bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent and possible future trends in abortion.
Authors: Lafitte F
Published: November 2008

The regularly published abortion statistics are insufficiently detailed to make it easy to assess the significance of increases or decreases in the annual number of abortions. Numbers of abortions are related only to a few broad age groups of the women at risk, the size of those age groups is not normally stated, and the age and marital status groupings employed differ from those used for comparable data about trends in child bearing. By matching demographic data on trends in pregnancies which are deliberately terminated (abortion) and those which are not (fertility), this note attempts a) to assess the true impact of abortion among women living in England and Wales during 1973-76, and b) to consider whether the annual volume of abortions may increase over the next decade and what such an increase might signify.
The 'no lose' philosophy in medicine.
Authors: Galbraith S
Published: November 2008

This article as the series title suggests focuses our attention on decisions, both medical and ethical, which face doctors and related personnel in the medical profession daily. Many of these decisions take the form of a choice to one thing or another without being very sure of the outcome of either action. Mr Galbraith explores the pros and cons of what he calls the 'no lose' philosophy in medicine and which plays a large part in medical decision making. He concludes that possibly we may need a new philosophy rather than continuing to use more and more of our resources on care, which is perhaps being carried out as a means of avoiding making value judgements and thus possibly, prevents us from solving some of today's difficult ethical problems.
Teaching medical ethics: University of Nijmegen, The Netherlands.
Authors: De Wachter M A
Published: November 2008

During his internship the medical student often feels a basic need for ethical discussion. The department of medical ethics at the University of Nijmegen offers a monthly discussion in single clinical departments. The ethicist is then assisted by staff responsible for guiding the interns. These discussions, based on daily experience, aim at critical evaluation of ways the profession is being exercised. As such they form an essential counterpart to the more theoretical learning in classrooms and seminars during previous years. The method is rather flexible. Either an inventory of problems is made, followed by a selection and discussion of one problem. Or a discussion is initiated by an introduction by either staff or ethicist. The actual programme and its origin, the objectives and some of the problems of such a programme are presented in this article.
The assessment of pain in advanced cancer.
Authors: Twycross R G
Published: November 2008

This is one of a group of papers read at the London Medical Group conference of "Pain: a necessity?",' which was held in Charing Cross Hospital Medical School, London in February 1978. Dr Twycross argues that complete assessment implies the ability not only to make a diagnosis but also to initiate appropriate treatment. Describing the site, severity and quality of the pain is only the first step. A doctor needs to: 1) Be aware of the range of diagnostic possibilities 2) Appreciate the influences of non-physical factors such as mood and morale 3) Be aware of the range of treatemnt options 4) Establish realistic objectives with the patient 5) Reassess at appropriate intervals to review treatment, monitor side-effects, and develop and maintain a good working relationship with the patient.
The donation and transplantation of kidneys: should the law be changed?
Authors: Kennedy I
Published: November 2008

It is now eighteen years on since the Human Tissue Act 1961, but this legislation is still unchanged in England, Scotland and Wales. Ian Kennedy, in this paper, lays before us the law as it is, the problems of its interpretation and his opinion of what government should be doing to help clarify the situation and remove some of the problems which exist daily for the doctors who face the dilemma of seeking consent for transplants at the moment of extreme grief for the surviving spouses or relatives of the patient who has been in his care only moments before. Ian Kennedy suggests that by doing nothing the Department of Health and the government are being both callous and less than honest.
Cost-benefit analysis and medical ethics.
Authors: Mooney G H
Published: November 2008

The issue of assessing priorities is one that has become the subject of much debate in the National Health Service particularly in the wake of various documents on priorities from central Government. It has become even more so with the prospect of real cuts in expenditure. Economists claim that their science, or perhaps more accurately art can assist in determining not only how best to achieve various ends but also whether and to what extent competing objectives should be pursued. Such choices cannot be made in the absence of some ethical considerations and it is important that health service decision makers (and in particular the medical profession) are aware if the relationship between economics (and especially cost-benefit analysis) and medical ethics.
Medical experiments on human beings.
Authors: Towers B
Published: November 2008

Throughout the scientific age it has been increasingly realised that the path to knowledge is through carefully-controlled experimentation. Medicine must never, however, treat human beings as objects, or as the means to achieving increased knowledge. Ultimately the goal of human evolution will be served by the willing collaboration of members of society in the advancement of knowledge through carefully planned experimentation. As of now, however, many safeguards must be built into the system to ensure that no exploitation occurs. Experimenters are charged with the task of designing the most ingenious experiments, to give maximum information with a minimum of trauma and always to ensure the fully informed consent of the participants. This paper was read to a conference on human rights in relation to forensic science organised by Centro Internazionale di Richerche e Studi Penale e Penitanziari, in cooperation with UNESCO, held in Messina, Italy, in March 1980.
STRONG DOMAIN FILTERING CONSISTENCIES FOR NON-BINARY CONSTRAINT SATISFACTION PROBLEMS
Authors: STERGIOU KOSTAS
Published: November 2008

