bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of the eNOS-NO System in Regulating the Antiproteinuric Effects of VEGF Receptor 2 Inhibition in Diabetes
Authors: Advani Andrew , Connelly Kim A. , Advani Suzanne L. , Thai Kerri , Zhang Yuan , Kelly Darren J. , Gilbert Richard E.
Published: August 2013

Subtle perturbations in intraglomerular VEGF/VEGFR-2 signaling or in the influencing microenvironment can profoundly affect renal function, resulting in the apparently paradoxical observation that VEGF blockade attenuates proteinuria development in experimental diabetes despite exerting the opposite effect under other circumstances. In the present study, we sought to explore the role of eNOS-NO activity in regulating the differential response to VEGF blockade in the diabetic and nondiabetic settings. In a rodent model of accelerated renal injury, the transgenic (mRen-2)27 (Ren-2) rat, VEGFR-2 inhibition with the small molecule vandetanib resulted in an increase in urine protein excretion preceding a subsequent rise in systolic blood pressure. When compared to their normoglycaemic counterparts, diabetic Ren-2 rats exhibited an increase in the renal expression of eNOS and in urinary excretion of nitric oxide (NO) metabolites. In contrast to the heavy proteinuria observed with vandetanib in nondiabetic TGR(mRen-2)27 rats, VEGFR-2 inhibition reduced urine protein excretion in diabetic animals, despite a comparable magnitude of histological injury. However, proteinuria was markedly increased by concomitant treatment of diabetic Ren-2 rats with vandetanib and the nitric oxide synthase inhibitor L-NAME. These observations highlight the pivotal role that the eNOS-NO system plays in regulating the biologic response to VEGF within the glomerulus.
Fixed Point Theorems on Ordered Metric Spaces through a Rational Contraction
Authors: Kumam Poom , Rouzkard Fayyaz , Imdad Mohammad , Gopal Dhananjay
Published: August 2013

Ran and Reurings (2004) established an interesting analogue of Banach Contraction Principle in a complete metric space equipped with a partial ordering and also utilized the same oneto discuss the existence of solutions to matrix equations. Motivated by this paper, we prove results on coincidence points for a pair of weakly increasing mappings satisfying a nonlinear contraction condition described by a rational expression on an ordered complete metric space. The uniqueness of common fixed point is also discussed. Some examples are furnished to demonstrate the validity of the hypotheses of our results. As an application, we derive an existence theorem for the solution of an integral equation.
Spectrophotometric Method for Determination of Five 1,4-Dihydropyridine Drugs UsingN-Bromosuccinimide and Indigo Carmine Dye
Authors: El Hamd Mohamed A. , Derayea Sayed M. , Abdelmageed Osama H. , Askal Hassan F.
Published: August 2013

Indirect spectrophotometric method is described for quantification of five of 1,4-dihydropyridine (1,4-DHP) drugs usingN-bromosuccinimide (NBS) with the aid of indigo carmine (INC) dye. The method is based on addition of known excess of NBS to an acidified solution of 1,4-DHP drugs and determining the residual of NBS through its ability to bleach the colour of the used dye; the amount of NBS that reacted corresponded to the amount of drugs. Beer’s law is obeyed in the concentration range 1.25–13.00 μg/mL. Good correlation coefficients (0.998-0.999) were found between the absorbance values and the corresponding concentrations. Limits of detections ranged from 0.141 to 0.500 μg/mL. The proposed method was successfully applied to the analysis of dosage forms; percent of recoveries ranged from 97.31 to 99.46% without interference from any common excipients. The statistical comparison by Student’st-test and variance ratioF-test showed no significant difference between the proposed and official or reported methods.
Towards a Traceability System Based on RFID Technology to Check the Content of Pallets within Electronic Devices Supply Chain
Authors: Angulo Ignacio , Perallos Asier , Azpilicueta Leire , Falcone Francisco , Hernandez-Jayo Unai , Moreno Asier , García Zuazola Ignacio Julio
Published: August 2013

In the last few years there has been a growing interest in smart solutions capable of dealing with the traceability of products and materials to improve logistical processes. Most of the existing solutions have been designed without considering the difficulties of deploying traceability systems in the storehouses currently working, not dealing with specific needs, such as environment characteristics or time required to be handled by workers. In this paper, in order to test the viability of its application, a first prototype of a traceability system capable of checking the content of pallets loaded with electronic devices is presented. It is based on ultra-high frequency (UHF) radio frequency identification (RFID) technology using passive tags. A holistic approach has been adopted to design the system: it begins with a radioelectrical characterization of the environment where the check points will be implemented, continues with the integration of a set of data acquisition and wireless communication devices, and ends with a logistics information system able to provide final user services. The combination of physical layer analysis with a top layer system view can aid the planning as well as operational phase of this type of RFID system within a logistic chain.
Reductions and New Exact Solutions of ZK, Gardner KP, and Modified KP Equations via Generalized Double Reduction Theorem
Authors: Naz R. , Ali Z. , Naeem I.
Published: August 2013

