bluuebunny/crossref_metadata_2025 huggingface dataset:
Noise and time delay induce critical point in a bistable system
Authors: Zhang Jianqiang , Nie Linru , Yu Lilong , Zhang Xinyu
Published: July 2014

We study relaxation time Tc of time-delayed bistable system driven by two cross-correlated Gaussian white noises that one is multiplicative and the other is additive. By means of numerical calculations, the results indicate that: (i) Combination of noise and time delay can induce two critical points about the relaxation time at some certain noise cross-correlation strength λ under the condition that the multiplicative intensity D equals to the additive noise intensity α. (ii) For each fixed D or α, there are two symmetrical critical points which locates in the regions of positive and negative correlations, respectively. Namely, as λ equals to the critical value λc, Tc is independent of the delay time and the result of Tc versus τ is a horizontal line, but as |λ|>|λc| (or |λ|<|λc|), the relaxation time Tc monotonically increases (or decreases) with the delay time increasing. (iii) In the presence of D = α, the change of λc with D is two symmetrical curves about the axis of λc = 0, and the critical value λc is close to zero for a smaller D, which approaches to +1 or -1 for a greater D.
Detecting communities in networks using a Bayesian nonparametric method
Authors: Hu Shengze , Wang Zhenwen
Published: July 2014

In the real world, a large amount of systems can be described by networks where nodes represent entities and edges the interconnections between them. Community structure in networks is one of the interesting properties revealed in the study of networks. Many methods have been developed to extract communities from networks using the generative models which give the probability of generating networks based on some assumption about the communities. However, many generative models require setting the number of communities in the network. The methods based on such models are lack of practicality, because the number of communities is unknown before determining the communities. In this paper, the Bayesian nonparametric method is used to develop a new community detection method. First, a generative model is built to give the probability of generating the network and its communities. Next, the model parameters and the number of communities are calculated by fitting the model to the actual network. Finally, the communities in the network can be determined using the model parameters. In the experiments, we apply the proposed method to the synthetic and real-world networks, comparing with some other community detection methods. The experimental results show that the proposed method is efficient to detect communities in networks.
ENERGY EFFICIENT REVERSIBLE BUILDING BLOCKS RESISTANT TO POWER ANALYSIS ATTACKS
Authors: SARAVANAN P. , KALPANA P.
Published: July 2014

Reversible logic circuits consist of a chain of reversible gates with many stages. The existing transmission gate-based implementation of reversible gates severely suffers from voltage degradation because of the inherent resistive voltage drop when cascaded. In addition, the propagation delay increases quadratically with the number of transmission gates cascaded in reversible circuits. To circumvent these problems in cascaded circuits, static CMOS buffers or latches are generally inserted at intermediate stages. But the static CMOS latches are inherently irreversible and cannot be used in reversible circuits. In this work, a novel adiabatic reversible latch is proposed to regenerate the voltage levels at intermediate stages in cascaded reversible circuits. The proposed latch is placed at the target line of each transmission gate-based reversible gate implementation to restore the logic to their respective voltage levels and at the same time reduces the energy consumption significantly. In addition, the proposed adiabatic reversible gate implementations show resistance against power analysis attacks as the current drawn from the power supply matches for all cases of input stimulus.
Exact Solution of the Elastica with Transverse Shear Effects
Authors: Zalmanovici Adrian Marcel , da Fonseca Brasil Reyolando Manoel Lopes Rebello , Balthazar José Manoel
Published: July 2014

A new derivation of Euler's Elastica with transverse shear effects included is presented. The elastic potential energy of bending and transverse shear is set up. The work of the axial compression force is determined. The equation of equilibrium is derived using the variation of the total potential. Using substitution of variables an exact solution is derived. The equation is transcendental and does not have a closed form solution. It is evaluated in a dimensionless form by using a numerical procedure. Finally, numerical examples of laminates made of composite material (fiber reinforced) and sandwich panels are provided.
USING SHORT-TIME FOURIER TRANSFORM AND WAVELET PACKET TRANSFORM TO ATTENUATE NOISE FROM HEART SOUND SIGNAL FOR WEARABLE E-HEALTHCARE DEVICE
Authors: ZENG KEHAN , TAN ZHEN , DONG MINGCHUI
Published: July 2014

A soft-computing method attenuating noise from heart sound (HS) signal for wearable e-healthcare device is proposed. The HS signal is decomposed by third-level wavelet packet transform (WPT). An automatic HS cycle detection algorithm is applied to find HS cycles in the (3, 0) leaf signal of WPT tree. Based on the quasi-cyclic feature of HS, short-time Fourier transform is implemented for cycles of each WPT tree leaf signal to decompose each cycle into time-frequency fragments which are called particles. Furthermore, the novel cuboid method is proposed to identify constituents of HS and noise from such generated particles. The particles representing HS are then retained and merged into noise-quasi-free WPT tree leaf signals. Eventually the inverse WPT (IWPT) is employed to build the noise-quasi-free HS signal. The method is assessed using mean square error (MSE) and compared with wavelet multi-threshold method (WMTM) and Tang's method. The experimental results show that the proposed method not only filters HS signal effectively but also well retains its pathological information.
Chapter 15 The rock coasts of oceanic islands
Authors: Woodroffe Colin D.
Published: July 2014

