bluuebunny/crossref_metadata_2025 huggingface dataset:
MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation
Authors: Kean Thomas J. , Lin Paul , Caplan Arnold I. , Dennis James E.
Published: August 2013

Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the “first-pass” accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.
Oxidized LDL and LOX-1 in Experimental Sepsis
Authors: Al-Banna Nadia , Lehmann Christian
Published: August 2013

Oxidized low-density lipoproteins (oxLDL) and the lectin-like oxLDL receptor-1 (LOX-1) are upregulated in inflammation. Because of the importance of inflammation and capillary leakage in the impairment of the microcirculation, which in turn contributes to the development of sepsis and multiorgan failure, the role of oxidized LDL and LOX-1 as players of intestinal inflammation is of great interest. In fact, the blockade of LOX-1 during experimental endotoxemia was effective in reducing leukocyte activation. There are several mechanisms by which oxLDL can participate in local and systemic inflammation, including cell proliferation, apoptosis, capillary perfusion, leukocyte-endothelial cell interactions, and endothelial activation. This review highlights the evidence relating oxLDL and LOX-1 to proinflammatory disease mechanisms. We also indicate situations when oxLDL, because of exposure time, dose, or degree of oxidization, is involved in disease resolution. Modulation of LOX-1 response could be utilized for the treatment of local and systemic inflammation, but the successful use of this target requires further understanding of its broad effects.
Flow‐Field Characteristics of High‐Temperature Annular Buoyant Jets and Their Development Laws Influenced by Ventilation System
Authors: Wang Yi , Huang Yanqiu , Liu Jiaping , Wang Hai , Liu Qiuhan
Published: August 2013

The flow‐field characteristics of high‐temperature annular buoyant jets as well as the development laws influenced by ventilation system were studied using numerical methods to eliminate the pollutants effectively in this paper. The development laws of high‐temperature annular buoyant jets were analyzed and compared with previous studies, including radial velocity distribution, axial velocity and temperature decay, reattachment position, cross‐section diameter, volumetric flow rate, and velocity field characteristics with different pressures at the exhaust hood inlet. The results showed that when the ratio of outer diameter to inner diameter of the annulus was smaller than 5/2, the flow‐field characteristics had significant difference compared to circular buoyant jets with the same outer diameter. For similar diameter ratios, reattachment in this paper occurred further downstream in contrast to previous study. Besides, the development laws of volumetric flow rate and cross‐section diameter were given with different initial parameters. In addition, through analyzing air distribution characteristics under the coupling effect of high‐temperature annular buoyant jets and ventilation system, it could be found that the position where maximum axial velocity occurred was changing gradually when the pressure at the exhaust hood inlet changed from 0 Pa to −5 Pa.
Role ofCampylobacter jejuniInfection in the Pathogenesis of Guillain-Barré Syndrome: An Update
Authors: Nyati Kishan Kumar , Nyati Roopanshi
Published: August 2013

Our current knowledge onCampylobacter jejuniinfections in humans has progressively increased over the past few decades. Infection withC. jejuniis the most common cause of bacterial gastroenteritis, sometimes surpassing other infections due toSalmonella,Shigella, andEscherichia coli.Most infections are acquired due to consumption of raw or undercooked poultry, unpasteurized milk, and contaminated water. After developing the diagnostic methods to detectC. jejuni, the possibility to identify the association of its infection with new diseases has been increased. After the successful isolation ofC. jejuni, reports have been published citing the occurrence of GBS followingC. jejuniinfection. Thus,C. jejuniis now considered as a major triggering agent of GBS. Molecular mimicry between sialylated lipooligosaccharide structures on the cell envelope of these bacteria and ganglioside epitopes on the human nerves that generates cross-reactive immune response results in autoimmune-driven nerve damage. ThoughC. jejuniis associated with several pathologic forms of GBS, axonal subtypes followingC. jejuniinfection may be more severe. Ample amount of existing data covers a large spectrum of GBS; however, the studies onC. jejuni-associated GBS are still inconclusive. Therefore, this review provides an update on theC. jejuniinfections engaged in the pathogenesis of GBS.
Fuzzy Logic-Based Histogram Equalization for Image Contrast Enhancement
Authors: Magudeeswaran V. , Ravichandran C. G.
Published: August 2013

Fuzzy logic-based histogram equalization (FHE) is proposed for image contrast enhancement. The FHE consists of two stages. First, fuzzy histogram is computed based on fuzzy set theory to handle the inexactness of gray level values in a better way compared to classical crisp histograms. In the second stage, the fuzzy histogram is divided into two subhistograms based on the median value of the original image and then equalizes them independently to preserve image brightness. The qualitative and quantitative analyses of proposed FHE algorithm are evaluated using two well-known parameters like average information contents (AIC) and natural image quality evaluator (NIQE) index for various images. From the qualitative and quantitative measures, it is interesting to see that this proposed method provides optimum results by giving better contrast enhancement and preserving the local information of the original image. Experimental result shows that the proposed method can effectively and significantly eliminate washed-out appearance and adverse artifacts induced by several existing methods. The proposed method has been tested using several images and gives better visual quality as compared to the conventional methods.
Saussurea lappaClarke-Derived Costunolide Prevents TNFα-Induced Breast Cancer Cell Migration and Invasion by Inhibiting NF-κB Activity
Authors: Choi Youn Kyung , Cho Sung-Gook , Woo Sang-Mi , Yun Yee Jin , Jo Jeakyung , Kim Wooyoung , Shin Yong Cheol , Ko Seong-Gyu
Published: August 2013

