bluuebunny/crossref_metadata_2025 huggingface dataset:
A theoretical study of the nitration of eugenol with the nitronium ion
Authors: Ugarte Ricardo , Salgado Guillermo , Basáez Luis
Published: December 2011

The nitration of eugenol was investigated by using density functional theory (DFT) calculations. Potential energy surface and molecular electrostatic potential of eugenol was constructed in order to find, respectively, the minimum energy conformers and the possible sites for electrophilic attack. Stationary points were located and characterized at the B3LYP/6-311++G(2d,2p) level of theory. A strongly bound π-complex was found, in which the distance between the nitrogen atom of the NO2 moiety and the C1 carbon atom of the aromatic ring is 2.15 Å in the gas phase and 2.06 Å in dichloromethane. The most favorable σ-complex or Wheland intermediate is the result from the interaction between the nitrogen and the C6 ring carbon atom. The transition state that connects both complexes is more resembling the σ-complex. The nitronium ion exothermically reacts with eugenol to give the π-complex without an energy barrier. The next stage of the reaction pathway, π-complex → σ-complex, is endothermic and involves a Gibbs energy of activation of 7.9–8.0 kcal mol–1 (gas phase) and 8.3–8.9 kcal mol–1 (CH2Cl2).
Teams under pressure in the emergency department: an interview study
Authors: Flowerdew Lynsey , Brown Ruth , Russ Stephanie , Vincent Charles , Woloshynowych Maria
Published: December 2011

Objective

To identify key stressors for emergency department (ED) staff, investigate positive and negative behaviours associated with working under pressure and consider interventions that may improve how the ED team functions.

Methods

This was a qualitative study involving semistructured interviews. Data were collected from staff working in the ED of a London teaching hospital. A purposive sampling method was employed to recruit staff from a variety of grades and included both doctors and nurses.

Results

22 staff members took part in the study. The most frequently mentioned stressors included the ‘4-hour’ target, excess workload, staff shortages and lack of teamwork, both within the ED and with inpatient staff. Leadership and teamwork were found to be mediating factors between objective stress (eg, workload and staffing) and the subjective experience. Participants described the impact of high pressure on communication practices, departmental overview and the management of staff and patients. The study also revealed high levels of misunderstanding between senior and junior staff. Suggested interventions related to leadership and teamwork training, advertising staff breaks, efforts to help staff remain calm under pressure and addressing team motivation.

Conclusions

This study highlights the variety of stressors that ED staff are subject to and considers a number of cost-efficient interventions. Medical education needs to expand to include training in leadership and other ‘non-technical’ skills in addition to traditional clinical skills.
Oestrus detection in dairy cattle
Authors: Gordon Paddy
Published: December 2011

Achieving reproductive targets in artificially inseminated cattle herds relies on oestrus (heat) detection, which can be identified directly and indirectly from behavioural changes in cows. Increased herd size and reduced oestrus expression have been linked to suboptimal detection. This article reviews current knowledge of oestrus detection and highlights the opportunities for veterinary surgeons to become further involved in its management through training, monitoring and the identification of appropriate aids for oestrus detection.
Porencephaly and hydranencephaly in six dogs
Authors: Davies E. S. S. , Volk H. A. , Behr S. , Summers B. , de Lahunta A. , Syme H. , Jull P. , Garosi L.
Published: December 2011

A retrospective study was performed to identify dogs with cerebrospinal fluid‐filled cavitatory lesions on MRI. Six dogs were included and the lesions were classified. In the three dogs in the present study with hydranencephaly, unilateral but complete loss of the temporal and parietal lobes was noted and had almost complete loss of the occipital and frontal lobes of a cerebral hemisphere. In the three dogs with porencephaly, there was unilateral incomplete loss of the parietal lobe and one dog had additional partial loss of the temporal and frontal lobes. Two of the dogs with porencephaly had seizures; the third showed no associated clinical signs. The dogs with hydranencephaly had mentation changes and circled compulsively. The two porencephalic dogs with seizures were treated with phenobarbitone. One of the dogs with hydranencephaly showed increased frequency and duration of circling; one dog's clinical signs did not progress and the third dog was euthanased due to increasing aggression. The dog with increased circling had ventriculoperitoneal shunt placement and the circling frequency reduced.
Assessment of biomass functions for calculating bark proportions and ash contents of refined biomass fuels derived from major boreal tree species
Authors: Lestander Torbjörn A. , Lundström Anders , Finell Michael
Published: December 2011