Domain filtering local consistencies, such as inverse consistencies, that only delete values and do not add new constraints are particularly useful in Constraint Programming. Although many such consistencies for binary constraints have been proposed and evaluated, the situation with non-binary constraints is quite different. Only very recently have domain filtering consistencies stronger than GAC started to attract interest. Following this line of research, we define a number of strong domain filtering consistencies for non-binary constraints and theoretically compare their pruning power. We prove that three of these consistencies are equivalent to maxRPC in binary CSPs while another is equivalent to PIC. We also describe a generic algorithm for domain filtering consistencies in non-binary CSPs. We show how this algorithm can be instantiated to enforce some of the proposed consistencies and analyze the worst-case complexities of the resulting algorithms. Finally, we make a preliminary empirical study.
A STRIP PACKING SOLVING METHOD USING AN INCREMENTAL MOVE BASED ON MAXIMAL HOLES
Authors: NEVEU BERTRAND , TROMBETTONI GILLES , ARAYA IGNACIO , RIFF MARIA-CRISTINA
Published: November 2008

When handling 2D packing problems, numerous incomplete and complete algorithms maintain a so-called bottom-left (BL) property: no rectangle placed in a container can be moved more left or bottom. While it is easy to make a rectangle BL when it is added in a container, it is more expensive to maintain all the placed pieces BL when a rectangle is removed. This prevents researchers from designing incremental moves for metaheuristics or efficient complete optimization algorithms. This paper investigates the possibility of violating the BL property. Instead, we propose to maintain the set of maximal holes, which allows incremental additions and removals of rectangles.

To validate our alternative approach, we have designed an incremental move, maintaining maximal holes, for the strip packing problem, a variant of the famous 2D bin-packing. We have also implemented a metaheuristic, with no user-defined parameter, using this move and standard greedy heuristics. We have finally designed two variants of this incomplete method. In the first variant, a better first layout is provided by a hyperheuristic proposed by some of the authors. In the second variant, a fast repacking procedure recovering the BL property is occasionally called during the local search.

Experimental results show that the approach is competitive with the best known incomplete algorithms.
SYNTHESIS AND CHARACTERIZATION OF Si3N4@Al(OH)3–Y(OH)3 CORE-SHELL COMPOSITE PARTIC3LES
Authors: SONG JIE-GUANG , JI GANG-CHANG , LI SHI-BIN , ZHANG LIAN-MENG
Published: November 2008

Silicon nitride ( Si 3 N 4) has attracted substantial interest because of its extreme chemical and physical properties, but the sintering densification of Si 3 N 4 is difficult, and it is easily oxidized in the high-temperature air to impact high-temperature strength, which restricts its applied range. In order to decrease the oxidization and improve the strength of Si 3 N 4 at high temperature, the surface of Si 3 N 4 is coated with Al ( OH )3 and Y ( OH )3 to synthesis Si 3 N 4@ Al ( OH )3– Y ( OH )3 core-shell composite particles. Through TEM, XRD, and BET analysis, when pH is about 9, Si 3 N 4@ Al ( OH )3– Y ( OH )3 core-shell composite particles are successfully synthesized by co-precipitation methods. Coating layer is about 200 nm, which is compaction and conformability. Dispersion of coated Si 3 N 4 with Al ( OH )3 and Y ( OH )3 particles are very good. Synthesis of Si 3 N 4@ Al ( OH )3– Y ( OH )3 core-shell composite powder will lay the foundation for preparing high-performance YAG/Si 3 N 4 multiphase ceramic materials.
MACRODROPLET REDUCTION AND GROWTH MECHANISMS IN CATHODIC ARC PHYSICAL VAPOR DEPOSITION OF TiN FILMS
Authors: ALI MUBARAK , HAMZAH ESAH , ABBAS TAHIR , HJ. MOHD TOFF MOHD RADZI , QAZI ISHTIAQ A.
Published: November 2008

Cathodic arc physical vapor deposition (CAPVD) a technique used for the deposition of hard coatings for tooling applications has many advantages. The main drawback of this technique is the formation of macrodroplets (MDs) during deposition resulting in films with rougher morphology. The MDs contamination and growth mechanisms was investigated in TiN coatings over high-speed steel, as a function of metal ion etching, substrate bias, and nitrogen gas flow rate; it was observed that the latter is the most important factor in controlling the size and number of the macrodroplets.
OPTIMAL INTERCONNECTION OF AD HOC INJECTION NETWORKS
Authors: DANOY GREGOIRE , ALBA ENRIQUE , BOUVRY PASCAL
Published: November 2008

Multi-hop ad hoc networks allow establishing local groups of communicating devices in a self-organizing way. However, when considering realistic mobility patterns, such networks most often get divided in a set of disjoint partitions. This presence of partitions is an obstacle to communication within these networks. Ad hoc networks are generally composed of devices capable of communicating in a geographical neighborhood for free (e.g. using Wi-Fi or Bluetooth). In most cases a communication infrastructure is available. It can be a set of access point as well as a GSM/UMTS network. The use of such an infrastructure is billed, but it permits to interconnect distant nodes, through what we call “bypass links”. The objective of our work is to optimize the placement of these long-range links. To this end we rely on small-world network properties, which consist in a high clustering coefficient and a low characteristic path length. In this article we investigate the use of three genetic algorithms (generational, steady-state, and cooperative coevolutionary) to optimize three instances of this topology control problem and present initial evidence of their capacity to solve it.
Domain specific language implementation via compile-time meta-programming
Authors: Tratt Laurence
Published: November 2008