We study here the Lie symmetries, conservation laws, reductions, and new exact solutions of (2+1) dimensional Zakharov-Kuznetsov (ZK), Gardner Kadomtsev-Petviashvili (GKP), and Modified Kadomtsev-Petviashvili (MKP) equations. The multiplier approach yields three conservation laws for ZK equation. We find the Lie symmetries associated with the conserved vectors, and three different cases arise. The generalized double reduction theorem is then applied to reduce the third-order ZK equation to a second-order ordinary differential equation (ODE) and implicit solutions are established. We use the Sine-Cosine method for the reduced second-order ODE to obtain new explicit solutions of ZK equation. The Lie symmetries, conservation laws, reductions, and exact solutions via generalized double reduction theorem are computed for the GKP and MKP equations. Moreover, for the GKP equation, some new explicit solutions are constructed by applying the first integral method to the reduced equations.
Effect of Bee Venom Acupuncture on Oxaliplatin-Induced Cold Allodynia in Rats
Authors: Lim Bong-Soo , Moon Hak Jin , Li Dong Xing , Gil Munsoo , Min Joon Ki , Lee Giseog , Bae Hyunsu , Kim Sun Kwang , Min Byung-Il
Published: August 2013

Oxaliplatin, a chemotherapy drug, often leads to neuropathic cold allodynia after a single administration. Bee venom acupuncture (BVA) has been used in Korea to relieve various pain symptoms and is shown to have a potent antiallodynic effect in nerve-injured rats. We examined whether BVA relieves oxaliplatin-induced cold allodynia and which endogenous analgesic system is implicated. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat’s tail into cold water (4°C) and measuring the withdrawal latency. BVA (1.0 mg/kg, s.c.) at Yaoyangguan (GV3), Quchi (LI11), or Zusanli (ST36) acupoints significantly reduced cold allodynia with the longest effect being shown in the GV3 group. Conversely, a high dose of BVA (2.5 mg/kg) at GV3 did not show a significant antiallodynic effect. Phentolamine (α-adrenergic antagonist, 2 mg/kg, i.p.) partially blocked the relieving effect of BVA on allodynia, whereas naloxone (opioid antagonist, 2 mg/kg, i.p.) did not. We further confirmed that an intrathecal administration of idazoxan (α2-adrenergic antagonist, 50 μg) blocked the BVA-induced anti-allodynic effect. These results indicate that BVA alleviates oxaliplatin-induced cold allodynia in rats, at least partly, through activation of the noradrenergic system. Thus, BVA might be a potential therapeutic option in oxaliplatin-induced neuropathy.
Effect of Size Distribution on the Dust Acoustic Solitary Waves in Dusty Plasma with Two Kinds of Nonthermal Ions
Authors: Sharif Moghadam Samira , Dorranian Davoud
Published: August 2013

Effect of dust size, mass, and charge distributions on the nonlinear dust acoustic solitary waves (DASWs) in a dusty plasma including negatively charged dust particles, electrons, and nonthermal ions has been studied analytically. Dust particles masses and electrical charges are assumed to be proportional with dust size. Using reductive perturbation methods the Kadomtsev-Petviashvili (KP) equation is derived and its solitary answers are extracted. The coefficients of nonlinear term of KP equation are affected strongly by the size of dust particles when the relative size (the ratio of the largest dust radius to smallest dust radius) is smaller than 2. These coefficients are very sensitive toα, the nonthermal coefficient. According to the results, only rarefactive DASWs will generate in such dusty plasma. Width of DASW increases with increasing the relative size and nonthermal coefficient, while their amplitude decreases. The dust cyclotron frequency changes with relative size of dust particles.
Berberine Reduces the Metastasis of Chondrosarcoma by Modulating theαvβ3 Integrin and the PKCδ, c-Src, and AP-1 Signaling Pathways
Authors: Wu Chi-Ming , Li Te-Mao , Tan Tzu-Wei , Fong Yi-Chin , Tang Chih-Hsin
Published: August 2013

Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis, especially to the lungs. Patients diagnosed with chondrosarcoma have poor prognosis. Berberine, an active component of the Ranunculaceae and Papaveraceae families of plant, has been proven to induce tumor apoptosis and to prevent the metastasis of cancer cells. However, the effects of berberine in human chondrosarcoma are largely unknown. In this study, we found that berberine did not induce cell apoptosis in human primary chondrocytes and chondrosarcoma cells. However, at noncytotoxic concentrations, berberine reduced the migration and invasion of chondrosarcoma cancer cells. Integrins are the major adhesive molecules in mammalian cells and have been associated with the metastasis of cancer cells. We also found that incubation of chondrosarcoma cells with berberine reduced mRNA transcription for, and cell surface expression of, theαvβ3 integrin, with additional inhibitory effects on PKCδ, c-Src, and NF-κB activation. Thus, berberine may be a novel antimetastasis agent for the treatment of metastatic chondrosarcoma.
Stimulation of MMP-1 and CCL2 by NAMPT in PDL Cells
Authors: Nokhbehsaim Marjan , Eick Sigrun , Nogueira Andressa Vilas Boas , Hoffmann Per , Herms Stefan , Fröhlich Holger , Jepsen Søren , Jäger Andreas , Cirelli Joni Augusto , Deschner James
Published: August 2013

