bluuebunny/crossref_metadata_2025 huggingface dataset:
Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications
Authors: Salvemini Daniela , Kim Sangwon F. , Mollace Vincenzo
Published: February 2013

The nitric oxide (NO) and cyclooxygenase (COX) pathways share a number of similarities. Nitric oxide is the mediator generated from the NO synthase (NOS) pathway, and COX converts arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. Two major forms of NOS and COX have been identified to date. The constitutive isoforms critically regulate several physiological states. The inducible isoforms are overexpressed during inflammation in a variety of cells, producing large amounts of NO and prostaglandins, which may underlie pathological processes. The cross-talk between the COX and NOS pathways was initially reported by Salvemini and colleagues in 1993, when they demonstrated in a series of in vitro and in vivo studies that NO activates the COX enzymes to produce increased amounts of prostaglandins. Those studies led to the concept that COX enzymes represent important endogenous “receptor” targets for amplifying or modulating the multifaceted roles of NO in physiology and pathology. Since then, numerous studies have furthered our mechanistic understanding of these interactions in pathophysiological settings and delineated potential clinical outcomes. In addition, emerging evidence suggests that the canonical nitroxidative species (NO, superoxide, and/or peroxynitrite) modulate biosynthesis of prostaglandins through non-COX-related pathways. This article provides a comprehensive state-of-the art overview in this area.
Study of Swarm Behavior in Modeling and Simulation of Cluster Formation in Nanofluids
Authors: Pirani Mohammad , Basirat Tabrizi Hassan , Farshad Ali
Published: February 2013

Modeling the multiagents cooperative systems inspired from biological self-organized systems in the context of swarm model has been under great considerations especially in the field of the cooperation of multi robots. These models are trying to optimize the behavior of artificial multiagent systems by introducing a consensus, which is a mathematical model between the agents as an intelligence property for each member of the swarm set. The application of this novel approach in the modeling of nonintelligent multi agents systems in the field of cohesion and cluster formation of nanoparticles in nanofluids has been investigated in this study. This goal can be obtained by applying the basic swarm model for agents that are more mechanistic by considering their physical properties such as their mass, diameter, as well as the physical properties of the flow. Clustering in nanofluids is one of the major issues in the study of its effects on heat transfer. Study of the cluster formation dynamics in nanofluids using the swarm model can be useful in controlling the size and formation time of the clusters as well as designing appropriate microchannels, which the nanoparticles are plunged into.
An Assessment of the Intestinal Lumen as a Site for Intervention in Reducing Body Burdens of Organochlorine Compounds
Authors: Jandacek Ronald J. , Genuis Stephen J.
Published: February 2013

Many individuals maintain a persistent body burden of organochlorine compounds (OCs) as well as other lipophilic compounds, largely as a result of airborne and dietary exposures. Ingested OCs are typically absorbed from the small intestine along with dietary lipids. Once in the body, stored OCs can mobilize from adipose tissue storage sites and, along with circulating OCs, are delivered into the small intestine via hepatic processing and biliary transport. Retained OCs are also transported into both the large and small intestinal lumen via non‐biliary mechanisms involving both secretion and desquamation from enterocytes. OCs and some other toxicants can be reabsorbed from the intestine, however, they take part in enterohepatic circulation(EHC). While dietary fat facilitates the absorption of OCs from the small intestine, it has little effect on OCs within the large intestine. Non‐absorbable dietary fats and fat absorption inhibitors, however, can reduce the re‐absorption of OCs and other lipophiles involved in EHC and may enhance the secretion of these compounds into the large intestine—thereby hastening their elimination. Clinical studies are currently underway to determine the efficacy of using non‐absorbable fats and inhibitors of fat absorption in facilitating the elimination of persistent body burdens of OCs and other lipophilic human contaminants.
Current and Future Therapies for Multiple Sclerosis
Authors: Minagar Alireza
Published: February 2013

With the introduction of interferon-β1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and its natural course was permanently changed. Currently, seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon-β1a intramuscular (Avonex), interferon-β1a subcutaneous (Rebif), interferon-β1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone (Novantrone). In addition, a large number of clinical trials are being conducted to assess the safety and efficacy of various experimental agents in patients with multiple sclerosis, including alemtuzumab, dimethyl fumarate, laquinimod, rituximab, daclizumab, and cladribine. In this paper, the author presents a concise and comprehensive review of present and potential treatments for this incurable disease.
What Is thede-qi-Related Pattern of BOLD Responses? A Review of Acupuncture Studies in fMRI
Authors: Sun Jinbo , Zhu Yuanqiang , Yang Yang , Jin Lingmin , von Deneen Karen M. , Qin Wei , Tian Jie
Published: February 2013

