bluuebunny/crossref_metadata_2025 huggingface dataset:
Basal levels of glutathione peroxidase correlate with onset of radiation induced lung disease in inbred mouse strains
Authors: Kunwar Amit , Haston Christina K.
Published: August 2014

Biomarkers predicting for the radiation-induced lung responses of pneumonitis or fibrosis are largely unknown. Herein we investigated whether markers of oxidative stress and intracellular antioxidants, measured within days of radiation exposure, are correlated with the lung tissue injury response occurring weeks later. Mice of the eight inbred strains differing in their susceptibility to radiation-induced pulmonary fibrosis, and in the duration of asymptomatic survival, received 18 Gy whole thorax irradiation and were killed 6 h, 24 h, or 7 days later. Control mice were not irradiated. Lung levels of antioxidants superoxide dismutase, catalase, glutathione peroxidase (GPx), and glutathione, and of oxidative damage [reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine (8-OHdG)], were biochemically determined. GPx was additionally measured through gene expression and immunohistochemical assessment of lung tissue, and activity in serum. ROS and 8-OHdG were increased postirradiation and exhibited significant strain and time-dependent variability, but were not strongly predictive of radiation-induced lung diseases. Antioxidant measures were not dramatically changed postirradiation and varied significantly among the strains. Basal GPx activity ( r = 0.73, P = 0.04) in the lung and the pulmonary expression of GPx2 ( r = 0.94, P = 0.0003) correlated with postirradiation asymptomatic survival, whereas serum GPx activity was inversely correlated ( r = −0.80, P = 0.01) with fibrosis development. In conclusion, pulmonary oxidative stress and antioxidant markers were more affected by inbred strain than radiation over 7 days posttreatment. Lung GPx activity, and GPx2 expression, predicted for survival from lethal pneumonitis, and serum GPx for fibrosis, in this panel of mice.
Development of Novel ADCs: Conjugation of Tubulysin Analogues to Trastuzumab Monitored by Dual Radiolabeling
Authors: Cohen Ruth , Vugts Danielle J. , Visser Gerard W.M. , Stigter-van Walsum Marijke , Bolijn Marije , Spiga Marco , Lazzari Paolo , Shankar Sreejith , Sani Monica , Zanda Matteo , van Dongen Guus A.M.S.
Published: August 2014

Tubulysins are highly toxic tubulin-targeting agents with a narrow therapeutic window that are interesting for application in antibody–drug conjugates (ADC). For full control over drug–antibody ratio (DAR) and the effect thereof on pharmacokinetics and tumor targeting, a dual-labeling approach was developed, wherein the drug, tubulysin variants, and the antibody, the anti-HER2 monoclonal antibody (mAb) trastuzumab, are radiolabeled. 131I-radioiodination of two synthetic tubulysin A analogues, the less potent TUB-OH (IC50 > 100 nmol/L) and the potent TUB-OMOM (IC50, ∼1 nmol/L), and their direct covalent conjugation to 89Zr-trastuzumab were established. Radioiodination of tubulysins was 92% to 98% efficient and conversion to N-hydroxysuccinimide (NHS) esters more than 99%; esters were isolated in an overall yield of 68% ± 5% with radiochemical purity of more than 99.5%. Conjugation of 131I-tubulysin–NHS esters to 89Zr-trastuzumab was 45% to 55% efficient, resulting in ADCs with 96% to 98% radiochemical purity after size-exclusion chromatography. ADCs were evaluated for their tumor-targeting potential and antitumor effects in nude mice with tumors that were sensitive or resistant to trastuzumab, using ado-trastuzumab emtansine as a reference. ADCs appeared stable in vivo. An average DAR of 2 and 4 conferred pharmacokinetics and tumor-targeting behavior similar to parental trastuzumab. Efficacy studies using single-dose TUB-OMOM–trastuzumab (DAR 4) showed dose-dependent antitumor effects, including complete tumor eradications in trastuzumab-sensitive tumors in vivo. TUB-OMOM–trastuzumab (60 mg/kg) displayed efficacy similar to ado-trastuzumab emtansine (15 mg/kg) yet more effective than trastuzumab. Our findings illustrate the potential of synthetic tubulysins in ADCs for cancer treatment. Cancer Res; 74(20); 5700–10. ©2014 AACR.
Reduced Nicotine Cigarettes: Smoking Behavior and Biomarkers of Exposure among Smokers Not Intending to Quit
Authors: Hammond David , O'Connor Richard J.
Published: August 2014

Background: The U.S. FDA has the authority to limit the nicotine content of cigarettes; however, there are concerns that reduced nicotine cigarettes will be smoked more intensely and, therefore, will increase exposure to toxic chemicals in smoke. This study examined changes in consumer behavior and exposure in response to cigarettes with substantially reduced nicotine content.

Methods: Seventy-two adult smokers completed an unblinded trial of reduced nicotine cigarettes. Participants completed a 7-day baseline period during which they smoked their usual cigarette brand, followed by consecutive 7-day periods smoking cigarettes with progressively lower nicotine levels (0.6, 0.3, and 0.05 mg emission Quest cigarettes). Nicotine dependence and withdrawal, smoking behavior, and biomarkers of exposure were assessed for each 7-day period.