Oceanic plates are geologically young, forming at mid-ocean ridges and becoming deeper and older with distance away from these spreading centres, to be subducted into ocean trenches. Most of the islands that occur on these oceanic plates are basaltic, formed at hot spots, and carried into deeper water as the plate migrates. In tropical reef-forming seas, volcanic islands are usually protected by coral reefs, and undergo transition from fringing reefs, to barrier reefs, to atolls, as envisaged by Darwin. Linear island chains comprise volcanic islands at successive stages in the progression from volcano through coral reefs to seamounts and guyots. Erosion occurs rapidly in the early stages once eruption has ceased, and older islands are conspicuously dissected by fluvial action, as observed by Dana. Many are subject to submarine slumping. In the absence of coral reefs, marine abrasion truncates islands, producing near-vertical cliffs, and islands may be entirely bevelled; Balls Pyramid in the southern Pacific appears to be at the penultimate stage of this planation with a broad shelf around it. Coral reefs protect the shoreline, which is usually deeply embayed, with progressive subsidence until volcanic residuals are all that remain on ‘almost-atolls’. Reef limestones indicate earlier phases of reef formation, and there are limestone cliffs around many tropical islands composed of Last Interglacial limestone often veneering older reef terraces. In some cases, the morphology of these limestone coasts contains prominent notches or surf benches reflecting different degrees of exposure to wave energy, or subtle flexure and vertical displacement. Islands provide discrete examples of rocky coasts, with contrasts between adjacent islands, or islands of different ages, providing many insights into the evolutionary stages and the morphodynamics of bold coasts.
Chapter 16 The rock coasts of polar and sub-polar regions
Authors: Hansom J. D. , Forbes D. L. , Etienne S.
Published: July 2014

Polar and subpolar coasts are distinctive owing to the presence of ice on land as permafrost, ground ice and glacier ice, and in the sea as tidewater glaciers, icebergs, ice shelves and sea ice. Most of these coasts remain glaciated or are recently deglaciated so their geomorphology carries a strong glacial signature. The morphogenetic environment of polar and subpolar coasts is dominated by extreme seasonality with winter development of sea ice and a shore-fast ice foot that excludes wave activity and is primarily protective. However, sea ice may also be erosional at any time of year but is most effective as an erosional agent on polar coasts between freeze-up and break-up, when wave activity forces sea ice to repeatedly impact the shore. Depending on latitude, the short summers are characterized by wave and sea ice erosion at high latitudes and by wave activity at lower latitudes. The contribution of frost weathering to cliff and shore platform development in polar and subpolar rock coasts is unclear, but is likely to be an important influence. Rock coasts are widespread in the Arctic and sub-Arctic, including Iceland, and in the Antarctic and sub-Antarctic the limited ice-free coast is almost entirely rock-dominated.
Chapter 4 The rock coast of the British Isles: shore platforms
Authors: Moses Cherith A.
Published: July 2014

Rock shore platforms, present on at least half of the 20 500 km-long coastline of the British Isles, are usually backed by cliffs of varying heights. They form in a range of material types from soft cohesive sediment to sedimentary and metamorphic rocks of varying strengths to very resistant igneous rocks. Lithology influences platform erosion rates: glacial till>London Clay>chalk>schist>limestone>basalt and granite. Chalk platform erosion rates adjacent to engineering structures are significantly higher than elsewhere on the platform. There are no published reports of erosion rates on British platforms developed in igneous rocks such as basalt and granite because they have proved too resistant to record values using a micro-erosion meter. The most intensively studied shore platforms in the British Isles are on Blue Lias limestone in south Wales and Cretaceous chalk in SE England and there is a need for more detailed studies on additional rock types, particularly for understanding key controls on platform morphology and rates of erosion. The issue of whether the shore platforms exposed at present day mean sea-level are inherited from earlier periods remains. The role of platform erosion in helping to drive cliff retreat is understudied and evidence that engineering structures may enhance platform erosion rates comes from only one rock type. Predicted climate change and sea-level rise scenarios combined with more intensive management of coastal systems mean that it is important to improve understanding of platform systems and their link to cliffs. There is much scope, using established and new methods of investigation, to address the issues raised by existing studies of shore platforms of the British Isles.
Chapter 8 The rock coast of Canada
Authors: Trenhaile A. S.
Published: July 2014

Canada's coasts, which are primarily rocky, extend along three oceans and four Great Lakes. Many processes operate here in the same way as in other places, but glacio-isostatic uplift, coastal permafrost and ground and sea ice assume particular importance in the Canadian context. Only small amounts of wave erosion have occurred on the very resistant rocks of the Canadian Shield, where rapid changes in relative sea-level have limited the time that marine processes operated at any particular level. The Pacific coast and most of the northern Atlantic coast consist of fiords and most steep coastal slopes have been cut by glaciers. Marine processes have been more effective on weaker substrates in southern Canada, where there are a variety of stacks, arches, wave-eroded cliffs and wide shore platforms. Most work has been conducted on the southern Great Lakes, where rapid erosion and recession of glacial clay cliffs threaten human populations and infrastructure, and on the subhorizontal and sloping shore platforms of Atlantic Canada and eastern Québec.
Health, Risk, and Resilience: Interdisciplinary Concepts and Applications
Authors: Panter-Brick Catherine
Published: July 2014