Periodontitis is an inflammatory disease caused by pathogenic microorganisms and characterized by the destruction of the periodontium. Obese individuals have an increased risk of periodontitis, and elevated circulating levels of adipokines, such as nicotinamide phosphoribosyltransferase (NAMPT), may be a pathomechanistic link between both diseases. The aim of this in vitro study was to examine the regulation of periodontal ligament (PDL) cells by NAMPT and its production under inflammatory and infectious conditions. NAMPT caused a significant upregulation of 9 genes and downregulation of 3 genes, as analyzed by microarray analysis. Eight of these genes could be confirmed by real-time PCR: NAMPT induced a significant upregulation of EGR1, MMP-1, SYT7, ITPKA, CCL2, NTM, IGF2BP3, and NRP1. NAMPT also increased significantly the MMP-1 and CCL2 protein synthesis. NAMPT was significantly induced by interleukin-1βand the periodontal microorganismP. gingivalis. NAMPT may contribute to periodontitis through upregulation of MMP-1 and CCL2 in PDL cells. Increased NAMPT levels, as found in obesity, may therefore represent a mechanism whereby obesity could confer an increased risk of periodontitis. Furthermore, microbial and inflammatory signals may enhance the NAMPT synthesis in PDL cells and thereby contribute to the increased gingival and serum levels of this adipokine, as found in periodontitis.
Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients
Authors: D’Angelo Rosalia , Alafaci Concetta , Scimone Concetta , Ruggeri Alessia , Salpietro Francesco Maria , Bramanti Placido , Tomasello Francesco , Sidoti Antonina
Published: August 2013

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes:CCM1(K-Rev interaction trapped 1 (KRIT1)),CCM2(MGC4607), andCCM3(PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM.
Magnetic Resonance Imaging of Cardiovascular Fibrosis and Inflammation: From Clinical Practice to Animal Studies and Back
Authors: Doltra Adelina , Stawowy Philipp , Dietrich Thore , Schneeweis Christopher , Fleck Eckart , Kelle Sebastian
Published: August 2013

Late gadolinium enhancement is the technique of choice for detecting myocardial fibrosis. Although this technique is used in a wide range of cardiovascular pathologies, ischemic cardiomyopathy and the workup for myocarditis and other cardiomyopathies make up a significant proportion of the total indications. Multiple studies during the last decade have demonstrated its utility to adequately characterize myocardial tissue and offer diagnostic and prognostic information. Recent T1 mapping techniques aim to overcome the limitations of late gadolinium enhancement to assess diffuse fibrosis.19F magnetic resonance has recently emerged as a promising technique for the assessment of inflammation. In the following review we will discuss the basic aspects of fibrosis assessment with MR and its utility for diagnostic and prognostic evaluation. We will also address the topic of cardiovascular inflammation imaging with19F as a potential new development that may broaden the indications for MR in the future.
Tundish Cover Flux Thickness Measurement Method and Instrumentation Based on Computer Vision in Continuous Casting Tundish
Authors: Lu Meng , Qing He , Zhi Xie , Weimin Yang , Ying Ci , Chuanyi Zhang , Hongliang Gao
Published: August 2013

Thickness of tundish cover flux (TCF) plays an important role in continuous casting (CC) steelmaking process. Traditional measurement method of TCF thickness is single/double wire methods, which have several problems such as personal security, easily affected by operators, and poor repeatability. To solve all these problems, in this paper, we specifically designed and built an instrumentation and presented a novel method to measure the TCF thickness. The instrumentation was composed of a measurement bar, a mechanical device, a high-definition industrial camera, a Siemens S7-200 programmable logic controller (PLC), and a computer. Our measurement method was based on the computer vision algorithms, including image denoising method, monocular range measurement method, scale invariant feature transform (SIFT), and image gray gradient detection method. Using the present instrumentation and method, images in the CC tundish can be collected by camera and transferred to computer to do imaging processing. Experiments showed that our instrumentation and method worked well at scene of steel plants, can accurately measure the thickness of TCF, and overcome the disadvantages of traditional measurement methods, or even replace the traditional ones.
Mandibular Bone and Soft Tissues Necrosis Caused by an Arsenical Endodontic Preparation Treated with Piezoelectric Device
Authors: Giudice A. , Cristofaro M. G. , Barca I. , Novembre D. , Giudice M.
Published: August 2013

This paper describes a case of wide mandibular bone necrosis associated with significant soft tissues injury after using an arsenical endodontic preparation in the right lower second molar for endodontic purpose. Authors debate about the hazardous effects of the arsenic paste and the usefulness of piezosurgery for treatment of this drug related bone necrosis.
Routing Attacks and Countermeasures in the RPL-Based Internet of Things
Authors: Wallgren Linus , Raza Shahid , Voigt Thiemo
Published: August 2013