Domain specific languages (DSLs) are mini-languages that are increasingly seen as being a valuable tool for software developers and non-developers alike. DSLs must currently be created in an ad-hoc fashion, often leading to high development costs and implementations of variable quality. In this article, I show how expressive DSLs can be hygienically embedded in the Converge programming language using its compile-time meta-programming facility, the concept of DSL blocks, and specialised error reporting techniques. By making use of pre-existing facilities, and following a simple methodology, DSL implementation costs can be significantly reduced whilst leading to higher quality DSL implementations.
Correlative multilabel video annotation with temporal kernels
Authors: Qi Guo-Jun , Hua Xian-Sheng , Rui Yong , Tang Jinhui , Mei Tao , Wang Meng , Zhang Hong-Jiang
Published: November 2008

Automatic video annotation is an important ingredient for semantic-level video browsing, search and navigation. Much attention has been paid to this topic in recent years. These researches have evolved through two paradigms. In the first paradigm, each concept is individually annotated by a pre-trained binary classifier. However, this method ignores the rich information between the video concepts and only achieves limited success. Evolved from the first paradigm, the methods in the second paradigm add an extra step on the top of the first individual classifiers to fuse the multiple detections of the concepts. However, the performance of these methods can be degraded by the error propagation incurred in the first step to the second fusion one. In this article, another paradigm of the video annotation method is proposed to address these problems. It simultaneously annotates the concepts as well as model correlations between them in one step by the proposed
Correlative Multilabel
(CML) method, which benefits from the compensation of complementary information between different labels. Furthermore, since the video clips are composed by temporally ordered frame sequences, we extend the proposed method to exploit the rich temporal information in the videos. Specifically, a temporal-kernel is incorporated into the CML method based on the discriminative information between
Hidden Markov Models
(HMMs) that are learned from the videos. We compare the performance between the proposed approach and the state-of-the-art approaches in the first and second paradigms on the widely used TRECVID data set. As to be shown, superior performance of the proposed method is gained.
Equipment allocation in video-on-demand network deployments
Authors: Thouin Frederic , Coates Mark
Published: November 2008

Video-on-Demand (VoD) services are very user-friendly, but also complex and resource demanding. Deployments involve careful design of many mechanisms where content attributes and usage models should be taken into account. We define, and propose a methodology to solve, the
VoD Equipment Allocation Problem
of determining the number and type of streaming servers with directly attached storage (VoD servers) to install at each potential location in a metropolitan area network topology such that deployment costs are minimized. We develop a cost model for VoD deployments based on streaming, storage and transport costs and train a parametric function that maps the amount of available storage to a worst-case hit ratio. We observe the impact of having to determine the amount of storage and streaming cojointly, and determine the minimum demand required to deploy replicas as well as the average hit ratio at each location. We observe that common video-on-demand server configurations lead to the installation of excessive storage, because a relatively high hit-ratio can be achieved with small amounts of storage so streaming requirements dominate.
Examining presence and lightweight messaging in a social television experience
Authors: Metcalf Crysta , Harboe Gunnar , Tullio Joe , Massey Noel , Romano Guy , Huang Elaine M. , Bentley Frank
Published: November 2008

We report on a field evaluation of a prototype social television system (Social TV) that incorporates lightweight messaging as well as ambient awareness of user presence on the system. This evaluation was conducted over a two-week period and involved the participation of ten households. Participants appreciated the ability to see their buddies' presence on the system, the ability to see or suggest the programs they were currently watching, and the ability to send short messages to one another. The presence facilities available in Social TV also allowed participants to learn more about one another's TV viewing habits and preferences, and fostered a sense of connectedness between them. However, they also felt constrained by the limitations of the communication options available to them and demanded free-form text or voice chat to be able to fully express themselves.
Automated module assignment in stacked-Vdd designs for high-efficiency power delivery
Authors: Zhan Yong , Sapatnekar Sachin S.
Published: November 2008

With aggressive reductions in feature sizes and the integration of multiple functionalities on the same die, bottlenecks due to I/O pin limitations have become a critical issue in today's VLSI designs, especially for 3D IC technologies. To alleviate the pin limitation problem, a stacked-Vdd circuit paradigm has recently been proposed in the literature. However, for a circuit designed using this paradigm, a significant amount of power may be wasted if modules are not carefully assigned to different Vdd domains. In this article, we present a partition-based algorithm for efficiently assigning modules at the floorplanning level, so as to reuse currents between Vdd domains and minimize the power wasted during the operation of the circuit. Experimental results on both 3D and 2D ICs show that compared with assigning modules to different Vdd domains using enumeration and simulated annealing, our algorithm can generate circuits with competitive power and IR noise performance, while being orders of magnitude faster.
Apoptosis is not required for acantholysis in pemphigus vulgaris
Authors: Schmidt Enno , Gutberlet Judith , Siegmund Daniela , Berg Daniela , Wajant Harald , Waschke Jens
Published: November 2008