Saussurea lappaClarke (SLC) has been used as a traditional medicine in Korea, China, and Japan for the treatment of abdominal pain and tenesmus. Costunolide, a sesquiterpene lactone isolated from SLC, has diverse medicinal effects. However, the anticancer effects of costunolide are still unclear in breast cancer. In this study, we demonstrate that costunolide suppresses tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNFα-induced NF-κB activation. Costunolide inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in thein vivomouse orthotopic tumor growth assays. In addition, costunolide inhibitedin vitroTNFα-induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNFα-induced NF-κB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-κB-dependent gene to mediate breast cancer cell growth and metastases. Therefore, we conclude that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNFα-induced NF-κB activation, suggesting that costunolide as well as SLC may be promising anticancer drugs, especially for metastatic breast cancer.
Neurotensin Modulates the Migratory and Inflammatory Response of Macrophages under Hyperglycemic Conditions
Authors: Moura Liane I. F. , Silva Lucília , Leal Ermelindo C. , Tellechea Ana , Cruz Maria Teresa , Carvalho Eugénia
Published: August 2013

Diabetic foot ulcers (DFUs) are characterized by an unsatisfactory inflammatory and migratory response. Skin inflammation involves the participation of many cells and particularly macrophages. Macrophage function can be modulated by neuropeptides; however, little is known regarding the role of neurotensin (NT) as a modulator of macrophages under inflammatory and hyperglycemic conditions. RAW 264.7 cells were maintained at 10/30 mM glucose, stimulated with/without LPS (1 μg/mL), and treated with/without NT(10 nM). The results show that NT did not affect macrophage viability. However, NT reverted the hyperglycemia-induced impair in the migration of macrophages. The expression of IL-6 and IL-1βwas significantly increased under 10 mM glucose in the presence of NT, while IL-1βand IL-12 expression significantly decreased under inflammatory and hyperglycemic conditions. More importantly, high glucose modulates NT and NT receptor expression under normal and inflammatory conditions. These results highlight the effect of NT on cell migration, which is strongly impaired under hyperglycemic conditions, as well as its effect in decreasing the proinflammatory status of macrophages under hyperglycemic and inflammatory conditions. These findings provide new insights into the potential therapeutic role of NT in chronic wounds, such as in DFU, characterized by a deficit in the migratory properties of cells and a chronic proinflammatory status.
Posterior Intravaginal Slingplasty versus Unilateral Sacrospinous Ligament Fixation in Treatment of Vaginal Vault Prolapse
Authors: Nyyssönen Virva , Talvensaari-Mattila Anne , Santala Markku
Published: August 2013

Objective. To investigate the differences in efficacy, postoperative complications, and patient satisfaction between posterior intravaginal slingplasty (PIVS) and unilateral sacrospinous ligament fixation (SSLF) procedures. Study Design. A retrospective study of thirty-three women who underwent PIVS or SSLF treatment for vaginal vault prolapse in Oulu University Hospital. The patients were invited to a follow-up visit to evaluate the objective and subjective outcomes. Median follow-up time was 16 months (range 6–52). The anatomical outcome was detected by the Pelvic Organ Prolapse Quantification (POP-Q) system. Information on urinary, bowel, and sexual dysfunctions and overall satisfaction was gathered with specific questionnaire. The data were analyzed using Mann-Whitney U test and Fisher’s exact test. Results. Mesh erosion was found in 4 (25%) patients in the PIVS group. Anatomical stage II prolapse or worse (any POP-Q point ≥−1) was detected in 8 (50%) patients in the PIVS group and 9 (53%) patients in the SSLF group. Overall satisfaction rates were 62% and 76%, respectively. Conclusion. The efficacy of PIVS and SSLF is equally poor, and the rate of vaginal erosion is intolerably high with the PIVS method. Based on our study, we cannot recommend the usage of either technique in operative treatment of vaginal vault prolapse.
Effect of Wenxin Granule on Ventricular Remodeling and Myocardial Apoptosis in Rats with Myocardial Infarction
Authors: Wu Aiming , Zhai Jianying , Zhang Dongmei , Lou Lixia , Zhu Haiyan , Gao Yonghong , Chai Limin , Xing Yanwei , Lv Xiying , Zhu Lingqun , Zhao Mingjing , Wang Shuoren
Published: August 2013