Results: Significant reductions in nicotine intake were observed between usual brand smoking (∼1.2 mg nicotine) and the 0.3 and 0.05 mg nicotine emission cigarettes, but not the 0.6 mg cigarette. The findings provide little evidence of compensatory smoking of Quest cigarettes, with no increases in exhaled breath carbon monoxide levels, smoking intensity, or levels of 1-hydroxypyrene across study periods. No significant differences were observed for smoking urges or measures of nicotine dependence.

Conclusions: The study adds to the evidence that cigarettes with markedly reduced nicotine content are not associated with increased smoking intensity or exposure to smoke toxicants.

Impact: The findings add to the evidence base on reduced nicotine content cigarettes and have the potential to inform FDA policy on nicotine levels. Cancer Epidemiol Biomarkers Prev; 23(10); 2032–40. ©2014 AACR.
A Peripheral Circulating TH1 Cytokine Profile Is Inversely Associated with Prostate Cancer Risk in CLUE II
Authors: Bhavsar Nrupen A. , Bream Jay H. , Meeker Alan K. , Drake Charles G. , Peskoe Sarah B. , Dabitao Djeneba , De Marzo Angelo M. , Isaacs William B. , Platz Elizabeth A.
Published: August 2014

Background: TH1 cytokines, such as IFNγ and TNFα, and potentially innate cytokines, such as IL6, can potentiate the immune response to tumor. Cytokines, such as IL1β, IL8, and IL10, may suppress anticancer immunity. Thus, we prospectively evaluated the association between peripheral-cytokine concentrations and prostate cancer.

Methods: We conducted an age-race matched case–control study (268 pairs) of incident prostate cancer in CLUE-II. We measured plasma IFNγ, IL10, IL12p70, IL1β, IL6, IL8, and TNFα concentrations using an ultrasensitive multiplex kit. ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression.

Results: The OR of prostate cancer decreased across quartiles of IFNγ (highest vs. lowest quartiles: OR, 0.49; 95% CI, 0.30–0.81; Ptrend = 0.006), TNFα (OR, 0.56; 95% CI, 0.33–0.96; Ptrend = 0.01), and IL6 (OR, 0.46; 95% CI, 0.26–0.79; Ptrend = 0.007). Higher TNFα (OR, 0.28; 95% CI, 0.09–0.85; Ptrend = 0.01) and IL6 (OR, 0.20; 95% CI, 0.06–0.67; Ptrend = 0.003) concentrations were associated with lower Gleason sum ≥7 disease risk. Other cytokines were not as clearly associated with risk.

Conclusions: Men with a prediagnostic circulating TH1 profile and higher IL6 may have a lower risk of prostate cancer, including aggressive disease. Whether this profile reflects (i) an intraprostatic immune environment in benign tissue that protects against prostate cancer, (ii) the immune milieu in response to a prostate adenocarcinoma that inhibits tumor growth and detectability, and/or (iii) a systemic immune profile that mediates the influence of modifiable factors on risk, warrants additional study.

Impact: Identifying specific inflammatory cytokines associated with prostate cancer may lead to improved prevention and treatment strategies. Cancer Epidemiol Biomarkers Prev; 23(11); 2561–7. ©2014 AACR.
Racial Differences in Adipose Tissue Distribution and Risk of Aggressive Prostate Cancer among Men Undergoing Radiotherapy
Authors: Allott Emma H. , Howard Lauren E. , Song Hai-Jun , Sourbeer Katharine N. , Koontz Bridget F. , Salama Joseph K. , Freedland Stephen J.
Published: August 2014

Background: Although elevated body mass index (BMI) has been associated with increased risk of aggressive prostate cancer, the importance of adipose tissue distribution is not well understood. We examined associations between overall and visceral obesity and aggressive prostate cancer risk. Moreover, given racial differences in adipose tissue distribution, we examined whether race modified these associations.

Methods: We conducted a cross-sectional analysis of 308 radiotherapy-treated patients with prostate cancer within the Durham VA from 2005 to 2011. Multivariable logistic regression examined the association between BMI categories and tertiles of waist circumference (WC), visceral fat area (VFA), and periprostatic adipose tissue area (PPAT) with high-grade prostate cancer risk (Gleason score ≥7 vs. ≤6). Models stratified by race examined whether these associations differed between black and nonblack men.

Results: Both elevated BMI (Ptrend = 0.054) and WC (Ptrend = 0.040) were associated with increased high-grade prostate cancer risk, with similar results between races, although the association with BMI was not statistically significant. In contrast, elevated VFA was associated with increased aggressive prostate cancer risk in black men (Ptrend = 0.002) but not nonblack men (Ptrend = 0.831), with a significant interaction between race and VFA (Pinteraction = 0.035). Though similar patterns were observed for PPAT, none was statistically significant.

Conclusions: Among men undergoing radiotherapy for prostate cancer, visceral obesity is associated with increased aggressive prostate cancer risk, particularly among black men. If confirmed in future studies, these results suggest that adipose tissue distribution differences may contribute to prostate cancer racial disparity.