The autoimmune blistering skin disease pemphigus vulgaris (PV) is caused primarily by autoantibodies against desmosomal cadherins. It was reported that apoptosis can be detected in pemphigus skin lesions and that apoptosis can be induced by PV-IgG in cultured keratinocytes. However, the role of apoptosis in PV pathogenesis is unclear at present. In this study, we provide evidence that apoptosis is not required for acantholysis in PV. In skin lesions from two PV patients, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positivity, but not cleaved caspase-3, was detected in single keratinocytes in some lesions but was completely absent in other lesions from the same patients. In cultures of human keratinocytes (HaCaT and normal human epidermal keratinocytes), PV-IgG from three different PV patients caused acantholysis, fragmented staining of Dsg 3 staining, and cytokeratin retraction in the absence of nuclear fragmentation, TUNEL positivity, and caspase-3 cleavage and hence in the absence of detectable apoptosis. To further rule out the contribution of apoptotic mechanisms, we used two different approaches that are effective to block apoptosis induced by various stimuli. Inhibition of caspases by z-VAD-fmk as well as overexpression of Fas-associated death domain-like interleukin-1β-converting enzyme (FLICE)-like inhibitory proteins FLIPL and FLIPS to inhibit receptor-mediated apoptosis did not block PV-IgG-induced effects, indicating that apoptosis was not required. Taken together, we conclude that apoptosis is not a prerequisite for skin blistering in PV but may occur secondary to acantholysis.
Spiperone, identified through compound screening, activates calcium-dependent chloride secretion in the airway
Authors: Liang Lihua , MacDonald Kelvin , Schwiebert Erik M. , Zeitlin Pamela L. , Guggino William B.
Published: November 2008

Cystic fibrosis (CF) is caused by mutations in the gene producing the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR functions as a Cl−channel. Its dysfunction limits Cl−secretion and enhances Na+absorption, leading to viscous mucus in the airway. Ca2+-activated Cl−channels (CaCCs) are coexpressed with CFTR in the airway surface epithelia. Increases in cytosolic Ca2+activate the epithelial CaCCs, which provides an alternative Cl−secretory pathway in CF. We developed a screening assay and screened a library for compounds that could enhance cytoplasmic Ca2+, activate the CaCC, and increase Cl−secretion. We found that spiperone, a known antipsychotic drug, is a potent intracellular Ca2+enhancer and demonstrated that it stimulates intracellular Ca2+, not by acting in its well-known role as an antagonist of serotonin 5-HT2or dopamine D2receptors, but through a protein tyrosine kinase-coupled phospholipase C-dependent pathway. Spiperone activates CaCCs, which stimulates Cl−secretion in polarized human non-CF and CF airway epithelial cell monolayers in vitro and in CFTR-knockout mice in vivo. In conclusion, we have identified spiperone as a new therapeutic platform for correction of defective Cl−secretion in CF via a pathway independent of CFTR.
Transcriptome response of enterocytes to dietary lipids: impact on cell architecture, signaling, and metabolism genes
Authors: Béaslas Olivier , Torreilles François , Casellas Pierre , Simon Dominique , Fabre Gérard , Lacasa Michel , Delers François , Chambaz Jean , Rousset Monique , Carrière Véronique
Published: November 2008

Intestine contributes to lipid homeostasis through the absorption of dietary lipids, which reach the apical pole of enterocytes as micelles. The present study aimed to identify the specific impact of these dietary lipid-containing micelles on gene expression in enterocytes. We analyzed, by microarray, the modulation of gene expression in Caco-2/TC7 cells in response to different lipid supply conditions that reproduced either the permanent presence of albumin-bound lipids at the basal pole of enterocytes or the physiological delivery, at the apical pole, of lipid micelles, which differ in their composition during the interprandial (IPM) or the postprandial (PPM) state. These different conditions led to distinct gene expression profiles. We observed that, contrary to lipids supplied at the basal pole, apical lipid micelles modulated a large number of genes. Moreover, compared with the apical supply of IPM, PPM specifically impacted 46 genes from three major cell function categories: signal transduction, lipid metabolism, and cell adhesion/architecture. Results from this first large-scale analysis underline the importance of the mode and polarity of lipid delivery on enterocyte gene expression. They demonstrate specific and coordinated transcriptional effects of dietary lipid-containing micelles that could impact the structure and polarization of enterocytes and their functions in nutrient transfer.
Hydrogen sulfide stimulates catecholamine secretion in rainbow trout (Oncorhynchus mykiss)
Authors: Perry Steve F. , McNeill Brian , Elia Eshay , Nagpal Ashish , Vulesevic Branka
Published: November 2008

We tested the hypothesis that endogenously produced hydrogen sulfide (H2S) can potentially contribute to the adrenergic stress response in rainbow trout by initiating catecholamine secretion from chromaffin cells. During acute hypoxia (water Po2= 35 mmHg), plasma H2S levels were significantly elevated concurrently with a rise in circulating catecholamine concentrations. Tissues enriched with chromaffin cells (posterior cardinal vein and anterior kidney) produced H2S in vitro when incubated with l-cysteine. In both tissues, the production of H2S was eliminated by adding the cystathionine β-synthase inhibitor, aminooxyacetate. Cystathionine β-synthase and cystathionine γ-lyase were cloned and sequenced and the results of real-time PCR demonstrated that with the exception of white muscle, mRNA for both enzymes was broadly distributed within the tissues that were examined. Electrical field stimulation of an in situ saline-perfused posterior cardinal vein preparation caused the appearance of H2S and catecholamines in the outflowing perfusate. Perfusion with the cholinergic receptor agonist carbachol (1 × 10−6M) or depolarizing levels of KCl (1 × 10−2M) caused secretion of catecholamines without altering H2S output, suggesting that neuronal excitation is required for H2S release. Addition of H2S (at concentrations exceeding 5 × 10−7M) to the perfusion fluid resulted in a marked stimulation of catecholamine secretion that was not observed when Ca2+-free perfusate was used. These data, together with the finding that H2S-induced catecholamine secretion was unaltered by the nicotinic receptor blocker hexamethonium, suggest that H2S is able to directly elicit catecholamine secretion via membrane depolarization followed by Ca2+-mediated exocytosis.
β-Subunit overexpression alters the stoicheometry of assembled Na-K-ATPase subunits in MDCK cells
Authors: Clifford Rebecca J. , Kaplan Jack H.
Published: November 2008

