bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cathedral Square substation anchored excavation, Vancouver, British Columbia
Authors: Garga Vinod K. , Carey Edward I. , Milne Robert W.
Published: December 2008

The paper describes the design of and construction experiences at a 20 m deep vertical excavation that was required in the heavily built-up downtown Vancouver area. The subsurface conditions may be generalized as an upper 3 m of sand and gravel followed by a sandstone sequence from fine to coarse with increasing depth. Depending on grain size and cementation, the compressive strength of sandstone varied from 6 to 30 MPa.The excavation support system consisted of soldier piles and posttensioned anchors in the overburden and posttensioned anchors and shotcrete in the rock face. Drainage control was provided by a system of deep, vertical perimeter drains connected to a number of near-horizontal drains in the rock face.The paper describes design considerations for the excavation, including an estimate of seismic-induced deformations. The construction aspects described include the use of a rapid cure method to predict grout strength, the use of couplers in anchor bars, and anchor load tests. During construction, a number of failures, attributed to stress corrosion, occurred in high tensile strength steel anchors. The details of the investigation and testing program used to provide an estimate of remaining anchor life are described. Finally, the paper summarizes results from the field instrumentation. Key words: anchors, construction, corrosion, deformation, drainage, excavation, failure, grout, instrumentation, stress.
An analytical solution to the problem of seepage into counterfort drains
Authors: Bromhead Edward Nicholas
Published: December 2008

Recently, J. N. Hutchinson has collected data on the design and performance of trench and counterfort drains. This article presents an analytical solution to one of these cases, that of seepage into counterfort drains which penetrate the full thickness of a layer of soil, down to the impermeable base on which it rests. The soil is assumed to have uniform permeability.The findings of a small study, by Hutchinson, of seepage patterns to such drains, made with the use of finite element methods, are found to be validated by the theoretical approach in this article. This solution also provides a convenient benchmark against which approximate numerical methods can be assessed.Finally, a design chart based on the theory is presented, with examples of its application to the design of counterfort drain installations for slope stabilization.
Quantitative analysis of debris torrent hazards for design of remedial measures
Authors: Hungr O. , Morgan G. C. , Kellerhals R.
Published: December 2008

Debris torrents, which are rapid flows of soil and organic debris down steep mountain channels, are a major natural hazard in many parts of British Columbia.A series of recent occurrences along the Squamish Highway, north of Vancouver, led the provincial government to initiate a systematic study of debris torrents in this area. This 2 year study involved hazard risk assessment and resulted in the design of a comprehensive system of remedial measures comprising debris retention barriers and basins, channel improvements and diversions, and the reconstruction of bridges. It was necessary in the course of this effort to formulate new design procedures covering the dynamic behaviour of debris torrents, as there was no accepted practical methodology suitable for Western Canadian conditions.This paper provides an approach to determining magnitude (volume of debris material involved), frequency, peak discharge, velocity, conditions for deposition, runout distance, behaviour in bends and run-up against barriers, and dynamic thrust and impact loadings. The procedures are based on some of the more practical concepts available in the specialized literature, supplemented by simple original theories and calibrated against several recent debris torrent events from British Columbia for which sufficiently detailed observational data exists. To be generally applicable, the procedures require a wider and more thorough calibration. They are presented here as working hypotheses that can be used as a guide to the assembly of additional data and provide a rational design tool to supplement the application of experience and judgement. Key words: debris torrents, debris flows, slope hazards, landslide dynamics, remedial measures, engineering design.
THE HIGGS PORTAL AND AN UNIFIED MODEL FOR DARK ENERGY AND DARK MATTER
Authors: BERTOLAMI O. , ROSENFELD R.
Published: December 2008

We examine a scenario where the Higgs boson is coupled to an additional Standard Model singlet scalar field from a hidden sector. We show that, in the case where this field is very light and has already relaxed to its nonzero vacuum expectation value, one gets a very stringent limit on the mixing angle between the hidden sector scalar and the Higgs field from fifth force experiments. However, this limit does not imply in a small coupling due to the large difference of vacuum expectation values. In the case that the hidden sector scalar is identified with the quintessence field, responsible for the recent acceleration of the universe, the most natural potential describing the interaction is disfavored since it results in a time-variation of the Fermi scale. We show that an ad hoc modification of the potential describing the Higgs interaction with the quintessence field may result in an unified picture of dark matter and dark energy, where dark energy is the zero-mode classical field rolling the usual quintessence potential and the dark matter candidate is the quantum excitation (particle) of the field, which is produced in the universe due to its coupling to the Higgs boson. This coupling also generates a mass for the new particle that, contrary to usual quintessence models, does not have to be small, since it does not affect the evolution of classical field. In this scenario, a feasible dark matter density can be, under conditions, obtained.
Compiling mappings to bridge applications and databases
Authors: Melnik Sergey , Adya Atul , Bernstein Philip A.
Published: December 2008