de-qi, comprising mostly subjective sensations during acupuncture, is traditionally considered as a very important component for the possible therapeutic effects of acupuncture. However, the neural correlates ofde-qiare still unclear. In this paper, we reviewed previous fMRI studies from the viewpoint of the neural responses ofde-qi. We searched on Pubmed and identified 111 papers. Fourteen studies distinguishingde-qiand sharp pain and eight studies with the mixed sensations were included in further discussions. We found that the blood oxygenation level-dependent (BOLD) responses associated withde-qiwere activation dominated, mainly around cortical areas relevant to the processing of somatosensory or pain signals. More intense and extensive activations were shown for the mixed sensations. Specific activations of sharp pain were also shown. Similar BOLD response patterns betweende-qievoked by acupuncture stimulation andde-qi-like sensations evoked by deep pain stimulation were shown. We reckon that a standardized method of qualification and quantification ofde-qi, deeper understanding of grouping strategy ofde-qiand sharp pain, and making deep pain stimulation as a control, as well as a series of improvements in the statistical method, are crucial factors for revealing the neural correlates ofde-qiand neural mechanisms of acupuncture.
Heart Rate Variability Analysis in Patients with Allergic Rhinitis
Authors: Lan Ming-Ying , Lee Guo-She , Shiao An-Suey , Ko Jen-Hung , Shu Chih-Hung
Published: February 2013

Background. Very few studies investigate the role of the autonomic nervous system in allergic rhinitis. In this study, we evaluated the autonomic nervous system in allergic rhinitis patients using heart rate variability (HRV) analysis. Methods. Eleven patients with allergic rhinitis and 13 healthy controls, aged between 19 and 40 years old, were enrolled in the study. Diagnosis of allergic rhinitis was based on clinical history, symptoms, and positive Phadiatop test. Electrocardiographic recordings on the sitting and supine positions were obtained for HRV analysis. Results. In the supine position, there were no significant statistical differences in very‐low‐frequency power (VLF, ≤0.04 Hz), low‐frequency power (LF, 0.04–0.15 Hz), high‐frequency power (HF, 0.15–0.40 Hz), and the ratio of LF to HF (LF/HF) between the patient and control groups. The mean RR intervals significantly increased, while LF% and LF/HF significantly decreased in the patient group in the sitting position. Moreover, mean RR intervals, LF, and LF/HF, which were significantly different between the two positions in the control group, did not show a significant change with the posture change in the patient group. Conclusion. These suggest that patients with allergic rhinitis may have poor sympathetic modulation in the sitting position. Autonomic dysfunction may therefore play a role in the pathophysiology of allergic rhinitis.
Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans
Authors: Breitbach Caroline J. , Arulanandam Rozanne , De Silva Naomi , Thorne Steve H. , Patt Richard , Daneshmand Manijeh , Moon Anne , Ilkow Carolina , Burke James , Hwang Tae-Ho , Heo Jeong , Cho Mong , Chen Hannah , Angarita Fernando A. , Addison Christina , McCart J. Andrea , Bell John C. , Kirn David H.
Published: February 2013

Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, β-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-naïve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically. Cancer Res; 73(4); 1265–75. ©2012 AACR.
Melanoma Genetic Testing, Counseling, and Adherence to Skin Cancer Prevention and Detection Behaviors
Authors: Glanz Karen , Volpicelli Kathryn , Kanetsky Peter A. , Ming Michael E. , Schuchter Lynn M. , Jepson Christopher , Domchek Susan M. , Armstrong Katrina
Published: February 2013

Background: Little is known about the impact of knowledge of CDKN2A and MC1R genotype on melanoma prevention behaviors like sun avoidance and skin examination in the context of familial melanoma.

Methods: Seventy-three adults with a family history of melanoma were randomly assigned to be offered individualized CDKN2A and MC1R genotyping results in the context of a genetic counseling session, or the standard practice of not being offered counseling or disclosure of genotyping results. Mixed effects or longitudinal logistic models were used to determine whether the intervention affected change in sun protection habits, skin examinations, and perception and beliefs related to melanoma risk, prevention, and genetic counseling.

Results: All participants in the intervention group who attended genetic counseling sessions chose to receive their test results. From baseline to follow-up, participants in the intervention group reported an increase in the frequency of skin self-examinations compared with a slight decrease in the control group (P = 0.002). Participants in the intervention group reported a smaller decrease in frequency of wearing a shirt with long sleeves than did participants in the control group (P = 0.047). No effect of the intervention was noted for other outcomes.

Conclusions: Feedback of CDKN2A and MC1R genotype among families without known pathogenic CDKN2A mutations does not seem to decrease sun protection behaviors.