Impact: These findings highlight the need to elucidate mechanisms contributing to racial differences in the association between visceral obesity and aggressive prostate cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2404–12. ©2014 AACR.
Development and Validation of a Gene Profile Predicting Benefit of Postmastectomy Radiotherapy in Patients with High-Risk Breast Cancer: A Study of Gene Expression in the DBCG82bc Cohort
Authors: Tramm Trine , Mohammed Hayat , Myhre Simen , Kyndi Marianne , Alsner Jan , Børresen-Dale Anne-Lise , Sørlie Therese , Frigessi Arnoldo , Overgaard Jens
Published: August 2014

Purpose: To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT).

Experimental Design: The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients.

Results: Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into “high LRR risk” and “low LRR risk” groups. PMRT significantly reduced risk of LRR in “high LRR risk” patients, whereas “low LRR risk” patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients.

Conclusions: A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT. Clin Cancer Res; 20(20); 5272–80. ©2014 AACR.
CDK2 Transcriptional Repression Is an Essential Effector in p53-Dependent Cellular Senescence—Implications for Therapeutic Intervention
Authors: Zalzali Hasan , Nasr Bilal , Harajly Mohamad , Basma Hussein , Ghamloush Farah , Ghayad Sandra , Ghanem Noël , Evan Gerard I , Saab Raya
Published: August 2014

Cellular senescence, a form of cell-cycle arrest, is a tumor-suppressor mechanism triggered by multiple tumor-promoting insults, including oncogenic stress and DNA damage. The role of cyclin-dependent kinase 2 (CDK2) regulation has been evaluated in models of replicative senescence, but little is known regarding its role in other senescence settings. Using in vitro and in vivo models of DNA damage–and oncogene-induced cellular senescence, it was determined that activation of the tumor-suppressor protein p53 (TP53) resulted in repression of the CDK2 transcript that was dependent on intact RB. Ectopic CDK2 expression was sufficient to bypass p53-dependent senescence, and CDK2-specific inhibition, either pharmacologically (CVT313) or by use of a dominant-negative CDK2, was sufficient to induce early senescence. Pharmacologic inhibition of CDK2 in an in vivo model of pineal tumor decreased proliferation and promoted early senescence, and it also decreased tumor penetrance and prolonged time to tumor formation in animals lacking p53. In conclusion, for both oncogene- and DNA damage–induced cellular senescence, CDK2 transcript and protein are decreased in a p53- and RB-dependent manner, and this repression is necessary for cell-cycle exit during senescence.

Implications: These data show that CDK2 inhibition may be useful for cancer prevention in premalignant hyperproliferative lesions, as well as established tumors. Mol Cancer Res; 13(1); 29–40. ©2014 AACR.
The Risk of High-Grade Squamous Intraepithelial Lesions in Women with Low Serum Levels of Vitamin A
Authors: Eleutério Jr. José , Giraldo Paulo César , Gonçalves Ana Katherine , Eleutério Renata Mirian Nunes , Barbosa Rita de Cássia Carvalho , Cavalcante Diane Isabelle Magno
Published: August 2014

Background: The progression of the cervical squamous intraepithelial lesion (SIL) is associated with many cofactors, and nutritional aspects are gradually assuming an important role in understanding the physiopathogenesis. Objective: To assess the serum levels of retinol in women from a poor region of Brazil with a histological diagnosis of cervical high-grade SIL (HSIL). Methods: A cross-sectional study was conducted in 62 women aged 14-48 years who had a cervical biopsy and were treated at the Federal University of Ceara in Fortaleza, Brazil. Serum retinol levels were measured in peripheral blood by a spectrophotometry technique. Values were categorized as subnormal (<20 µg/dl) or normal (≥20 µg/dl). Multivariate logistic regression was used to determine the association between serum levels of retinol and HSIL for a confidence interval of 95%. Results: Twenty-six out of 62 women (42%) had a negative histopathological result for SIL and 36 (58%) were diagnosed with SIL (20 low SIL and 16 high SIL). The level of retinol was more frequently low in women with HSIL, but there was no statistical significance [p = 0.409, OR: 2.26 (0.33-15.59)]. Conclusion: There was no association between high SIL and low levels of retinol in peripheral blood.
Impact of Intelligent Volume-Assured Pressure Support on Sleep Quality in Stable Hypercapnic Chronic Obstructive Pulmonary Disease Patients: A Randomized, Crossover Study
Authors: Ekkernkamp Emelie , Storre Jan H. , Windisch Wolfram , Dreher Michael
Published: August 2014

