Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Therapeutic DNA vaccination of vertically HIV-infected children: Report of the first pediatric randomised trial (PEDVAC)

Subjects: Twenty vertically HIV-infected children, 6–16 years of age, with stable viral load control and CD4+ values above 400 cells/mm³. Intervention: Ten subjects continued their ongoing antiretroviral treatment (ART, Group A) and 10 were immunized with a HIV-DNA vaccine in addition to their previous therapy (ART and vaccine, Group B). The genetic vaccine represented HIV-1 subtypes A, B and C, encoded Env, Rev, Gag and RT and had no additional adjuvant. Immunizations took place at weeks 0, 4 and 12, with a boosting dose at week 36. Monitoring was performed until week 60 and extended to week 96. Results: Safety data showed good tolerance of the vaccine. Adherence to ART remained high and persistent during the study and did not differ significantly between controls and vaccinees. Neither group experienced either virological failure or a decline of CD4+ counts from baseline. Higher HIV-specific cellular immune responses were noted transiently to Gag but not to other components of the vaccine. Lymphoproliferative responses to a virion antigen HIV-1 MN were higher in the vaccinees than in the controls (p = 0.047), whereas differences in reactivity to clade-specific Gag p24, RT or Env did not reach significance. Compared to baseline, the percentage of HIV-specific CD8+ lymphocytes releasing perforin in the Group B was higher after the vaccination schedule had been completed (p = 0.031). No increased CD8+ perforin levels were observed in control Group A. Conclusions: The present study demonstrates the feasibility, safety and moderate immunogenicity of genetic vaccination in vertically HIV-infected children, paving the way for amplified immunotherapeutic approaches in the pediatric population. Trial registration: clinicaltrialsregister.eu 2007-002359-18; 2007-002359-18/I

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies

Mitigating systematic error in topographic models for geomorphic change detection: Accuracy, precision and considerations beyond off‐nadir imagery

Unmanned aerial vehicles (UAVs) and structure-from-motion photogrammetry enable detailed quantification of geomorphic change. However, rigorous precision-based change detection can be compromised by survey accuracy problems producing systematic topographic error (e.g. 'doming'), with error magnitudes greatly exceeding precision estimates. Here, we assess survey sensitivity to systematic error, directly correcting topographic data so that error magnitudes align more closely with precision estimates. By simulating conventional grid-style photogrammetric aerial surveys, we quantify the underlying relationships between survey accuracy, camera model parameters, camera inclination, tie point matching precision and topographic relief, and demonstrate a relative insensitivity to image overlap. We show that a current doming-mitigation strategy of using a gently inclined ( 0 center dot 3 m, representing accuracy issues an order of magnitude greater than precision-based error estimates. For higher-relief topography, and for nadir-imaging surveys of the lower-relief topography, systematic error was <0 center dot 09 m. Modelling and subtracting the systematic error directly from the topographic data successfully reduced error magnitudes to values consistent with twice the estimated precision. Thus, topographic correction can provide a more robust approach to uncertainty-based detection of event-scale geomorphic change than designing surveys with small off-nadir camera inclinations and, furthermore, can substantially reduce ground control requirements. (c) 2020 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Lt

Mechanisms of hypoxic up-regulation of versican gene expression in macrophages

Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up-regulated much more highly (&gt;600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression

The ‘Biophilic Organization’: An Integrative Metaphor for Corporate Sustainability

This paper proposes a new organizational metaphor, the ‘Biophilic Organization’, which aims to counter the bio-cultural disconnection of many organizations despite their espoused commitment to sustainability. This conceptual research draws on multiple disciplines such as evolutionary psychology and architecture to not only develop a diverse bio-cultural connection but to show how this connection tackles sustainability, in a holistic and systemic sense. Moreover, the paper takes an integrative view of sustainability, which effectively means that it embraces the different emergent tensions. Three specific tensions are explored: efficiency versus resilience, organizational versus personal agendas and isomorphism versus institutional change. In order to illustrate how the Biophilic Organization could potentially provide a synthesis strategy for such tensions, healthcare examples are drawn from the emerging fields of Biophilic Design in Singapore and Generative Design in the U.S.A. Finally, an example is provided which highlights how a Taoist cultural context has impacted on a business leader in China, to illustrative the significance of a transcendent belief system to such a bio-cultural narrative