Impact: While disclosure of CDKN2A and MC1R genotype did not have negative effects on prevention, the benefits of communicating this information remain unclear. The small number of families who tested positive for CDKN2A mutations in this study is a limitation. Cancer Epidemiol Biomarkers Prev; 22(4); 607–14. ©2013 AACR.
Urinary Cytology of Prostatic Duct Adenocarcinoma – A Clinicopathologic Analysis
Authors: Sathiyamoorthy Srividya , Ali Syed Z.
Published: February 2013

Objective: To review atypical/positive urine cytology specimens from patients with confirmed prostatic duct adenocarcinoma (PDA), describe the cytomorphologic features and discuss the differential diagnosis. Study Design: A retrospective review of the cytopathology archives of The Johns Hopkins Hospital revealed 14 cases of abnormal urinary cytology in patients with histologically confirmed PDAs. Cytologic material was reviewed; cytomorphologic characteristics were analyzed and correlated with histopathologic features wherever possible. Results: There were 7 patients ranging in age from 52 to 80 years (mean age: 68 years). The clinical presentation included; hematuria, bladder obstruction and perineal mass. The cytomorphologic characteristics were: large crowded sheets and three-dimensional fragments (some with papillary architecture) of columnar epithelium with scant amphophilic cytoplasm, basally placed round to oval nuclei with coarse chromatin and absent or inconspicuous nucleoli. Histologic findings showed papillary and cribriform architecture of columnar cells with crowding, nuclear stratification and overlapping with or without nucleoli. Conclusion: PDAs usually present at an advanced clinical stage and may exfoliate owing to their location in the central prostatic urethra. Differentiating PDA from acinar prostatic adenocarcinoma, urothelial carcinoma and metastatic adenocarcinoma is important due to the differences in patient management. Since prostate-specific antigen values are variable, urine cytology may provide a valuable tool for the early detection of these aggressive lesions.
Performance of the CellSolutions Glucyte Liquid-Based Cytology in Comparison with the ThinPrep and SurePath Methods
Authors: Alaghehbandan Reza
Published: February 2013

Objective: Glucyte liquid-based cytology (LBC; BestPrep™;CellSolutions, LLC, Greensboro, N.C., USA) is a recently developed method. Its performance was assessed in comparison with ThinPrep (Hologic Inc., Marlborough, Mass., USA) and SurePath (BD Diagnostics, Burlington, N.C., USA) LBC platforms. Study Design: Two cervical samples obtained from each of 331 patients presenting for colposcopy were utilized. The first sample was placed in PreservCyt (Hologic) and the second in SurePath medium, and both were processed in accordance with the manufacturers’ protocols. From the residual SurePath sample, a Glucyte slide was prepared, stained, and read as per the manufacturer’s instructions. Results: Considering a threshold cytologic diagnosis of atypical squamous cells of undetermined significance and using a histologic diagnosis of high-grade cervical intraepithelial neoplasia or worse (CIN 2+) as the end point, there was no significant difference in the sensitivity of Glucyte for the detection of CIN 2+ compared with ThinPrep and SurePath (86.9 vs. 81.9% and 83.7%, respectively). However, Glucyte showed a specificity of 49.2% compared with 61.6% for ThinPrep (p = 0.002) and 66.9% for SurePath (p < 0.001). Considering a threshold cytologic diagnosis of high-grade squamous intraepithelial lesion, Glucyte showed a sensitivity of 40.5% for detecting CIN 2+ compared with 20.5% for ThinPrep (p = 0.003) and 54.7% for SurePath (p = 0.013). The corresponding specificities were 93.8, 99.1, and 94.3%. The rate of unsatisfactory specimens for Glucyte was 1.2% compared with ThinPrep (4.8%) and SurePath (0%). Conclusion: Glucyte appeared to perform reasonably well compared with ThinPrep and SurePath. It offers an alternative to these well recognized LBC systems.
Fine Needle Aspiration Cytology: A Tool to Diagnose Cervical and Vaginal Endometriosis in Low-Income Places
Authors: Oliveira-Filho Manoel , Rao Vietla S. , Eleutério Jr. José , Medeiros Francisco C.
Published: February 2013

Regarded as infrequent, vaginal and cervical endometriosis is probably more common than is generally realized. The apparent rarity of the lesion may be ascribed to the limited awareness of its clinical appearance, combined with technical difficulty in obtaining suitable biopsy material for confirmation. Thus, clinical recognition and tissue confirmation become essential. This paper focuses on vaginal and cervical endometriosis, documenting the clinical, macroscopic, cytological and colposcopic findings in 4 cases seen at a single physical vaginal examination. Diagnosis in these patients was facilitated and improved by fine needle aspiration cytology and confirmed by histology. This technique, which is not used for the diagnosis of endometriosis, could be an option in low-income areas.
Usefulness of Intraoperative Imprint Cytology in Ovarian Germ Cell Tumors
Authors: Abe Akiko , Sugiyama Yuko , Furuta Reiko , Furuta Noriyuki , Matoda Maki , Takeshima Nobuhiro
Published: February 2013