Knowledge of the components of above-ground biomass of low-quality stems harvested to produce biofuel pellets is important, since bark has higher ash contents (a key quality parameter for the pellets) than wood. Therefore, single-tree biomass functions by Marklund (1988. Rep. 45. Department of Forest Survey, Swedish University of Agricultural Sciences, Umea, Sweden.) were evaluated using a sample population of 1612 Scots pine ( Pinus sylvestris L.), Norway spruce ( Pices abies (L.) Karst.), and birch ( Betula pendula Roth and Betula pubescens Ehrh.) trees and three methods to model bark proportions. Bark percentages calculated subtractively using functions for stem biomass over and under bark showed anomalous patterns, especially for pine and birch. However, additive use of biomass functions for bark biomass and stem biomass under bark resulted in similar patterns to bark percentages traditionally calculated from bark biomass and stem biomass over bark. Published ash contents of bark and stemwood indicate that pine, birch, and spruce stems with breast height (1.3 m) diameters of 4–40, 4–30, and >19 cm, respectively, have <0.7% ash contents (the current limit for the highest quality fuel pellets). However, if the highest recorded ash contents are used, only pine stems meet this criterion. Thus, material of different species and stem dimensions may need to be carefully mixed when whole-stem biomass is used as feedstock for pelletizing.
Susceptibility of pretreated wood sections of Norway spruce (Picea abies) clones to enzymatic hydrolysis
Authors: Puentes Rodriguez Yohama , Puhakka-Tarvainen Helena , Pastinen Ossi , Siika-aho Matti , Alvila Leila , Turunen Ossi , Morales Luis , Pappinen Ari
Published: December 2011

The structure of softwoods, which confers resistance to degradation through hydrolysis and decay, currently limits their use for the production of biofuels. However, since wood is very heterogeneous, it is possible that differences in wood properties within and between trees could differentially affect its processability. In this research, heartwood (inner) and sapwood (outer) from Norway spruce ( Picea abies (L.) Karst.) clones were enzymatically hydrolyzed by Trichoderma viride cellulases after concentrated acid pretreatment. Wood sections with two particle sizes were compared based on their susceptibility to enzymatic hydrolysis, evaluated by assaying the formation of hydrolysis products and measured as reducing sugar yield (RSY). We also studied the relationship between RSY and the susceptibility to Heterobasidion parviporum wood decay and whether these traits are reflected in wood density and yield. Wood from the outer section produced more RSY with higher glucan but lower lignin content than wood from the inner section. Furthermore, susceptibility to enzymatic hydrolysis was positively correlated with H. parviporum wood decay, while both processes were negatively correlated with wood density. Our results revealed the importance of clonal trials for identifying suitable lignocellulosic biomass when considering wood properties and indicate that potential genotypes for the production of biofuels are not necessarily the most productive.
Recovery time of snowshoe hare habitat after commercial thinning in boreal Quebec
Authors: Bois Guylaine , Imbeau Louis , Mazerolle Marc J.
Published: December 2011

As short-term effects of partial cuts generally decrease available cover for snowshoe hare ( Lepus americanus Erxleben), most studies have shown negative effects of such treatments on this keystone species in boreal ecosystems. This study aims to determine the long-term impact of commercial thinning on snowshoe hare habitat, and we hypothesized that habitat quality, as well as habitat use, recovers with time since treatment. We selected stands aged 50–90 years dominated by black spruce ( Picea mariana (Mill.) Britton, Sterns & Poggenb.) in Abitibi (Quebec). We used models of habitat parameters to explain the abundance of snowshoe hare tracks and pellets in 20 commercially thinned stands treated between 1989 and 1999 and 12 control stands. Lateral cover was the dominant parameter influencing snowshoe hare habitat use. On average, commercially thinned stands had a lower lateral cover than controls (–18%). We also found that snowshoe hare use of commercially thinned stands increases with time since treatment. However, 11–18 years are needed before commercially thinned stands return to the same level of lateral cover and snowshoe hare signs as control stands. Commercial thinning is generally followed by harvesting all merchantable stems 15 years after treatment. Thus, we suggest that commercial thinning as currently practiced should be avoided if the objective is to maintain quality habitat for snowshoe hare and its associated predators.
ELECTROMAGNETIC EXCITATIONS OF HALL SYSTEMS ON FOUR-DIMENSIONAL SPACE
Authors: DAOUD MOHAMMED , JELLAL AHMED , GUEJDI ABDELLAH OUELD
Published: December 2011