Translating data and data access operations between applications and databases is a longstanding data management problem. We present a novel approach to this problem, in which the relationship between the application data and the persistent storage is specified using a declarative mapping, which is compiled into bidirectional views that drive the data transformation engine. Expressing the application model as a view on the database is used to answer queries, while expressing the database schema as a view on the application model allows us to leverage view maintenance algorithms for update translation. This approach has been implemented in a commercial product. It enables developers to interact with a relational database via a conceptual schema and an object-oriented programming surface. We outline the implemented system and focus on the challenges of mapping compilation, which include rewriting queries under constraints and supporting nonrelational constructs.
Estimating statistical aggregates on probabilistic data streams
Authors: Jayram T. S. , McGregor Andrew , Muthukrishnan S. , Vee Erik
Published: December 2008

The probabilistic stream model was introduced by Jayram et al. [2007]. It is a generalization of the data stream model that is suited to handling
probabilistic
data, where each item of the stream represents a probability distribution over a set of possible events. Therefore, a probabilistic stream determines a distribution over a potentially exponential number of classical
deterministic
streams, where each item is deterministically one of the domain values.

We present algorithms for computing commonly used aggregates on a probabilistic stream. We present the first one pass streaming algorithms for estimating the expected mean of a probabilistic stream. Next, we consider the problem of estimating frequency moments for probabilistic data. We propose a general approach to obtain unbiased estimators working over probabilistic data by utilizing unbiased estimators designed for standard streams. Applying this approach, we extend a classical data stream algorithm to obtain a one-pass algorithm for estimating
F
2
, the second frequency moment. We present the first known streaming algorithms for estimating
F
0
, the number of distinct items on probabilistic streams. Our work also gives an efficient one-pass algorithm for estimating the median, and a two-pass algorithm for estimating the range.
On the expressiveness of implicit provenance in query and update languages
Authors: Buneman Peter , Cheney James , Vansummeren Stijn
Published: December 2008

Information describing the origin of data, generally referred to as
provenance
, is important in scientific and curated databases where it is the basis for the trust one puts in their contents. Since such databases are constructed using operations of both query and update languages, it is of paramount importance to describe the effect of these languages on provenance.

In this article we study provenance for query and update languages that are closely related to SQL, and compare two ways in which they can manipulate provenance so that elements of the input are rearranged to elements of the output:
implicit provenance
, where a query or update only provides the rearranged output, and provenance is provided implicitly by a default provenance semantics; and
explicit provenance
, where a query or update provides both the output and the description of the provenance of each component of the output. Although explicit provenance is in general more expressive, we show that the classes of implicit provenance operations expressible by query and update languages correspond to natural semantic subclasses of the explicit provenance queries.

One of the consequences of this study is that provenance separates the expressive power of query and update languages. The model is also relevant to annotation propagation schemes in which annotations on the input to a query or update have to be transferred to the output or vice versa.
Efficient sort-based skyline evaluation
Authors: Bartolini Ilaria , Ciaccia Paolo , Patella Marco
Published: December 2008

Skyline queries compute the set of Pareto-optimal tuples in a relation, that is, those tuples that are not
dominated
by any other tuple in the same relation. Although several algorithms have been proposed for efficiently evaluating skyline queries, they either necessitate the relation to have been indexed or have to perform the dominance tests on
all
the tuples in order to determine the result. In this article we introduce salsa, a novel skyline algorithm that exploits the idea of presorting the input data so as to effectively
limit
the number of tuples to be read and compared. This makes salsa also attractive when skyline queries are executed on top of systems that do not understand skyline semantics, or when the skyline logic runs on clients with limited power and/or bandwidth. We prove that, if one considers symmetric sorting functions, the number of tuples to be read is minimized by sorting data according to a “minimum coordinate,” minC, criterion, and that performance can be further improved if data distribution is known and an asymmetric sorting function is used. Experimental results obtained on synthetic and real datasets show that salsa consistently outperforms state-of-the-art sequential skyline algorithms and that its performance can be accurately predicted.
Competitive buffer management for shared-memory switches
Authors: Aiello William , Kesselman Alex , Mansour Yishay
Published: December 2008

We consider buffer management policies for shared memory switches. We study the case of overloads resulting in packet loss, where the constraint is the limited shared memory capacity. The goal of the buffer management policy is that of maximizing the number of packets transmitted. The problem is online in nature, and thus we use competitive analysis to measure the performance of the buffer management policies. Our main result is to show that the well-known preemptive Longest Queue Drop (
LQD
) policy is at most 2-competitive and at least √2-competitive. We also demonstrate a general lower bound of 4/3 on the performance of any deterministic online policy. Finally, we consider some other popular non-preemptive policies including Complete Partition, Complete Sharing, Static Threshold and Dynamic Threshold and derive almost tight bounds on their performance.
Approximating rank-width and clique-width quickly
Authors: Oum Sang-Il
Published: December 2008