Objective: This study retrospectively investigated the usefulness of intraoperative diagnosis based on imprint cytology and frozen sections for ovarian germ cell tumor. Study Design: Intraoperative studies were reviewed for 23 cases with ovarian germ cell tumor treatment for which both frozen sections and imprint cytology were available. Final histopathologic diagnoses were compared with those based on intraoperative examinations. Results: Underlying pathologies included dysgerminoma (n = 6), yolk sac tumor (n = 1), non-gestational choriocarcinoma (n = 1), mature cystic teratoma with malignant transformation (n = 1), immature teratoma (n = 11), and mixed germ cell tumor (n = 3). Discrepancies between intraoperative imprint cytology and definitive histologic diagnosis were seen in 6 of the 23 cases. Accuracy was 54.5% (6/11) for immature teratoma and 91.7% (11/12) for other tumors. Cytologic examination facilitated accurate diagnosis in both of our cases, and intraoperative diagnosis by frozen section proved inaccurate. Conclusion: These results demonstrate that intraoperative assessment based on imprint cytology for immature teratoma has a relatively lower sensitivity, but an acceptable sensitivity for other germ cell tumors. Diagnostic approaches combining frozen sections and imprint cytology are advisable to improve the yield for intraoperative diagnosis.
Cognitive Improvement in Patients with Severe Carotid Artery Stenosis after Transcervical Stenting with Protective Flow Reversal
Authors: Ortega Gemma , Álvarez Beatriz , Quintana Manuel , Ribó Marc , Matas Manuel , Álvarez-Sabin José
Published: February 2013

Impaired cognitive function is often reported in patients with carotid artery stenosis. Revascularization by transcervical carotid artery stenting (CAS) with flow reversal is associated with increased cognition regardless of age, asymtomatic status, previous stroke events, baseline brain parenchyma status, and contralateral carotid artery stenosis. The findings of this preliminary prospective study suggest that transcervical CAS and stenting with flow reversal for cerebral protection is a safe technique that will improve, or at least not worsen, cognitive performance.
Malnutrition in Older Adults - Urgent Need for Action: A Plea for Improving the Nutritional Situation of Older Adults
Authors: Volkert Dorothee
Published: February 2013

During the past decades, malnutrition has attracted increasing scientific attention and is by now regarded as a true geriatric syndrome characterized by multifactorial causality, identified by symptoms and accompanied by frailty, disability and poor outcome. This viewpoint summarizes our present knowledge and the usual current handling of malnutrition in older people and highlights the urgent need for action in this field. Age-related changes in the complex system of appetite regulation, resulting in the so-called anorexia of aging, predispose older adults to a decrease in food intake which may lead to malnutrition, if additional risk factors like health or social problems occur. Consequently, malnutrition is widespread in the older population, notably in those who are institutionalized. Despite the fact that effective interventions are available, prevention and treatment of malnutrition do not currently receive appropriate attention. As an important first step towards better awareness, screening for malnutrition should become a mandatory integral part of the comprehensive geriatric assessment. Furthermore, practical local guidelines should be implemented in all geriatric hospital wards and nursing homes in order to improve nutritional care in the daily routine. Important to note is that reasonable nutritional management is not possible without qualified staff in adequate numbers allowing appropriate individual nutritional care. Regarding future research, studies at the cellular, metabolic and clinical levels and the linking of information from different research approaches are required to better understand the transition from good nutritional health and independence of old people to malnutrition, functional impairment and poor health. In parallel to well-designed observational and intervention studies, standardized documentation of nutritional information in daily routine would enable the uniform collection of data for research as well as for political decisions. In summary, the time is ripe for better inclusion of nutrition in geriatric health care. This will not only bring about improved nutritional status and outcome, and thus individual benefit for the affected person, but also economic benefits both for the institution and the health-care system.
Mitochondrial Factors and VACTERL Association-Related Congenital Malformations
Authors: Siebel S. , Solomon B.D.
Published: February 2013

VACTERL/VATER association is a group of congenital malformations characterized by at least 3 of the following findings: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity. VACTERL/VATER association has many overlapping characteristics with other congenital disorders that involve multiple malformations. In addition to these other conditions, some of which have known molecular causes, certain aspects of VACTERL/VATER association have similarities with the manifestations of disorders caused by mitochondrial dysfunction. Mitochondrial dysfunction can result from a number of distinct causes and can clinically manifest in diverse presentations; accurate diagnosis can be challenging. Case reports of individuals with VACTERL association and confirmed mitochondrial dysfunction allude to the possibility of mitochondrial involvement in the pathogenesis of VACTERL/VATER association. Further, there is biological plausibility involving mitochondrial dysfunction as a possible etiology related to a diverse group of congenital malformations, including those seen in at least a subset of individuals with VACTERL association.
Retinal Venous Occlusions: Diagnosis and Choice of Treatments
Authors: Querques Giuseppe , Triolo Giacinto , Casalino Giuseppe , García-Arumí José , Badal Josep , Zapata Miguel , Boixadera Ana , Castillo Vicente Martinez , Bandello Francesco
Published: February 2013