The noncommutativity of a four-dimensional phase space is introduced from a purely symplectic point of view. We show that there is always a coordinate map to locally eliminate the gauge fluctuations inducing the deformation of the symplectic structure. This uses the Moser's lemma; a refined version of the celebrated Darboux theorem. We discuss the relation between the coordinates change arising from Moser's lemma and the Seiberg–Witten map. As illustration, we consider the quantum Hall systems on CP2. We derive the action describing the electromagnetic interaction of Hall droplets. In particular, we show that the velocities of the edge field, along the droplet boundary, are noncommutativity parameters-dependents.
GEOMETRIC STRUCTURES ON PATH SPACES
Authors: BISWAS INDRANIL , CHATTERJEE SAIKAT
Published: December 2011

Let M be a C∞ manifold, and let [Formula: see text] be the space of all smooth maps from [0, 1] to M. We investigate geometric structures on [Formula: see text] constructed from the geometric structures on M. In particular, we show that a generalized (almost) complex structure on M produce a generalized (almost) complex structure on [Formula: see text].
POST QUANTUM CRYPTOGRAPHY FROM MUTANT PRIME KNOTS
Authors: MARZUOLI ANNALISA , PALUMBO GIANDOMENICO
Published: December 2011

By resorting to basic features of topological knot theory we propose a (classical) cryptographic protocol based on the "difficulty" of decomposing complex knots generated as connected sums of prime knots and their mutants. The scheme combines an asymmetric public key protocol with symmetric private ones and is intrinsically secure against quantum eavesdropper attacks.
THE WEIERSTRASS CRITERION AND THE LEMAÎTRE–TOLMAN–BONDI MODELS WITH COSMOLOGICAL CONSTANT Λ
Authors: BOCHICCHIO IVANA , CAPOZZIELLO SALVATORE , LASERRA ETTORE
Published: December 2011

We analyze Lemaître–Tolman–Bondi models in presence of the cosmological constant Λ through the classical Weierstrass criterion. Precisely, we show that the Weierstrass approach allows us to classify the dynamics of these inhomogeneous spherically symmetric Universes taking into account their relationship with the sign of Λ.
Accelerators for Neutron Generation and Their Applications
Authors: Mank Guenter , Bauer Guenter , Mulhauser Françoise
Published: December 2011

This article briefly reviews the most important points of neutron generation using accelerators in the small and medium energy ranges. The interest in neutron research is still growing, due to improvement of detectors and analyzing tools. Smaller accelerator-based neutron sources can serve for proof-of-principle experiments and for data generation. In developing and emerging economies they may replace underutilized research reactors, if there is a need for neutron research. The complementarity of neutron research to synchrotron and X-ray analysis will always keep some focus on effective and lower cost options for neutron production.
Development of Accelerator Mass Spectrometry and Its Applications
Authors: Chen Jiaer , Guo Zhiyu , Liu Kexin , Zhou Liping
Published: December 2011

With over 30 years' development, accelerator mass spectrometry (AMS) technology has been applied in almost all domains of science and technology. In this article, we first provide a brief description of the basic principles of AMS and then a review of recent technical developments. Selected examples of applications are given to show the impact and potential of AMS in earth and environmental sciences, archeology, art authentication, biomedical sciences, nuclear astrophysics and nuclear environmental safeguards. Finally, the trends and challenges of AMS development are briefly discussed.
P2X7-mediated calcium influx triggers a sustained, PI3K-dependent increase in metabolic acid production by osteoblast-like cells
Authors: Grol Matthew W. , Zelner Irene , Dixon S. Jeffrey
Published: December 2011

The P2X7 receptor is an ATP-gated cation channel expressed by a number of cell types, including osteoblasts. Genetically modified mice with loss of P2X7 function exhibit altered bone formation. Moreover, activation of P2X7 in vitro stimulates osteoblast differentiation and matrix mineralization, although the underlying mechanisms remain unclear. Because osteogenesis is associated with enhanced cellular metabolism, our goal was to characterize the effects of nucleotides on metabolic acid production (proton efflux) by osteoblasts. The P2X7 agonist 2′,3′- O-(4-benzoylbenzoyl)ATP (BzATP; 300 μM) induced dynamic membrane blebbing in MC3T3-E1 osteoblast-like cells (consistent with activation of P2X7 receptors) but did not induce cell death. Using a Cytosensor microphysiometer, we found that 9-min exposure to BzATP (300 μM) caused a dramatic increase in proton efflux from MC3T3-E1 cells (∼2-fold), which was sustained for at least 1 h. In contrast, ATP or UTP (100 μM), which activate P2 receptors other than P2X7, failed to elicit a sustained increase in proton efflux. Specific P2X7 receptor antagonists A 438079 and A 740003 inhibited the sustained phase of the BzATP-induced response. Extracellular Ca2+ was required during P2X7 receptor stimulation for initiation of sustained proton efflux, and removal of extracellular glucose within the sustained phase abolished the elevation elicited by BzATP. In addition, inhibition of phosphatidylinositol 3-kinase blocked the maintenance but not initiation of the sustained phase. Taken together, we conclude that brief activation of P2X7 receptors on osteoblast-like cells triggers a dramatic, Ca2+-dependent stimulation of metabolic acid production. This increase in proton efflux is sustained and dependent on glucose and phosphatidylinositol 3-kinase activity.
Generation and characterization of a mouse model of the metabolic syndrome: apolipoprotein E and aromatase double knockout mice
Authors: Scott Nicola J. A. , Cameron Vicky A. , Raudsepp Sara , Lewis Lynley K. , Simpson Evan R. , Richards A. Mark , Ellmers Leigh. J.
Published: December 2011