Rank-width was defined by Oum and Seymour [2006] to investigate clique-width. They constructed an algorithm that either outputs a rank-decomposition of width at most
f
(
k
) for some function
f
or confirms that rank-width is larger than
k
in time
O
(|
V
|
9
log |
V
|) for an input graph
G
= (
V
,
E
) and a fixed
k
. We develop three separate algorithms of this kind with faster running time. We construct an
O
(|
V
|
4
)-time algorithm with
f
(
k
) = 3
k
+ 1 by constructing a subroutine for the previous algorithm; we avoid generic algorithms minimizing submodular functions used by Oum and Seymour. Another one is an
O
(|
V
|
3
)-time algorithm with
f
(
k
) = 24
k
, achieved by giving a reduction from graphs to binary matroids; then we use an approximation algorithm for matroid branch-width by Hliněný [2005]. Finally we construct an
O
(|
V
|
3
)-time algorithm with
f
(
k
) = 3
k
− 1 by combining the ideas of the two previously cited papers.
Aesthetics and experience-centered design
Authors: Wright Peter , Wallace Jayne , McCarthy John
Published: December 2008

The aesthetics of human-computer interaction and interaction design are conceptualized in terms of a pragmatic account of human experience. We elaborate this account through a framework for aesthetic experience built around three themes: (1) a holistic approach wherein the person with feelings, emotions, and thoughts is the focus of design; (2) a constructivist stance in which self is seen as continuously engaged and constituted in making sense of experience; and (3) a dialogical ontology in which self, others, and technology are constructed as multiple centers of value. We use this framework to critically reflect on research into the aesthetics of interaction and to suggest sensibilities for designing aesthetic interaction. Finally, a digital jewelery case study is described to demonstrate a design approach that is open to the perspectives presented in the framework and to consider how the framework and sensibilities are reflected in engagement with participants and approach to design.
CTO Roundtable: Storage Part II
Authors: Bourne Stephen
Published: December 2008

Featuring seven world-class storage experts, this discussion is the first in a new series of CTO Roundtable forums focusing on the near-term challenges and opportunities facing the commercial computing community. Overseen by the ACM Professions Board, this series has as its goal to provide working IT managers with expert advice so they can make better decisions when investing in new architectures and technologies. This is the first installment of the discussion, with a second installment slated for publication in a later issue.
XML Fever
Authors: Wilde Erik , Glushko Robert J.
Published: December 2008

XML (Extensible Markup Language), which just celebrated its 10th birthday, is one of the big success stories of the Web. Apart from basic Web technologies (URIs, HTTP, and HTML) and the advanced scripting driving the Web 2.0 wave, XML is by far the most successful and ubiquitous Web technology. With great power, however, comes great responsibility, so while XML’s success is well earned as the first truly universal standard for structured data, it must now deal with numerous problems that have grown up around it. These are not entirely the fault of XML itself, but instead can be attributed to exaggerated claims and ideas of what XML is and what it can do.
Review: Concurrent and Real-time Programming in Ada (3rd edition) Alan Burns, Andy Wellings, Cambridge University Press, 2007, $75.00, ISBN: 9780521866972
Authors: Wolf Markus
Published: December 2008

Review: Concurrent and Real-time Programming in Ada (3rd edition) Alan Burns, Andy Wellings, Cambridge University Press, 2007, $75.00, ISBN: 9780521866972
Calendar
Authors: Stanik John
Published: December 2008

ApacheCon
Classroom issues
Authors: Walker Henry M.
Published: December 2008

One of the true joys of being a computer scientist is the opportunity to work at multiple levels of abstraction when solving a problem. For example, in writing a software application, we consider high-level requirements, a design that includes encapsulation of data elements and options, individual coding pieces (files, classes, or objects), etc. This column observes that teaching computer science entails the same attention to multiple levels of activity.
Distance education
Authors: Gal-Ezer Judith
Published: December 2008

Opening Books for Academic Learning is a relative new trend, taking advantage of the potential of the Internet and computers.

In this issue I am honored to host a dear colleague, Dr. Yoav Yair, Head of the Center for Technology in Distance Education, at The Open University of Israel, who will describe a new initiative the university is engaged in, which might encourage other international academic institutions who haven't done so, to follow.
A step further
Authors: Yair Yoav
Published: December 2008

The ground-breaking launch of MIT's Open Course-Ware initiative (http://ocw.mit.edu) in 2002 marked a major shift in the paradigm of restricted access to academic materials. MIT decided to open its ~1800 courses to the general public, allowing free usage of course materials, syllabi, exercises, presentations and lecture notes for anyone who wishes to. Faculty members were encouraged to publish their study materials, and with a clever design and a sophisticated portal, achieved rapid publication and dissemination of course materials on-line. This new "Open Course-Ware" term sent a huge shock wave throughout the higher-education establishment.
Percolations
Authors: Kaczmarczyk Lisa
Published: December 2008

Passions run deep in the most unexpected places. A Praying Mantis bites its partner's head off after sex, and the Portia spider lulls a fellow spider into complacency, then lunges at it and eats it. Whether appalled or fascinated, we understand intellectually that these bizarre behaviors must contribute to species survival. On the other hand, the intended victims sometimes learn to deflect their aggressor and yet have as much "fun" as they want. That too contributes to species survival because the resilient spider or mantis achieves far more satisfaction and future productivity than either their aggressor or the deceased. Believe it or not, after attending ITiCSE, I see the connection between these behaviors and innovative computing education.
Introducing recursion by parking cars
Authors: Wirth Michael
Published: December 2008