Aim. To determine the effect of a Chinese herbal compound named Wenxin Granule on ventricular remodeling and myocardial apoptosis in rats with myocardial infarction (MI).Methods. Male Sprague-Dawley (SD) rats were randomly divided into four groups: the control group, the model group, the metoprolol group, and the Wenxin Granule group (WXKL group) with sample size (n) of 7 rats in each group. An MI model was established in all rats by occlusion of the left anterior descending coronary artery (the control group was without occlusion). Wenxin Granule (1.35 g/kg/day), metoprolol (12 mg/kg/day), and distilled water (5 mL/kg/day for the control and model groups) were administered orally for 4 weeks. Ultrasonic echocardiography was used to examine cardiac structural and functional parameters. Myocardial histopathological changes were observed using haematoxylin and eosin (H&E) dyeing. Myocardial apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Serum angiotensin II (Ang II) concentration was measured using the enzyme-linked immunosorbent assay (ELISA).Results. It was found that Wenxin Granule could partially reverse ventricular remodeling, improve heart function, alleviate the histopathological damage, inhibit myocardial apoptosis, and reduce Ang II concentration in rats with MI.Conclusions. The results of the current study suggest that Wenxin Granule may be a potential alternative and complementary medicine for the treatment of MI.
Double Minute Chromosomes in Glioblastoma Multiforme Are Revealed by Precise Reconstruction of Oncogenic Amplicons
Authors: Sanborn J. Zachary , Salama Sofie R. , Grifford Mia , Brennan Cameron W. , Mikkelsen Tom , Jhanwar Suresh , Katzman Sol , Chin Lynda , Haussler David
Published: August 2013

DNA sequencing offers a powerful tool in oncology based on the precise definition of structural rearrangements and copy number in tumor genomes. Here, we describe the development of methods to compute copy number and detect structural variants to locally reconstruct highly rearranged regions of the tumor genome with high precision from standard, short-read, paired-end sequencing datasets. We find that circular assemblies are the most parsimonious explanation for a set of highly amplified tumor regions in a subset of glioblastoma multiforme samples sequenced by The Cancer Genome Atlas (TCGA) consortium, revealing evidence for double minute chromosomes in these tumors. Further, we find that some samples harbor multiple circular amplicons and, in some cases, further rearrangements occurred after the initial amplicon-generating event. Fluorescence in situ hybridization analysis offered an initial confirmation of the presence of double minute chromosomes. Gene content in these assemblies helps identify likely driver oncogenes for these amplicons. RNA-seq data available for one double minute chromosome offered additional support for our local tumor genome assemblies, and identified the birth of a novel exon made possible through rearranged sequences present in the double minute chromosomes. Our method was also useful for analysis of a larger set of glioblastoma multiforme tumors for which exome sequencing data are available, finding evidence for oncogenic double minute chromosomes in more than 20% of clinical specimens examined, a frequency consistent with previous estimates. Cancer Res; 73(19); 6036–45. ©2013 AACR.
Identification of Transcriptional Subgroups in EGFR-Mutated and EGFR/KRAS Wild-Type Lung Adenocarcinoma Reveals Gene Signatures Associated with Patient Outcome
Authors: Planck Maria , Isaksson Sofi , Veerla Srinivas , Staaf Johan
Published: August 2013

Purpose: In lung adenocarcinoma, EGFR and KRAS mutations dominate the mutational spectrum and have clear therapeutic implications. We sought to determine whether transcriptional subgroups of clinical relevance exist within EGFR-mutated, KRAS-mutated, or EGFR and KRAS wild-type (EGFRwt/KRASwt) adenocarcinomas.

Experimental Design: Gene expression profiles from 1,186 adenocarcinomas, including 215 EGFR-mutated, 84 KRAS-mutated, and 219 EGFRwt/KRASwt tumors, were assembled and divided into four discovery (n = 522) and four validation cohorts (n = 664). Subgroups within the mutation groups were identified by unsupervised consensus clustering, significance analysis of microarrays (SAM) analysis, and centroid classification across discovery cohorts. Genomic alterations in identified mutation subgroups were assessed by integration of genomic profiles for 158 cases with concurrent data. Multicohort expression subgroup predictors were built for each mutation group using the discovery cohorts, and validated in the four validation cohorts.

Results: Consensus clustering within the mutation groups identified reproducible transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt tumors, but not in KRAS-mutated tumors. Subgroups displayed differences in genomic alterations, clinicopathologic characteristics, and overall survival. Multicohort gene signatures derived from the mutation subgroups added independent prognostic information in their respective mutation group, for adenocarcinoma in general and stage I tumors specifically, irrespective of mutation status, when applied to the validation cohorts. Consistent with their worse clinical outcome, high-risk subgroups showed higher expression of proliferation-related genes, higher frequency of copy number alterations/amplifications, and association with a poorly differentiated tumor phenotype.