Risk and resilience research articulates major explanatory frameworks regarding the persistence of health disparities. Specifically, scholars have advocated a sophisticated knowledge of risk, a more grounded understanding of resilience, and comprehensive and meaningful measurements of risk and resilience pathways across cultures. The goal is to operationalize research issues into sustainable health practice and equity-focused policy. This article synthesizes current understandings on risk and resilience from the lens of medical anthropology: It reviews key insights gained from the standpoint of cultural narratives, political economy, and life history theory, as well as current shortcomings. The emergent literature on health-related risk and resilience is breathing new life into collaboration and dialogue across diverse fields of research and policy.
Reflections on My Career as a Marine Physical Chemist, and Tales of the Deep
Authors: Millero Frank J.
Published: July 2014

This is a personal review of how one can apply the principles of physical chemistry to study the ocean and other natural waters. Physical chemistry is the study of chemical thermodynamics, kinetics, and molecular structure. My long-term interest in the chemistry of seawater is an extension of my early work on water and the interactions that occur in aqueous electrolyte solutions, which I began as part of my PhD research on the thermodynamics of organic acids in water. Over the years, I have attempted to apply the tools of physical chemistry to elucidate the structures of seawater, brines, lakes, and rivers. I have developed and continue to work on ionic interaction models that can be applied to all natural waters. Here, I reflect on how my students, postdocs, research assistants, and scientific colleagues have influenced my life, my career, and the field of marine physical chemistry. My hope was and is to use these tools to understand the molecular structures of natural waters.
Why Sleep Is Important for Health: A Psychoneuroimmunology Perspective
Authors: Irwin Michael R.
Published: July 2014

Sleep has a critical role in promoting health. Research over the past decade has documented that sleep disturbance has a powerful influence on the risk of infectious disease, the occurrence and progression of several major medical illnesses including cardiovascular disease and cancer, and the incidence of depression. Increasingly, the field has focused on identifying the biological mechanisms underlying these effects. This review highlights the impact of sleep on adaptive and innate immunity, with consideration of the dynamics of sleep disturbance, sleep restriction, and insomnia on (a) antiviral immune responses with consequences for vaccine responses and infectious disease risk and (b) proinflammatory immune responses with implications for cardiovascular disease, cancer, and depression. This review also discusses the neuroendocrine and autonomic neural underpinnings linking sleep disturbance and immunity and the reciprocal links between sleep and inflammatory biology. Finally, interventions are discussed as effective strategies to improve sleep, and potential opportunities are identified to promote sleep health for therapeutic control of chronic infectious, inflammatory, and neuropsychiatric diseases.
The Evolution of Altruism in Humans
Authors: Kurzban Robert , Burton-Chellew Maxwell N. , West Stuart A.
Published: July 2014

Humans are an intensely social species, frequently performing costly behaviors that benefit others. Efforts to solve the evolutionary puzzle of altruism have a lengthy history, and recent years have seen many important advances across a range of disciplines. Here we bring together this interdisciplinary body of research and review the main theories that have been proposed to explain human prosociality, with an emphasis on kinship, reciprocity, indirect reciprocity, punishment, and morality. We highlight recent methodological advances that are stimulating research and point to some areas that either remain controversial or merit more attention.
Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis
Authors: Yu Linda Chia-Hui , Shih Yi-An , Wu Li-Ling , Lin Yang-Ding , Kuo Wei-Ting , Peng Wei-Hao , Lu Kuo-Shyan , Wei Shu-Chen , Turner Jerrold R. , Ni Yen-Hsuan
Published: July 2014

Antibiotic usage promotes intestinal colonization of antibiotic-resistant bacteria. However, whether resistant bacteria gain dominance in enteric microflora or disseminate to extraintestinal viscera remains unclear. Our aim was to investigate temporal diversity changes in microbiota and transepithelial routes of bacterial translocation after antibiotic-resistant enterobacterial colonization. Mice drinking water with or without antibiotics were intragastrically gavaged with ampicillin-resistant (Amp-r) nonpathogenic Escherichia coli ( E. coli) and given normal water afterward. The composition and spatial distribution of intestinal bacteria were evaluated using 16S rDNA sequencing and fluorescence in situ hybridization. Bacterial endocytosis in epithelial cells was examined using gentamicin resistance assay and transmission electromicroscopy. Paracellular permeability was assessed by tight junctional immunostaining and measured by tissue conductance and luminal-to-serosal dextran fluxes. Our results showed that antibiotic treatment enabled intestinal colonization and transient dominance of orally acquired Amp-r E. coli in mice. The colonized Amp-r E. coli peaked on day 3 postinoculation and was competed out after 1 wk, as evidenced by the recovery of commensals, such as Escherichia, Bacteroides, Lachnospiraceae, Clostridium, and Lactobacillus. Mucosal penetration and extraintestinal dissemination of exogenous and endogenous enterobacteria were correlated with abnormal epithelial transcytosis but uncoupled with paracellular tight junctional damage. In conclusion, antibiotic-induced enteric dysbiosis predisposes to exogenous infection and causes systemic dissemination of both antibiotic-resistant and commensal enterobacteria through transcytotic routes across epithelial layers. These results may help explain the susceptibility to sepsis in antibiotic-resistant enteric bacterial infection.
Lactobacillus acidophilus attenuates downregulation of DRA function and expression in inflammatory models
Authors: Singh Varsha , Kumar Anoop , Raheja Geetu , Anbazhagan Arivarasu N. , Priyamvada Shubha , Saksena Seema , Jhandier Muhammad Nauman , Gill Ravinder K. , Alrefai Waddah A. , Borthakur Alip , Dudeja Pradeep K.
Published: July 2014