Many approaches to teaching recursion in textbooks focus on classical examples such as Fibonacci, factorial, or the Towers of Hanoi. As established as these algorithms are, they don't really illustrate the potential of recursion. This paper explores the use of a novel recursive algorithm which requires innovative thinking, and the use of random numbers. The algorithm looks at the use of recursion to randomly park cars on a street.
Automatic generation of web survey for assessment purposes in computer science
Authors: Yang Kuo-pao , Beaubouef Theresa
Published: December 2008

This paper discusses the development and implementation of an engine that automatically creates web survey tool pages from course documents. Issues related to assessment practices in computer science are addressed and the benefits of this new assessment mechanism are presented.
How to create an online internet course
Authors: Lorenzen Torben , Sattar Abdul
Published: December 2008

The authors have developed two hybrid internet courses with one weekly meeting per week instead of the traditional two or three meetings. One course teaches how to use Microsoft Office and is a service course. The other teaches Computer Graphics to computer science majors. The internet materials are structured to use each of the three student learning styles: visual, auditory, and kinesthetic. The steps the authors used to create the internet materials with Adobe Captivate© are presented and parts of a sample lecture are available for download.
Girls, computer science, and games
Authors: Carmichael Gail
Published: December 2008

An innovative week long mini-course for girls has successfully used video game development as the main motivation by teaching related computer science topics at the same time. Students split their time between creating their own game in the lab and learning about game design, usability, graphics, and artificial intelligence. They became more comfortable with the subject and say they are more likely to pursue computer science in high school because of this course.
Lifelong Safari: The Story of a 93-Year-Old Peripatetic Insect Hunter
Authors: Ross Edward S.
Published: December 2008

Edward Shearman Ross’ lifelong interest in insects began in his youth in San Francisco and was encouraged by his artist father. He attended Linfield College, which was endowed by his family, and then transferred to the University of California, Berkeley, to major in entomology, where he was E.O. Essig's teaching assistant. Before his PhD was conferred, he was employed as curator of insects at the California Academy of Sciences. During World War II, he served as Commanding Officer of an army malaria survey unit in combat zones of New Guinea and the Philippines. A Guggenheim Grant enabled Ross to photograph insects in Amazonian forests. As he searched for embiids in Mexico, Central and South America, and throughout Africa, India, Asia, and Australia, he photographed tribal peoples. He produced scientific and popular articles and taught insect biology at U.C. Berkeley. After 70 years at the Academy, he continues to work in his home lab and office and curate the 350,000 embiid specimens.
Adaptation and Invasiveness of Western Corn Rootworm: Intensifying Research on a Worsening Pest
Authors: Gray Michael E. , Sappington Thomas W. , Miller Nicholas J. , Moeser Joachim , Bohn Martin O.
Published: December 2008

The western corn rootworm, Diabrotica virgifera virgifera LeConte, is an established insect pest of maize (Zea mays L.) in North America. The rotation of maize with another crop, principally soybeans, Glycine max (L.), was the primary management strategy utilized by North American producers and remained highly effective until the mid-1990s. In 1995, widespread and severe root injury occurred in east-central Illinois and northern Indiana maize fields that had been annually rotated with soybeans on a regular basis for several decades. The failure of this cultural tactic from a pest management perspective was attributed to a behavioral adaptation by a variant western corn rootworm that had lost fidelity to maize for egg laying. In 1992, an infestation of western corn rootworm was found within a small maize field near the Belgrade Airport. By 2007, the presence of this insect pest had been confirmed in 20 European countries. More recent molecular studies have confirmed that at least three separate invasions (until 2004) of western corn rootworms have occurred in Europe, increasing the risk that rotation-resistant western corn rootworms will be introduced into a new continent. Although biological control and use of conventional resistant maize hybrids have not achieved widespread success in the management of western corn rootworms in North America, these tactics are being evaluated in Europe.
Fitness Costs of Insect Resistance to Bacillus thuringiensis
Authors: Gassmann Aaron J. , Carrière Yves , Tabashnik Bruce E.
Published: December 2008

Evolution of resistance by insect pests threatens the continued effectiveness of Bacillus thuringiensis (Bt) toxins in sprays and transgenic crops. Fitness costs of Bt resistance occur when, in the absence of Bt toxins, fitness is lower for resistant insects than for susceptible insects. Modeling results show that fitness costs can delay resistance by selecting against Bt-resistant genotypes in refuges where insects are not exposed to Bt toxins. In 77 studies including 18 species, fitness costs were detected in 62% of experiments testing for declines in resistance and in 34% of fitness component comparisons. Mean fitness costs were 15.5% for survival, 7.4% for development time, and 2.5% for mass. Although most fitness costs were recessive, nonrecessive costs can select more strongly against resistance. Because fitness costs vary with ecological conditions, refuges designed to increase the dominance or magnitude of fitness costs could be especially useful for delaying pest resistance.
Species Interactions Among Larval Mosquitoes: Context Dependence Across Habitat Gradients
Authors: Juliano Steven A.
Published: December 2008