Background: Noninvasive positive-pressure ventilation (NPPV) using intelligent volume-assured pressure support (iVAPS) combines volume- and pressure-preset NPPV and therefore uses a variation of inspiratory positive airway pressures. Objectives: The effect of iVAPS on sleep quality in stable hypercapnic patients with chronic obstructive pulmonary disease (COPD) has not been determined. Methods: In this randomized, open-label, two-treatment, two-period, crossover study, patients were randomized to receive high-intensity (HI)-NPPV and then iVAPS or iVAPS and then HI-NPPV. Patients were studied in hospital for 2 consecutive nights, employing full polysomnography (PSG), transcutaneous partial pressure of CO2 (PtcCO2) monitoring, blood gas analysis and a visual analog scale (VAS)-based sleep questionnaire. After discharge, patients used HI-NPPV and iVAPS at home, each for 6 weeks. They had to answer a VAS question concerning sleep every morning, and were telephoned weekly and asked additional questions. At the end of each treatment period, they were visited at home for the determination of blood gases and treatment adherence, and to change the NPPV mode. Results: Fourteen patients were enrolled. In-hospital PSG measurements showed no difference in sleep quality between iVAPS and HI-NPPV. At home, patients reported more restful sleep during iVAPS than HI-NPPV (p = 0.04). Blood gases during spontaneous breathing at home did not differ with iVAPS and HI-NPPV, and there was a greater decrease in PtcCO2 during iVAPS than during HI-NPPV (p = 0.003). Conclusion: Although sleep quality in hospital was not different between iVAPS and HI-NPPV, COPD patients with chronic hypercapnic respiratory failure reported a trend towards more restful sleep at home with iVAPS. In addition, nocturnal hypercapnia was effectively treated with iVAPS.
Shear Stress–Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos
Authors: Li Rongsong , Beebe Tyler , Jen Nelson , Yu Fei , Takabe Wakako , Harrison Michael , Cao Hung , Lee Juhyun , Yang Hongbo , Han Peidong , Wang Kevin , Shimizu Hirohito , Chen Jaunian , Lien Ching-Ling , Chi Neil C. , Hsiai Tzung K.
Published: August 2014

Objective—

Fluid shear stress intimately regulates vasculogenesis and endothelial homeostasis. The canonical Wnt/β-catenin signaling pathways play an important role in differentiation and proliferation. In this study, we investigated whether shear stress activated angiopoietin-2 (Ang-2) via the canonical Wnt signaling pathway with an implication in vascular endothelial repair.

Approach and Results—

Oscillatory shear stress upregulated both TOPflash Wnt reporter activities and the expression of Ang-2 mRNA and protein in human aortic endothelial cells accompanied by an increase in nuclear β-catenin intensity. Oscillatory shear stress–induced Ang-2 and Axin-2 mRNA expression was downregulated in the presence of a Wnt inhibitor, IWR-1, but was upregulated in the presence of a Wnt agonist, LiCl. Ang-2 expression was further downregulated in response to a Wnt signaling inhibitor, DKK-1, but was upregulated by Wnt agonist Wnt3a. Both DKK-1 and Ang-2 siRNA inhibited endothelial cell migration and tube formation, which were rescued by human recombinant Ang-2. Both Ang-2 and Axin-2 mRNA downregulation was recapitulated in the heat-shock–inducible transgenic
Tg(hsp70l:dkk1-GFP
) zebrafish embryos at 72 hours post fertilization. Ang-2 morpholino injection of
Tg (kdrl:GFP
) fish impaired subintestinal vessel formation at 72 hours post fertilization, which was rescued by zebrafish Ang-2 mRNA coinjection. Inhibition of Wnt signaling with IWR-1 also downregulated Ang-2 and Axin-2 expression and impaired vascular repair after tail amputation, which was rescued by zebrafish Ang-2 mRNA injection.

Conclusions—

Shear stress activated Ang-2 via canonical Wnt signaling in vascular endothelial cells, and Wnt-Ang-2 signaling is recapitulated in zebrafish embryos with a translational implication in vascular development and repair.
Apolipoprotein A-I Increases Insulin Secretion and Production From Pancreatic β-Cells via a G-Protein-cAMP-PKA-FoxO1–Dependent Mechanism
Authors: Cochran Blake J. , Bisoendial Radjesh J. , Hou Liming , Glaros Elias N. , Rossy Jérémie , Thomas Shane R. , Barter Philip J. , Rye Kerry-Anne
Published: August 2014

Objective—

Therapeutic interventions that increase plasma levels of high-density lipoproteins and apolipoprotein A-I (apoA-I) A-I, the major high-density lipoprotein apolipoprotein, improve glycemic control in people with type 2 diabetes mellitus. High-density lipoproteins and apoA-I also enhance insulin synthesis and secretion in isolated pancreatic islets and clonal β-cell lines. This study identifies the signaling pathways that mediate these effects.

Approach and Results—

Incubation with apoA-I increased cAMP accumulation in Ins-1E cells in a concentration-dependent manner. The increase in cAMP levels was inhibited by preincubating the cells with the cell-permeable, transmembrane adenylate cyclase inhibitor, 2′5′ dideoxyadenosine, but not with KH7, which inhibits soluble adenylyl cyclases. Incubation of Ins-1E cells with apoA-I resulted in colocalization of ATP-binding cassette transporter A1 with the Gαs subunit of a heterotrimeric G-protein and a Gαs subunit-dependent increase in insulin secretion. Incubation of Ins-1E cells with apoA-I also increased protein kinase A phosphorylation and reduced the nuclear localization of forkhead box protein O1 (FoxO1). Preincubation of Ins-1E cells with the protein kinase A–specific inhibitors, H89 and PKI amide, prevented apoA-I from increasing insulin secretion and mediating the nuclear exclusion of FoxO1. Transfection of Ins-1E cells with a mutated FoxO1 that is restricted to the nucleus confirmed the requirement for FoxO1 nuclear exclusion by blocking insulin secretion in apoA-I–treated Ins-1E cells. ApoA-I also increased Irs1, Irs2, Ins1, Ins2, and Pdx1 mRNA levels.