The aim of this study was to create a comprehensive mouse model of the metabolic syndrome by crossing aromatase-deficient ( ArKO) mice with apolipoprotein E-deficient ( ApoE−/−) mice. Successive crossbreeding of ArKO with ApoE−/−-deficient mice generated double knockout, MetS-Tg mice. The phenotypic characteristics of the MetS-Tg mice were assessed at 3, 6, and 12 mo of age and compared with age- and sex-matched wild-type (WT) controls. Blood pressure and heart rate were recorded by a noninvasive, computerized tail-cuff system. Oral glucose and intraperitoneal insulin tolerance tests were performed. Serum cholesterol levels were measured by a combined quantitative colorimetric assay. Plasma adiponectin, C-reactive protein (CRP), insulin, interleukin-6 (IL-6), leptin, resistin, and tumor necrosis factor-α (TNF-α) were measured by multiplexed ELISA. MetS-Tg mice displayed significantly increased body weight, central obesity, and elevated blood pressure at all three ages compared with WT mice. Elevated serum cholesterol was associated with higher triglycerides and LDL/VLDL cholesterol particles and was accompanied by a decrease in HDL and histological evidence of fatty liver. MetS-Tg mice of all ages showed impaired glucose tolerance. At 12 mo, MetS-Tg mice had elevated plasma levels of CRP, IL-6, leptin, and TNF-α, but resistin levels were largely unchanged. We now report that this combination of gene knockouts produces a novel strain of mice that display the diverse clinical features of the metabolic syndrome, including central obesity, progressive hypertension, an adverse serum lipid profile, fatty liver, glucose intolerance, insulin resistance, and evidence of an inflammatory state.
An Optimal Homotopy Asymptotic Approach Applied to Nonlinear MHD Jeffery‐Hamel Flow
Authors: Marinca Vasile , Herişanu Nicolae
Published: December 2011

A simple and effective procedure is employed to propose a new analytic approximate solution for nonlinear MHD Jeffery‐Hamel flow. This technique called the Optimal Homotopy Asymptotic Method (OHAM) does not depend upon any small/large parameters and provides us with a convenient way to control the convergence of the solution. The examples given in this paper lead to the conclusion that the accuracy of the obtained results is growing along with increasing the number of constants in the auxiliary function, which are determined using a computer technique. The results obtained through the proposed method are in very good agreement with the numerical results.
Delayed Airway Obstruction after Internal Jugular Venous Catheterization in a Patient with Anticoagulant Therapy
Authors: Wu Pei-Ju , Chau Siu-Wah , Lu I-Cheng , Hsu Hung-Te , Cheng Kuang-I
Published: December 2011

Delayed onset of neck hematoma following central venous catheterization without arterial puncture is uncommon. Herein, we present a patient who developed a delayed neck hematoma after repeated attempts at right internal jugular venous puncture and subsequent enoxaparin administration. Progressive airway obstruction occurred on the third day after surgery. Ultrasound examination revealed diffuse hematoma of the right neck, and fibreoptic examination of the airway revealed pharyngeal edema. After emergent surgical removal of the hematoma, the patient was extubated uneventfully.
Scalable RFCMOS Model for 90 nm Technology
Authors: Tong Ah Fatt , Lim Wei Meng , Sia Choon Beng , Yu Xiaopeng , Yang Wanlan , Yeo Kiat Seng
Published: December 2011