In eukaryotic cells, the apparent maintenance of 1:1 stoicheometry between the Na-K-ATPase α- and β-subunits led us to question whether this was alterable and thus if some form of regulation was involved. We have examined the consequences of overexpressing Na-K-ATPase β1-subunits using Madin-Darby canine kidney (MDCK) cells expressing flag-tagged β1-subunits (β1flag) or Myc-tagged β1-subunits (β1myc) under the control of a tetracycline-dependent promoter. The induction of β1flag subunit synthesis in MDCK cells, which increases β1-subunit expression at the plasma membrane by more than twofold, while maintaining stable α1expression levels, revealed that all mature β1-subunits associate with α1-subunits, and no evidence of “free” β1-subunits was obtained. Consequently, the ratio of assembled β1- to α1-subunits is significantly increased when “extra” β-subunits are expressed. An increased β1/α1stoicheometry is also observed in cells treated with tunicamycin, suggesting that the protein-protein interactions involved in these complexes are not dependent on glycosylation. Confocal images of cocultured β1myc-expressing and β1flag-expressing MDCK cells show colocalization of β1myc and β1flag subunits at the lateral membranes of neighboring cells, suggesting the occurrence of intercellular interactions between the β-subunits. Immunoprecipitation using MDCK cells constitutively expressing β1myc and tetracycline-regulated β1flag subunits confirmed β-β-subunit interactions. These results demonstrate that the equimolar ratio of assembled β1/α1-subunits of the Na-K-ATPase in kidney cells is not fixed by the inherent properties of the interacting subunits. It is likely that cellular mechanisms are present that regulate the individual Na-K-ATPase subunit abundance.
Signaling pathways utilized by PTH and dopamine to inhibit phosphate transport in mouse renal proximal tubule cells
Authors: Cunningham Rochelle , Biswas Rajatsubhra , Brazie Marc , Steplock Deborah , Shenolikar Shirish , Weinman Edward J.
Published: November 2008

The present experiments were designed to detail factors regulating phosphate transport in cultured mouse proximal tubule cells by determining the response to parathyroid hormone (PTH), dopamine, and second messenger agonists and inhibitors. Both PTH and dopamine inhibited phosphate transport by over 30%. The inhibitory effect of PTH was completely abolished in the presence of chelerythrine, a PKC inhibitor, but not by Rp-cAMP, a PKA inhibitor. By contrast, both chelerythrine and Rp-cAMP blocked the inhibitory effect of dopamine. Chelerythrine inhibited PTH-mediated cAMP accumulation but also blocked the inhibitory effect of 8-bromo-cAMP on phosphate transport. On the other hand, Rp-cAMP had no effect on the ability of DOG, a PKC activator, to inhibit phosphate transport. PD98059, an inhibitor of MAPK, had no effect on PTH- or dopamine-mediated inhibition of sodium-phosphate cotransport. Finally, compared with 8-bromo-cAMP, 8-pCPT-2′- O-Me-cAMP, an activator of EPAC, had no effect on phosphate transport. These results outline significant differences in the signaling pathways utilized by PTH and dopamine to inhibit renal phosphate transport. Our results also suggest that activation of MAPK is not critically involved in PTH- or dopamine-mediated inhibition of phosphate transport in mouse renal proximal tubule cells in culture.
Renal hemodynamic and excretory responses to intra-arterial infusion of peroxynitrite in anesthetized rats
Authors: Matavelli Luis C. , Kadowitz Philip J. , Navar L. Gabriel , Majid Dewan S. A.
Published: November 2008

Peroxynitrite (ONOO−) is formed endogenously by the reaction of nitric oxide (NO) and superoxide (O2−). To examine the hypothesis that OONO−cause renal vasodilation at low concentrations but cause vasoconstriction at higher concentrations, we examined renal responses to intra-arterial infusion of incremental doses of OONO−(10, 20, and 40 μg·kg−1·min−1; 45 min each) in anesthetized rats. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. In control rats ( n = 6), low dose (10 μg·kg−1·min−1) of OONO−increased RBF by 10 ± 3% and GFR by 15 ± 5%. The higher doses (20 and 40 μg·kg−1·min−1) mostly reversed these responses which were −7 ± 4 and −27 ± 7% ( P < 0.05) in RBF and −0.1 ± 4.8 and −14 ± 12% in GFR, respectively. There were no appreciable changes in urine flow (V) and sodium excretion (UNaV) during OONO−infusion. However, in rats pretreated with NO synthase (NOS) inhibitor, l-NAME (50 μg·kg−1·min−1; n = 5), these doses of ONOO−significantly reduced RBF (−26 ± 7, −27 ± 6, and −44 ± 3%) and GFR (−21 ± 6, −25 ± 8, and −32 ± 12%) with variable increases in V or UNaV. Long-term infusion of OONO−(10 μg·kg−1·min−1for 75 min) in another set of control rats ( n = 5) also showed similar vasodilator and hyperfiltration responses. These data indicate that ONOO−acts as an oxidant at high concentration but provides renoprotective function at low concentration that depends on intact NOS activity.
Gaze Pursuit Responses in Nucleus Reticularis Tegmenti Pontis of Head-Unrestrained Macaques
Authors: Suzuki David A. , Betelak Kathleen F. , Yee Robert D.
Published: November 2008

