Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda ≤ 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.

The ASAS criteria for axial spondyloarthritis: Strengths, weaknesses, and proposals for a way forward

Classification criteria should facilitate selection of similar patients for clinical and epidemiologic studies, therapeutic trials, and research on etiopathogenesis to enable comparison of results across studies from different centers. We critically appraise the validity and performance of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial spondyloarthritis (axSpA). It is still debatable whether all patients fulfilling these criteria should be considered as having true axSpA. Patients with radiographically evident disease by the ASAS criteria are not necessarily identical with ankylosing spondylitis (AS) as classified by the modified New York criteria. The complex multi-arm selection design of the ASAS criteria induces considerable heterogeneity among patients so classified, and applying them in settings with a low prevalence of axial spondyloarthritis (SpA) greatly increases the proportion of subjects falsely classified as suffering from axial SpA. One of the unmet needs in non-radiographic form of axial SpA is to have reliable markers that can identify individuals at risk for progression to AS and thereby facilitate early intervention trials designed to prevent such progression. We suggest needed improvements of the ASAS criteria for axSpA, as all criteria sets should be regarded as dynamic concepts open to modifications or updates as our knowledge advances.

Visual fingerprints of the acoustic environment: The use of acoustic indices to characterise natural habitats

Acoustic recordings play an increasingly important role in monitoring terrestrial environments. However, due to rapid advances in technology, ecologists are accumulating more audio than they can listen to. Our approach to this big-data challenge is to visualize the content of long-duration audio recordings by calculating acoustic indices. These are statistics which describe the temporal-spectral distribution of acoustic energy and reflect content of ecological interest. We combine spectral indices to produce false-color spectrogram images. These not only reveal acoustic content but also facilitate navigation. An additional analytic challenge is to find appropriate descriptors to summarize the content of 24-hour recordings, so that it becomes possible to monitor long-term changes in the acoustic environment at a single location and to compare the acoustic environments of different locations. We describe a 24-hour ‘acoustic-fingerprint’ which shows some preliminary promise.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Biophilic urbanism: Contributions to holistic urban greening for urban renewal

Purpose – The purpose of this paper is to consider how biophilic urbanism complements and potentially enhances approaches for the built environment profession to holistically integrate nature into cities. Urban nature – also referred to as urban greening and green infrastructure – has increasingly been considered from many perspectives to address challenges such as population pressures, climate change and resource shortages. Within this context, the authors highlight how “biophilic urbanism” complements and may enhance approaches and efforts for urban greening. Design/methodology/approach – The paper provides a review of existing literature in “urban nature” to clarify and discuss the concept of biophilic urbanism. Drawing on this literature review, the authors present a systematic clustering and scaling of “biophilic elements” that could facilitate responding to twenty-first century challenges. Findings – Biophilic urbanism can be applied at multiple scales in urban environments, through a range of multi-functional features that address the pervasive false dichotomy of urban development and environmental protection. Biophilic urbanism can complement urban greening efforts to enable a holistic approach, which is conducive to comprehensive, intentional and strategic urban greening. Originality/value – This paper situates the emerging concept of biophilic urbanism within existing research from multiple disciplines, providing insight for how this can be applied in practice, particularly to the topical challenge of “urban renewal”.

CCD: Connected Component Descriptor for Robust Mosaicing of Camera-Captured Document Images

We propose a robust method for mosaicing of document images using features derived from connected components. Each connected component is described using the Angular Radial Tran. form (ART). To ensure geometric consistency during feature matching, the ART coefficients of a connected component are augmented with those of its two nearest neighbors. The proposed method addresses two critical issues often encountered in correspondence matching: (i) The stability of features and (ii) Robustness against false matches due to the multiple instances of characters in a document image. The use of connected components guarantees a stable localization across images. The augmented features ensure a successful correspondence matching even in the presence of multiple similar regions within the page. We illustrate the effectiveness of the proposed method on camera captured document images exhibiting large variations in viewpoint, illumination and scale.