The Routing Protocol for Low-Power and Lossy Networks (RPL) is a novel routing protocol standardized for constrained environments such as 6LoWPAN networks. Providing security in IPv6/RPL connected 6LoWPANs is challenging because the devices are connected to the untrusted Internet and are resource constrained, the communication links are lossy, and the devices use a set of novel IoT technologies such as RPL, 6LoWPAN, and CoAP/CoAPs. In this paper we provide a comprehensive analysis of IoT technologies and their new security capabilities that can be exploited by attackers or IDSs. One of the major contributions in this paper is our implementation and demonstration of well-known routing attacks against 6LoWPAN networks running RPL as a routing protocol. We implement these attacks in the RPL implementation in the Contiki operating system and demonstrate these attacks in the Cooja simulator. Furthermore, we highlight novel security features in the IPv6 protocol and exemplify the use of these features for intrusion detection in the IoT by implementing a lightweight heartbeat protocol.
Towards an Extensible and Secure Cloud Architecture Model for Sensor Information System
Authors: You Pengfei , Huang Zhen
Published: August 2013

Sensor information system is a specific distributed information management system for applying sensor data and aims to effectively process, manage, and analyze data emanating from sensor networks. Recently, with the development of sensor networks, sensor information system encounters many challenges, such as huge and diverse data, heterogeneous clients, scalability, and security. In this paper, we propose an extensible and secure cloud architecture model for sensor information system. Firstly, we describe the composition and mechanism of the architecture model using cloud paradigm. Secondly, we design the security solution for accessing sensor data and information services inside the architecture. This security solution ensures legal access and use for sensor data and information services and avoids illegal breach for user data in the cloud environment. In particular, a certificate authority (CA) based Kerberos protocol is proposed to provide strong identity authentication. At last, we introduce the experiment deployment for the architecture. This architecture fully utilizes the virtualization technology and cloud service functions and builds an extensible cloud platform environment supplying scalable, flexible, reliable, and secure sensor information services, which aims to solve the challenges encountered by the present sensor information system. The simulation experiment results show that the architecture gets high performance and stability throughout, while keeping scalability and flexibility brought by cloud.
Possible Future Monoclonal Antibody (mAb)-Based Therapy against Arbovirus Infections
Authors: Sautto Giuseppe , Mancini Nicasio , Gorini Giacomo , Clementi Massimo , Burioni Roberto
Published: August 2013

More than 150 arboviruses belonging to different families are known to infect humans, causing endemic infections as well as epidemic outbreaks. Effective vaccines to limit the occurrence of some of these infections have been licensed, while for the others several new immunogens are under development mostly for their improvements concerning safety and effectiveness profiles. On the other hand, specific and effective antiviral drugs are not yet available, posing an urgent medical need in particular for emergency cases. Neutralizing monoclonal antibodies (mAbs) have been demonstrated to be effective in the treatment of several infectious diseases as well as in preliminaryin vitroandin vivomodels of arbovirus-related infections. Given their specific antiviral activity as well-tolerated molecules with limited side effects, mAbs could represent a new therapeutic approach for the development of an effective treatment, as well as useful tools in the study of the host-virus interplay and in the development of more effective immunogens. However, before their use as candidate therapeutics, possible hurdles (e.g., Ab-dependent enhancement of infection, occurrence of viral escape variants) must be carefully evaluated. In this review are described the main arboviruses infecting humans and candidate mAbs to be possibly used in a future passive immunotherapy.
Three-Dimensional Microwave Holographic Imaging Employing Forward-Scattered Waves Only
Authors: Amineh Reza K. , Ravan Maryam , McCombe Justin , Nikolova Natalia K.
Published: August 2013

We propose a three-dimensional microwave holographic imaging method based on the forward-scattered waves only. In the proposed method, one transmitter and multiple receivers perform together a two-dimensional scan on two planar apertures on opposite sides of the inspected domain. The ability to achieve three-dimensional imaging without back-scattered waves enables the imaging of high-loss objects, for example, tissues, where the back-scattered waves may not be available due to low signal-to-noise ratio or nonreciprocal measurement setup. The simulation and experimental results demonstrate the satisfactory performance of the proposed method in providing three-dimensional images. Resolution limits are derived and confirmed with simulation examples.
Validation and Application of a New Reversed Phase HPLC Method forIn VitroDissolution Studies of Rabeprazole Sodium in Delayed-Release Tablets
Authors: Nawaz Md. Saddam
Published: August 2013