Conclusions—

ApoA-I increases insulin synthesis and secretion via a heterotrimeric G-protein-cAMP-protein kinase A-FoxO1–dependent mechanism that involves transmembrane adenylyl cyclases and increased transcription of key insulin response and β-cell survival genes.
Implantable Defibrillators for Secondary Prevention of Sudden Cardiac Death in Cardiac Surgery Patients With Perioperative Ventricular Arrhythmias
Authors: Nageh Maged F. , Kim John J. , Chen Lie‐Hong , Yao Janis F.
Published: August 2014

Background

Randomized studies of implantable cardioverter defibrillators (
ICD
) have excluded sudden cardiac death survivors who had revascularization
before
or
after
an arrhythmic event. To evaluate the role of
ICD
and the effects of clinical variables including degree of revascularization, we studied cardiac surgery patients who had an
ICD
implanted for sustained perioperative ventricular arrhythmias.

Methods and Results

The electronic database for Southern California Kaiser Foundation hospitals was searched for patients who had cardiac surgery between 1999 and 2005 and an
ICD
implanted within 3 months of surgery. One hundred sixty‐four patients were identified; 93/164 had an
ICD
for sustained pre‐ or postoperative ventricular tachycardia or fibrillation requiring resuscitation. Records were reviewed for the following: presenting arrhythmia, ejection fraction, and degree of revascularization. The primary end point was total mortality (
TM
) and/or appropriate
ICD
therapy (
ICD
‐T), and secondary end points are
TM
and
ICD
‐T. During the mean follow up of 49 months, the primary endpoint of
TM
+
ICD
‐T and individual end points of
TM
and
ICD
‐T were observed in 52 (56%), 35 (38%), and 28 (30%) patients, respectively, with 55% of
TM
, and 23% of
ICD
‐T occurring within 2 years of implant. In multivariate risk analysis, none of the following was associated with any of the end points: incomplete revascularization, presenting ventricular arrhythmia, and timing of arrhythmias.

Conclusion

Our data supports the recent guidelines for
ICD
in this cohort of patients, as the presence of irreversible substrate and triggers of ventricular arrhythmias, cannot be reliably excluded even with complete revascularization. Further studies are needed to understand this complex group of patients.
Automated Quantification of Myocardial Salvage in a Rat Model of Ischemia–Reperfusion Injury Using 3D High‐Resolution Magnetic Resonance Imaging (MRI)
Authors: Grieve Stuart M. , Mazhar Jawad , Callaghan Fraser , Kok Cindy Y. , Tandy Sarah , Bhindi Ravinay , Figtree Gemma A.
Published: August 2014

Background

Quantification of myocardial “area at risk” (
AAR
) and myocardial infarction (
MI
) zone is critical for assessing novel therapies targeting myocardial ischemia–reperfusion (
IR
) injury. Current “gold‐standard” methods perfuse the heart with Evan's Blue and stain with triphenyl tetrazolium chloride (
TTC
), requiring manual slicing and analysis. We aimed to develop and validate a high‐resolution 3‐dimensional (3D) magnetic resonance imaging (MRI) method for quantifying
MI
and
AAR
.

Methods and Results

Forty‐eight hours after
IR
was induced, rats were anesthetized and gadopentetate dimeglumine was administered intravenously. After 10 minutes, the coronary artery was re‐ligated and a solution containing iron oxide microparticles and Evan's Blue was infused (for comparison). Hearts were harvested and transversally sectioned for
TTC
staining. Ex vivo
MR
images of slices were acquired on a 9.4‐T magnet. T2* data allowed visualization of
AAR
, with microparticle‐associated signal loss in perfused regions. T1 data demonstrated gadolinium retention in infarcted zones. Close correlation (
r
=0.92 to 0.94;
P
<0.05) of
MRI
and Evan's Blue/
TTC
measures for both
AAR
and
MI
was observed when the combined techniques were applied to the same heart slice. However, 3D
MRI
acquisition and analysis of whole heart reduced intra‐observer variability compared to assessment of isolated slices, and allowed automated segmentation and analysis, thus reducing interobserver variation. Anatomical resolution of 81 μm
3
was achieved (versus ≈2 mm with manual slicing).

Conclusions

This novel, yet simple,
MRI
technique allows precise assessment of infarct and
AAR
zones. It removes the need for tissue slicing and provides opportunity for 3D digital analysis at high anatomical resolution in a streamlined manner accessible for all laboratories already performing
IR
experiments.
Cardioprotection by Controlling Hyperamylinemia in a “Humanized” Diabetic Rat Model
Authors: Despa Sanda , Sharma Savita , Harris Todd R. , Dong Hua , Li Ning , Chiamvimonvat Nipavan , Taegtmeyer Heinrich , Margulies Kenneth B. , Hammock Bruce D. , Despa Florin
Published: August 2014

Background

Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart.