This paper presents the formation of the parasitic components that exist in the RF MOSFET structure during its high-frequency operation. The parasitic components are extracted from the transistor's S-parameter measurement, and its geometry dependence is studied with respect to its layout structure. Physical geometry equations are proposed to represent these parasitic components, and by implementing them into the RF model, a scalable RFCMOS model, that is, valid up to 49.85 GHz is demonstrated. A new verification technique is proposed to verify the quality of the developed scalable RFCMOS model. The proposed technique can shorten the verification time of the scalable RFCMOS model and ensure that the coded scalable model file is error-free and thus more reliable to use.
Hedgehog Signaling Inhibition Blocks Growth of Resistant Tumors through Effects on Tumor Microenvironment
Authors: Heller Emanuela , Hurchla Michelle A. , Xiang Jingyu , Su Xinming , Chen Sara , Schneider Jochen , Joeng Kyu-Sang , Vidal Marcos , Goldberg Leah , Deng Hongju , Hornick Mary C. , Prior Julie L. , Piwnica-Worms David , Long Fanxin , Cagan Ross , Weilbaecher Katherine N.
Published: December 2011

Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1+/−) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch1+/− mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. Cancer Res; 72(4); 897–907. ©2011 AACR.
Molecular Pathways: Beta-Adrenergic Signaling in Cancer
Authors: Cole Steven W. , Sood Anil K.
Published: December 2011

Beta-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial–mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor–mediated activation of protein kinase A and exchange protein activated by adenylyl cyclase signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression, and now suggests a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and preclinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology. Clin Cancer Res; 18(5); 1201–6. ©2011 AACR.
Silencing hsp25/hsp27 Gene Expression Augments Proteasome Activity and Increases CD8+ T-Cell–Mediated Tumor Killing and Memory Responses
Authors: Nagaraja Ganachari M. , Kaur Punit , Neumann William , Asea Edwina E. , Bausero María A. , Multhoff Gabriele , Asea Alexzander
Published: December 2011

Relatively high expression of Hsp27 in breast and prostate cancer is a predictor of poor clinical outcome. This study elucidates a hitherto unknown mechanism by which Hsp27 regulates proteasome function and modulates tumor-specific T-cell responses. Here, we showed that short-term silencing of Hsp25 or Hsp27 using siRNA or permanent silencing of Hsp25 using lentivirus RNA interference technology enhanced PA28α mRNA expression, PA28α protein expression, and proteasome activity; abrogated metastatic potential; induced the regression of established breast tumors by tumor-specific CD8+ T cells; and stimulated long-lasting memory responses. The adoptive transfer of reactive CD8+ T cells from mice bearing Hsp25-silenced tumors efficiently induced the regression of established tumors in nontreated mice which normally succumb to tumor burden. The overexpression of Hsp25 and Hsp27 resulted in the repression of normal proteasome function, induced poor antigen presentation, and resulted in increased tumor burden. Taken together, this study establishes a paradigm shift in our understanding of the role of Hsp27 in the regulation of proteasome function and tumor-specific T-cell responses and paves the way for the development of molecular targets to enhance proteasome function and concomitantly inhibit Hsp27 expression in tumors for therapeutic gain. Cancer Prev Res; 5(1); 122–37. ©2011 AACR.
Anticancer Effects of Imperatorin Isolated from Angelica dahurica: Induction of Apoptosis in HepG2 Cells through both Death-Receptor- and Mitochondria-Mediated Pathways
Authors: Luo Ke-wang , Sun Jian-guo , Chan Judy Yuet-Wa , Yang Lu , Wu Shi-hua , Fung Kwok-Pui , Liu Fei-yan
Published: December 2011

Background: Imperatorin (IM) is a furanocoumarin isolated from the root of Angelica dahurica, which is reported to have anticonvulsant and anticancer effects. In this study, the antiproliferative effect of IM on 9 human cancer cell lines was examined, and human hepatoma HepG2 cells were chosen as the target for preferential killing by IM. Particularly, the mechanism of IM-induced apoptosis and in vivo animal effects were also studied. Methods: Cell viability was measured using MTT assay, and apoptosis was detected by Hoechst staining, annexin V-PI staining, and DNA laddering assay. Mitochondrial membrane potential was detected by JC-1 staining. Western blot analysis was employed to detect the expression of apoptosis-related proteins. In addition, the in vivo anticancer effect of IM was examined in nude mice bearing HepG2 cells. Results: IM inhibited the proliferation of HepG2 cells through apoptosis induction in a time- and dose-dependent manner by observation of the nuclear morphology, DNA fragmentation, phosphatidylserine externalization, loss of mitochondrial membrane potential, release of cytochrome c into cytosol, and activation of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase cleavage. As cell death could partly be prevented by the caspase-8 or caspase-9 inhibitor and was evidenced by the results of Western blot analysis, our results also suggest that IM-induced apoptosis is mediated through both death receptor and mitochondrial pathways. In the animal model, IM was found to effectively suppress tumor growth by 31.93 and 63.18% at dosages of 50 and 100 mg/kg, respectively, after treatment for 14 days. No significant weight loss or toxicity to the hosts was found. Conclusions: IM can function as a cancer suppressor by inducing apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways. Furthermore, the in vivo antitumor activities of IM are significant with negligible weight loss and damage to the host.
Comparison of Estimated Protein Output and Urine Protein:Creatinine Ratio in First and Second Voids with 24-Hour Urine Protein
Authors: Selvarajah Viknesh , Flynn Robert , Isles Chris
Published: December 2011