The purpose of this study was to develop and validate a new reversed phase high performance liquid chromatographic (RP-HPLC) method to quantifyin vitrodissolution assay of rabeprazole sodium in pharmaceutical tablet dosage form. Method development was performed on C 18,100×4.6 mm ID, and 10 μm particle size column, and injection volume was 20 μL using a diode array detector (DAD) to monitor the detection at 280 nm. The mobile phase consisted of buffer: acetonitrile at a ratio of 60 : 40 (v/v), and the flow rate was maintained at 1.0 mL/min. The method was validated in terms of suitability, linearity, specificity, accuracy, precision, stability, and sensitivity. Linearity was observed over the range of concentration 0.05–12.0 μg/mL, and the correlation coefficient was found excellent >0.999. The method was specific with respect to rabeprazole sodium, and the peak purity was found 99.99%. The method was precise and had relative standard deviations (RSD) less than 2%. Accuracy was found in the range of 99.9 to 101.9%. The method was robust in different variable conditions and reproducible. This proposed fast, reliable, cost-effective method can be used as quality control tool for the estimation of rabeprazole sodium in routine dissolution test analysis.
The Existence and Uniqueness of Positive Periodic Solutions for a Class of Nicholson-Type Systems with Impulses and Delays
Authors: Zhang Ruojun , Lian Fuyun
Published: August 2013

By establishing the equivalence, respectively, to the existence and uniqueness of positive periodic solutions for corresponding delay Nicholson-type systems without impulses, some criteria for the existence and uniqueness of positive periodic solutions for a class of Nicholson-type systems with impulses and delays are established. The results of this paper extend some earlier works reported in the literature.
Targeting FSTL1 Prevents Tumor Bone Metastasis and Consequent Immune Dysfunction
Authors: Kudo-Saito Chie , Fuwa Takafumi , Murakami Kouichi , Kawakami Yutaka
Published: August 2013

Bone metastasis greatly deteriorates the quality of life in patients with cancer. Although mechanisms have been widely investigated, the relationship between cancer bone metastasis and antitumor immunity in the host has been much less studied. Here, we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail+ tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis—in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45−ALCAM+ cells derived from bone marrow. CD45−ALCAM+ cells induced bone metastasis de novo, but they also generated CD8low T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNA interference-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM+ cells and CD8low T cells. These effects were accompanied by heightened antitumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM+ cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in patients with cancer. Cancer Res; 73(20); 6185–93. ©2013 AACR.
Activation of MAPK Pathways due to DUSP4 Loss Promotes Cancer Stem Cell-like Phenotypes in Basal-like Breast Cancer
Authors: Balko Justin M. , Schwarz Luis J. , Bhola Neil E. , Kurupi Richard , Owens Phillip , Miller Todd W. , Gómez Henry , Cook Rebecca S. , Arteaga Carlos L.
Published: August 2013

Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically approved targeted therapy. Traditional chemotherapy is effective in BLBC, but it spares the cancer stem cell (CSC)-like population, which is likely to contribute to cancer recurrence after the initial treatment. Dual specificity phosphatase-4 (DUSP4) is a negative regulator of the mitogen-activated protein kinase (MAPK) pathway that is deficient in highly aggressive BLBCs treated with chemotherapy, leading to aberrant MAPK activation and resistance to taxane-induced apoptosis. Herein, we investigated how DUSP4 regulates the MAP–ERK kinase (MEK) and c-jun-NH2-kinase (JNK) pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines interleukin (IL)-6 and IL-8. These effects were caused in part by loss of control of the MEK and JNK pathways and involved downstream activation of the ETS-1 and c-JUN transcription factors. Enforced expression of DUSP4 reduced the CD44+/CD24− population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. Our findings support the evaluation of MEK and JNK pathway inhibitors as therapeutic agents in BLBC to eliminate the CSC population. Cancer Res; 73(20); 6346–58. ©2013 AACR.
Physical Activity in Different Periods of Life, Sedentary Behavior, and the Risk of Ovarian Cancer in the NIH-AARP Diet and Health Study
Authors: Xiao Qian , Yang Hannah P. , Wentzensen Nicolas , Hollenbeck Albert , Matthews Charles E.
Published: August 2013

Background: Physical activity and sedentary behavior may influence ovarian cancer risk, but clear evidence is lacking.

Methods: We prospectively investigated the relations of self-reported physical activity and sedentary behavior to ovarian cancer incidence in a cohort of 148,892 U.S. women ages 50–71 years at baseline (1995–1996), who were followed through 2006. Multivariate Cox proportional hazard models were used to estimate relative risks (RR) and 95% confidence intervals (CI). We also conducted analysis by hormone use, body mass index (BMI), and cancer subtype.

Results: We identified 753 incident epithelial ovarian cancers. Overall, neither physical activity nor sedentary behavior at baseline was associated with ovarian cancer risk. Compared with women who never or rarely engaged in vigorous physical activity in the past year, women who reported more than 5 times/week of vigorous physical activity had an RR of 1.05 (95% CI, 0.84–1.32). Women who sat 7+ hours/day had an RR of 1.05 (95% CI, 0.80–1.37) compared with those reporting <3 hours of sitting. The associations were not modified by hormone use or BMI and were similar for both serous and non-serous subtypes.

Conclusions: Physical activity and sedentary behavior in middle and older ages were not associated with ovarian cancer risk.