Probiotics, including Lactobacilli, are commensal bacteria that have been used in clinical trials and experimental models for the prevention and treatment of diarrheal disorders. Our previous studies have shown that Lactobacillus acidophilus (LA) and its culture supernatant (CS) stimulated Cl−/HCO3− exchange activity, acutely via an increase in the surface levels of downregulated in adenoma (DRA, SLC26A3) and in long-term treatments via increasing its expression involving transcriptional mechanisms. However, the role of LA in modulating DRA activity under inflammatory conditions is not known. Current in vitro studies using human intestinal epithelial Caco-2 cells examined the efficacy of LA or its CS in counteracting the inhibitory effects of interferon-γ (IFN-γ) on Cl−/HCO3− exchange activity. Pretreatment of cells with LA or LA-CS for 1 h followed by coincubation with IFN-γ significantly alleviated the inhibitory effects of IFN-γ on Cl−/HCO3− exchange activity. In the in vivo model of dextran sulfate sodium-induced experimental colitis (3% in drinking water for 7 days) in C57BL/6J mice, administration of live LA (3 × 109 colony-forming units) via oral gavage attenuated colonic inflammation. LA administration also counteracted the colitis-induced decrease in DRA mRNA and protein levels. Efficacy of LA or its secreted soluble factors in alleviating inflammation and inflammation-associated dysregulation of DRA activity could justify their therapeutic potential in inflammatory diarrheal diseases.
Novel mechanisms and signaling pathways of esophageal ulcer healing: the role of prostaglandin EP2 receptors, cAMP, and pCREB
Authors: Ahluwalia Amrita , Baatar Dolgor , Jones Michael K. , Tarnawski Andrzej S.
Published: July 2014

Clinical studies indicate that prostaglandins of E class (PGEs) may promote healing of tissue injury e.g., gastroduodenal and dermal ulcers. However, the precise roles of PGEs, their E-prostanoid (EP) receptors, signaling pathways including cAMP and cAMP response element-binding protein (CREB), and their relation to VEGF and angiogenesis in the tissue injury healing process remain unknown, forming the rationale for this study. Using an esophageal ulcer model in rats, we demonstrated that esophageal mucosa expresses predominantly EP2 receptors and that esophageal ulceration triggers an increase in expression of the EP2 receptor, activation of CREB (the downstream target of the cAMP signaling), and enhanced VEGF gene expression. Treatment of rats with misoprostol, a PGE1analog capable of activating EP receptors, enhanced phosphorylation of CREB, stimulated VEGF expression and angiogenesis, and accelerated esophageal ulcer healing. In cultured human esophageal epithelial (HET-1A) cells, misoprostol increased intracellular cAMP levels (by 163-fold), induced phosphorylation of CREB, and stimulated VEGF expression. A cAMP analog (Sp-cAMP) mimicked, whereas an inhibitor of cAMP-dependent protein kinase A (Rp-cAMP) blocked, these effects of misoprostol. These results indicate that the EP2/cAMP/protein kinase A pathway mediates the stimulatory effect of PGEs on angiogenesis essential for tissue injury healing via the induction of CREB activity and VEGF expression.
Tis7 deletion reduces survival and induces intestinal anastomotic inflammation and obstruction in high-fat diet-fed mice with short bowel syndrome
Authors: Garcia Amy M. , Wakeman Derek , Lu Jianyun , Rowley Christopher , Geisman Taylor , Butler Catherine , Bala Shashi , Swietlicki Elzbieta A. , Warner Brad W. , Levin Marc S. , Rubin Deborah C.
Published: July 2014

Effective therapies are limited for patients with parenteral nutrition-dependent short bowel syndrome. We previously showed that intestinal expression of the transcriptional coregulator tetradecanoyl phorbol acetate-induced sequence 7 ( tis7) is markedly increased during the adaptive response following massive small bowel resection and tis7 plays a role in normal gut lipid metabolism. Here, we further explore the functional implications of tis7 deletion in intestinal lipid metabolism and the adaptive response following small bowel resection. Intestinal tis7 transgenic ( tis7tg), tis7−/−, and wild-type (WT) littermates were subjected to 50% small bowel resection. Mice were fed a control or a high-saturated-fat (42% energy) diet for 21 days. Survival, body weight recovery, lipid absorption, mucosal lipid analysis, and the morphometric adaptive response were analyzed. Quantitative real-time PCR was performed to identify tis7 downstream gene targets. Postresection survival was markedly reduced in high-fat, but not control, diet-fed tis7−/− mice. Decreased survival was associated with anastomotic inflammation and intestinal obstruction postresection. High-fat, but not control, diet-fed tis7−/− mice had increased intestinal IL-6 expression. Intestinal lipid trafficking was altered in tis7−/− compared with WT mice postresection. In contrast, high-fat diet-fed tis7tg mice had improved survival postresection compared with WT littermates. High-fat diet feeding in the setting of tis7 deletion resulted in postresection anastomotic inflammation and small bowel obstruction. Tolerance of a calorie-rich, high-fat diet postresection may require tis7 and its target genes. The presence of luminal fat in the setting of tis7 deletion promotes an intestinal inflammatory response postresection.
Heat stress protects against mechanical ventilation-induced diaphragmatic atrophy
Authors: Ichinoseki-Sekine Noriko , Yoshihara Toshinori , Kakigi Ryo , Sugiura Takao , Powers Scott K. , Naito Hisashi
Published: July 2014

