Nemo: a computational tool for analyzing nematode locomotion

The nematode Caenorhabditis elegans responds to an impressive range of chemical, mechanical and thermal stimuli and is extensively used to investigate the molecular mechanisms that mediate chemosensation, mechanotransduction and thermosensation. The main behavioral output of these responses is manifested as alterations in animal locomotion. Monitoring and examination of such alterations requires tools to capture and quantify features of nematode movement. In this paper, we introduce Nemo (nematode movement), a computationally efficient and robust two-dimensional object tracking algorithm for automated detection and analysis of C. elegans locomotion. This algorithm enables precise measurement and feature extraction of nematode movement components. In addition, we develop a Graphical User Interface designed to facilitate processing and interpretation of movement data. While, in this study, we focus on the simple sinusoidal locomotion of C. elegans, our approach can be readily adapted to handle complicated locomotory behaviour patterns by including additional movement characteristics and parameters subject to quantification. Our software tool offers the capacity to extract, analyze and measure nematode locomotion features by processing simple video files. By allowing precise and quantitative assessment of behavioral traits, this tool will assist the genetic dissection and elucidation of the molecular mechanisms underlying specific behavioral responses.Comment: 12 pages, 2 figures. accepted by BMC Neuroscience 2007, 8:8

Mammographic density does not correlate with Ki-67 expression or cytomorphology in benign breast cells obtained by random periareolar fine needle aspiration from women at high risk for breast cancer

BACKGROUND:Ki-67 expression is a possible risk biomarker and is currently being used as a response biomarker in chemoprevention trials. Mammographic breast density is a risk biomarker and is also being used as a response biomarker. We previously showed that Ki-67 expression is higher in specimens of benign breast cells exhibiting cytologic atypia that are obtained by random periareolar fine needle aspiration (RPFNA). It is not known whether there is a correlation between mammographic density and Ki-67 expression in benign breast ductal cells obtained by RPFNA.METHODS:Included in the study were 344 women at high risk for developing breast cancer (based on personal or family history), seen at The University of Kansas Medical Center high-risk breast clinic, who underwent RPFNA with cytomorphology and Ki-67 assessment plus a mammogram. Mammographic breast density was assessed using the Cumulus program. Categorical variables were analyzed by ?2 test, and continuous variables were analyzed by nonparametric test and linear regression.RESULTS:Forty-seven per cent of women were premenopausal and 53% were postmenopausal. The median age was 48 years, median 5-year Gail Risk was 2.2%, and median Ki-67 was 1.9%. The median mammographic breast density was 37%. Ki-67 expression increased with cytologic abnormality (atypia versus no atypia; P = 0.001) and younger age (=50 years versus >50 years; P = 0.001). Mammographic density was higher in premenopausal women (P = 0.001), those with lower body mass index (P < 0.001), and those with lower 5-year Gail risk (P = 0.001). Mammographic density exhibited no correlation with Ki-67 expression or cytomorphology.CONCLUSION:Given the lack of correlation of mammographic breast density with either cytomorphology or Ki-67 expression in RPFNA specimens, mammographic density and Ki-67 expression should be considered as potentially complementary response biomarkers in breast cancer chemoprevention trials

Experimental manipulation of radiographic density in mouse mammary gland

INTRODUCTION: Extensive mammographic density in women is associated with increased risk for breast cancer. Mouse models provide a powerful approach to the study of human diseases, but there is currently no model that is suited to the study of mammographic density. METHODS: We performed individual manipulations of the stromal, epithelial and matrix components of the mouse mammary gland and examined the alterations using in vivo and ex vivo radiology, whole mount staining and histology. RESULTS: Areas of density were generated that resembled densities in mammographic images of the human breast, and the nature of the imposed changes was confirmed at the cellular level. Furthermore, two genetic models, one deficient in epithelial structure (Pten conditional tissue specific knockout) and one with hyperplastic epithelium and mammary tumors (MMTV-PyMT), were used to examine radiographic density. CONCLUSION: Our data show the feasibility of altering and imaging mouse mammary gland radiographic density by experimental and genetic means, providing the first step toward modelling the biological processes that are responsible for mammographic density in the mouse

Acoustic Nonlinearities in Adhesive Joints

Ultrasonic techniques have been used successfully to measure important bond parameters and to detect various defects in adhesive joints for about twenty years. Recent reviews of nondestructive testing of adhesively bonded structures can be found in the literature [1–3]. For direct strength assessment, the reliability of these techniques leaves much to be desired. Linear acoustic parameters are only indirectly correlated to material and bond strength, therefore we must rely on dubious empirical relations between the measured parameter (e.g., velocity or attenuation) and the sought strength parameter on a case-to-case basis. On the other hand, it is well known that failure of most materials and bonds is usually preceded by some kind of nonlinear mechanical behavior, well before appreciable plastic deformation occurs, i.e. within the range of nondestructive testing. This macroscopic nonlinearity is due to a number of different causes such as weakening of covalent bonds with increased atomic spacing, reduction in the number of these bonds, etc. It seems to be reasonable to assume that nonlinear parameters measured at approximately 10–20% of the ultimate stress level are more directly correlated to mechanical strength than linear ones measured at negligibly low ultrasonic amplitudes:</p

