychologists working with female student athletes are provided.
The Effect of Proximity, Tall Man Lettering, and Time Pressure on Accurate Visual Perception of Drug Names
Authors: Irwin Amy , Mearns Kathryn , Watson Margaret , Urquhart Jim
Published: September 2012

Objective:

The aim of this study is to assess the effect of proximity and time pressure on accurate and effective visual search during medication selection from a computer screen.

Background:

The presence of multiple similar objects in proximity to a target object increases the difficulty of a visual search. Visual similarity between drug names can also lead to selection error. The proximity of several similarly named drugs within a visual field could, therefore, adversely affect visual search.

Method:

In Study 1, 60 nonpharmacy participants selected a target drug name from an array of mock drug packets shown on a computer screen, where one or four similarly named nontargets might be present. Of the participants, 30 completed the task with a time constraint, and the remainder did not. In Study 2, the same experiment was repeated with 28 pharmacy staff.

Results:

In Study 1, the proximity of multiple similarly named nontargets within the specified visual field reduced selection accuracy and increased reaction times in the nonpharmacists. Time constraint also had an adverse effect. In Study 2, the pharmacy participants showed increased reaction times when multiple nontargets were present, but the time constraint had no effect. There was no effect of Tall Man lettering.

Conclusion:

The presence of multiple similarly named medications in close proximity to a target medication increases the difficulty of the visual search for the target. Tall Man lettering has no impact on this adverse effect.

Application:

The widespread use of the alphabetical system in medication storage increases the risk of proximity-based errors in drug selection.
Market Orientation as a Strategy for the Rural Tourism Sector
Authors: Polo Peña Ana Isabel , Frías Jamilena Dolores María , Rodríguez Molina Miguel Ángel
Published: September 2012

The aim of the present work is to ascertain the importance of market orientation as a business strategy within the rural tourism sector. To this end, we took a business-to-customer (B2C) perspective. First, the adoption of market orientation was measured from the firm’s point of view. Second, tourist perceptions were analyzed using two variables, perceived value and behavioral intentions. The sample consisted of 100 rural tourism enterprises and 572 of their customers. The findings reveal that the market orientation undertaken by the firm has a direct effect on its outcomes (its financial results, the improvements to the rural destination, and the more personal, intangible impact on the owner-manager) and on perceived value; and that perceived value has a direct effect on consumers’ behavioral intentions toward the firm.
Health Blogging
Authors: Rains Stephen A. , Keating David M.
Published: September 2012

The reported study explored the implications of making public, written disclosures about illness-related experiences in the context of health blogging. The outcomes associated with specific forms of expression used by bloggers and their readers were investigated. A panel study was conducted among 72 individuals who live with and blog about their experiences with a specific health condition. The results, although modest, show that elements of health blogging are associated with improvements in bloggers’ well-being. Bloggers’ use of insight words was associated with decreased health-related uncertainty and, among bloggers who posted relatively more frequently, increased purpose in life. Additionally, for those bloggers whose readers commented more frequently, readers’ use of negative emotion words was associated with increased perceptions of personal growth among bloggers.
“Pirates of Our Spirituality”
Authors: Bell Elizabeth R.
Published: September 2012

Maya spirituality serves as a locus of enunciation for the ongoing negotiation between local expressive culture and a changing globalized society. In recent years the Mayas of Guatemala have subversively used the global market provided by tourism to survive economically, recover their cultural property, and reclaim their heritage. Lacking voice and representation in an environment that has historically threatened their way of life, they assert their heritage in order to valorize their culture. They employ public knowledge and experience of natural disasters to demonstrate not just the accuracy of the 2012 prophecies of change at the end of the Maya calendar’s long count, but also the value of the knowledge systems that produced them.

La espiritualidad maya sirve como un lugar de enunciación de la negociación en curso entre la cultura local expresiva y la sociedad cambiante y globalizada. En los últimos años los mayas de Guatemala han utilizado subversivamente el mercado global provisto por el turismo para sobrevivir económicamente, recuperar su patrimonio cultural, y recuperar su patrimonio. Careciendo de voz y representación en un ambiente que históricamente ha amenazado su modo de vida, han afirmado su patrimonio con el fin de valorar su cultura. Ellos emplean el conocimiento público y la experiencia de los desastres naturales para demostrar no sólo la exactitud de las profecías del 2012 del cambio al final de la cuenta larga del calendario maya, sino también el valor de los sistemas de conocimiento que los produjo.
Gender Mainstreaming in European Union Development Policy toward Latin America
Authors: Debusscher Petra
Published: September 2012

An examination of gender mainstreaming in the Latin American development policy of the European Union through quantitative and qualitative analysis of policy programming documents suggests that the transformative potential of this approach has been neglected. The language used in the documents is more the typical “Women in Development” language than one that reflects the inclusion of both women and men in the planning for the achievement of gender equality. Exclusion of women’s organizations from the drafting process and the gap between civil society’s and the European Union’s framings of gender (in)equality in Latin America may be responsible for this situation.