Biotic interactions involving mosquito larvae are context dependent, with effects of interactions on populations altered by ecological conditions. Relative impacts of competition and predation change across a gradient of habitat size and permanence. Asymmetrical competition is common and ecological context changes competitive advantage, potentially facilitating landscape-level coexistence of competitors. Predator effects on mosquito populations sometimes depend on habitat structure and on emergent effects of multiple predators, particularly interference among predators. Nonlethal effects of predators on mosquito oviposition, foraging, and life history are common, and their consequences for populations and for mosquito-borne disease are poorly understood. Context-dependent beneficial effects of detritus shredders on mosquitoes occur in container habitats, but these interactions appear to involve more than simple resource modification by shredders. Investigations of context-dependent interactions among mosquito larvae will yield greater understanding of mosquito population dynamics and provide useful model systems for testing theories of context dependence in communities.
Parsing Pain Perception Between Nociceptive Representation and Magnitude Estimation
Authors: Baliki M. N. , Geha P. Y. , Apkarian A. V.
Published: December 2008

Assessing the size of objects rapidly and accurately clearly has survival value. A central multisensory module for subjective magnitude assessment is therefore highly likely, suggested by psychophysical studies, and proposed on theoretical grounds. Given that pain perception is fundamentally an assessment of stimulus intensity, it must necessarily engage such a central module. Accordingly, we compared functional magnetic resonance imaging (fMRI) activity of pain magnitude ratings to matched visual magnitude ratings in 14 subjects. We show that brain activations segregate into two groups, one preferentially activated for pain and another equally activated for both visual and pain magnitude ratings. The properties of regions in the first group were consistent with encoding nociception, whereas those in the second group with attention and task control. Insular cortex responses similarly segregated to a pain-specific area and an area (extending to the lateral prefrontal cortex) conjointly representing perceived magnitudes for pain and vision. These two insular areas were differentiated by their relationship to task variance, ability to encode perceived magnitudes for each stimulus epoch, temporal delay differences, and brain intrinsic functional connectivity. In a second group of subjects ( n = 11) we contrasted diffusion tensor imaging–based white matter connectivity for these two insular areas and observed anatomical connectivity closely corresponding to the functional connectivity identified with fMRI. These results demonstrate that pain perception is due to the transformation of nociceptive representation into subjective magnitude assessment within the insula. Moreover, we argue that we have identified a multisensory cortical area for “how much” complementary and analogous to the “where” and “what” as described for central visual processing.
On Combining Triads and Unrelated Subjects Data in Candidate Gene Studies: An Application to Data on Testicular Cancer
Authors: Hsu Li , Starr Jacqueline R. , Zheng Yingye , Schwartz Stephen M.
Published: December 2008

Combining data collected from different sources is a cost-effective and time-efficient approach for enhancing the statistical efficiency in estimating weak-to-modest genetic effects or gene-gene or gene-environment interactions. However, combining data across studies becomes complicated when data are collected under different study designs, such as family-based and unrelated individual-based (e.g., population-based case-control design). In this paper, we describe a general method that permits the joint estimation of effects on disease risk of genes, environmental factors, and gene-gene/gene-environment interactions under a hybrid design that includes cases, parents of cases, and unrelated individuals. We provide both asymptotic theory and statistical inference. Extensive simulation experiments demonstrate that the proposed estimation and inferential methods perform well in realistic settings. We illustrate the method by an application to a study of testicular cancer.
The Role of Cytokines in the Regulation of Neurotransmission
Authors: Camacho-Arroyo I. , López-Griego L. , Morales-Montor J.
Published: December 2008

Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped in several protein families, namely tumor necrosis factors, interleukins, interferons and colony-stimulating factors. In recent years, evidence has elucidated that some of these proteins as well as their receptors are also produced in the central nervous system (CNS) by specific neural cell lineages under physiological and pathological conditions. Cytokines regulate a variety of processes in the CNS, including neurotransmission. The current data let us to suggest that cytokines play an important role in the regulation of both excitatory and inhibitory neurotransmission in the CNS. This knowledge could be fundamental for the proposal of new therapeutic approaches to neurological and psychiatric disorders.
Mitochondrial Polymorphisms Are Associated Both with Increased and Decreased Longevity
Authors: Castri Loredana , Melendez-Obando Mauricio , Villegas-Palma Ramon , Barrantes Ramiro , Raventos Henrieta , Pereira Reynaldo , Luiselli Donata , Pettener Davide , Madrigal Lorena
Published: December 2008