Methods and Results

By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (
HIP
rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca
2+
dysregulation. In time,
HIP
rats developed cardiac hypertrophy and left‐ventricular dilation. We then tested whether metabolites with antiaggregation properties, such as eicosanoid acids, limit myocardial amylin deposition. Rats were treated with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades endogenous eicosanoids. Treatment doubled the blood concentration of eicosanoids, which drastically reduced incorporation of aggregated amylin in cardiac myocytes and blood cells, without affecting pancreatic amylin secretion. Animals in the treated group showed reduced cardiac hypertrophy and left‐ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin‐induced cardiac oxidative stress and Ca
2+
dysregulation.

Conclusions

The results suggest blood amylin as a novel therapeutic target in diabetic heart disease and elevating blood levels of antiaggregation metabolites as a pharmacological strategy to reduce amylin aggregation and amylin‐mediated cardiotoxicity.
Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation‐Wide Cohort Study
Authors: Blicher Thalia Marie , Hommel Kristine , Kristensen Søren Lund , Torp‐Pedersen Christian , Madsen Mette , Kamper Anne‐Lise , Olesen Jonas Bjerring
Published: August 2014

Background

The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (
MI
) in patients with and without chronic kidney disease (
CKD
).

Methods and Results

By linking nation‐wide registries, information about patients admitted with incident
MI
was found. Primary endpoints were all‐cause and cardiovascular (
CV
) mortality, a composite of all‐cause mortality and recurrent
MI
, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (
PCI
) treatment.

A total of 69 082 incident
MI
patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (
HR
s) for the combined endpoint of all‐cause mortality and recurrent
MI
in
PCI
‐treated patients of 0.90 (95% confidence interval [
CI
], 0.47 to 1.72) in renal replacement therapy (
RRT
) patients, 0.59 (95%
CI
: 0.40 to 0.88) in non‐end‐stage
CKD
patients and 0.69 (95%
CI
, 0.61 to 0.77) in patients without kidney disease (
P
for interaction=0.60). In patients not treated with
PCI
,
HR
s were 0.90 (95%
CI
, 0.68 to 1.21) in
RRT
patients, 0.86 (95%
CI
, 0.75 to 0.99) in non‐end‐stage
CKD
patients, and 0.91 (95%
CI
, 0.87 to 0.95) in patients without kidney disease (
P
for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing
PCI
and for non‐end‐stage
CKD
patients undergoing
PCI
, whereas clopidogrel was associated with less bleedings in
PCI
‐treated
RRT
patients and patients without kidney disease.

Conclusions

During a 1‐year follow‐up, after
MI
, clopidogrel was associated with improved outcomes in patients with non‐end‐stage
CKD
. Even though no effect difference, compared to patients without
CKD
, was observed, the benefit associated with the use of clopidogrel after
MI
in patients requiring
RRT
is less clear.
Eligibility and Preference of New Oral Anticoagulants in Patients With Atrial Fibrillation
Authors: Yoon Chang Hyo , Park Yoon Kyung , Kim Suk Jae , Lee Mi-ji , Ryoo Sookyung , Kim Gyeong-Moon , Chung Chin-Sang , Lee Kwang Ho , Kim June Soo , Bang Oh Young
Published: August 2014

Background and Purpose—

Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy

Methods—

We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured.

Results—

The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%–40.5%) and planned cardioversion (5.1%–7.7%) for nonstroke patients, and a low creatinine clearance (5.6%–9.2%) and higher risk of bleeding (15.2%–20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) (
P
<0.05 in both cases).

Conclusions—

Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs.
Vagus Nerve Stimulation During Rehabilitative Training Improves Functional Recovery After Intracerebral Hemorrhage
Authors: Hays Seth A. , Khodaparast Navid , Hulsey Daniel R. , Ruiz Andrea , Sloan Andrew M. , Rennaker Robert L. , Kilgard Michael P.
Published: August 2014

Background and Purpose—

Vagus nerve stimulation (VNS) delivered during rehabilitative training enhances neuroplasticity and improves recovery in models of cortical ischemic stroke. However, VNS therapy has not been applied in a model of subcortical intracerebral hemorrhage (ICH). We hypothesized that VNS paired with rehabilitative training after ICH would enhance recovery of forelimb motor function beyond rehabilitative training alone.

Methods—

Rats were trained to perform an automated, quantitative measure of forelimb function. Once proficient, rats received an intrastriatal injection of bacterial collagenase to induce ICH. Rats then underwent VNS paired with rehabilitative training (VNS+Rehab; n=14) or rehabilitative training without VNS (Rehab; n=12). Rehabilitative training began ≥9 days after ICH and continued for 6 weeks.

Results—

VNS paired with rehabilitative training significantly improved recovery of forelimb function when compared with rehabilitative training without VNS. The VNS+Rehab group displayed a 77% recovery of function, whereas the Rehab group only exhibited 29% recovery. Recovery was sustained after cessation of stimulation. Both groups performed similar amounts of trials during rehabilitative, and lesion size was not different between groups.