Eye-head gaze pursuit–related activity was recorded in rostral portions of the nucleus reticularis tegmenti pontis (rNRTP) in alert macaques. The head was unrestrained in the horizontal plane, and macaques were trained to pursue a moving target either with their head, with the eyes stationary in the orbits, or with their eyes, with their head voluntarily held stationary in space. Head-pursuit–related modulations in rNRTP activity were observed with some cells exhibiting increases in firing rate with increases in head-pursuit frequency. For many units, this head-pursuit response appeared to saturate at higher frequencies (>0.6 Hz). The response phase re:peak head-pursuit velocity formed a continuum, containing cells that could encode head-pursuit velocity and those encoding head-pursuit acceleration. The latter cells did not exhibit head position–related activity. Sensitivities were calculated with respect to peak head-pursuit velocity and averaged 1.8 spikes/s/deg/s. Of the cells that were tested for both head- and eye-pursuit–related activity, 86% exhibited responses to both head- and eye-pursuit and therefore carried a putative gaze-pursuit signal. For these gaze-pursuit units, the ratio of head to eye response sensitivities averaged ∼1.4. Pursuit eccentricity seemed to affect head-pursuit response amplitude even in the absence of a head position response per se. The results indicated that rNRTP is a strong candidate for the source of an active head-pursuit signal that projects to the cerebellum, specifically to the target-velocity and gaze-velocity Purkinje cells that have been observed in vermal lobules VI and VII.
Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse
Authors: Chen Gang , Popa Laurentiu S. , Wang Xinming , Gao Wangcai , Barnes Justin , Hendrix Claudia M. , Hess Ellen J. , Ebner Timothy J.
Published: November 2008

The tottering mouse is an autosomal recessive disorder involving a missense mutation in the gene encoding P/Q-type voltage-gated Ca2+channels. The tottering mouse has a characteristic phenotype consisting of transient attacks of dystonia triggered by stress, caffeine, or ethanol. The neural events underlying these episodes of dystonia are unknown. Flavoprotein autofluorescence optical imaging revealed transient, low-frequency oscillations in the cerebellar cortex of anesthetized and awake tottering mice but not in wild-type mice. Analysis of the frequencies, spatial extent, and power were used to characterize the oscillations. In anesthetized mice, the dominant frequencies of the oscillations are between 0.039 and 0.078 Hz. The spontaneous oscillations in the tottering mouse organize into high power domains that propagate to neighboring cerebellar cortical regions. In the tottering mouse, the spontaneous firing of 83% (73/88) of cerebellar cortical neurons exhibit oscillations at the same low frequencies. The oscillations are reduced by removing extracellular Ca2+and blocking L-type Ca2+channels. The oscillations are likely generated intrinsically in the cerebellar cortex because they are not affected by blocking AMPA receptors or by electrical stimulation of the parallel fiber–Purkinje cell circuit. Furthermore, local application of an L-type Ca2+agonist in the tottering mouse generates oscillations with similar properties. The beam-like response evoked by parallel fiber stimulation is reduced in the tottering mouse. In the awake tottering mouse, transcranial flavoprotein imaging revealed low-frequency oscillations that are accentuated during caffeine-induced attacks of dystonia. During dystonia, oscillations are also present in the face and hindlimb electromyographic (EMG) activity that become significantly coherent with the oscillations in the cerebellar cortex. These low-frequency oscillations and associated cerebellar cortical dysfunction demonstrate a novel abnormality in the tottering mouse. These oscillations are hypothesized to be involved in the episodic movement disorder in this mouse model of episodic ataxia type 2.
Measuring and Modeling the Interaction Among Reward Size, Delay to Reward, and Satiation Level on Motivation in Monkeys
Authors: Minamimoto Takafumi , La Camera Giancarlo , Richmond Barry J.
Published: November 2008