Impact: We found no clear support for a role of physical activity and sedentary behavior in ovarian cancer risk. Cancer Epidemiol Biomarkers Prev; 22(11); 2000–8. ©2013 AACR.
Molecular Pathways: Estrogen Pathway in Colorectal Cancer
Authors: Barzi Afsaneh , Lenz Annika Medea , Labonte Melissa J. , Lenz Heinz-Josef
Published: August 2013

Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% [95% confidence interval (CI), 0.38–0.81; P = 0.003]. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03–0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents. Clin Cancer Res; 19(21); 5842–8. ©2013 AACR.
Promoter CpG Island Methylation of Genes in Key Cancer Pathways Associates with Clinical Outcome in High-Grade Serous Ovarian Cancer
Authors: Dai Wei , Zeller Constanze , Masrour Nahal , Siddiqui Nadeem , Paul James , Brown Robert
Published: August 2013

Purpose: We aimed to identify DNA methylation biomarkers of progression-free survival (PFS) to platinum-based chemotherapy in high-grade serous ovarian cancer (HGSOC) within biologically relevant ovarian cancer-associated pathways.

Experimental Design: Association with PFS of CpG island (CGI) promoter DNA methylation at genes in the pathways Akt/mTOR, p53, redox, and homologous recombination DNA repair was sought with PFS as the primary objective in a prospectively collected ovarian cancer cohort (n = 150). Significant loci were validated for associations between PFS, methylation, and gene expression in an independent The Cancer Genome Atlas (TCGA) data set of HGSOC (n = 311).

Results: DNA methylation at 29 CGI loci linked to 28 genes was significantly associated with PFS, independent from conventional clinical prognostic factors (adjusted P < 0.05). Of 17 out of the 28 genes represented in the TCGA data set, methylation of VEGFB, VEGFA, HDAC11, FANCA, E2F1, GPX4, PRDX2, RAD54L, and RECQL4 was prognostic in this independent patient cohort (one-sided P < 0.05, false discovery rate < 10%). A multivariate Cox model was constructed, with clinical parameters (age, stage, grade, and histologic type) and significant loci. The final model included NKD1, VEGFB, and PRDX2 as the three best predictors of PFS (P = 6.62 × 10−6, permutation test P < 0.05). Focussing only on known VEGFs in the TCGA cohort showed that methylation at promoters of VEGFA, VEGFB, and VEGFC was significantly associated with PFS.

Conclusions: A three loci model of DNA methylation could identify two distinct prognostic groups of patients with ovarian cancer (PFS: HR = 2.29, P = 3.34 × 10−5; overall survival: HR = 1.87, P = 0.007) and patients more likely to have poor response to chemotherapy (OR = 3.45, P = 0.012). Clin Cancer Res; 19(20); 5788–97. ©2013 AACR.
Hemorrhage after Tonsillectomy: Does the Surgical Technique Really Matter?
Authors: Gysin Claudine , Dulguerov Pavel
Published: August 2013

A thorough review of the publications on surgical techniques used for tonsillectomy is provided, emphasizing randomized studies and meta-analysis. In the assessment of the data it is important to clearly define and categorize the types of posttonsillectomy bleeding (PTB), as well as the various factors that have been associated with increased PTB. In recent audits of a large number of tonsillectomies, the PTB rates seem to concur: 1% early and 2.5% delayed PTB; 10% anamnestic, 2% objective, and 2% re-operation PTB. Objective PTB rates beyond 10% should require an audit. The bipolar technique seems associated with the least early PTB, while the cold technique is associated with the least delayed PTB. Because of the lack of large well-conducted randomized trials, it is difficult to conclude which technique is the best. With electrocautery techniques, the current power should be adjusted to the minimal level providing hemostasis. Surgical techniques for tonsillectomy that should probably be abandoned include monopolar electrocautery, Coblation, various lasers, and the harmonic scalpel. Vessel-sealing systems might hold promise and deserve further evaluation. Tonsillotomy might be associated with less postoperative pain, but the hemorrhagic advantage in randomized studies is not obvious. Tonsil regrowth rates and efficacy to treat obstruction need also further evaluation.
The Steroid Controversy: Where Are We?
Authors: Keller Matthew , Brigger Matthew T.
Published: August 2013

Dexamethasone is widely administered to children during elective tonsillectomy to reduce the rate of postoperative nausea and vomiting, as well as decrease postoperative use of pain medications. Over the past two decades, there has been a wealth of literature advocating the practice that has led to endorsement by a variety of anesthesia and otolaryngology professional associations. However, the publication of a trial that was halted due to a potential dose-dependent association between postoperative hemorrhage and dexamethasone raised significant scrutiny regarding the practice in 2008. As a result, significant re-evaluation of existing data as well as the development and execution of additional trials have been pursued in recent years. Ultimately, the body of evidence that currently exists appears to support the concept that a single dose of perioperative dexamethasone is not associated with undue risk. A decision to withdraw dexamethasone from use in pediatric tonsillectomy needs to be weighed against the potential of causing increased postoperative nausea, vomiting, pain, and resultant hospital readmission. At this point, surgeons and anesthesiologists should feel comfortable giving perioperative dexamethasone but must remain vigilant for bleeding complications.
Serious Complications following Tonsillectomy: How Frequent Are They Really?
Authors: Windfuhr Jochen P.
Published: August 2013