Previous work compared frequency of longevity-associated polymorphisms (LAPS) in long-lived individuals and in controls from the general population (primarily in Europe and Japan), suggesting the polymorphisms are responsible for unusual longevity. However, individuals from the general population are not the control group for long-lived subjects because both were born in different periods. We report results of a project which collected mtDNA from living subjects in Costa Rica, and traced back their maternal genealogy. Since mtDNA does not recombine and its probability of mutation is low, we can assume that the maternal ancestors had the same mtDNA of their descendants. We compared the longevity of individuals with LAPS with the longevity of controls born in the same time period. We did not confirm previous associations for several markers, but found that the 5178A mutation in haplogroup D is associated with decreased longevity, whereas the 150T mutation is associated with increased longevity. These associations however, are not significant for all time periods under study. While our data confirm that mtDNA make up affects longevity, they also indicate that the time period in which a person was born had a much greater impact on longevity than presence or absence of a marker.
Genotyping Error Detection in Samples of Unrelated Individuals without Replicate Genotyping
Authors: Liu Nianjun , Zhang Dabao , Zhao Hongyu
Published: December 2008

Objective: Identifying genotyping errors is an important issue in genetic research, yet it has been relatively less studied in samples consisting of unrelated individuals. In this article, we consider several models of genotyping errors, which were originally proposed for pedigree data, for unrelated population samples with single nucleotide polymorphism (SNP) genotype data. The mathematical constraints are investigated for detecting genotyping errors without resampling replicates or genotyping relatives. Methods: For the various proposed genotyping error models, we unveil the conditions under which the parameters are identifiable. These results are verified through applications to simulated and real SNP data. Results: We show that, with constraints, two particular models provide both identifiable error rate and allele frequencies of an SNP for unrelated population data. The simulation study shows that these two models present unbiased estimates for the allele frequencies. One of the models also gives an unbiased estimate for the genotyping error rate. Conclusion: While the Hardy-Weinberg equilibrium test can be used to detect genotyping errors, a key advantage of these models is the explicit estimates of genotyping error rates and allele frequencies. This work may help researchers to estimate error rates and to use the estimates in their analysis to increase power and decrease bias, without the extra work of genotyping family members or replicates.
Population Genetics and Comparative Genetics of CLDN1, a Gene Involved in Hepatitis C Virus Entry
Authors: Bekker Vincent , O’Brien Thomas R. , Chanock Stephen
Published: December 2008

The claudin-1 gene (CLDN1) is a member of a family of genes that encodes proteins found in tight junctions and it has recently been implicated as one of several receptors for late stage binding of hepatitis C virus (HCV). Exploration of the population genetics of this gene could be informative, especially in the investigation of a possible genetic contribution to HCV infection. Comparison to a highly similar gene, claudin-7 (CLDN7) could provide insight into the recent molecular evolution of CLDN1. Mean interspecies conservation score was 0.11 (SD 0.28) for CLDN1 and 0.31 (SD 0.43) for CLDN7. Re-sequence analysis was performed across all exons and evolutionarily conserved regions in CLDN1 (13 kb in total) and CLDN7 (2 kb in total) in 204 chromosomes drawn from the SNP500Cancer resource of four self-described ethnic groups in the US. For CLDN1, 133 SNPs were identified as well as 8 indels and an AC repeat length polymorphism. For CLDN7, 5 SNPs were identified. Assessment of nucleotide diversity (includingFst, θ and π statistics) did not show evidence for recent positive or negative selection in either gene. The pattern of linkage disequilibrium was determined for each group and there is substantial difference for common SNPS (>5%) between populations as well as genes, further supporting the absence of signatures of recent selection.
Pretreatment to Enhance Protoporphyrin IX Accumulation in Photodynamic Therapy
Authors: Gerritsen M.J.P. , Smits T. , Kleinpenning M.M. , van de Kerkhof P.C.M. , van Erp P.E.J.
Published: December 2008

The response rates of photodynamic therapy (PDT) vary widely. Limited uptake of topically applied 5-aminolaevulinic acid (ALA), or its methyl ester (MAL), and suboptimal production of protoporphyrin IX (PpIX) may account for these differences. Recently, we demonstrated that hyperkeratosis is an important negative factor in ALA uptake. This review has its focus on pretreatment of the skin in order to improve the clinical outcome of ALA/MAL PDT. Pretreatment of hyperkeratosis can be achieved with keratolytics, curettage/debulking, tape stripping, microdermabrasion or laser ablation. Penetration enhancers may alter the composition or organization of the intercellular lipids of the stratum corneum. Several studies have been performed on the use of dimethyl sulfoxide, azone, glycolic acid, oleic acid and iontophoresis to increase the penetration of ALA. As PpIX production is also dominated by temperature-dependent processes, elevating skin temperature during ALA application may also improve treatment results. Another approach is the use of additives that interact with the heme biosynthetic pathway, e.g. by removing ferrous iron with iron-chelating substances such as: ethylenediaminetetraacetic acid; 3-hydroxypyridin-4-ones; 1,2-diethyl-3-hydroxypyridin-4-one-hydrochloride; and desferrioxamine. In conclusion, simple pretreatments or additions to the regular practice of PDT, aimed to optimize intralesional PpIX content, improve the clinical outcome.
Evaluation of enoxaparin dosing requirements in infants and children
Authors: Belletrutti Mark , Bajzar Laszlo , Black Karina , Kuhle Stefan , Bauman Michelle , Massicotte M. Patricia , Bauman Mary
Published: December 2008