Motivation is usually inferred from the likelihood or the intensity with which behavior is carried out. It is sensitive to external factors (e.g., the identity, amount, and timing of a rewarding outcome) and internal factors (e.g., hunger or thirst). We trained macaque monkeys to perform a nonchoice instrumental task (a sequential red-green color discrimination) while manipulating two external factors: reward size and delay-to-reward. We also inferred the state of one internal factor, level of satiation, by monitoring the accumulated reward. A visual cue indicated the forthcoming reward size and delay-to-reward in each trial. The fraction of trials completed correctly by the monkeys increased linearly with reward size and was hyperbolically discounted by delay-to-reward duration, relations that are similar to those found in free operant and choice tasks. The fraction of correct trials also decreased progressively as a function of the satiation level. Similar (albeit noiser) relations were obtained for reaction times. The combined effect of reward size, delay-to-reward, and satiation level on the proportion of correct trials is well described as a multiplication of the effects of the single factors when each factor is examined alone. These results provide a quantitative account of the interaction of external and internal factors on instrumental behavior, and allow us to extend the concept of subjective value of a rewarding outcome, usually confined to external factors, to account also for slow changes in the internal drive of the subject.
Race/Ethnicity and Multiple Cancer Risk Factors among Individuals Seeking Smoking Cessation Treatment
Authors: Kendzor Darla E. , Costello Tracy J. , Li Yisheng , Vidrine Jennifer Irvin , Mazas Carlos A. , Reitzel Lorraine R. , Cinciripini Paul M. , Cofta-Woerpel Ludmila M. , Businelle Michael S. , Wetter David W.
Published: November 2008

Smoking in combination with other behavioral risk factors is known to have a negative influence on health, and individuals who smoke typically engage in multiple risk behaviors. However, little is known about the clustering of risk behaviors among smokers of varying race/ethnicity. The purpose of this study was to examine patterns of cancer risk behaviors and to identify predictors of multiple risk behaviors in a racially/ethnically diverse sample of individuals seeking smoking cessation treatment. Overweight/obesity, at-risk alcohol consumption, and insufficient physical activity were measured in 424 smokers (African American, n = 144; Latino, n = 141; and Caucasian, n = 139). Results indicated that 90% of participants reported behavioral cancer risk factors in addition to smoking. Approximately 70% of participants were overweight or obese, 48% engaged in at-risk drinking, and 27% were insufficiently physically active. Univariate analyses indicated that race/ethnicity (P < 0.001), smoking level (P = 0.03), and marital status (P = 0.04) were significant predictors of multiple risk behaviors, although only race/ethnicity remained a significant predictor (P < 0.001), when gender, smoking level, age, education, household income, marital status, and health insurance status were included in a multivariate model. Multivariate analysis indicated that the odds of engaging in multiple risk behaviors were significantly higher among Latinos (odds ratio = 2.85) and African Americans (odds ratio = 1.86) than Caucasians. Our findings highlight the need for research aimed at identifying determinants of racial/ethnic differences in multiple risk behaviors and indicate the importance of developing culturally sensitive interventions that target multiple risk behaviors. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2937–45)
Too Many Referrals of Low-Risk Women for BRCA1/2 Genetic Services by Family Physicians
Authors: White Della Brown , Bonham Vence L. , Jenkins Jean , Stevens Nancy , McBride Colleen M.
Published: November 2008

The increasing availability and public awareness of BRCA1/2 genetic testing will increase women's self-referrals to genetic services. The objective of this study was to examine whether patient characteristics influence the referral decisions of family physicians when a patient requests BRCA1/2 genetic testing. Family physicians (n = 284) completed a Web-based survey in 2006 to assess their attitudes and practices related to the use of genetics in their clinical practice. Using a 2 × 2 × 2 factorial design, we tested the effects of a hypothetical patient's race, level of worry, and insurance status on the decisions of family physicians to refer her for BRCA1/2 testing. The patient was not appropriate for referral based on U.S. Preventive Services Task Force guidelines. No patient characteristics were associated with the family physicians' referral decisions. Although referral was not indicated, only 8% did not refer to genetic services; 92% referred for genetic services, and 50% referred to genetic counseling. Family physicians regarded it unlikely that the patient carried a mutation, but 65% of family physicians believed that if they refused to refer for genetic services it would harm their relationship with the patient. Despite scarce and costly genetic services, family physicians were likely to inappropriately refer a low-risk patient who requested BRCA1/2 testing. The implications of this inappropriate referral on women's screening behavior, genetic services, and health care costs are unknown. Clinicians and patients could benefit from education about the appropriate use of genetic services so that both are more comfortable with a decision against referral. (Cancer Epidemiol Biomarkers Prev 2008;17(11):2980–6)
Correlation between Circadian Gene Variants and Serum Levels of Sex Steroids and Insulin-like Growth Factor-I
Authors: Chu Lisa W. , Zhu Yong , Yu Kai , Zheng Tongzhang , Chokkalingam Anand P. , Stanczyk Frank Z. , Gao Yu-Tang , Hsing Ann W.
Published: November 2008