Conclusions: We identified transcriptional subgroups in EGFR-mutated and EGFRwt/KRASwt adenocarcinomas with significant differences in clinicopathologic characteristics and patient outcome, not limited to a mutation-specific setting. Clin Cancer Res; 19(18); 5116–26. ©2013 AACR.
HLA and Killer Immunoglobulin-like Receptor Genes as Outcome Predictors of Hepatitis C Virus–Related Hepatocellular Carcinoma
Authors: Cariani Elisabetta , Pilli Massimo , Zerbini Alessandro , Rota Cristina , Olivani Andrea , Zanelli Paola , Zanetti Adele , Trenti Tommaso , Ferrari Carlo , Missale Gabriele
Published: August 2013

Purpose: We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)–related hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA).

Experimental Design: Sixty-one consecutive patients with HCV-related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype.

Results: Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P < 0.03 each). Homozygous HLA-C1 (P < 0.02) and HLA-Bw4I80 (P < 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P < 0.02) and HLA-Bw4T80 (P < 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P < 0.03) and HLA-C1 (P < 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P < 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P < 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56dim) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3.

Conclusions: These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes. Clin Cancer Res; 19(19); 5465–73. ©2013 AACR.
Overcoming Platinum Resistance in Preclinical Models of Ovarian Cancer Using the Neddylation Inhibitor MLN4924
Authors: Jazaeri Amir A. , Shibata Etsuko , Park Jonghoon , Bryant Jennifer L. , Conaway Mark R. , Modesitt Susan C. , Smith Peter G. , Milhollen Michael A. , Berger Allison J. , Dutta Anindya
Published: August 2013

The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for patients with ovarian cancer. In this investigation, we evaluated the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, in ovarian cancer cells. Efficacy of MLN4924 both alone and in combination with platinum was assessed. Overall, single-agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. However, the combination of MLN4924 with cisplatin or carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as in primary ovarian cancer cell lines established from high-grade serous, clear cell, and serous borderline ovarian tumors. The efficacy of cisplatin plus MLN4924 was also evident in several in vitro models of platinum-resistant ovarian cancer. Mechanistically, the combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An siRNA screen was used to investigate the contribution of each member of the cullin RING ligase (CRL) family of E3 ubiquitin ligases, the best-characterized downstream mediators of MLN4924's biologic effects. Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3 ovarian cancer cells. This investigation identifies inhibition of neddylation as a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer. Mol Cancer Ther; 12(10); 1958–67. ©2013 AACR.
A Urokinase Receptor–Derived Peptide Inhibiting VEGF-Dependent Directional Migration and Vascular Sprouting
Authors: Bifulco Katia , Longanesi-Cattani Immacolata , Liguori Eleonora , Arra Claudio , Rea Domenica , Masucci Maria Teresa , De Rosa Mario , Pavone Vincenzo , Stoppelli Maria Patrizia , Carriero Maria Vincenza
Published: August 2013

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration, and uPAR88–92 is the minimal sequence required to induce cell motility. We previously showed that soluble forms of uPAR elicit angiogenic responses through their uPAR88–92 chemotactic sequence and that the synthetic peptide SRSRY exerts similar effects. By a drug design approach, based on the conformational analysis of the uPAR88–92 sequence, we developed peptides (pERERY, RERY, and RERF) that potently inhibit signaling triggered by uPAR88–92. In this study, we present evidence that these peptides are endowed also with a clear-cut antiangiogenic activity, although to different extents. The most active, RERF, prevents tube formation by human endothelial cells exposed to SRSRY. RERF also inhibits VEGF-triggered endothelial cell migration and cord-like formation in a dose-dependent manner, starting in the femtomolar range. RERF prevents F-actin polymerization, recruitment of αvβ3 integrin at focal adhesions, and αvβ3/VEGFR2 complex formation in endothelial cells exposed to VEGF. At molecular level, the inhibitory effect of RERF on VEGF signaling is shown by the decreased amount of phospho-FAK and phospho-Akt in VEGF-treated cells. In vivo, RERF prevents VEGF-dependent capillary sprouts originating from the host vessels that invaded angioreactors implanted in mice and neovascularization induced by subcorneal implantation of pellets containing VEGF in rabbits. Consistently, RERF reduced the growth and vascularization rate of tumors formed by HT1080 cells injected subcutaneously in the flanks of nude mice, indicating that RERF is a promising therapeutic agent for the control of diseases fuelled by excessive angiogenesis such as cancer. Mol Cancer Ther; 12(10); 1981–93. ©2013 AACR.
Characterization of a New Class of Androgen Receptor Antagonists with Potential Therapeutic Application in Advanced Prostate Cancer
Authors: Li Huifang , Hassona Mohamed D.H. , Lack Nathan A. , Axerio-Cilies Peter , Leblanc Eric , Tavassoli Peyman , Kanaan Natalia , Frewin Kate , Singh Kriti , Adomat Hans , Böhm Konrad J. , Prinz Helge , Guns Emma Tomlinson , Rennie Paul S. , Cherkasov Artem
Published: August 2013

The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer. Mol Cancer Ther; 12(11); 2425–35. ©2013 AACR.
A Case of Spontaneous Extracranial Epidural Emphysema
Authors: Gokhale Sankalp , Gokhale Sanjay
Published: August 2013