Thin-Layer Chromatography with Ultraviolet and Mass Spectrometric Detection: From Preparative-Layer to Miniaturized Ultra-Thin-Layer Technique

The present challenge in drug discovery is to synthesize new compounds efficiently in minimal time. The trend is towards carefully designed and well-characterized compound libraries because fast and effective synthesis methods easily produce thousands of new compounds. The need for rapid and reliable analysis methods is increased at the same time. Quality assessment, including the identification and purity tests, is highly important since false (negative or positive) results, for instance in tests of biological activity or determination of early-ADME parameters in vitro (the pharmacokinetic study of drug absorption, distribution, metabolism, and excretion), must be avoided. This thesis summarizes the principles of classical planar chromatographic separation combined with ultraviolet (UV) and mass spectrometric (MS) detection, and introduces powerful, rapid, easy, low-cost, and alternative tools and techniques for qualitative and quantitative analysis of small drug or drug-like molecules. High performance thin-layer chromatography (HPTLC) was introduced and evaluated for fast semi-quantitative assessment of the purity of synthesis target compounds. HPTLC methods were compared with the liquid chromatography (LC) methods. Electrospray ionization mass spectrometry (ESI MS) and atmospheric pressure matrix-assisted laser desorption/ionization MS (AP MALDI MS) were used to identify and confirm the product zones on the plate. AP MALDI MS was rapid, and easy to carry out directly on the plate without scraping. The PLC method was used to isolate target compounds from crude synthesized products and purify them for bioactivity and preliminary ADME tests. Ultra-thin-layer chromatography (UTLC) with AP MALDI MS and desorption electrospray ionization mass spectrometry (DESI MS) was introduced and studied for the first time. Because of the thinner adsorbent layer, the monolithic UTLC plate provided 10 100 times better sensitivity in MALDI analysis than did HPTLC plates. The limits of detection (LODs) down to low picomole range were demonstrated for UTLC AP MALDI and UTLC DESI MS. In a comparison of AP and vacuum MALDI MS detection for UTLC plates, desorption from the irregular surface of the plates with the combination of an external AP MALDI ion source and an ion trap instrument provided clearly less variation in mass accuracy than the vacuum MALDI time-of-flight (TOF) instrument. The performance of the two-dimensional (2D) UTLC separation with AP MALDI MS method was studied for the first time. The influence of the urine matrix on the separation and the repeatability was evaluated with benzodiazepines as model substances in human urine. The applicability of 2D UTLC AP MALDI MS was demonstrated in the detection of metabolites in an authentic urine sample.

Shooting from the Wild Zone : A Study of the Chicana Art Photographers Laura Aguilar, Celia Álvarez Muñoz, Delilah Montoya, and Kathy Vargas

The dissertation analyzes and elaborates upon the changing map of U.S. ethno-racial formation from the vantage point of North American Studies, multi-disciplinary cultural studies, and the criticism of visual culture. The focus is on four contemporary Mexican American (Chicana) women photographers, whose art production is discussed, on the one hand, in the context of the Euro-American history of photographic genres and, on the other hand, in the context of so-called decolonizing cultural and academic discourses produced by Mexican Americans themselves. The manuscript consists of two parts. Part I outlines the theoretical and methodological domain of the study, positioning it in the interstices of American studies, European postmodern criticism, postcolonial feminist theory, and the theories of visual culture, particularly of art photography. In addition, the main issues and paradigms of Chicano Studies (Mexican American ethnic studies) are introduced. Part II consists of seven essays, each of which discusses rather independently a particular photographic work or a series of photographs, formulating and defending arguments about their meaning, position in the history of photographic genres, and their cultural and socio-political significance. The study closes with a discussion about ethno-racial identity formation and the role of Chicana photography therein - in embodying and reproducing new subjectivities, alternative categories of knowledge, and open ended historical narratives. It is argued that, symbolically, the "Wild Zone" of gendered and race-specific knowledge becomes associated with the body of the mother, a recurrent image in Chicana art works under discussion. Embedded in this image, the construction of an alternative notion of a family thus articulates the parameters of a matrifocal ethno-racial community unified by the proliferation of differences rather than by conformities typical of nationalistic ideologies. While focusing on art photography, the study as a whole simultaneously constructs, from a European vantage point, a "thick" description of Mexican American history, identities, communities, cultural practices, and self-representations about which very little is known in Finland.