Retinal vascular occlusive disorders constitute one of the major causes of blindness and impaired vision. There is marked controversy on their pathogeneses, clinical features and particularly their management. Recently, advances in clinical research added antivascular endothelial growth factor, corticosteroids and sustained-release implants to our armamentarium in the management of retinal vein occlusions. The purpose of our paper is to provide an update and a brief review on the current treatment options of retinal vein occlusions.
Interindividual Transcriptional Regulation of the Human
biglycan
Gene Involves Three Common Molecular Haplotypes
Authors: Schmitz Boris , Salomon Andrea , Rötrige Alois , Ritter Martin , Ringelstein E. Bernd , Fischer Jens W. , Paul Martin , Brand Eva , Brand Stefan-Martin
Published: February 2013

Objective—

The extracellular matrix proteoglycan biglycan (BGN) is involved in cardiovascular disease pathophysiology, as it mediates the subendothelial retention of atherogenic apolipoprotein B-containing lipoproteins, affects adaptive remodeling after myocardial infarction, and exerts proinflammatory effects in macrophages. In a cardiovascular disease-related setting of vascular endothelial cells and human monocytes, we examined the molecular mechanisms of common molecular haplotypes affecting human
BGN
transcriptional regulation.

Approach and Results—

After the molecular characterization of the
BGN
promoter, we determined the prevalence of
BGN
promoter variants (1199 base pair portion) in 87 individuals of European ancestry, and identified 3 molecular haplotypes by subcloning and sequencing of subjects’ single DNA strands: MolHap1 [G
-578
-G
-151
-G
+94
] MolHap2 [G
-578
-A
-151
-T
+94
] and MolHap3 [A
-578
-G
-151
-G
+94
]. By 5′ rapid amplification of cDNA-ends, we detected 1 additional upstream transcription start site at position –46 in EA.hy926 endothelial cells. Reporter gene assays located the
BGN
core promoter to the region spanning positions –39 and +162. Strongest promoter activity was mapped to the region between –1231 and –935. The introduction of MolHap2 and MolHap3 into the active
BGN
promoter led to a significant loss of transcriptional activity (all probability values <0.05), compared with MolHap1. By use of electrophoretic mobility shift assays, chromatin immunoprecipitation assays, and cotransfection of transcription factors, we identified specificity protein 1, v-ets erythroblastosis virus E26 oncogene homolog (ETS) family members, and an activator protein-1 complex to interact differentially with the
BGN
promoter in the context of each individual MolHap.

Conclusions—

Our results indicate that molecular haplotypes within the
BGN
promoter may contribute to the molecular basis of interindividually different transcriptional
BGN
regulation, possibly modulating the predisposition to cardiovascular disease-related phenotypes.
Activator Protein-2α Mediates Carbon Monoxide–Induced Stromal Cell–Derived Factor-1α Expression and Vascularization in Ischemic Heart
Authors: Lin Heng-Huei , Chen Yen-Hui , Chiang Ming-Tsai , Huang Pei-Ling , Chau Lee-Young
Published: February 2013

Objective—

Increased cardiac stromal cell-derived factor-1α (SDF-1α) expression promotes neovascularization and myocardial repair after ischemic injury through recruiting stem cells and reducing cardiomyocyte death. Previous studies have shown that heme oxygenase-1 and its reaction byproduct, carbon monoxide (CO), induce SDF-1α expression in ischemic heart. However, the mechanism underlying heme oxygenase-1/CO-induced cardiac SDF-1α expression remains elusive. This study aims to investigate the signaling pathway and the transcriptional factor that mediate CO-induced SDF-1α gene expression and cardioprotection.

Approach and Results—

CO gas and a CO-releasing compound, tricarbonyldichlororuthenium (II) dimer, dose-dependently induced SDF-1α expression in primary neonatal cardiomyocytes and H9C2 cardiomyoblasts. Promoter luciferase-reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation demonstrated that the activator protein 2α (AP-2α) mediated tricarbonyldichlororuthenium (II) dimer-induced SDF-1α gene transcription. Tricarbonyldichlororuthenium (II) dimer induced AP-2α expression via protein kinase B (AKT)-dependent signaling. AKT inhibition or AP-2α knockdown reduced tricarbonyldichlororuthenium (II) dimer-induced SDF-1α expression. Coronary ligation induced transient increases of cardiac AP-2α and SDF-1α expression, which were declined at 1 week postinfarction in mice. Periodic exposure of coronary-ligated mice to CO (250 ppm for 1 hour/day, 6 days) resumed the induction of AP-2α and SDF-1α gene expression in infarcted hearts. Immunohistochemistry and echocardiography performed at 4 weeks after coronary ligation revealed that CO treatment enhanced neovascularization in the myocardium of peri-infarct region and improved cardiac function. CO-mediated SDF-1α expression and cardioprotection was ablated by intramyocardial injection of lentivirus bearing specific short hairpin RNA targeting AP-2α.