Objective: To report a rare case of spontaneous extracranial epidural emphysema. Clinical Presentation and Intervention: An 18-year-old woman with a recent diagnosis of squamous cell carcinoma of the esophagus presented with acute onset of cough, dyspnea and subcutaneous emphysema. An esophageal endoscopy revealed an ulcerative lesion in the upper third of the esophagus that was diagnosed as squamous cell carcinoma. A computed tomographic scan of the chest showed spinal epidural emphysema in addition to pneumomediastinum and pneumoperitoneum. A few days later, the patient died of aspiration pneumonia and persistent epidural emphysema. Conclusion: The spontaneous extracranial epidural emphysema in our case resulted from a bout of cough with tracking of air from the pneumomediastinum through the emaciated tissue planes into the epidural space.
Vaccinia Virus Outperforms a Panel of Other Poxviruses as a Potent Oncolytic Agent for the Control of Head and Neck Squamous Cell Carcinoma Cell Lines
Authors: Nichols Anthony C. , Yoo John , Um Sung , Mundi Neil , Palma David A. , Fung Kevin , MacNeil S. Danielle , Koropatnick James , Mymryk Joe S. , Barrett John W.
Published: August 2013

Background: Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. Existing therapies for advanced tumors have high failure rates and can have severe consequences in terms of pain, disfigurement, and poor speech and swallowing function. New treatment strategies are needed to improve outcomes for patients suffering with this disease and oncolytic viruses represent a promising approach. Methods: We infected six well-characterized HNSCC cell lines (Cal27, Detroit562, FaDu, SCC4, SCC15, SCC25), with increasing doses of a panel of poxviruses (including myxoma, vaccinia, raccoonpox and tanapox viruses) modified to express green fluorescence protein to determine which virus was the most effective oncolytic agent in cell-based assays. Results: While myxoma, raccoonpox and tanapox displayed differing efficacy in the panel of cell lines, vaccinia virus was the most potent of the tested poxviruses and was highly effective in controlling cell growth in all cell lines. Conclusion: Oncolytic poxviruses, particularly vaccinia virus, were effective in killing HNSCC in vitro and hold promise as potential treatments for patients with HNSCC.
Pulpal Involvement-Roots-Sepsis Index: A New Method for Describing the Clinical Consequences of Untreated Dental Caries
Authors: Baginska Joanna , Stokowska Wanda
Published: August 2013

Objectives: To describe a modification of the index of clinical consequences of untreated dental caries [pulpal involvement, ulceration, fistula and abscess (PUFA/pufa) index] to pulpal involvement-roots-sepsis (PRS/prs) and to compare the two indices using the example of caries in primary molar teeth in children aged 6-8 years. Subjects andMethods: The study sample included 542 children aged 6-8 years, from five randomly selected schools in the Bialystok District, Poland. The occurrence of clinical consequences of untreated caries in deciduous molars using the pufa and prs indices was evaluated. Data were analysed to express the prevalence, the experience and the distribution of particular pufa and prs codes in the sample population. The differences in layout of the pufa and prs components were expressed. Results: The response rate was 77.6%. The prevalence of the clinical consequences of untreated caries was 40.77%, mean pufa and prs were the same (0.85 ± 1.33). According to the pufa index, the following mean values were obtained: p = 0.79, u = 0.01, f = 0.04 and a = 0.01. For the prs index, the mean values were as follows: p = 0.45, r = 0.35 and s = 0.05. Conclusion: The proposed prs index was a useful epidemiological instrument for the evaluation of the clinical consequences of untreated caries in the surveyed population. The PRS instrument could be a good alternative to the PUFA index.
Differential Translocation of the Fatty Acid Transporter, FAT/CD36, and the Glucose Transporter, GLUT4, Coordinates Changes in Cardiac Substrate Metabolism During Ischemia and Reperfusion
Authors: Heather Lisa C. , Pates Katharine M. , Atherton Helen J. , Cole Mark A. , Ball Daniel R. , Evans Rhys D. , Glatz Jan F. , Luiken Joost J. , Griffin Julian L. , Clarke Kieran
Published: August 2013

Background—

Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to regulate substrate metabolism acutely. We hypothesised that during ischemia fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma to limit fatty acid uptake when fatty acid oxidation is inhibited.

Methods and Results—

Wistar rat hearts were perfused during preischemia, low-flow ischemia, and reperfusion, using
3
H-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation. During ischemia, there was a 32% decrease in sarcolemmal FAT/CD36 accompanied by a 95% decrease in fatty acid oxidation rates, with no change in intramyocardial lipids. Concomitantly, the sarcolemmal content of the glucose transporter, GLUT4, increased by 90% during ischemia, associated with an 86% increase in glycolytic rates, 45% decrease in glycogen content, and a 3-fold increase in phosphorylated AMP-activated protein kinase. Following reperfusion, decreased sarcolemmal FAT/CD36 persisted, but fatty acid oxidation rates returned to preischemic levels, resulting in a 35% decrease in myocardial triglyceride content. Elevated sarcolemmal GLUT4 persisted during reperfusion; in contrast, glycolytic rates decreased to 30% of preischemic rates, accompanied by a 5-fold increase in intracellular citrate levels and restoration of glycogen content.