‘New Medicine Service’: supporting adherence in people starting a new medication for a long-term condition: 26-week follow-up of a pragmatic randomised controlled trial

OBJECTIVE: To examine the effectiveness and cost-effectiveness of the community pharmacy New Medicine Service (NMS) at 26 weeks. METHODS: Pragmatic patient-level parallel randomised controlled trial in 46 English community pharmacies. 504 participants aged ≥14, identified in the pharmacy when presenting a prescription for a new medicine for predefined long-term conditions, randomised to receive NMS (n=251) or normal practice (n=253) (NMS intervention: 2 consultations 1 and 2 weeks after prescription presentation). Adherence assessed through patient self-report at 26-week follow-up. Intention-to-treat analysis employed. National Health Service (NHS) costs calculated. Disease-specific Markov models estimating impact of non-adherence combined with clinical trial data to calculate costs per extra quality-adjusted life-year (QALY; NHS England perspective). RESULTS: Unadjusted analysis: of 327 patients still taking the initial medicine, 97/170 (57.1%) and 103/157 (65.6%) (p=0.113) patients were adherent in normal practice and NMS arms, respectively. Adjusted intention-to-treat analysis: adherence OR 1.50 (95% CI 0.93 to 2.44, p=0.095), in favour of NMS. There was a non-significant reduction in 26-week NHS costs for NMS: -£104 (95% CI -£37 to £257, p=0.168) per patient. NMS generated a mean of 0.04 (95% CI -0.01 to 0.13) more QALYs per patient, with mean reduction in lifetime cost of -£113.9 (-1159.4, 683.7). The incremental cost-effectiveness ratio was -£2758/QALY (2.5% and 97.5%: -38 739.5, 34 024.2. NMS has an 89% probability of cost-effectiveness at a willingness to pay of £20 000 per QALY. CONCLUSIONS: At 26-week follow-up, NMS was unable to demonstrate a statistically significant increase in adherence or reduction in NHS costs, which may be attributable to patient attrition from the study. Long-term economic evaluation suggested NMS may deliver better patient outcomes and reduced overall healthcare costs than normal practice, but uncertainty around this finding is high. TRIAL REGISTRATION NUMBER: NCT01635361, ISRCTN23560818, ISRCTN23560818, UKCRN12494

Can the stroma provide the clue to the cellular basis for mammographic density?

Mammographic density is recognised as a useful phenotypic biomarker of breast cancer risk. Deeper understanding is needed of the cellular basis, but evidence is limited because of difficulty in designing studies to validate hypotheses. The ductal epithelial components do not adequately explain the physical and dynamic features observed. The stroma is thought to interact with ductal structures in cancer initiation. Stromal tissues might account for the mammographic features, and this interplay can be hypothesised to relate risk to density. In a paper in this issue of Breast Cancer Research, Alowami has shown a relationship between density and stromal proteins, which might provide useful insight into mammographic density

A genome-wide linkage study of mammographic density, a risk factor for breast cancer

Abstract Introduction Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD). Methods Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel. Results Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study. Conclusions The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer

Characteristics of the Early Immune Response Following Transplantation of Mouse ES Cell Derived Insulin-Producing Cell Clusters

Background The fully differentiated progeny of ES cells (ESC) may eventually be used for cell replacement therapy (CRT). However, elements of the innate immune system may contribute to damage or destruction of these tissues when transplanted. Methodology/Principal Findings Herein, we assessed the hitherto ill-defined contribution of the early innate immune response in CRT after transplantation of either ESC derived insulin producing cell clusters (IPCCs) or adult pancreatic islets. Ingress of neutrophil or macrophage cells was noted immediately at the site of IPCC transplantation, but this infiltration was attenuated by day three. Gene profiling identified specific inflammatory cytokines and chemokines that were either absent or sharply reduced by three days after IPCC transplantation. Thus, IPCC transplantation provoked less of an early immune response than pancreatic islet transplantation. Conclusions/Significance Our study offers insights into the characteristics of the immune response of an ESC derived tissue in the incipient stages following transplantation and suggests potential strategies to inhibit cell damage to ensure their long-term perpetuation and functionality in CRT

The United States, PMSCs and the state monopoly on violence: Leading the way towards norm change

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Sage.The proliferation of private military and security companies (PMSCs) in Iraq and Afghanistan has raised many questions regarding the use of armed force by private contractors. This article addresses the question of whether the increased acceptance of PMSCs indicates a transformation of the international norm regarding the state monopoly on the legitimate use of armed force. Drawing on theoretical approaches to the analysis of norm change, the article employs four measures to investigate possible changes in the strength and meaning of this norm: modifications in state behaviour, state responses to norm violation, the promulgation of varying interpretations of the norm in national and international laws and regulations, and changes in norm discourse. Based on an analysis of empirical evidence from the United States of America and its allies, the article concludes that these measures suggest that the USA is leading the way towards a transformation of the international norm of the state monopoly on violence, involving a revised meaning. Although this understanding has not yet been formally implemented in international law, it has allowed a growing number of countries to tolerate, accept or legalize the use of armed force by PMSCs in the international arena.The Alexander von Humboldt Foundation and the Peace Research Institute Frankfurt