Conclusions—

Our data demonstrate that AKT-dependent upregulation of AP-2α is essential for CO-induced SDF-1α expression and myocardial repair after ischemic injury.
Genetic Variation in
PEAR1
Is Associated With Platelet Aggregation and Cardiovascular Outcomes
Authors: Lewis Joshua P. , Ryan Kathleen , O’Connell Jeffrey R. , Horenstein Richard B. , Damcott Coleen M. , Gibson Quince , Pollin Toni I. , Mitchell Braxton D. , Beitelshees Amber L. , Pakzy Ruth , Tanner Keith , Parsa Afshin , Tantry Udaya S. , Bliden Kevin P. , Post Wendy S. , Faraday Nauder , Herzog William , Gong Yan , Pepine Carl J. , Johnson Julie A. , Gurbel Paul A. , Shuldiner Alan R.
Published: February 2013

Background—

Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.

Methods and Results—

We measured ex vivo platelet aggregation before and after dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post–dual antiplatelet therapyplatelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (
PEAR1
) gene to be most strongly associated with dual antiplatelet therapy response (
P
=7.66×10
−9
). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96–7.10;
P
=0.059; and hazard ratio, 3.97; 95% confidence interval, 1.10–14.31;
P
=0.035, respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01–4.09;
P
=0.048).

Conclusion—

Common genetic variation in
PEAR1
may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00799396 and NCT00370045
Outcomes and Care of Patients With Acute Heart Failure Syndromes and Cardiac Troponin Elevation
Authors: Braga Juarez R. , Tu Jack V. , Austin Peter C. , Chong Alice , You John J. , Farkouh Michael E. , Ross Heather J. , Lee Douglas S.
Published: February 2013

Background—

Cardiac troponins (cTn) may be elevated among patients with acute heart failure syndromes (AHFS). However, the optimal approach to management of AHFS with elevated cTn is unknown.

Methods and Results—

We compared the care and outcomes of 13 656 patients with AHFS seeking care in the emergency department stratified by presence (cTn+, n=1845, 13.5%) or absence (cTn−) of elevated troponin. Clinically abstracted data on patients who were admitted or discharged from the emergency department in Ontario, Canada (April 1999 to March 2001 and April 2004 to March 2007) were examined. In an exploratory 2:1 propensity-matched analysis, we examined whether early coronary revascularization (within 14 days of emergency department visit) was associated with survival, stratified by cTn status. For cTn+ AHFS, rates of coronary angiography (21.8 vs 11.4 patients/100 person-years;
P
<0.001) and coronary revascularization (8.8 vs 3.2 patients/100 person-years;
P
<0.001) were higher than cTn−. Instantaneous 30-day adjusted hazard ratios for cTn+ versus cTn− patients were 9.17 (95% confidence interval [CI], 8.31–10.12;
P
<0.001) for death, 5.14 (95% CI, 4.66–5.67;
P
<0.001) for cardiovascular readmission, and 13.08 (95% CI, 10.95–15.62;
P
<0.001) for ischemic heart disease hospitalization. In propensity-matched analysis of 143 individuals with cTn+ AHFS, early coronary revascularization was associated with reduced mortality (adjusted hazard ratio, 0.29; 95% CI, 0.09–0.92;
P
=0.036) compared with those who were not revascularized. Mortality was not significantly reduced among 210 cTn− patients undergoing early coronary revascularization (adjusted hazard ratio, 0.61; 95% CI, 0.36–1.03;
P
=0.065).

Conclusions—

Elevated cTn was associated with increased risk of death and cardiovascular hospitalizations. Highly selected cTn+ patients who underwent early coronary revascularization for obstructive coronary artery disease experienced improved survival.
Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator for Intracerebral Hemorrhage Evacuation Decreases Perihematomal Edema
Authors: Mould W. Andrew , Carhuapoma J. Ricardo , Muschelli John , Lane Karen , Morgan Timothy C. , McBee Nichol A. , Bistran-Hall Amanda J. , Ullman Natalie L. , Vespa Paul , Martin Neil A. , Awad Issam , Zuccarello Mario , Hanley Daniel F.
Published: February 2013

Background and Purpose—

Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it.

Methods—

Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans.

Results—

Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm
3
for the surgical cohort and 40.7±13.9 cm
3
for the medical cohort (
P
<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm
3
than medical cohort: 41.7±14.6 cm
3
(
P
<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (
P
<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (ρ=0.658;
P
<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm
3
; and surgical aspiration only, 24.5±14.0 cm
3
(
P
=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm
3
and 24.4±8.6 cm
3
in surgical aspiration only (
P
=0.41).