Critical remarks on "On the compensation effect"

A critical assessment of a published paper (by Agrawal) is presented. The procedure proposed and used by Agrawal to distinguish a false compensation effect from a true one is shown not to be correct.

Ufologia ja ufokokemukset uskonnollisina ilmiönä : Teoreettinen tutkimus

The main question of my doctoral thesis is whether ufology and UFO experiences are or can be explained as religious phenomena. My research is theoretical in the sense that I combine and systematise cultural scientific knowledge concerning the religiosity of ufology and UFO experiences and complete this theoretical effort with empirical subject matter. The research material for my study consists of theoretical literature and empirical texts written by ufologists and those who have had UFO experiences. I defined the material in a way that it became full and extensive with regard to ufology, stories about UFO experiences and the cultural scientific literature concerning them. In addition, I present a source criticism for the literature because it is in part informal. The method is analysing and synthesising the material in the context of spiral of hermeneutic inferential process. Definitions of religion, ufology and UFO experience, developed by myself, serve as guide lines for the process. The conclusions of my research are as follows. For the most part, ufology and UFO experiences belong to the category of religion and only a fraction of these instances can be explained as something else, for example psychiatric phenomena. From the religious viewpoint I explain ufology and UFO experiences on four different but interlinked levels: historical, comparative, sociological and psychological. Historically ufology and UFO experiences include esoteristic, Christian and folk religious elements. In addition UFO experiences have significant similarities with folk religious stories and shamanistic experiences. From the perspective of the sociology, of religion ufology and UFO experiences can be analysed as products of our scientific and technological Western culture. Social crisis and social psychological group mechanisms affect the appearance of ufological ideas and UFO experiences. Psychologically, in the background of religious UFO experiences there can be found several factors, such as wishful thinking. Concerning UFO sightings these are misinterpretations of certain ordinary and some rare or exotic natural and technical phenomena. Intense UFO experiences, such as UFO abductions, are stimulated for the most part by hallucinations, sleep paralysis disorders, lively fantasies (in case of fantasy prone personalities) and false memories. In group cases social pressure, small group delusion and the guilt of exposing the true nature of a story come into play. A UFO experience can be traumatising because of certain inferential mechanisms and cognitive dissonance involved in the process of conversion as a UFO experiencer. UFO religiosity is a cross cultural, widespread and a significant field of phenomena, which can offer insight about religious developments in the future. However, UFO religiosity has not been studied extensively. This research is one effort to address this lack of documentation. The motivation behind my thesis was to make ufology and UFO experiences more understandable.

An optimal design for screening trials

Yao, Begg, and Livingston (1996, Biometrics 52, 992-1001) considered the optimal group size for testing a series of potentially therapeutic agents to identify a promising one as soon as possible for given error rates. The number of patients to be tested with each agent was fixed as the group size. We consider a sequential design that allows early acceptance and rejection, and we provide an optimal strategy to minimize the sample sizes (patients) required using Markov decision processes. The minimization is under the constraints of the two types (false positive and false negative) of error probabilities, with the Lagrangian multipliers corresponding to the cost parameters for the two types of errors. Numerical studies indicate that there can be a substantial reduction in the number of patients required.