CSR and related terms in SME owner-managers' mental models in six European countries: national context matters

As a contribution to the emerging field of corporate social responsibility (CSR) cognition, this article reports on the findings of an exploratory study that compares SME owner–managers’ mental models with regard to CSR and related concepts across six European countries (Belgium, Italy, Norway, France, UK, Spain). Utilising Repertory Grid Technique, we found that the SME owner–managers’ mental models show a few commonalities as well as a number of differences across the different country samples. We interpret those differences by linking individual cognition to macro-environmental variables, such as language, national traditions and dissemination mechanisms. The results of our exploratory study show that nationality matters but that classifications of countries as found in the comparative capitalism literature do not exactly mirror national differences in CSR cognition and that these classifications need further differentiation. The findings from our study raise questions on the universality of cognition of academic management concepts and warn that promotion of responsible business practice should not rely on the use of unmediated US American management terminology

Introducing evidence based medicine to the journal club, using a structured pre and post test: a cohort study

BACKGROUND: Journal Club at a University-based residency program was restructured to introduce, reinforce and evaluate residents understanding of the concepts of Evidence Based Medicine. METHODS: Over the course of a year structured pre and post-tests were developed for use during each Journal Club. Questions were derived from the articles being reviewed. Performance with the key concepts of Evidence Based Medicine was assessed. Study subjects were 35 PGY2 and PGY3 residents in a University based Family Practice Program. RESULTS: Performance on the pre-test demonstrated a significant improvement from a median of 54.5 % to 78.9 % over the course of the year (F 89.17, p < .001). The post-test results also exhibited a significant increase from 63.6 % to 81.6% (F 85.84, p < .001). CONCLUSIONS: Following organizational revision, the introduction of a pre-test/post-test instrument supported achievement of the learning objectives with a better understanding and utilization of the concepts of Evidence Based Medicine

An Ultrasonic Based System to Measure Inter Spinous Process Distance in Humans: A Pilot Study

ABSTRACT The objective of this research project was to develop an ultrasonic based testing system and evaluate its application on human volunteers to locate and assess the distance between adjacent lumbar vertebrae. Tests were performed on ten volunteers aged between 19 and 29 years old during two sessions. The participants were asked to lie face down on a table with lower back section uncovered while the tests were executed. A computer controlled ultrasonic system was designed for this application. A single element 3.5 MHz immersion transducer held by a customized assembly was used to propagate and receive the ultrasonic signals. The transducer was moved along the assembly to fully scan at least two contiguous spinous processes. A Lab view based program was designed to generate a twodimensional image (B-scan) that display the shape and position of the bone tips as well as the distance between them. The standard deviation obtained from the measurements of the distance between the tips of the spinous processes of human subjects, in a given session ranged from 0.1-0.48mm. The difference between two sessions had a mean of 0.85-0.95 mm and a standard deviation of 0.87-1.03mm with reliability coefficients greater than 0.95. The study demonstrated the viability of utilizing ultrasound to precisely measure the distance between spinous processes of adjacent lumbar vertebrae

Acute appendicitis caused by endometriosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Endometriosis is a well-recognized gynecological condition in the reproductive age group. Surgical texts present the gynecological aspects of the disease in detail, but the published literature on unexpected manifestations, such as appendiceal disease, is inadequate. The presentation to general surgeons may be atypical and pose diagnostic difficulty. Thus, a definitive diagnosis is likely to be established only by the histological examination of a specimen.</p> <p>Case presentation</p> <p>We report a case of endometriosis of the appendix in a 25-year-old Caucasian woman who presented with symptoms of acute appendicitis and was treated by appendectomy, which resulted in a good outcome.</p> <p>Conclusions</p> <p>We discuss special aspects of acute appendicitis caused by endometriosis to elucidate the pathologic entity of this variant of acute appendicitis.</p