Conclusions—

Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.
Subarachnoid Extension of Primary Intracerebral Hemorrhage is Associated With Poor Outcomes
Authors: Maas Matthew B. , Nemeth Alexander J. , Rosenberg Neil F. , Kosteva Adam R. , Guth James C. , Liotta Eric M. , Prabhakaran Shyam , Naidech Andrew M.
Published: February 2013

Background and Purpose—

Extension of hemorrhage into the subarachnoid space is observed in primary intracerebral hemorrhage (ICH), yet the phenomenon has undergone limited study and is of unknown significance. The objective of this study is to evaluate the incidence, characteristics, and clinical consequences of subarachnoid hemorrhage extension (SAHE) in ICH on functional outcomes.

Methods—

Patients with primary ICH were enrolled into a prospective registry between December 2006 and June 2012. Patients were managed and serial neuroimaging was obtained per a structured protocol. Presence of any subarachnoid blood on imaging was identified as SAHE by expert reviewers blinded to outcomes. Regression models were developed to test whether the occurrence of SAHE was an independent predictor of functional outcomes as measured with the modified Rankin Scale.

Results—

Of 234 patients with ICH, 93 (39.7%) had SAHE. Interrater agreement for SAHE was excellent (kappa=0.991). SAHE was associated with lobar hemorrhage location (65% of SAHE vs 19% of non-SAHE cases;
P
<0.001) and larger hematoma volumes (median 23.8 vs 6.7;
P
<0.001). Fever (69.9% vs 51.1%;
P
=0.005) and seizures (8.6% vs 2.8%;
P
=0.07) were more common in patients with SAHE. SAHE was a predictor of death by day 14 (odds ratio, 4.45; 95% confidence interval, 1.88–10.53;
P
=0.001) and of higher (worse) modified Rankin Scale scores at 28 days (odds ratio, 1.76 per mRS point; 95% confidence interval, 1.01–3.05;
P
=0.012) after adjustment for ICH score.

Conclusions—

SAHE is associated with worse modified Rankin Scale independent of traditional ICH severity measures. Underlying mechanisms and potential treatments of SAHE require further study.
The Differential Impact of Education on Young People’s Political Activism: Comparing Italy and the United Kingdom
Authors: Grasso Maria
Published: February 2013

Abstract

It is a common theme in the literature on voter turnout that advanced Western democracies have entered a period of political disengagement and that it is young people, in particular, that participate less. In this paper, I analyse data from the three waves of the European Social Survey and show that while young people are in general less likely to be politically involved than their elders, these differences are greater in the United Kingdom than in Italy. In addition, I show that controlling for education accounts for differences in political participation between young and older people in Italy. However, education does not appear to mediate youth political involvement in the United Kingdom so that normative concerns about youth political disengagement appear to be more appropriate for the latter of the two countries.
Deconstructing Service and Investment Negotiating Stance: A case study of India at WTO GATS and Investment Fora
Authors: Chakraboty Debashis , Chaisse Julien , Mukherjee Jaydeep
Published: February 2013

While India has gradually embraced a unilateral liberal policy on the limit of inward foreign investment in the country, its negotiating position on the same at the multilateral forum, i.e., WTO, is still comparatively defensive. The key question raised by the current analysis is, whether India is right to adopt a hard negotiating stand at WTO on investment issues, covered under GATS Mode 3 and Trade and Investment Negotiations. An associated concern is whether a softening of India’s present standpoint is expected in coming future. For this purpose, the current study explores the long-run co-integrating relationship between India’s FDI and economic growth, in addition to exploring their direction of causality applying Granger causality test. The obtained empirical results lead to the following observations. First, regarding the question of the justifiability of the Indian standpoint, it is observed that though foreign investment inflow in the country continues to benefit several sectors through backward and forward linkage effects, the role of FDI on overall growth has not been statistically significant. Second, it can be concluded from the findings of the Granger causality test that a number of foreign investors has targeted India in recent period, given the high growth rate witnessed by Indian economy even in the aftermath of the 2009 recession vis-à-vis other developing economies. We conclude that India’s present standpoint at WTO negotiations on investment reflects the uncertain trade-off between growth repercussion expectations from the incremental FDI inflows resulting from the additional multilateral commitments. Therefore, a quick transformation of the present negotiating standpoint is not expected in India’s case.
The Evolving Nature of the Fair and Equitable Treatment (FET) Standard: Challenging Its Increasing Pervasiveness in Light of Developing Countries’ Concerns - The Case for Regulatory Rebalancing
Authors: Haynes Jason
Published: February 2013

The fair and equitable treatment (FET) standard is undoubtedly a key feature of most International Investment Agreements concluded by developing countries today. In practice however, the standard raises a number of potent concerns which have not gone unnoticed. This article accordingly attempts to critically analyze the increasing intrusiveness of the FET standard in light of growing concerns expressed by developing countries following a number of large arbitral awards which have been handed down against them. In this regard, the article not only challenges the conceptual underpinnings of the standard but also the substantive elements which have become synonymous with it. It concludes by providing an approach to regulatory balancing which would reposition the FET standard in the context of other investment protection standards as well as the standing of developing countries.
Double Remedies in Non-Market Economies
Authors: Lei Cai Carrie
Published: February 2013