Shared common variants in prostate cancer and blood lipids

Background Epidemiological and clinical studies suggest comorbidity between prostate cancer (PCA) and cardiovascular disease (CVD) risk factors. However, the relationship between these two phenotypes is still not well understood. Here we sought to identify shared genetic loci between PCA and CVD risk factors. Methods We applied a genetic epidemiology method based on conjunction false discovery rate (FDR) that combines summary statistics from different genome-wide association studies (GWAS), and allows identification of genetic overlap between two phenotypes. We evaluated summary statistics from large, multi-centre GWA studies of PCA (n = 50 000) and CVD risk factors (n = 200 000) [triglycerides (TG), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes (T2D)]. Enrichment of single nucleotide polymorphisms (SNPs) associated with PCA and CVD risk factors was assessed with conditional quantile-quantile plots and the Anderson-Darling test. Moreover, we pinpointed shared loci using conjunction FDR. Results We found the strongest enrichment of P-values in PCA was conditional on LDL and conditional on TG. In contrast, we found only weak enrichment conditional on HDL or conditional on the other traits investigated. Conjunction FDR identified altogether 17 loci; 10 loci were associated with PCA and LDL, 3 loci were associated with PCA and TG and additionally 4 loci were associated with PCA, LDL and TG jointly (conjunction FDR < 0.01). For T2D, we detected one locus adjacent to HNF1B. Conclusions We found polygenic overlap between PCA predisposition and blood lipids, in particular LDL and TG, and identified 17 pleiotropic gene loci between PCA and LDL, and PCA and TG, respectively. These findings provide novel pathobiological insights and may have implications for trials using targeting lipid-lowering agents in a prevention or cancer setting.

An Algorithm for Tracking a Maneuvering Target in Clutter

We consider the problem of tracking a maneuvering target in clutter. In such an environment, missed detections and false alarms make it impossible to decide, with certainty, the origin of received echoes. Processing radar returns in cluttered environments consists of three functions: 1) target detection and plot formation, 2) plot-to-track association, and 3) track updating. Two inadequacies of the present approaches are 1) Optimization of detection characteristics have not been considered and 2) features that can be used in the plot-to-track correlation process are restricted to a specific class. This paper presents a new approach to overcome these limitations. This approach facilitates tracking of a maneuvering target in clutter and improves tracking performance for weak targets.

Èto i to v povesti Staruha Daniila Harmsa

This dissertation focuses on the short story Starukha (The Old Woman), one of the last works of the Russian writer Daniil Kharms (1905-1942). The story, written in 1939, is analysed using the Kharmsian concepts èto and to (this and that) as a heuristic interpretative model. The first chapter gives a detailed analysis of this model, as well as a survey of the critical work done to date on Kharms and Starukha. In the second chapter the model is applied to study the different states of consciousness of the male protagonist. This is significant, because he is the "I" of the work, from whose point of view everything is being told. The third chapter takes a closer look at the reality of the world that exists independently of the consciousness of the protagonist. Physical objects can be said to bear - besides their everyday meaning - a hidden symbolic meaning. Similarly, the characters can be considered as representatives of everyday reality and otherworldliness. The fourth chapter deals with the narrative devices of Starukha. The problematics of the relation between fact and fiction plays an essential role in the story. Kharms's use of Ich-Erzählung and different tenses, which contributes to achieving a complicated elaboration of this kind of problematics, is examined in detail. The fifth chapter provides an intertextual reading of Starukha, based on its allusions to the Bible and the Christian tradition. As a result, the whole story can be seen as a kind of meditation on the Passion of Christ. The final chapter examines how the important Kharmsian concepts of the grotesque and the absurd manifest themselves in Starukha. The old woman represents in a grotesque way two opposite systems: the religious and the totalitarian. The absurdity of Starukha can be claimed to be illusory. Therefore, it is better to speak about paradoxicality. Starukha itself is a kind of paradox, in the sense that it tries to say something of the ultimate truth of reality, which inevitably remains ineffable.