Mechanical ventilation (MV) is a life-saving intervention in patients who are incapable of maintaining adequate pulmonary gas exchange due to respiratory failure or other disorders. However, prolonged MV is associated with the development of respiratory muscle weakness. We hypothesized that a single exposure to whole body heat stress would increase diaphragm expression of heat shock protein 72 (HSP72) and that this treatment would protect against MV-induced diaphragmatic atrophy. Adult male Wistar rats ( n = 38) were randomly assigned to one of four groups: an acutely anesthetized control group (CON) with no MV; 12-h controlled MV group (CMV); 1-h whole body heat stress (HS); or 1-h whole body heat stress 24 h prior to 12-h controlled MV (HSMV). Compared with CON animals, diaphragmatic HSP72 expression increased significantly in the HS and HSMV groups ( P < 0.05). Prolonged MV resulted in significant atrophy of type I, type IIa, and type IIx fibers in the costal diaphragm ( P < 0.05). Whole body heat stress attenuated this effect. In contrast, heat stress did not protect against MV-induced diaphragm contractile dysfunction. The mechanisms responsible for this heat stress-induced protection remain unclear but may be linked to increased expression of HSP72 in the diaphragm.
Cardiac function is preserved following 4 weeks of voluntary wheel running in a rodent model of chronic kidney disease
Authors: Kuczmarski James M. , Martens Christopher R. , Kim Jahyun , Lennon-Edwards Shannon L. , Edwards David G.
Published: July 2014

The purpose of this investigation was to determine the effect of 4 wk of voluntary wheel running on cardiac performance in the 5/6 ablation-infarction (AI) rat model of chronic kidney disease (CKD). We hypothesized that voluntary wheel running would be effective in preserving cardiac function in AI. Male Sprague-Dawley rats were divided into three study groups: 1) sham, sedentary nondiseased control; 2) AI-SED, sedentary AI; and 3) AI-WR, wheel-running AI. Animals were maintained over a total period of 8 wk following AI and sham surgery. The 8-wk period included 4 wk of disease development followed by a 4-wk voluntary wheel-running intervention/sedentary control period. Cardiac performance was assessed using an isolated working heart preparation. Left ventricular (LV) tissue was used for biochemical tissue analysis. In addition, soleus muscle citrate synthase activity was measured. AI-WR rats performed a low volume of exercise, running an average of 13 ± 2 km, which resulted in citrate synthase activity not different from that in sham animals. Isolated AI-SED hearts demonstrated impaired cardiac performance at baseline and in response to preload/afterload manipulations. Conversely, cardiac function was preserved in AI-WR vs. sham hearts. LV nitrite + nitrate and expression of LV nitric oxide (NO) synthase isoforms 2 and 3 in AI-WR were not different from those of sham rats. In addition, LV H2O2 in AI-WR was similar to that of sham and associated with increased expression of LV superoxide-dismutase-2 and glutathione peroxidase-1/2. The findings of the current study suggest that a low-volume exercise intervention is sufficient to maintain cardiac performance in rats with CKD, potentially through a mechanism related to improved redox homeostasis and increased NO.
Acute volume loading and exercise capacity in postural tachycardia syndrome
Authors: Figueroa Rocío A. , Arnold Amy C. , Nwazue Victor C. , Okamoto Luis E. , Paranjape Sachin Y. , Black Bonnie K. , Diedrich Andre , Robertson David , Biaggioni Italo , Raj Satish R. , Gamboa Alfredo
Published: July 2014