Conclusions—

During ischemia, FAT/CD36 moved away from the sarcolemma as GLUT4 moved toward the sarcolemma, associated with a shift from fatty acid oxidation to glycolysis, while intramyocardial lipid accumulation was prevented. This relocation was maintained during reperfusion, which was associated with replenishing glycogen stores as a priority, occurring at the expense of glycolysis and mediated by an increase in citrate levels.
Race Influences the Safety and Efficacy of Spironolactone in Severe Heart Failure
Authors: Vardeny Orly , Cavallari Larisa H. , Claggett Brian , Desai Akshay S. , Anand Inder , Rossignol Patrick , Zannad Faiez , Pitt Bertram , Solomon Scott D.
Published: August 2013

Background—

The incidence of hyperkalemia caused by mineralocorticoid receptor antagonists may vary by race, but whether race influences efficacy of mineralocorticoid receptor antagonists in heart failure (HF) is unknown.

Methods and Results—

We assessed hyperkalemia and outcomes in African Americans (AAs; n=120) and non-AAs (n=1543; white 93%) with New York Heart Association (NYHA) class III or IV HF and left ventricular dysfunction who were randomized to spironolactone, titrated to 25 or 50 mg daily or placebo, in the Randomized Aldactone Evaluation Study (RALES). AA participants were significantly younger, less likely to have an ischemic HF pathogenesis, more likely to be NYHA functional class IV, and more likely to have a higher estimated glomerular filtration rate and heart rate, less hypertension, diabetes mellitus, or history of myocardial infarction compared with non-AA participants. Potassium increased with spironolactone in non-AAs (4.29±0.5–4.55±0.49 mmol/L) but not in AAs (4.32±0.54–4.31±0.49 mmol/L; race by treatment interaction,
P
=0.03) during the first month and remained higher throughout the trial. Compared with AAs, non-AAs were more likely to attain maximal spironolactone dose (13.9% versus 5.8%;
P
=0.04) and had higher rates of hyperkalemia (potassium>5.5 mmol/L; 9.7% versus 4.2%;
P
<0.046), as well as lower rates of hypokalemia (potassium<3.5 mmol/L; 5.6% versus 17.9%;
P
<0.001). After adjustment for differences in baseline characteristics and achieved study drug dose, spironolactone reduced the combined end point of death or hospitalization for HF in non-AAs (hazard ratio, 0.63; 95% confidence interval, 0.55–0.73) but not in AAs (hazard ratio, 1.07; 95% confidence interval, 0.67–1.71;
P
value for interaction=0.032).

Conclusions—

AAs with HF exhibited less hyperkalemia and more hypokalemia with spironolactone compared with non-AAs and seemed to derive less clinical benefit. These hypothesis-generating findings suggest that safety and efficacy of mineralocorticoid receptor antagonists may differ by race.
Amelioration of Angiotensin II–Induced Salt-Sensitive Hypertension by Liver-Type Fatty Acid–Binding Protein in Proximal Tubules
Authors: Osaki Ken , Suzuki Yusuke , Sugaya Takeshi , Tanifuji Chiaki , Nishiyama Akira , Horikoshi Satoshi , Tomino Yasuhiko
Published: August 2013

Inappropriate activation of the intrarenal renin–angiotensin system induces generation of reactive oxygen species and tubulointerstitial inflammation, which contribute to salt-sensitive hypertension (SSHT). Liver-type fatty acid–binding protein is expressed in proximal tubules in humans, but not in rodents, and may play an endogenous antioxidative role. The objective of the present study was to examine the antioxidative effect of liver-type fatty acid–binding protein on post–angiotensin II SSHT model in transgenic mice with selective overexpression of human liver-type fatty acid–binding protein in the proximal tubules. The transgenic mice showed marked protection against angiotensin II–induced SSHT. Overexpression of tubular liver-type fatty acid–binding protein prevented intrarenal T-cell infiltration and also reduced reactive oxygen species generation, intrarenal renin–angiotensin system activation, and monocyte chemotactic protein-1 expression. We also performed an in vitro study using the murine proximal tubular cell lines with or without recombinant liver-type fatty acid–binding protein and murine proximal tubular cell lines transfected with human liver-type fatty acid–binding protein, and found that gene transfection of liver-type fatty acid–binding protein and, in part, recombinant liver-type fatty acid–binding protein administration had significantly attenuated angiotensin II–induced reactive oxygen species generation and the expression of angiotensinogen and monocyte chemotactic protein-1 in murine proximal tubular cell lines. These findings indicated that liver-type fatty acid–binding protein in the proximal tubules may protect against angiotensin II–induced SSHT by attenuating activation of the intrarenal renin–angiotensin system and reducing oxidative stress and tubulointerstitial inflammation. Present data suggest that liver-type fatty acid–binding protein in the proximal tubules may be a novel therapeutic target for SSHT.
Walking and Running Produce Similar Reductions in Cause-Specific Disease Mortality in Hypertensives
Authors: Williams Paul T.
Published: August 2013