Background: Current UK guidelines for the identification, management and referral of chronic kidney disease advise an early-morning urine sample for the albumin:creatinine ratio or the protein:creatinine ratio (PCR) in order to quantify proteinuria. Estimated protein output (EPO) is an alternative and possibly better method of quantifying proteinuria which takes lean weight into consideration. Methods: We carried out a single-centre study of 36 adult patients with proteinuric nephropathy over a period of 18 months. Urinary PCR and EPO estimates of 24-hour urine protein were compared with 24-hour urine collections by Bland-Altman analysis. Results: Average 24-hour urine protein was 1.6 g (range 0.2–5.1 g). Best agreement with 24-hour protein was for first-void EPO (limits of agreement 0.33–1.59) followed by a second-void EPO (0.40–1.76), then second-void PCR (0.40–2.08) and lastly first-void PCR (0.28–2.03). None of the differences between estimates of urine protein excretion and 24-hour urine protein were statistically significant. All estimates of protein output had wide confidence intervals confirming that spot urine samples, while simple and convenient to do, are imprecise measures of 24-hour urine protein excretion. Conclusion: When estimating 24-hour urine protein from a spot urine sample, EPO may be marginally more accurate than PCR, and first-void urine samples slightly better than second-void urine samples, but a first- or second-void PCR will suffice in most instances.
‘Ideal Criteria’ for Starting Chronic Hemodialysis: Numbers, Symptoms or an Alerting ‘Traffic Light’ System?
Authors: Arici Mustafa
Published: December 2011

A definite criteria for starting chronic hemodialysis treatment is still lacking even after 50 years of regular hemodialysis treatment. Although none of the current guidelines have designated a certain glomerular filtration rate (GFR) level to start hemodialysis, most favor an ‘earlier’ start after GFR falls below 15 ml/min. Hence, since mid-1990s, more patients have initiated dialysis on higher GFR levels. Most of the observational data and one randomized trial, however, failed to find any benefit, but even harm, from an earlier start in various patient populations including the healthiest groups. This paper has reviewed the available evidence and criticized the use of only ‘GFR level’ in the absence of a validated method in end-stage kidney disease patients. A new patient scoring system mimicking traffic lights was proposed in which patients were placed into green, yellow or red zones for deciding the ideal time to start hemodialysis. This scoring system should include not only validated GFR criteria but also a wide set of demographic and clinical parameters.
Genetic and Structural Analysis of HIV-1 Rev Responsive Element Related to V38A and T18A Enfuvirtide Resistance Mutations
Authors: Dimonte Salvatore , Mercurio Fabio , Svicher Valentina , Perno Carlo-Federico , Ceccherini-Silberstein Francesca
Published: December 2011

Background: For the expression of late viral genes, HIV-1 efficiently exploits the nuclear export by using Rev viral protein, which specifically binds the RNA Rev Responsive Element (RRE). This region is contained within the gp120-gp41 encoding sequence. Enfuvirtide is the first approved HIV-1 fusion-inhibitor, and gp41 codons associated with primary enfuvirtide-resistance (amino-acids 36–45) are localized within the RRE structure. We previously found the co-presence of V38A+T18A resistance mutations in patients failing enfuvirtide. Methods: Collecting 476 and 135 HIV-1 B-subtype gp41 sequences from enfuvirtide-naïve and enfuvirtide-treated patients, respectively, two mutations previously found associated with enfuvirtide treatment, T18A and V38A, were analyzed. Moreover, the RNA secondary structure was displayed by CONTRAfold-software and the gp41 evolutionary pathways by a mutagenetic tree. Results: By modeling the RRE structure, we show that the T18 and V38 codons are base pairing within the RRE-stem-IIA, an important domain involved in Rev binding. While a structural RRE impairment in the presence of V38A alone was found, a restoration of the original RRE structure occurred in co-presence of V38A+T18A. By mutagenetic tree analysis, a compensatory evolution confirming our hypothesis on the structural modification mechanism was observed. Conclusion: We show that enfuvirtide pressure may also affect specific RRE domains involved in Rev binding, thus requiring a compensatory evolution able to preserve the secondary structure of the RRE.
The contribution of thrombin-induced platelet activation to thrombus growth is diminished under pathological blood shear conditions
Authors: Lee Hannah , Sturgeon Sharelle , Jackson Shaun , Hamilton Justin
Published: December 2011