Postural tachycardia syndrome (POTS) is associated with exercise intolerance, hypovolemia, and cardiac atrophy, which may contribute to reduced stroke volume and compensatory exaggerated heart rate (HR) increases. Acute volume loading with intravenous (iv) saline reduces HR and improves orthostatic tolerance and symptoms in POTS, but its effect on exercise capacity is unknown. In this study, we determined the effect of iv saline infusion on peak exercise capacity (V̇o2peak) in POTS. Nineteen patients with POTS participated in a sequential study. V̇o2peak was measured on two separate study days, following administration of placebo or 1 liter of iv saline (NaCl 0.9%). Patients exercised on a semirecumbent bicycle with resistance increased by 25 W every 2 min until maximal effort was achieved. Patients exhibited blood volume deficits (−13.4 ± 1.4% ideal volume), consistent with mild to moderate hypovolemia. At baseline, saline significantly increased stroke volume (saline 80 ± 8 ml vs. placebo 64 ± 4 ml; P = 0.010), increased cardiac output (saline 6.9 ± 0.5 liter/min vs. placebo 5.7 ± 0.2 liter/min; P = 0.021), and reduced systemic vascular resistance (saline 992.6 ± 70.0 dyn-s/cm5 vs. placebo 1,184.0 ± 50.8 dyn-s/cm5; P = 0.011), with no effect on HR or blood pressure. During exercise, saline did not produce differences in V̇o2peak (saline 26.3 ± 1.2 mg·kg−1·min−1 vs. placebo 27.7 ± 1.8 mg·kg−1·min−1; P = 0.615), peak HR [saline 174 ± 4 beats per minute (bpm) vs. placebo 175 ± 3 bpm; P = 0.672] or other cardiovascular parameters. These findings suggest that acute volume loading with saline does not improve V̇o2peak or cardiovascular responses to exercise in POTS, despite improvements in resting hemodynamic function.
ADAM9 Promotes Lung Cancer Metastases to Brain by a Plasminogen Activator-Based Pathway
Authors: Lin Chen-Yuan , Chen Hung-Jen , Huang Cheng-Chung , Lai Liang-Chuan , Lu Tzu-Pin , Tseng Guan-Chin , Kuo Ting-Ting , Kuok Qian-Yu , Hsu Jennifer L. , Sung Shian-Ying , Hung Mien-Chie , Sher Yuh-Pyng
Published: July 2014

The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease. Cancer Res; 74(18); 5229–43. ©2014 AACR.
Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor–Modified T Cells in Solid Tumors
Authors: Nishio Nobuhiro , Diaconu Iulia , Liu Hao , Cerullo Vincenzo , Caruana Ignazio , Hoyos Valentina , Bouchier-Hayes Lisa , Savoldo Barbara , Dotti Gianpietro
Published: July 2014

The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195–205. ©2014 AACR.
Obesity, Cholesterol Metabolism, and Breast Cancer Pathogenesis
Authors: McDonnell Donald P. , Park Sunghee , Goulet Matthew T. , Jasper Jeff , Wardell Suzanne E. , Chang Ching-yi , Norris John D. , Guyton John R. , Nelson Erik R.
Published: July 2014

Obesity and altered lipid metabolism are risk factors for breast cancer in pre- and post-menopausal women. These pathologic relationships have been attributed in part to the impact of cholesterol on the biophysical properties of cell membranes and to the influence of these changes on signaling events initiated at the membrane. However, more recent studies have indicated that the oxysterol 27-hydroxycholesterol (27HC), and not cholesterol per se, may be the primary biochemical link between lipid metabolism and cancer. The enzyme responsible for production of 27HC from cholesterol, CYP27A1, is expressed primarily in the liver and in macrophages. In addition, significantly elevated expression of this enzyme within breast tumors has also been observed. It is believed that 27HC, acting through the liver X receptor in macrophages and possibly other cells, is involved in maintaining organismal cholesterol homeostasis. It has also been shown recently that 27HC is an estrogen receptor agonist in breast cancer cells and that it stimulates the growth and metastasis of tumors in several models of breast cancer. These findings provide the rationale for the clinical evaluation of pharmaceutical approaches that interfere with cholesterol/27HC synthesis as a means to mitigate the impact of cholesterol on breast cancer pathogenesis. Cancer Res; 74(18); 4976–82. ©2014 AACR.
“Companion Diagnostics”: Has Their Time Come and Gone?
Authors: Hirsch Fred R. , Bunn Paul A. , Herbst Roy S.
Published: July 2014

Rapid development of molecularly targeted drugs requires a “companion diagnostic” that could delay drug development and limit availability of active drugs for relevant patients. Were the negative results from MetMab studies in patients with advanced non–small cell lung cancer due to drug failure or failure of the right companion diagnostic? Clin Cancer Res; 20(17); 4422–4. ©2014 AACR.
Cytoskeletal Regulatory Gene Expression and Migratory Properties of B-cell Progenitors Are Affected by the ETV6–RUNX1 Rearrangement
Authors: Palmi Chiara , Fazio Grazia , Savino Angela M. , Procter Julia , Howell Louise , Cazzaniga Valeria , Vieri Margherita , Longinotti Giulia , Brunati Ilaria , Andrè Valentina , Della Mina Pamela , Villa Antonello , Greaves Mel , Biondi Andrea , D'Amico Giovanna , Ford Anthony , Cazzaniga Giovanni
Published: July 2014

Although the ETV6–RUNX1 fusion is a frequent initiating event in childhood leukemia, its role in leukemogenesis is only partly understood. The main impact of the fusion itself is to generate and sustain a clone of clinically silent preleukemic B-cell progenitors (BCP). Additional oncogenic hits, occurring even several years later, are required for overt disease. The understanding of the features and interactions of ETV6–RUNX1–positive cells during this “latency” period may explain how these silent cells can persist and whether they could be prone to additional genetic changes. In this study, two in vitro murine models were used to investigate whether ETV6–RUNX1 alters the cellular adhesion and migration properties of BCP. ETV6–RUNX1–expressing cells showed a significant defect in the chemotactic response to CXCL12, caused by a block in CXCR4 signaling, as demonstrated by inhibition of CXCL12-associated calcium flux and lack of ERK phosphorylation. Moreover, the induction of ETV6–RUNX1 caused changes in the expression of cell-surface adhesion molecules. The expression of genes regulating the cytoskeleton was also affected, resulting in a block of CDC42 signaling. The abnormalities described here could alter the interaction of ETV6–RUNX1 preleukemic BCP with the microenvironment and contribute to the pathogenesis of the disease.