Un análisis de gender mainstreaming en la política de desarrollo de América Latina de la Unión Europea basado en el análisis cuantitativo y cualitativo de los documentos de programación de la política sugiere que el potencial transformador de este enfoque ha sido abandonado. El lenguaje utilizado en los documentos es más típico del lenguaje de “Mujeres en Desarrollo” que uno que aspira a la inclusión de mujeres y hombres en la planificación para el logro de la igualdad de género. La exclusión de las organizaciones de mujeres en el proceso de redacción y la brecha entre los encuadros de la sociedad civil y de la Unión Europea de la (des) igualdad en América Latina pueden ser responsables por esta situación.
Random error modelling and compensation of accelerometer in airborne remote sensing stabilized platform
Authors: Zhang Yanshun , Du Chaochao , Mu Quanqi
Published: September 2012

This paper studies the impact of the accelerometer output error on the levelling accuracy in levelling mode of the airborne remote sensing stabilized platform. On the basis that the accelerometer output signal is non-stationary, a non-stationary time series model of ARIMA(3,0,1) is established, with which an adaptive Kalman filter is designed. In the Kalman filter, an online correction method for the forgetting factor based on real-time measurements is presented, achieving the automatic adjustment of the Kalman filter gain. The model of the accelerometer and the adaptive Kalman filter are applied to the airborne remote sensing stabilized platform principle prototype made by our research group. On one hand, the results show that the model is fit for the accelerometer. On the other hand, it is noted that the new filter has improved the measurement accuracy of the accelerometer, depressed the oscillations of the levelling progress of the platform and reduced the steady-state error of the platform. The levelling performance of the stabilized platform is efficiently improved after all these work.
Resource-Based Perspectives on Unit-Level Human Capital
Authors: Nyberg Anthony J. , Moliterno Thomas P. , Hale Donald , Lepak David P.
Published: September 2012

Scholarly interest in leveraging resource-based theory to explore the unit-level human capital resource (HCR) is undergoing a paradigmatic shift in the strategy and strategic human resource management (HRM) literatures. As they undertake this next generation of research, scholars will be informed by a rigorous examination of prior unit-level HCR research. To this end, we present a systematic and multidisciplinary review of scholarship that invokes resource-based theorizing in examining the unit’s HCR. We reviewed 156 articles published in the strategy and strategic HRM literatures that conceptualize HC as a unit-level resource. This review suggests that a multidimensional typology of the unit-level HCR has emerged. In particular, research has examined the HCR’s type, context, and antecedents. We build on our review of this multidimensional typology to propose a multilevel conceptual integration of current and future unit-level HCR research in the strategy and strategic HRM domains. Current scholarly work in these two areas suggests that these two literatures are converging, and the multidimensional HCR typology suggested by our review informs this convergence. We conclude with a discussion of future research domains that will advance the multilevel theoretical integration we propose.
Child Abuse Physicians
Authors: Flaherty Emalee G. , Schwartz Kimberly , Jones Rise D. , Sege Robert D.
Published: September 2012

This article explores how child abuse physicians (CAPs) experience the unique challenges of the emerging field of child abuse pediatrics. Practicing CAPs completed a written survey about known challenges in their field. Fifty-six CAPs completed the written survey and reported experiencing many negative consequences including: threats to their personal safety (52%), formal complaints to supervisors (50%) and licensing bodies (13%), negative stories in the media (23%), and malpractice suits (16%). A purposeful sample of CAPs participated in telephone interviews about these challenges. The 19 physicians who were interviewed described the challenges, while they spontaneously expressed satisfaction with their career and described some strategies for coping with the stresses of child abuse pediatrics. The findings highlight the stressors and challenges that may affect the ability to maintain an adequate CAP workforce. Better understanding of the challenges should help prepare physicians to practice this subspecialty.
Mirror therapy for patients with severe arm paresis after stroke – a randomized controlled trial
Authors: Thieme Holm , Bayn Maria , Wurg Marco , Zange Christian , Pohl Marcus , Behrens Johann
Published: September 2012

Objective:

To evaluate the effects of individual or group mirror therapy on sensorimotor function, activities of daily living, quality of life and visuospatial neglect in patients with a severe arm paresis after stroke.