Developing novel anti-platelet therapies is an important clinical strategy for the prevention of arterial thromboses which cause heart attacks and most strokes. Thrombin activates platelets via protease-activated receptors (PARs), and PAR antagonists are currently under investigation as antithrombotics. Yet despite these clinical advances, the importance of PARs to platelet activation during thromboses formed under pathological conditions has not been investigated. To this end, we examined the role of PAR-dependent platelet activation in thrombus formation in the presence of elevated blood shear rates. We used two in vivo thrombosis models and an ex vivo whole blood flow approach in PAR4-/-mice, whose platelets are unresponsive to thrombin, to show that the contribution of PAR-mediated platelet activation to thrombosis is diminished at pathological blood shear rates as a direct result of decreased incorporation of thrombin-activated platelets into growing thrombi. Our ex vivo observations were replicated in human whole blood treated with a PAR1 antagonist. These results define a novel, shear-regulated role for thrombin/PAR-dependent platelet activation during thrombosis and provide important insights into the conditions under which PAR antagonists may best be used for the prevention of acute coronary syndromes.
What Determines Meridional Heat Transport in Climate Models?
Authors: Donohoe Aaron , Battisti David S.
Published: December 2011

The annual mean maximum meridional heat transport (MHTMAX) differs by approximately 20% among coupled climate models. The value of MHTMAX can be expressed as the difference between the equator-to-pole contrast in absorbed solar radiation (ASR*) and outgoing longwave radiation (OLR*). As an example, in the Northern Hemisphere observations, the extratropics (defined as the region with a net radiative deficit) receive an 8.2-PW deficit of net solar radiation (ASR*) relative to the global average that is balanced by a 2.4-PW deficit of outgoing longwave radiation (OLR*) and 5.8 PW of energy import via the atmospheric and oceanic circulation (MHTMAX). The intermodel spread of MHTMAX in the Coupled Model Intercomparison Project Phase 3 (CMIP3) simulations of the preindustrial climate is primarily (R2 = 0.72) due to differences in ASR* while model differences in OLR* are uncorrelated with the MHTMAX spread. The net solar radiation (ASR*) is partitioned into contributions from (i) the equator-to-pole contrast in incident radiation acting on the global average albedo and (ii) the equator-to-pole contrast of planetary albedo, which is further subdivided into components due to atmospheric and surface reflection. In the observations, 62% of ASR* is due to the meridional distribution of incident radiation, 33% is due to atmospheric reflection, and 5% is due to surface reflection. The intermodel spread in ASR* is due to model differences in the equator-to-pole gradient in planetary albedo, which are primarily a consequence of atmospheric reflection differences (92% of the spread), and is uncorrelated with differences in surface reflection. As a consequence, the spread in MHTMAX in climate models is primarily due to the spread in cloud reflection properties.
Continental Shelf Wave Propagation in the Mid-Atlantic Bight: A General Dispersion Relation
Authors: Schulz William J. , Mied Richard P. , Snow Charlotte M.
Published: December 2011

The authors address the propagation of continental shelf waves in the Mid-Atlantic Bight. An analytical model of the bathymetry in the region is constructed by representing the continental shelf as a gently sloping bottom, which deepens linearly with offshore distance to the place where it meets the continental slope. Seaward of that point, the bathymetry is modeled with an exponentially decaying function of distance. The linearized, barotropic equations of hydrostatic motion, subject to the long-wave approximation, yield separate shelf and slope solutions, which are matched at the shelf break to specify the eigenfunctions. The associated eigenvalues define the dispersion relations for each of the modes. Wavenumber–frequency pairs derived from NOAA sea surface height stations along the coast are plotted on the first-mode dispersion curve, and the agreement is good. The theory also shows good agreement with the wave data of D. P. Wang.
Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia
Authors: Dayal Sanjana , Chauhan Anil K. , Jensen Melissa , Leo Lorie , Lynch Cynthia M. , Faraci Frank M. , Kruger Warren D. , Lentz Steven R.
Published: December 2011