Double remedies in the non-market economy (“NME”) context can be regarded as one of the most controversial issues arising from the simultaneous application of both anti-dumping and countervailing duties. In recent years, China has been the most frequent target of anti-dumping and countervailing duty investigations. This paper examines how double remedies come into being in the NME context such as China, and explores its origin, harm, and solutions.
IR Radiation from Trees to a Ski Run: A Case Study
Authors: Howard Rosie , Stull Roland
Published: February 2013

Accurately calculating the surface radiation budget of a groomed ski run is crucial when determining snow surface temperature and other snow-related variables, knowledge of which is important for ski racing. Downwelling longwave radiation can compose a large part of the surface radiation budget in mountainous terrain. At a location on a ski run, a portion of the downwelling longwave radiation comes from the sky and a portion comes from tall evergreen trees. Infrared photographs taken during daytime at a ski run on Whistler Mountain, British Columbia, Canada, for a clear-sky day in February 2012 show that trees can enhance the downwelling longwave radiation at the center of the ski run considerably, with a maximum estimated enhancement of 75.6 ± 16.8 W m−2 for trees in direct sunlight. The average needle and trunk brightness temperatures from the IR photographs were correlated with measured meteorological data. Regressions were found to allow estimation of longwave radiation from trees using nearby routine meteorological data. Absolute errors in tree longwave radiation estimations using the derived trunk and needle temperatures did not exceed 4 W m−2. The effect of the intervening air upon longwave radiative transfer between trees and the point of interest on the ski run was found to be small for these very short pathlengths of 50 m or less. These results can be used to improve calculations of the surface radiation budget of a groomed ski run under clear skies.
On Adding Thermodynamic Damping Mechanisms to Refine Two Classical Models of Katabatic Winds
Authors: Mo Ruping
Published: February 2013

The Prandtl and layer-averaged models of katabatic winds contain some nonphysical singularities in the analytical solutions, which give unbounded steady flow anomalies at zero slope angles or adiabatic lapse rates. This study presents some simple refinements of these two classical models, in which the aforementioned singularities are removed when Newtonian cooling and Rayleigh friction are included in the system. It is pointed out that, in the limit of zero slope angles or adiabatic lapse rates, the along-slope buoyancy force and the adiabatic heating caused by air descending approach zero. Under such circumstances, a bounded steady solution for the katabatic winds is impossible unless some damping mechanisms are included to retard the anomalies induced by the radiative cooling effect in the boundary layer. Newtonian cooling and Rayleigh friction are the two simplest thermodynamic damping mechanisms that can be included to balance the effects of eddy viscosity and eddy thermal conductivity in the katabatic-flow model. Physically speaking, the Newtonian cooling term represents a small partition of the radiative effect and the Rayleigh friction term represents an approximation of the bottom drag effect in a turbulent boundary layer.
Carbon–Concentration and Carbon–Climate Feedbacks in CMIP5 Earth System Models
Authors: Arora Vivek K. , Boer George J. , Friedlingstein Pierre , Eby Michael , Jones Chris D. , Christian James R. , Bonan Gordon , Bopp Laurent , Brovkin Victor , Cadule Patricia , Hajima Tomohiro , Ilyina Tatiana , Lindsay Keith , Tjiputra Jerry F. , Wu Tongwen
Published: February 2013

The magnitude and evolution of parameters that characterize feedbacks in the coupled carbon–climate system are compared across nine Earth system models (ESMs). The analysis is based on results from biogeochemically, radiatively, and fully coupled simulations in which CO2 increases at a rate of 1% yr−1. These simulations are part of phase 5 of the Coupled Model Intercomparison Project (CMIP5). The CO2 fluxes between the atmosphere and underlying land and ocean respond to changes in atmospheric CO2 concentration and to changes in temperature and other climate variables. The carbon–concentration and carbon–climate feedback parameters characterize the response of the CO2 flux between the atmosphere and the underlying surface to these changes. Feedback parameters are calculated using two different approaches. The two approaches are equivalent and either may be used to calculate the contribution of the feedback terms to diagnosed cumulative emissions. The contribution of carbon–concentration feedback to diagnosed cumulative emissions that are consistent with the 1% increasing CO2 concentration scenario is about 4.5 times larger than the carbon–climate feedback. Differences in the modeled responses of the carbon budget to changes in CO2 and temperature are seen to be 3–4 times larger for the land components compared to the ocean components of participating models. The feedback parameters depend on the state of the system as well the forcing scenario but nevertheless provide insight into the behavior of the coupled carbon–climate system and a useful common framework for comparing models.