To test prospectively in hypertensives whether moderate and vigorous exercise produces equivalent reductions in mortality, Cox-proportional hazard analyses were applied to energy expenditure (metabolic equivalents hours/d [METh/d]) in 6973 walkers and 3907 runners who used hypertensive medications at baseline. A total of 1121 died during 10.2-year follow-up: 695 cardiovascular disease (
International Classification of Diseases, Tenth Revision
[
ICD10
] I00–99; 465 underlying cause and 230 contributing cause), 124 cerebrovascular disease, 353 ischemic heart disease (
ICD10
I20–25; 257 underlying and 96 contributing), 122 heart failure (
ICD10
I50; 24 underlying and 98 contributing), and 260 dysrhythmias (
ICD10
I46–49; 24 underlying and 236 contributing). Relative to <1.07 METh/d, running or walking 1.8 to 3.6 METh/d produced significantly lower all-cause (29% reduction; 95% confidence interval [CI], 17%–39%;
P
=0.0001), cardiovascular disease (34% reduction; 95% CI, 20%–46%;
P
=0.0001), cerebrovascular disease (55% reduction; 95% CI, 27%–73%;
P
=0.001), dysrhythmia (47% reduction; 95% CI, 27%–62%;
P
=0.0001), and heart failure mortality (51% reduction; 95% CI, 21%–70%;
P
=0.003), as did ≥3.6 METh/d with all-cause (22% reduction; 95% CI, 6%–35%;
P
=0.005), cardiovascular disease (36% reduction; 95% CI, 19%–50%;
P
=0.0002), cerebrovascular disease (47% reduction; 95% CI, 6%–71%;
P
=0.03), and dysrhythmia mortality (43% reduction; 95% CI, 16%–62%;
P
=0.004). Diabetes mellitus and chronic kidney disease mortality also decreased significantly with METh/d. All results remained significant when body mass index adjusted. Merely meeting guideline levels (1.07–1.8 METh/d) did not significantly reduced mortality. The dose-response was significantly nonlinear for all end points except diabetes mellitus, and cerebrovascular and chronic kidney disease. Results did not differ between running and walking. Thus, walking and running produce similar reductions in mortality in hypertensives.
Atherosclerosis Susceptibility Loci Identified in an Extremely Atherosclerosis‐Resistant Mouse Strain
Authors: Rowlan Jessica S. , Li Qiongzhen , Manichaikul Ani , Wang Qian , Matsumoto Alan H. , Shi Weibin
Published: August 2013

Background

C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis, especially males. To understand the underlying genetic basis, we performed quantitative trait locus (
QTL
) analysis on a male F
2
(the second generation from an intercross between 2 inbred strains) cohort derived from an intercross between C3H and C57
BL
/6 (B6) apolipoprotein E–deficient (
Apoe
−/−
) mice.

Methods and Results

Two hundred forty‐six male F
2
mice were started on a Western diet at 8 weeks of age and kept on the diet for 5 weeks. Atherosclerotic lesions in the aortic root and fasting plasma lipid levels were measured. One hundred thirty‐four microsatellite markers across the entire genome were genotyped. Four significant
QTL
s on chromosomes (Chr) 2, 4, 9, and 15 and 4 suggestive loci on Chr1, Chr4, and Chr7 were identified for atherosclerotic lesions. Unexpectedly, the C3H allele was associated with increased lesion formation for 2 of the 4 significant
QTL
s. Six loci for high‐density lipoprotein (
HDL
), 6 for non‐
HDL
cholesterol, and 3 for triglycerides were also identified. The
QTL
for atherosclerosis on Chr9 replicated
Ath29
, originally mapped in a female F
2
cohort derived from B6 and C3H
Apoe
−/−
mice. This locus coincided with a
QTL
for
HDL
, and there was a moderate, but statistically significant, correlation between atherosclerotic lesion sizes and plasma
HDL
cholesterol levels in F
2
mice.

Conclusions

These data indicate that most atherosclerosis susceptibility loci are distinct from those for plasma lipids except for the Chr9 locus, which exerts effect through interactions with
HDL
.
On the Sources and Authorship of “A Letter From Father Abraham to His Beloved Son”
Authors: Slack Kevin
Published: August 2013

In 1967, J. A. Leo Lemay disputed the editors of The Papers of Benjamin Franklin for discounting Franklin's authorship of “A Letter From Father Abraham to His Beloved Son.” A preponderance of evidence, including newly identified sources for the “Letter's borrowings,” now seems to favor Lemay's position, although differently than he had supposed.
Comparing the Roles of Barotropic versus Baroclinic Feedbacks in the Atmosphere’s Response to Mechanical Forcing
Authors: Barnes Elizabeth A. , Thompson David W. J.
Published: August 2013

Do barotropic or baroclinic eddy feedbacks dominate the atmospheric circulation response to mechanical forcing?