Hyperhomocysteinemia confers a high risk for thrombotic vascular events, but homocysteine-lowering therapies have been ineffective in reducing the incidence of secondary vascular outcomes, raising questions regarding the role of homocysteine as a mediator of cardiovascular disease. Therefore, to determine the contribution of elevated homocysteine to thrombosis susceptibility, we studied Cbs−/− mice conditionally expressing a zinc-inducible mutated human CBS (I278T) transgene. Tg-I278T Cbs−/− mice exhibited severe hyperhomocysteinemia and endothelial dysfunction in cerebral arterioles. Surprisingly, however, these mice did not display increased susceptibility to arterial or venous thrombosis as measured by photochemical injury in the carotid artery, chemical injury in the carotid artery or mesenteric arterioles, or ligation of the inferior vena cava. A survey of hemostatic and hemodynamic parameters revealed no detectible differences between control and Tg-I278T Cbs−/− mice. Our data demonstrate that severe elevation in homocysteine leads to the development of vascular endothelial dysfunction but is not sufficient to promote thrombosis. These findings may provide insights into the failure of homocysteine-lowering trials in secondary prevention from thrombotic vascular events.
CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development
Authors: Finney Brenda A. , Schweighoffer Edina , Navarro-Núñez Leyre , Bénézech Cecile , Barone Francesca , Hughes Craig E. , Langan Stacey A. , Lowe Kate L. , Pollitt Alice Y. , Mourao-Sa Diego , Sheardown Steve , Nash Gerard B. , Smithers Nicholas , Reis e Sousa Caetano , Tybulewicz Victor L. J. , Watson Steve P.
Published: December 2011

The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation, and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the hematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other hematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that depends on CLEC-2 and Syk. These studies found that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behavior in vitro.
Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial
Authors: O'Connor Brian J , Collarini Sara , Poli Gianluigi , Brindicci Caterina , Spinola Monica , Acerbi Daniela , Barnes Peter J , Leaker Brian
Published: December 2011

Background

The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.

Methods

Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 μg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV1, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV1 area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV1 and analysis of variance for AMP challenge.

Results

Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV1 was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response.

Conclusions

The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients.

Trial Registration

ClinicalTrials.gov: NCT01343745
Video-assisted thoracoscopic surgery is more favorable than thoracotomy for administration of adjuvant chemotherapy after lobectomy for non-small cell lung cancer
Authors: Jiang Guanchao , Yang Fan , Li Xiao , Liu Jun , Li Jianfeng , Zhao Hui , Li Yun , Wang Jun
Published: December 2011

Background

Video-assisted thoracoscopic surgery (VATS) lobectomy is a newly developed type of surgery for lung cancer and has been demonstrated obvious minimally-invasive advantages compared with traditional thoracotomy. Theoretically, that less trauma leads to quicker recovery and may facilitate administration of adjuvant chemotherapy. We tested this hypothesis in this study.

Methods

One hundred and ten NSCLC patients underwent lobectomy and adjuvant chemotherapy from June 2004 to June 2010 was analyzed. The baseline characteristic criteria, variables related to surgery and accomplishing status of chemotherapy were analyzed.

Results

All 110 patients underwent lobectomy through VATS (n = 54) or thracotomy (n = 56) and adjuvant chemotherapy. There was no significant difference in patients' age, preoperative pulmonary function, co-morbidity, pathologic staging between the two groups, whereas, blood loss, operation time and postoperative complications, chest tube duration and length of stay were less in VATS group. There were no significant differences in time to initiation chemotherapy. Cases in VATS group received more cycles of chemotherapy (3.6 vs. 3.0, p = 0.002). A higher proportion of patients received full dose on schedule in VATS group (57.4% vs. 33.9%, p = 0.013) and a higher proportion of patients completed ≥75% planed dose, (88.9% vs. 71.4%, p = 0.022); slightly higher proportion of patients in thoracotomy group had grade 3 or more toxicity (20.4% vs. 35.7%, p = 0.074).

Conclusions

Patients underwent lobectomy by VATS have better compliance and fewer delayed or reduced dose on adjuvant chemotherapy than those by thoracotomy.
High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma
Authors: Wang Xiaoen , Zhang Liang , Goldberg S Nahum , Bhasin Manoj , Brown Victoria , Alsop David C , Signoretti Sabina , Mier James W , Atkins Michael B , Bhatt Rupal S
Published: December 2011

Background

Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.

Methods

Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.

Results

Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.

Conclusions

A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.