Conclusions—

VNS paired with rehabilitative training confers significantly improved forelimb recovery after ICH compared to rehabilitative training without VNS.
Changes of Firing Rate Induced by Changes of Phase Response Curve in Bifurcation Transitions
Authors: Sato Yasuomi D. , Aihara Kazuyuki
Published: August 2014

We study dynamical mechanisms responsible for changes of the firing rate during four different bifurcation transitions in the two-dimensional Hindmarsh-Rose (2DHR) neuron model: the saddle node on an invariant circle (SNIC) bifurcation to the supercritical Andronov-Hopf (AH) one, the SNIC bifurcation to the saddle-separatrix loop (SSL) one, the AH bifurcation to the subcritical AH (SAH) one, and the SSL bifurcation to the AH one. For this purpose, we study slopes of the firing rate curve with respect to not only an external input current but also temperature that can be interpreted as a timescale in the 2DHR neuron model. These slopes are mathematically formulated with phase response curves (PRCs), expanding the firing rate with perturbations of the temperature and external input current on the one-dimensional space of the phase [Formula: see text] in the 2DHR oscillator. By analyzing the two different slopes of the firing rate curve with respect to the temperature and external input current, we find that during changes of the firing rate in all of the bifurcation transitions, the calculated slope with respect to the temperature also changes. This is largely dependent on changes in the PRC size that is also related to the slope with respect to the external input current. Furthermore, we find phase transition–like switches of the firing rate with a possible increase of the temperature during the SSL-to-AH bifurcation transition.
Risk-Aware Control
Authors: Sanger Terence D.
Published: August 2014

Human movement differs from robot control because of its flexibility in unknown environments, robustness to perturbation, and tolerance of unknown parameters and unpredictable variability. We propose a new theory, risk-aware control, in which movement is governed by estimates of risk based on uncertainty about the current state and knowledge of the cost of errors. We demonstrate the existence of a feedback control law that implements risk-aware control and show that this control law can be directly implemented by populations of spiking neurons. Simulated examples of risk-aware control for time-varying cost functions as well as learning of unknown dynamics in a stochastic risky environment are provided.
Quarrying Beautiful Bekhen Stone for the Pharaoh: The Exploitation of Wadi Hammamat in the Reign of Amenemhat III
Authors: González-Tablas Nieto Javier
Published: August 2014

The greywacke quarries in Wadi Hammamat are one of the best known examples of this kind of activity due to the number of inscriptions preserved at the site. Although a number of approaches to these inscriptions have been made, it is quite usual to find general studies about epigraphic features or the activities of one important functionary. The aim of this paper is to focus on the royal activities in the quarries at the end of the Middle Kingdom, more precisely in the reign of Amenemhat III, analyzing for that purpose both epigraphic and comparative archaeological data, in order to build a comprehensive image of the Egyptian works at this quarrying site.
The ‘Responsibility Not to Veto’, Secondary Rules, and the Rule of Law
Authors: Reinold Theresa
Published: August 2014

In this article I argue that the concept of secondary rules provides a useful tool for analysing the interplay of politics and law in the evolution of the ‘responsibility not to veto’, which represents an attempt to subject the Security Council to the rule of law. Secondary rules help to maintain the law’s overall coherence, thereby bolstering its legitimacy and hence its ability to effectively govern human conduct. Most accounts of secondary rule-making overstate the role of power while underestimating the need for powerful states to argue within the parameters set by the law itself. This contribution, by contrast, explores the interaction of power and law, and the role of secondary rules therein. It shows that the international legal order currently lacks coherence as there is no consensus on overarching principles. Hence, the legitimacy crisis of the Security Council is at the same time a legitimacy crisis of international law.
The African Union, Responsible Sovereignty and Contested States
Authors: Geldenhuys Deon
Published: August 2014

Post-colonial Africa has experienced relatively few contested states, defined as entities whose purported statehood is widely challenged by existing states. During the 1960s and 1970s the self-proclaimed states of Katanga, Biafra and Rhodesia encountered serious deficits in international recognition. The same fate befell the independent Bantustans created by South Africa. Today only the Sahrawi Arab Democratic Republic and Somaliland fall in this category. The pair’s remarkable longevity shows that they cannot be wished away. Nor can Africa ignore the conflict potential attached to the very existence of the two disputed states. The African Union’s endorsement of the notion of sovereignty as responsibility provides moral obligations, pragmatic incentives and R2P-associated tools for dealing with the challenges posed by current and future contested states. The African Union could, however, consider two adaptations to R2P procedures. The first is the designation of established contested states as ‘territories of concern’ to highlight the necessity of collective R2P-type initiatives to resolve these situations. The second calls for the introduction of a ‘secessionism alert’ as part of the au’s early-warning system to try to prevent violent secession and the likely birth of contested states.
Usable Past for a Transbaikalian Borderline Town
Authors: Peshkov Ivan
Published: August 2014