To address this question, barotropic torques are imposed over a range of latitudes in both an idealized general circulation model (GCM) and a barotropic model. The GCM includes both baroclinic and barotropic feedbacks. The barotropic model is run in two configurations: 1) only barotropic feedbacks are present and 2) a baroclinic-like feedback is added by allowing the stirring region to move with the jet. The relationship between the latitude of the forcing and the response is examined by systematically shifting the torques between the tropics and the pole. The importance of the mean state is investigated by varying the position of the control jet.

Five main findings are presented: 1) Barotropic feedbacks alone are capable of producing the structure of the GCM response to mechanical forcing but are not capable of accounting for its full magnitude. 2) Baroclinic processes generally increase the magnitude of the response but do not strongly influence its structure. 3) For a given forcing, the largest response in all model configurations occurs 5°–10° poleward of the forcing latitude. 4) The maximum response occurs when the forcing is located approximately 10° poleward of the control jet. 5) The circulation response weakens as the mean jet is found at higher latitudes in all model configurations.
Laboratory Investigation of the Impact of Lateral Spreading on Buoyancy Flux in a River Plume
Authors: Yuan Yeping , Horner-Devine Alexander R.
Published: August 2013

The relationship between lateral spreading and mixing in stratified gravity currents is investigated by comparing laterally confined and unconfined currents in a series of laboratory experiments. The vertical turbulent buoyancy flux is determined using a control volume approach with velocity and density fields derived from combined particle image velocimetry (PIV) and planar-laser-induced fluorescence (PLIF). Lateral spreading is determined in the unconfined experiments based on plan-view imaging using the optical thickness method (OTM). The authors find that lateral spreading dramatically modifies the plume structure; the spreading plume layer consists of approximately linear density and velocity profiles that extend to the surface, whereas the channelized plume profiles are uniform near the surface. Lateral spreading decreases the average plume density relative to laterally confined currents with similar inflow conditions. However, the local turbulent buoyancy flux in the spreading experiments is approximately equal to that in the confined experiments. This apparent paradox is resolved when the plume areas are taken into account. The total mixing integrated over the horizontal plume area is significantly higher in the spreading experiments. Thus, the experiments suggest that spreading does not appreciably alter the turbulent mixing processes at the base of the plume. However, it significantly increases the area over which this mixing occurs and, through this mechanism, increases the net dilution of river water at a fixed distance from the river mouth. Finally, the authors hypothesize that the spreading does not significantly increase the local turbulent buoyancy flux because spreading occurs preferentially near the surface, whereas buoyancy flux is greatest in the core of the current.
Information exchanges, diplomatic networks and the construction of European knowledge in European Union foreign policy
Authors: Bicchi Federica
Published: August 2013

This article analyses how, within the European Union foreign policy system, information is gathered and knowledge is constructed. The analysis is based on the evidence provided by a unique dataset, comprising the Heads of Mission reports between 1998 and 2010 and the EU member states’ diplomatic networks. After distinguishing between information and knowledge, the article tackles three related aspects. First, it shows that the EU is able not only to favour information exchanges, but also to gather information and construct knowledge. Second, it argues that, while member states have an interest in contributing their own information and knowledge, European knowledge is also possible. This is demonstrated by means of an in-depth analysis of the preparation of the Heads of Mission report on East Jerusalem. Third, the article suggests that, depending on the reach of their diplomatic network, some member states are interested more than others in European information, but all member states are interested in European knowledge and in each other’s interpretation of current affairs.
The use of cutting carbon fiber fabric/epoxy composites as band-pass frequency selective surfaces
Authors: Li CL , Jiang DZ , Zeng JC , Ju S
Published: August 2013

Sandwich structures with frequency selective surfaces have been widely used to fabricate low-observable radomes. Traditional frequency selective surfaces were made of metals, such as copper and aluminum. There were problems when used the frequency selective surfaces with the sandwich structures, such as a bonding layer and thermal mismatch. Because of the thermal mismatch between the sandwich structures and the metals, mechanical properties of the sandwich structures usually decreased. To avoid these disadvantages, a new type of composite frequency selective surface was put forward in this study. A four-legged slot-array frequency selective surface and a square-aperture array frequency selective surface were fabricated by cutting carbon fiber/epoxy composites. Free-space method and finite-element method were carried out to evaluate the electromagnetic transmission characteristics of the frequency selective surface specimens, respectively. Results show that the composite frequency selective surface with four-legged slot array can realize the function of frequency selection, and its minimum transmission loss can be decreased by increasing the electrical conductivities of the composite material, adjusting the thickness, and increasing the aperture-to-cell ratio of it. For the composite frequency selective surface with square-aperture array, grating lobes come closely after its resonant frequency, although its minimum transmission loss is very close to zero.