Implications: Alterations in the expression of cytoskeletal regulatory genes and migration properties of BCP represent early events in the evolution of the disease, from the preleukemic phase to the clinical onset, and suggest new strategies for effective eradication of leukemia. Mol Cancer Res; 12(12); 1796–806. ©2014 AACR.
Photodynamic Diagnostic Ureterorenoscopy with Orally Administered 5-Aminolaevulinic Acid as Photosensitiser: How I Do It
Authors: Kata Slawomir G. , Nabi Ghulam , Eljamel Sam , Chlosta Piotr , Moseley Harry , Aboumarzouk Omar M.
Published: July 2014

Objective: To explain our use of photodynamic diagnostic ureterorenoscopy, we provide a detailed description of the choice of photosensitiser, equipment needed, a safety profile, and pointers on our technique. Technique: Patients are given oral 5-aminolaevulinic acid (5-ALA) as a photosensitiser 3-4 h pre-operatively, and by using a Xenon blue light source, an eyepiece which blocks light below 450 nm which is fitted onto the ureterorenoscope, we are able to conduct a thorough photodiagnosis of the upper urinary tract. Conclusion: Our technique of photodynamic diagnostic ureterorenoscopy has shown that the sensitivity, specificity and detection rates of upper urinary tract lesions can be significantly increased with the use of oral 5-ALA. Therefore, we provide a detailed explanation of the use of oral 5-ALA photosensitiser, indications and contraindications of the technique in addition to equipment used and potential complications of the procedures.
Synergic Effects of Pregabalin-Acetaminophen Combination in Somatic and Visceral Nociceptive Reactivity
Authors: Mititelu Tartau Liliana , Popa Eliza Gratiela , Lupusoru Raoul Vasile , Lupusoru Catalina Elena , Stoleriu Iulian , Ochiuz Lacramioara
Published: July 2014

Background/Aims: The present study investigates the effects of pregabalin (PGB), acetaminophen (ACET) and tenoxicam (TNX) administration in somatic and visceral nociception, using the tail flick test and the writhing test in mice. Methods: In the tail flick test, the substances were administered orally and the latency time response was recorded 15, 30, 60, 90 and 120 min after administration. In the writhing test, pain responses were scored every 5 min during a 30-min period after intraperitoneal injection of diluted acetic acid. Results: Our study demonstrated that oral administration of the combination PGB-ACET resulted in a stronger increase of latency reaction - statistically significant after 15 min compared to TNX and after 30 min compared to PGB in tail flick test. In the writhing test, the combination PGB-ACET, but also PGB-TNX, resulted in a stronger decrease of writhe numbers - statistically significant compared to the effects of the separate administration of each substance. This decrease was more intense in animals treated with the combination PGB-ACET than with PGB-TNX. Conclusion: These results suggest an antinociceptive activity which may be a consequence of the synergic action of the substances.
Chickadees with Bigger Brains Have Smaller Digestive Tracts: A Multipopulation Comparison
Authors: Kozlovsky Dovid Y. , Brown Shelby L. , Branch Carrie L. , Roth II Timothy C. , Pravosudov Vladimir V.
Published: July 2014

The factors leading to the evolution of large brain size remain controversial. Brains are metabolically expensive and larger brains demand higher maintenance costs. The expensive-tissue hypothesis suggests that when selection favors larger brains, evolutionary changes in brain size can occur without an overall increase in energetic costs when brain size represents a trade-off with the size of other expensive tissues, such as the digestive tract. Still, support for this hypothesis is equivocal. We compared mean brain mass, digestive tract mass (stomach and gut) and heart mass in 9 populations of black-capped chickadees along a gradient of winter climate severity. Mean brain mass and telencephalon volume showed significant population variation with larger brains associated with harsher winter conditions. Mean population brain mass and telencephalon volume were also negatively related to both stomach and gut mass. Mean population heart mass, on the other hand, was not significantly associated with either mean brain mass or winter climate severity. Mean brain mass was negatively associated with body mass, with chickadees from harsher environments being smaller but having larger brains and smaller digestive tracts. Our results are consistent with the expensive-tissue hypothesis, and suggest that a harsher winter climate might favor larger brains, which might be associated with a reduction in size of the digestive tract. These findings could potentially be a result of population differences in the winter climate diet related to the perishability of more efficient invertebrate-based food caches.
Diagnosis of Influenza: Only a Problem of Coding?
Authors: Amodio Emanuele , Tramuto Fabio , Costantino Claudio , Restivo Vincenzo , Maida Carmelo , Calamusa Giuseppe , Vitale Francesco
Published: July 2014