Introduction: Quality assurance in health care involves the evaluation of outcomes, cost-benefit ratios, and access to the delivery system. This literature review was undertaken to clarify the incidence of serious posttonsillectomy complications to better understand the outcome component of quality assurance. Material and Methods: A Medline review was undertaken using the key word ‘tonsillectomy' AND each of the following: ‘serious', ‘complications' and ‘review'; ‘meta-analysis', ‘Cochrane'; ‘life-threatening', ‘death' and ‘disability'. Results: 454 articles were identified with the following search items in combination with ‘tonsillectomy': ‘serious' (154), ‘complications', ‘review' (24), ‘meta-analysis' (38), ‘Cochrane' (43), ‘life-threatening' (87), ‘death' (91), ‘disability' (17). Sixty-seven articles described a complication rate and were therefore eligible for review: 22 case reports, 9 case series, 2 questionnaires and 33 studies with a more or less precise complication rate were obtainable. Most articles (n = 30) reported the rate of posttonsillectomy hemorrhage with a considerable range. Fifteen articles reported the incidence of death, which ranged from 1:7,132 to 1:170,000 and almost always resulted from excessive hemorrhage. All other complications were mentioned in case reports. Conclusion: The most common postoperative complication of tonsillectomy is bleeding. However, the incidence varies considerably across studies depending on the study design, follow-up and definition of postoperative bleeding. Other serious adverse events, such as neurological disabilities, emphysema (with or without pneumomediastinum), or vascular problems outside the neck are infrequent.
What Lessons Can Be Learned from the Austrian Events?
Authors: Sarny Stephanie , Habermann Walter , Ossimitz Guenther , Stammberger Heinz
Published: August 2013

Introduction: The death of 5 children in Austria below the age of 6 years due to posttonsillectomy haemorrhage in 2006 and 2007 led to an intensive discussion on the potential life-threatening risks of tonsil surgery. On this occasion, a consensus paper with clear recommendations for tonsil surgery was released by the Austrian Societies of Otorhinolaryngology, Head and Neck Surgery and Paediatrics followed by a nationwide multicentre study. Methods: All consecutive tonsillectomies, tonsillotomies and adenoidectomies performed in public hospitals in Austria within 9 months were assessed. Data on all participating patients were collected via an online questionnaire requesting patient characteristics, surgery details and postoperative haemorrhage. A strict definition for postoperative bleeding episodes with 7 severity grades was applied. Every bleeding episode after extubation was counted as postoperative bleeding event. Results: The study population - all younger than 18 years of age - consisted of 6,765 patients (tonsillectomy 2,080, 31%; tonsillotomy 1,292, 19%; adenoidectomy 3,393, 50%). Postoperative haemorrhage episodes were reported in 15% after tonsillectomy and in 2.3% after tonsillotomy, with the risk increasing parallel to age. Multiple bleeding episodes were recorded in one fourth of all tonsillectomy bleedings, but were rare after tonsillotomy. Surgical revision under general anaesthesia was necessary in 4.2% after tonsillectomy and in 0.9% after tonsillotomy. Discussion: As the incidence of tonsillectomy in children younger than 6 years has declined following the recommendations of the consensus paper issued in 2007, tonsillotomy has become more frequent in this age group. Overnight hospital admission and observation is suggested for all patients experiencing postoperative haemorrhage, as the occurrence of one minor bleeding doubled the risk of a second severe bleeding.
Factors Influencing the Indication for Tonsillectomy: A Historical Overview and Current Concepts
Authors: Hultcrantz Elisabeth , Ericsson Elisabeth
Published: August 2013

Tonsil surgery has been performed for more than 3,000 years. During the 19th century when anesthesia became available, techniques were refined and the number of procedures performed increased. Repeated throat infections often causing big tonsils was the reason why parents asked for the procedure. During the preantibiotic era, scarlet fever was feared since potential heart or kidney complications were life-threatening. The technique used before 1900 was tonsillotomy since neither a fingernail, snare nor the later ʼguillotineʼ were used extracapsularly. Bleeding was small and the surgery ambulatory. Extracapsular tonsillectomy developed around the turn of the 20th century with the purpose of avoiding remnants - the ‘focal infection theory' was prevailing. The whole tonsil was now extirpated with good visibility of the tonsillar area in a deeply anesthetized patient. During the first half of the 20th century, the two methods competed, but by 1950, total tonsillectomy had become the only ‘correct' tonsil surgery. The indication was still recurrent infections. The risk for serious bleeding increased; therefore large clinics arose where patients remained for at least a week after tonsillectomy. When oral penicillin for children became available during the 1960s, the threat of throat infection decreased and the number of tonsillectomies declined. The awareness of obstructive problems in children rose at the same time when obstructive sleep apnea syndrome became a disease for adults (1970s). Tonsillotomy was revived during the 1990s and is today used increasingly in many countries. The indication is mainly obstructive sleep apnea syndromeor sleep-disordered breathing, especially in small children. Total tonsillectomy is still preferred for recurrent infections, which include periodic fever/adenitis/pharyngitis/aphthous ulcer syndrome and recurrent peritonsillitis.
Indications of Pediatric Tonsillectomy
Authors: Gysin Claudine
Published: August 2013