This paper aims at analysing the depoliticisation process of a border region’s past from the perspective of simultaneous changes in biographies of people, objects and forbidden places. Turning the closed Soviet-Chinese border into a relatively open Russian–Chinese border meant not only opening the socialist borderline areas to the world, but also confronting Russian society with an intensely mythologised area and people connected with it. The combination of the totally Soviet symbolic space of the of the border town of Priargunsk in Eastern Transbaikalia with extremely differing attitudes towards the socialist past enables us to show the influence of borderline location on post-communist struggles with the trauma of long-lasting political confrontation in a different light. This new version of the past not only offers the possibility of including former enemies in the new post-communist border community, but also of establishing a fresh connection with Soviet objects, now defined as historically specific signs of the long Russian presence in the area. We are dealing with a peculiar post-Soviet case of an epistemic advantage of border, according to which the borderline and peripheral location of extreme ideological and cultural attitudes encourages unexpected forms of time and space perception, regardless of the incomplete reconciliation process following the Civil War.
Border Language
Authors: Namsaraeva Sayana
Published: August 2014

The conceptual framework of this paper is to view Mongolia as a ‘contact zone’ which geographically bridged the gap between two rapidly growing Eurasian empires—Russia and China. It allows a rethinking of the historical and social circumstances that led to the formation of Chinese Pidgin Russian (cpr)1 by highlighting the lexical and grammatical influence of the Mongolian language on contact languages in the China–Russia border area. In particular, it discusses Mongolian language in various encounters in Russian–Chinese interactions, such as the use of Mongolian as mediation language during the initial stage of Qing–Russian diplomatic relations and as lingua franca in caravan trade and border relations between Russia and China, as well as its influence on the formation of Transbaikal dialect (or Zabaikal’skoe narechie), which was widely spoken by Russians in Mongol-speaking colonial frontiers of Russia in Eastern Siberia. Moreover, the paper highlights the Mongolian elements in the first cpr, questioning a common scholarly perception that Kiakhta (or Maimacheng)2 pidgin consisted primarily of Russian and Chinese borrowings. Therefore, unique language hybridisation of these three languages continues to be noticeable in Russia–China trade hubs in Inner Mongolia nowadays, where transborder ethnic and economic contacts between Russia, China and Mongolia are becoming more complicated and diverse.
Hungarian Witnesses of Infrastructure Construction in Manchuria (1877–1931)
Authors: Sántha István
Published: August 2014

This paper presents accounts of seven travelogues, written by Hungarian travellers and professionals who visited or worked in Manchuria between the end of the nineteenth and beginning of the twentieth centuries. So far these texts have not received wide scholarly attention because they are accessible only in Hungarian, although they contain unique first-hand observations of the construction of the Eastern Chinese Railway and many ethnographic notes. The author suggests that some narratives, especially those written by Hungarians who worked as engineering specialists, present very balanced analysis of the situation, because they belonged neither to the colonising project in China, nor to the colonised side, but rather were enthusiasts of technological modernisation. As a theoretical frame, the author attempts to apply notions and concepts developed by infrastructural and cybernetic anthropology.
The genus Scirtothrips (Thysanoptera: Thripidae) in Malaysia, with four new species and comments on Biltothrips, a related genus
Authors: NG Y.F. , MOUND L.A. , AZIDAH A.A.
Published: August 2014

Species of the genus Scirtothrips are studied from Malaysia for the first time. Six species of this genus are here recorded from Malaysia: S. dobroskyi is newly recorded, and four new species: S. lantanae sp.n., S. lixinae sp.n., S. hitam sp.n. and S. malayensis sp.n. are described together with an illustrated identification key. Relationships were examined between S. dorsalis and the closely related S. hitam sp.n., based on the mitochondrial gene COI, and a redescription of the widespread pest species, dorsalis, is provided. Biltothrips minutus (Bhatti) is reported from Malaysia for the first time, and illustrations provided to distinguish this genus from Scirtothrips.
Inhomogeneous Background Error Modeling for WRF-Var Using the NMC Method
Authors: Wang Hongli , Huang Xiang-Yu , Sun Juanzhen , Xu Dongmei , Zhang Man , Fan Shuiyong , Zhong Jiqin
Published: August 2014

Background error modeling plays a key role in a variational data assimilation system. The National Meteorological Center (NMC) method has been widely used in variational data assimilation systems to generate a forecast error ensemble from which the climatological background error covariance can be modeled. In this paper, the characteristics of the background error modeling via the NMC method are investigated for the variational data assimilation system of the Weather Research and Forecasting (WRF-Var) Model. The background error statistics are extracted from short-term 3-km-resolution forecasts in June, July, and August 2012 over a limited-area domain. It is found 1) that background error variances vary from month to month and also have a feature of diurnal variations in the low-level atmosphere and 2) that u- and υ-wind variances are underestimated and their autocorrelation length scales are overestimated when the default control variable option in WRF-Var is used. A new approach of control variable transform (CVT) is proposed to model the background error statistics based on the NMC method. The new approach is capable of extracting inhomogeneous and anisotropic climatological information from the forecast error ensemble obtained via the NMC method. Single observation assimilation experiments show that the proposed method not only has the merit of incorporating geographically dependent covariance information, but also is able to produce a multivariate analysis. The results from the data assimilaton and forecast study of a real convective case show that the use of the new CVT improves synoptic weather system and precipitation forecasts for up to 12 h.