Objective: To evaluate the characteristics of hospital discharge diagnoses of influenza measured by using specific International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) codes. Subjects and Methods: The study was conducted for the 3 years 2007, 2008 and 2011. The database included (1) administrative and clinical data on Sicilian patients admitted to acute care hospitals and (2) data from the influenza virological surveillance of 10 European countries (FluNet database). All Sicilian patients diagnosed with at least 1 ICD-9 CM code for influenza (487.0, 487.1 and 487.9) were considered influenza cases. Results: Overall, 2,880 patients with an ICD-9 CM code attributable to influenza were hospitalized in Sicily: 2,119 (73.6%) were admitted from November to April, whereas 761 (26.4%) were admitted from May to October. In the 3 years studied, the analyzed European influenza surveillance systems recorded a peak of laboratory-confirmed influenza activity from November to April with 36,753 (99.7%) influenza cases, whereas only 124 cases (0.3%) were observed from May to October. Conclusions: In Sicily, more than one quarter of all hospital admissions with an ICD-9 CM code for influenza were observed in the months with a negligible circulation of influenza viruses. Our findings show that several hospital discharge records included ICD-9 CM codes for influenza with low levels of sensitivity, specificity and/or appropriateness for clinical information and support the need for improving medical education on the epidemiology and hospital management of influenza cases.
Sonographic Assessment of Renal Size in Healthy Adults
Authors: El-Reshaid Wael , Abdul-Fattah Husam
Published: July 2014

Objective: To assess the normal sonographic values of renal length and cortical thickness in healthy adults and establish reference ranges in our population for comparison when examining renal disease. Subjects and Methods: Sonographic assessment of renal length and cortical thickness were performed from January 2006 to December 2011 in 252 healthy individuals who were self-referred to the El-Reshaid Renal Clinic in Kuwait. They were screened for the absence of renal abnormalities. Weight and height were measured, and body mass index (BMI) and body surface area calculated. Patients were divided into 5 age groups: 18-30, 31-40, 41-50, 51-60 and 61 -80 years, in order to generate reference graphs for renal length and cortical thickness. Results: The mean renal lengths for the right and left kidney were 10.68 ± 1.4 and 10.71 ± 1.0 cm, respectively (p = 0.56) without a significant change with age. The minimum cortical thickness was 0.6 cm. The renal length correlated with the weight of the patients (p < 0.01) and their BMI (p < 0.01) but not with their height. There was no difference in renal size or cortical thickness in patients older than 60 years despite an age-related decline in the glomerular filtration rate (p < 0.001). Conclusions: Renal length and cortical thickness did not vary significantly with age. Renal length correlated well with weight and BMI but not with height. Hence, establishing normal ranges of renal parameters is essential for comparison in situations where possible renal disease is being investigated.
Extending the Surrogacy Analogy: Applying the Advance Directive Model to Biobanks
Authors: Solomon Stephanie , Mongoven Ann
Published: July 2014

Biobank donors and biobank governance face a conceptual challenge akin to clinical patients and their designated surrogate decision-makers, the necessity of making decisions and policies now that must be implemented under future unknown circumstances. We propose that biobanks take advantage of this parallel to learn lessons from the historical trajectory of advance directives and develop models analogous to current ‘best practice' advance directives such as Values Histories and TheFive Wishes. We suggest how such models could improve biobanks' engagement both with communities and with individual donors by being more honest about the limits of current disclosure and eliciting information to ensure the protection of donor interests more robustly through time than current ‘informed consent' processes in biobanking.
Associations of Common Variants in Methionine Metabolism Pathway Genes with Plasma Homocysteine and the Risk of Type 2 Diabetes in Han Chinese
Authors: Huang Tao , Sun Jianqin , Chen Yanqiu , Xie Hua , Xu Danfeng , Li Duo
Published: July 2014

Background/Aims: An association of genetic variants of homocysteine (Hcy) metabolic genes with type 2 diabetes mellitus (T2DM) has been reported. The objective of the present study was to investigate the relationship between the genetic variants in Hcy metabolism-related genes and plasma Hcy levels and T2DM susceptibility in Han Chinese. Methods: A total of 774 patients with T2DM and 500 healthy individuals were recruited. Single-nucleotide polymorphism was determined by standard methods. Results: The Hcy-increasing allele score was positively associated with plasma Hcy levels in both T2DM patients and healthy subjects (r = 0.171 and 0.247, respectively). Subjects with the genotype CC of MTHFR (rs1801131) had a significantly higher likelihood of T2DM compared with subjects with the AA or AA+AC genotypes (OR = 1.93 for CC vs. AA, p = 0.041; OR = 3.13 for CC vs. AA+AC, p = 0.017, respectively). Subjects with the genotype AA of the MTHFD variant (rs2236225) had a significantly lower likelihood of T2DM compared with subjects with the GG or GG+GA genotypes (OR = 0.36 for AA vs. GG, p = 0.027; OR = 0.36 for AA vs. GG+GA, p = 0.017, respectively). In addition, the genotype CT+TT of the PEMT (rs4646356) variants displayed a significant association with an increased risk of T2DM (OR = 1.52 for CT+TT vs. CC, p = 0.042). Conclusions:MTHFR rs1801131 C allele and PEMT rs4646356 T allele were associated with a high risk of T2DM in these Han Chinese.