Possible indications for tonsillectomy include sleep apnea and other obstructive sleep-related breathing disorders, recurrent tonsillitis, peritonsillar abscess, periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA), and other miscellaneous rare conditions. Over the last century indications have changed, with a decrease in infectious causes and an increase in sleep apnea disorders. Sleep apnea in children is difficult to diagnose short of polysomnography (PSG) which is expensive and disturbing, especially in young children. In sleep apnea confirmed by PSG, tonsillectomy relieves the trouble in close to 80% of patients. What remains unclear is how to diagnose sleep-related breathing disorders without PSG and the efficacy of tonsillectomy in this population. Recurrent tonsillitis is generally poorly documented and randomized studies assessing the efficacy of tonsillectomy are sparse. When frequent infections are present for several years (>7 episodes/1 year, >5/2, >3/3) some benefit from tonsillectomy could be found. If fewer infectious episodes are present, the benefit of tonsillectomy is low. Peritonsillar abscess tends to be treated with quinsy tonsillectomy. Some PFAPA and psoriasis children might benefit from tonsillectomy. Tonsillectomy for other conditions is not warranted.
How to Make Tonsillectomy a Safer Procedure: The Anaesthetist's View
Authors: Czarnetzki Christoph , Tramèr Martin
Published: August 2013

Anaesthetists use specific drugs peri-operatively to try to decrease the incidence and severity of postoperative pain and of postoperative nausea and vomiting. These drugs are usually administered pre-operatively with the premedication, or intra-operatively when the patient is still anaesthetised. The aim of this approach is to prevent the occurrence of intolerable pain or to avoid any nausea or vomiting symptoms which may be clearly unpleasant for the patient and which interfere with the patient's well-being, recovery and satisfaction. However, since most of these drugs are given prophylactically, and since not all patients will actually be suffering from intolerable pain or severe nausea and vomiting symptoms postoperatively, many patients will receive these drugs unnecessarily. Thus, for the individual patient, the risk of suffering from drug-related adverse reactions without profiting from any benefit may be relevant. Perhaps a ‘wait-and-see' approach should be considered; especially non-steroidal anti-inflammatory drugs or dexamethasone should not be given pre-operatively to all patients but should be provided exclusively to those in whom alternative analgesics (for instance, paracetamol combined with a weak opioid) or alternative anti-emetics (for instance, a setron or droperidol) have failed or are associated with unacceptable adverse effects. There is no evidence that prophylactic administration of an analgesic or an anti-emetic is more efficacious than the therapeutic administration. An interesting alternative to achieve satisfactory posttonsillectomy analgesia may be with local anaesthesia swabs that are applied onto the wound.
The liver and the kidney: two critical organs influencing the atherothrombotic risk in metabolic syndrome
Authors: Carbone Federico , Mach François , Pontremoli Roberto , Viazzi Francesca , Montecucco Fabrizio
Published: August 2013

The increased atherothrombotic risk in patients with metabolic syndrome (MetS) has been classically explained by the multiplicative effect of systemic concomitant pro-atherosclerotic factors. In particular, centripetal obesity, dyslipidaemia, glucose intolerance, hypertension (differently combined in the diagnosis of the disease) would be expected to act as classical cardiovascular risk conditions underlying accelerated atherogenesis. In order to better understand specific atherosclerotic pathophysiology in MetS, emerging evidence focused on the alterations in different organs that could serve as both pathophysiological targets and active players in the disease. Abnormalities in adipose tissue, heart and arteries have been widely investigated in a variety of basic research and clinical studies in MetS. In this narrative review, we focus on pathophysiological activities of the liver and kidney. Considering its key role in metabolism and production of soluble inflammatory mediators (such as C-reactive protein [CRP]), the liver in MetS has been shown to be altered both in its structure and function. In particular, a relevant amount of the fat accumulated within this organ has been shown to be associated with different degrees of inflammation and potential insulin resistance. In humans, non-alcoholic fatty liver disease (NAFLD) has been described as the hepatic manifestation of MetS. In an analogous manner, epidemiological evidence strongly suggested a “guilty“ association between MetS and chronic kidney disease (CKD). Some biomarkers of hepatic (such as C-reactive protein, TNF-alpha or other cytokines) and renal diseases (such as uric acid) associated with MetS might be particularly useful to better manage and prevent the atherothrombotic risk.