A variety of biological processes, including steroid hormone secretion, have circadian rhythms, which are influenced by nine known circadian genes. Previously, we reported that certain variants in circadian genes were associated with risk for prostate cancer. To provide some biological insight into these findings, we examined the relationship of five variants of circadian genes, including NPAS2 (rs2305160:G>A), PER1 (rs2585405:G>C), CSNK1E (rs1005473:A>C), PER3 (54-bp repeat length variant), and CRY2 (rs1401417:G>C), with serum levels of sex steroids and insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP3) in 241 healthy elderly Chinese men (mean age of 71.5). Age-adjusted and waist-to-hip ratio–adjusted ANOVA followed by likelihood ratio tests (LRT) showed that the NPAS2 variant A allele was associated with lower free and bioavailable testosterone (PLRT = 0.02 and 0.01, respectively) compared with the GG genotype. In addition, the PER1 variant was associated with higher serum levels of sex hormone-binding globulin levels (Ptrend = 0.03), decreasing 5α-androstane-3α, 17β-diol glucuronide levels (Ptrend = 0.02), and decreasing IGFBP3 levels (Ptrend = 0.05). Furthermore, the CSNK1E variant C allele was associated with higher testosterone to dihydrotestosterone ratios (PLRT = 0.01) compared with the AA genotype, whereas the longer PER3 repeat was associated with higher serum levels of IGF-I (PLRT = 0.03) and IGF-I to IGFBP3 ratios (PLRT = 0.04). The CRY2 polymorphism was not associated with any biomarkers analyzed. Our findings, although in need of confirmation, suggest that variations in circadian genes are associated with serum hormone levels, providing biological support for the role of circadian genes in hormone-related cancers. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3268–73)
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2-Ethyldeoxyguanosine as a Potential Biomarker for Assessing Effects of Alcohol Consumption on DNA
Authors: Balbo Silvia , Hashibe Mia , Gundy Sarolta , Brennan Paul , Canova Cristina , Simonato Lorenzo , Merletti Franco , Richiardi Lorenzo , Agudo Antonio , Castellsagué Xavier , Znaor Ariana , Talamini Renato , Bencko Vladimir , Holcátová Ivana , Wang Mingyao , Hecht Stephen S. , Boffetta Paolo
Published: November 2008

Head and neck cancers are causally related to alcohol consumption, but the underlying mechanisms are unclear. Ethanol is metabolized to acetaldehyde, an experimental carcinogen. Quantitation of the major DNA adduct of acetaldehyde, N2-ethylidenedeoxyguanosine, in human tissues could help to elucidate the mechanism of alcohol carcinogenicity. We applied a quantitative method for the analysis of this adduct, measured as the NaBH3CN reduction product N2-ethyldeoxyguanosine (N2-ethyl-dGuo) by liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring, on DNA (0.04 ± 0.03 mg) isolated from blood collected from control subjects recruited from two studies conducted in different areas of Europe between 1999 and 2005. The group selected from the first study (n = 127) included alcohol drinkers and abstainers while the group from the second study (n = 50) included only heavy drinkers. N2-ethyl-dGuo was detected in all DNA samples. After adjusting for potential confounders, in the first study, drinkers showed a higher level of N2-ethyl-dGuo (5,270 ± 8,770 fmol/μmol dGuo) compared with nondrinkers (2,690 ± 3040 fmol/μmol dGuo; P = 0.04). A significant trend according to dose was observed in both studies (P = 0.02 and 0.04, respectively). Taking into account the amount of alcohol consumption, adduct levels were higher in younger compared with older subjects (P = 0.01), whereas no differences were observed comparing men with women. These results show the feasibility of quantifying N2-ethyl-dGuo in small-volume blood samples and are consistent with the hypothesis that ethanol contributes to carcinogenesis through DNA adducts formation. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3026–32)
An Automated Approach for Estimation of Breast Density
Authors: Heine John J. , Carston Michael J. , Scott Christopher G. , Brandt Kathleen R. , Wu Fang-Fang , Pankratz Vernon Shane , Sellers Thomas A. , Vachon Celine M.
Published: November 2008

Breast density is a strong risk factor for breast cancer; however, no standard assessment method exists. An automated breast density method was modified and compared with a semi-automated, user-assisted thresholding method (Cumulus method) and the Breast Imaging Reporting and Data System four-category tissue composition measure for their ability to predict future breast cancer risk. The three estimation methods were evaluated in a matched breast cancer case-control (n = 372 and n = 713, respectively) study at the Mayo Clinic using digitized film mammograms. Mammograms from the craniocaudal view of the noncancerous breast were acquired on average 7 years before diagnosis. Two controls with no previous history of breast cancer from the screening practice were matched to each case on age, number of previous screening mammograms, final screening exam date, menopausal status at this date, interval between earliest and latest available mammograms, and residence. Both Pearson linear correlation (R) and Spearman rank correlation (r) coefficients were used for comparing the three methods as appropriate. Conditional logistic regression was used to estimate the risk for breast cancer (odds ratios and 95% confidence intervals) associated with the quartiles of percent breast density (automated breast density method, Cumulus method) or Breast Imaging Reporting and Data System categories. The area under the receiver operator characteristic curve was estimated and used to compare the discriminatory capabilities of each approach. The continuous measures (automated breast density method and Cumulus method) were highly correlated with each other (R = 0.70) but less with Breast Imaging Reporting and Data System (r = 0.49 for automated breast density method and r = 0.57 for Cumulus method). Risk estimates associated with the lowest to highest quartiles of automated breast density method were greater in magnitude [odds ratios: 1.0 (reference), 2.3, 3.0, 5.2; P trend < 0.001] than the corresponding quartiles for the Cumulus method [odds ratios: 1.0 (reference), 1.7, 2.1, and 3.8; P trend < 0.001] and Breast Imaging Reporting and Data System [odds ratios: 1.0 (reference), 1.6, 1.5, 2.6; P trend < 0.001] method. However, all methods similarly discriminated between case and control status; areas under the receiver operator characteristic curve were 0.64, 0.63, and 0.61 for automated breast density method, Cumulus method, and Breast Imaging Reporting and Data System, respectively. The automated breast density method is a viable option for quantitatively assessing breast density from digitized film mammograms. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3090–7)