Increasing the starting dose of enoxaparin results in the early achievement of therapeutic anti-factor Xa levels in children receiving enoxaparin which is critical for effective therapy and the reduction of venipunctures. The aim of this study was: i) to determine the enoxaparin dose required to achieve therapeutic anti-factor Xa levels in infants and children, and ii) to establish whether increasing the starting dose of enoxaparin influenced the time required to reach the therapeutic range and the number of venipunctures required for dose-adjustment, and iii) the radiographic outcome of the thrombosis, where applicable. A retrospective chart review of children who received enoxaparin was carried out at the Stollery Children’s Hospital, Edmonton, Alberta, Canada. Patients treated with standard-dose enoxaparin (1.5 mg/kg for children ≤3 months of age, 1.0 mg/kg for children ≥3 months of age), were compared with children who received a higher initial starting dose of enoxaparin (1.7 mg/kg for children ≥3 months of age, 1.2 mg/kg for children ≥3 months of age). Infants <3 months required an enoxaparin dose of 1.83 mg/kg, and those who received an increased initial enoxaparin dose resulted in faster attainment of therapeutic anti-factor Xa levels requiring significantly fewer venipunctures. Similarly, infants ≥3–12 months, 1–5 years, and 6–18 years, require enoxaparin 1.48 mg/kg, 1.23 mg/kg and 1.13 mg/kg, respectively, in order to achieve a therapeutic anti-factor Xa level. In conclusion, increasing the starting dose of enoxaparin may result in more rapid attainment of therapeutic range with fewer venipunctures, dose adjustments, and without an increase in adverse events.
Immature platelets in patients with acute coronary syndromes
Authors: Hvas Anne-Mette , Kristensen Steen Dalby , Grove Erik Lerkevang
Published: December 2008

Platelets newly released from the bone marrow are RNA-containing and more haemostatically active than mature platelets. Immature platelets are reliably quantified by flow cytometry, and the immature platelet fraction (IPF) reflects platelet production and the rate of platelet turnover. It was the objective of this study to evaluate the presence of immature platelets in healthy subjects, patients with stable coronary artery disease (CAD) and patients with acute coronary syndromes. Flow cytometric determination of immature platelets was performed with an automated analyzer (Sysmex XE-2100) using RNA fluorescent dyes. IPF was determined in 420 individuals: 22 healthy subjects, 39 patients with stable CAD, 182 patients with unstable angina/ non-ST-segment elevation myocardial infarction (non-STEMI) and 177 patients with acute STEMI. The geometric mean [95% confidence interval] of IPF was 2.51 [2.04–3.10] in healthy subjects, 2.87 [2.45–3.36] in CAD patients, 2.93 [2.72–3.15] in the non-STEMI/unstable angina group and 3.71 [3.45–3.99] in patients with STEMI (ANOVA: p < 0.0001). This difference remained significant after adjusting for baseline characteristics (p = 0.0003). In active smokers, IPF was 18% higher than in non-smoking individuals (p = 0.007), and IPF was 16% higher in diabetics compared with non-diabetics (p = 0.060). In conclusion, the fraction of immature platelets is increased in acute coronary syndromes, especially in the acute phase of STEMI. Immature platelets with an increased haemostatic potential may contribute to coronary thrombus formation.
Drug-eluting balloon: Very short-term exposure and overlapping
Authors: Speck Ulrich , Kaufels Nicola , Mahnkopf Dirk , Kühler Michael , Böhm Michael , Scheller Bruno , Cremers Bodo
Published: December 2008

Paclitaxel balloon coating has shown promising effects in inhibiting restenosis in initial clinical trials. The aim of the present study was to evaluate the influence of two critical features of drug-eluting balloon (DEB) application – inflation time and increased dose due to overlapping balloons. Fifty-six stainless steel stents were implanted in the left anterior descending and circumflex coronary arteries of 28 domestic pigs using a 1.2:1.0 overstretch ratio. Stents were mounted on conventional un-coated and paclitaxel-coated angioplasty balloon catheters. The animals were randomized to five different treatments with a range of short (10 seconds [s] inflation using 1 DEB) to extended (2x60 s inflation using 2 DEB) intima contact time. After 28 days, quantitative angiography and histomorphometry of the stented arteries was performed on a total of 23 pigs. Paclitaxel balloon coating led to a marked reduction of parameters characterizing in-stent stenosis: Late lumen loss was 1.37 ± 0.49 mm for uncoated balloons, 0.23 ± 0.42 mm for one coated balloon 60 s inflation time, 0.37 ± 0.28 mm for 10 s inflation time and 0.30 ± 0.19 mm for the vessel segment treated by two coated balloons with 60 s inflation each. Neointimal areas were 4.26 ± 1.18, 1.68 ± 0.23, 1.83 ± 0.40 and 1.67 ± 0.46 mm², respectively (p=0.001 versus control, p>0.05 between paclitaxel-treated groups). Despite the marked reduction of neointimal proliferation, endothelialization of stent struts was present in all samples. DEB were found to effectively reduce neointimal proliferation regardless of inflation time and dose within the tested range. No adverse reactions were seen as dose was increased to more than three times the clinically tested dose.
Clopidogrel versus prasugrel in rabbits
Authors: Watson Carol , Hua Ji , Schumacher William , Rehfuss Robert , Wong Pancras
Published: December 2008