Design:

Randomized controlled trial.

Setting:

Inpatient rehabilitation centre.

Subject:

Sixty patients with a severe paresis of the arm within three months after stroke.

Interventions:

Three groups: (1) individual mirror therapy, (2) group mirror therapy and (3) control intervention with restricted view on the affected arm.

Main measures:

Motor function on impairment (Fugl-Meyer Test) and activity level (Action Research Arm Test), independence in activities of daily living (Barthel Index), quality of life (Stroke Impact Scale) and visuospatial neglect (Star Cancellation Test).

Results:

After five weeks, no significant group differences for motor function were found ( P > 0.05). Pre–post differences for the Action Research Arm Test and Fugl-Meyer Test: individual mirror therapy: 3.4 (7.1) and 3.2 (3.8), group mirror therapy: 1.1 (3.1) and 5.1 (10.0) and control therapy: 2.8 (6.7) and 5.2 (8.7). However, a significant effect on visuospatial neglect for patients in the individual mirror therapy compared to control group could be shown ( P < 0.01). Furthermore, it was possible to integrate a mirror therapy group intervention for severely affected patients after stroke.

Conclusion:

This study showed no effect on sensorimotor function of the arm, activities of daily living and quality of life of mirror therapy compared to a control intervention after stroke. However, a positive effect on visuospatial neglect was indicated.
Validity of the Nintendo Wii® balance board for the assessment of standing balance in Parkinson’s disease
Authors: Holmes Jeffrey D , Jenkins Mary E , Johnson Andrew M , Hunt Michael A , Clark Ross A
Published: September 2012

Background:

Impaired postural stability places individuals with Parkinson’s at an increased risk for falls. Given the high incidence of fall-related injuries within this population, ongoing assessment of postural stability is important.

Objective:

To evaluate the validity of the Nintendo Wii® balance board as a measurement tool for the assessment of postural stability in individuals with Parkinson’s.

Subjects:

Twenty individuals with Parkinson’s participated.

Intervention:

Subjects completed testing on two balance tasks with eyes open and closed on a Wii® balance board and biomechanical force platform.

Main Measures:

Bland–Altman plots and a two-way, random-effects, single measure intraclass correlation coefficient model were used to assess concurrent validity of centre-of-pressure data.

Results:

Concurrent validity was demonstrated to be excellent across balance tasks (intraclass correlation coefficients = 0.96, 0.98, 0.92, 0.94).

Conclusions:

This study suggests that the Wii® balance board is a valid tool for the quantification of postural stability among individuals with Parkinson’s.
A randomized controlled trial on the efficacy of intermittent and continuous traction for patients with knee osteoarthritis
Authors: Alpayci Mahmut , Ozkan Yasemin , Yazmalar Levent , Hiz Ozcan , Ediz Levent
Published: September 2012

Objective:

To investigate the efficacy of intermittent and continuous traction in the treatment of knee osteoarthritis.

Design:

A randomized, controlled, observer-blind seven-week trial.

Setting:

Hospital-based outpatient practice.

Subjects:

Ninety-eight patients with stage 3 knee osteoarthritis according to Kellgren–Lawrence radiological rating scale.

Interventions:

All 98 patients were randomly assigned to three treatment groups, for three weeks (weekends excluded). The control group ( n=30, mean age: 59.30±8.16) received hot pack and short wave diathermy; the intermittent group ( n=30, mean age: 58.20±7.78) received hot pack, short wave diathermy and intermittent traction; and the continuous group ( n=30, mean age: 57.97±9.53) received hot pack, short wave diathermy and continuous traction.

Outcome measurements:

The values of the Turkish version of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale, and knee passive range of motion were measured at baseline, three-week and seven-week follow-up.

Results:

Compared with baseline at weeks 3 and 7, all the outcome measures, except range of motion, were significantly reduced in all groups (all P≤0.001). In terms of the change data from baseline to week 3, both traction groups were significantly superior to the control in the WOMAC physical function scores. Considering the change data from baseline to week 7, both traction groups were significantly superior to the control in the pain scores, physical function and total scores, while only the continuous group was significantly better than the control in the stiffness scores (control: 1.17 ± 1.64; continuous: 2.38 ± 1.44) ( P=0.014). Compared with baseline at weeks 3 and 7, range of motion values significantly increased in both traction groups ( P<0.05) but not in the control ( P>0.05). However, there were no significant differences among the three groups considering the change data from baseline to week 7 in range of motion values ( P=0.300).

Conclusions:

Joint traction was found to be beneficial for the improvement of pain and physical function loss related to knee osteoarthritis.