The new P2Y12 antagonist prasugrel produces greater inhibition of ADP-induced platelet aggregation (IPA) and reduction of thrombotic events in patients versus approved doses of clopidogrel, but increases major bleeding. We examined whether IPA level or P2Y12 receptor occupancy (RO) could be optimized to better balance the efficacy and bleeding effects of these thienopyridines and reduce the response variability in rabbits. Rabbits were given three daily oral doses of clopidogrel (0.3–30 mg/ kg/d), prasugrel (0.03–10 mg/kg/d) or vehicle (n=6–40/group). Electrically-induced carotid artery thrombosis (AT, % thrombus weight reduction), cuticle bleeding time (BT, fold-increase over control), IPA to 20 μM ADP (% inhibition of peak light transmission) and RO (% inhibition of [33P]-2MeS-ADP binding to P2Y1-blocked platelets) were determined 2–3 hours after the last dose. ED50 (doses for half-maximal effect, mg/kg/d) of AT, BT, IPA and RO were 1.6, 6.7, 1.9 and 1.4 for clopidogrel vs. 1.2, 1.9, 0.5 and 0.2 for prasugrel. IPA of 30–40% for both compounds produced the optimal balances of efficacy (AT: 50–60%) and BT of about 2-fold with significant RO of 70–80%. IPA of 50–60% achieved higher efficacy (AT: 60–80%), but with increased BT of five- to six-fold and >90% RO. Box-plot suggests no significant difference in the IPA and RO response variability between both compounds. Clopidogrel was 1.3–7 times less potent than prasugrel in rabbits, depending upon which biomarker was studied. The ratio of efficacy:bleeding was most favorable at a moderate IPA of 30% to 40%. Both compounds had similar IPA and RO response variability.
Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty
Authors: Roskell Neil , Plumb Jonathan , Caprini Joseph , Eriksson Bengt , Wolowacz Sorrel
Published: December 2008

Dabigatran etexilate has been investigated in three phase III trials for the prevention of venous thromboembolism (VTE). Health technology assessment agencies increasingly require meta-analyses of all relevant evidence for an intervention, if appropriate. The objective of this study was to perform a meta-analysis of efficacy and safety data for the recommended dose of dabigatran etexilate, 220 mg once daily (od), for VTE prophylaxis after total knee arthroplasty (TKA) and total hip arthroplasty (THA), and discuss the appropriateness of combining the data. Risk ratios (RR) for VTE and bleed end-points were estimated using fixed and random effects meta-analysis. Analyses were performed combining RE-MODEL and RE-NOVATE, which compared dabigatran etexilate with enoxaparin 40 mg od after TKA and THA, respectively, and also including RE-MOBILIZE, which compared dabigatran etexilate with enoxaparin 30 mg twice daily after TKA. Tests for statistical heterogeneity were performed using the Chi-squared statistic. No significant differences were detected between dabigatran etexilate and enoxaparin in any of the end-points analysed, either in the two trial analysis (all p>0.15), or when all three trials were combined ( all p>0.30). RRs (random effects) for the composite end-point total VTE and all-cause mortality were 0.95 [95% confidence intervals 0.82 – 1.10] and 1.05 [0.87 – 1.26] in the two and three trial analyses, respectively. Meta-analysis of RE-MODEL and RE-NOVATE supported the conclusions of the individual trials that dabigatran etexilate is non-inferior to enoxaparin 40 mg od, with a similar safety profile. Meta-analysis of all three trials found no significant differences between treatments in any of the end-points analysed. Heterogeneity between the trials cannot be ruled out.
The technique of measuring thrombin generation with fluorescent substrates: 4. The H-transform, a mathematical procedure to obtain thrombin concentrations without external calibration
Authors: Hemker Pieter , Dieri Raed Al , Hemker Coen
Published: December 2008

In fluorogenic thrombin generation (TG) experiments, thrombin concentrations cannot be easily calculated from the rate of the fluorescent signal increase, because the calibration coefficient increases during the experiment, due to substrate consumption and quenching of the fluorescent signal by the product. Continuous, external calibration via an in a parallel sample therefore was hitherto required for an accurate calculation of the TG curve. A technique is presented that allows mathematical transformation of experimental fluorescence intensities into “ideal” data, i.e. in the data that would have been obtained if substrate consumption and quenching by the product would not play a role. The method applies to fluorescence intensities up to 90% of the maximal fluorescent signal corresponding to total substrate conversion and thereby covers the entire region of interest encountered in practice. The first derivative of the transformed signal can then be converted into thrombin concentrations via a conventional, fixed calibration factor. This calibration factor can be obtained from a separate experiment but also by measuring the amidolytic activity of the α2macroglobulin-thrombin complex present in the reaction mixture (“serum”) after thrombin generation is over. This method halves the amount of sample required per experiment.