Understanding Mycobacterium abscessus pulmonary and disseminated disease

2017 Summer.Includes bibliographical references.Mycobacterium abscessus is an emerging human pathogen which is difficult to treat and results in increased mortality. Moreover, the cause of increasing case rates and also the pathogenesis of M. abscessus are poorly understood. M. abscessus belongs to the family of nontuberculous mycobacteria (NTM) classified as members of the rapidly growing mycobacteria (RGM). These environmental pathogens are ubiquitous and found in shower heads, tap water, natural water sources, and soil. Humans contract pulmonary or disseminated infections with M. abscessus by breathing in the aerosolized bacteria or ingesting contaminated water. Immunocompromised individuals such as HIV or AIDS patients, are more susceptible to infection with M. abscessus as are those with cystic fibrosis, bronchiectasis, and individuals on tumor necrosis factor α (TNFα) inhibitors. Strangely, an increasing population of patients becoming infected with M. abscessus are immunocompetent, tall, slender, Caucasian, non-smoking women. To expand our understanding of M. abscessus pathogenesis we developed mouse models that maintain high levels of bacterial infection to study immune responses induced by clinical strains of M. abscessus. Our results support the hypothesis that this bacteria can only persist in our animal models that possess a deficiency in macrophages and T cell function. Clustered bacterial strains obtained from Cystic Fibrosis patients are more virulent than unclustered bacterial strains obtained from Cystic Fibrosis patients. Additionally, counts of viable mycobacterial colony forming units and histological analysis in (Severe Combined Immunodeficiency) SCID mice on a beige background infected with clustered versus unclustered M. abscessus strains which were isolated from Cystic Fibrosis patients also supported the increased virulence exhibited by the clustered strains. Lastly, we show that major human M. abscessus outbreak strains, when infecting IL-3, GM-CSF deficient mice on an IL-2, Rag2 deficient background (GM/Rag-dblKO mice), result in increased bacterial replication and organ pathology and impaired protective immunity against this pathogen

Higher education, mature students and employment goals: policies and practices in the UK

This article considers recent policies of Higher Education in the UK, which are aimed at widening participation and meeting the needs of employers. The focus is on the growing population of part-time students, and the implications of policies for this group. The article takes a critical perspective on government policies, using data from a major study of mature part-time students, conducted in two specialist institutions in the UK, a London University college and a distance learning university. Findings from this study throw doubt on the feasibility of determining a priori what kind of study pathway is most conducive for the individual in terms of employment gains and opportunities for upward social mobility. In conclusion, doubts are raised as to whether policies such as those of the present UK government are likely to achieve its aims. Such policies are not unique to the UK, and lessons from this country are relevant to most of the developed world

Gender, foundation degrees and the knowledge economy

This article questions the concept of ‘education for employment’, which constructs a discourse of individual and societal benefit in a knowledge‐driven economy. Recent policy emphasis in the European Union promotes the expansion of higher education and short‐cycle vocational awards such as the intermediate two‐year Foundation Degree recently introduced into England and Wales. Studies of vocational education and training (VET) and the knowledge economy have focused largely on the governance of education and on the development and drift of policy. Many VET programmes have also been considered for their classed, raced and gendered take‐up and subsequent effect on employment. This article builds on both fields of study to engage with the finer cross‐analyses of gender, social class, poverty, race and citizenship. In its analysis of policy texts the article argues that in spite of a discourse of inclusivity, an expanded higher education system has generated new inequalities, deepening social stratification. Drawing on early analyses of national quantitative data sets, it identifies emerging gendered, classed and raced patterns and considers these in relation to occupationally and hierarchically stratified labour markets, both within and without the knowledge economy

Cell transformation assays for prediction of carcinogenic potential: State of the science and future research needs

Copyright @ 2011 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cell transformation assays (CTAs) have long been proposed as in vitro methods for the identification of potential chemical carcinogens. Despite showing good correlation with rodent bioassay data, concerns over the subjective nature of using morphological criteria for identifying transformed cells and a lack of understanding of the mechanistic basis of the assays has limited their acceptance for regulatory purposes. However, recent drivers to find alternative carcinogenicity assessment methodologies, such as the Seventh Amendment to the EU Cosmetics Directive, have fuelled renewed interest in CTAs. Research is currently ongoing to improve the objectivity of the assays, reveal the underlying molecular changes leading to transformation and explore the use of novel cell types. The UK NC3Rs held an international workshop in November 2010 to review the current state of the art in this field and provide directions for future research. This paper outlines the key points highlighted at this meeting

A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant staphylococcus aureus pandemic

The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens

Phylogeographical Analysis Reveals the Historic Origin, Emergence, and Evolutionary Dynamics of Methicillin-Resistant Staphylococcus aureus ST228.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common healthcare-associated pathogen that remains a major public health concern. Sequence type 228 (ST228) was first described in Germany and spread to become a successful MRSA clone in several European countries. In 2000, ST228 emerged in Lausanne and has subsequently caused several large outbreaks. Here, we describe the evolutionary history of this clone and identify the genetic changes underlying its expansion in Switzerland. We aimed to understand the phylogeographic and demographic dynamics of MRSA ST228/ST111 by sequencing 530 representative isolates of this clone that were collected from 14 European countries between 1997 and 2012. The phylogenetic analysis revealed distinct lineages of ST228 isolates associated with specific geographic origins. In contrast, isolates of ST111, which is a single locus variant of ST228 sharing the same spa type t041, formed a monophyletic cluster associated with multiple countries. The evidence points to a German origin of the sampled population, with the basal German lineage being characterized by spa type t001. The highly successful Swiss ST228 lineage diverged from this progenitor clone through the loss of the aminoglycoside-streptothricin resistance gene cluster and the gain of mupirocin resistance. This lineage was introduced first in Geneva and was subsequently introduced into Lausanne. Our results reveal the radiation of distinct lineages of MRSA ST228 from a German progenitor, as the clone spread into different European countries. In Switzerland, ST228 was introduced first in Geneva and was subsequently introduced into Lausanne

Lowering the glycemic index of white bread using a white bean extract

<p>Abstract</p> <p>Background</p> <p>Phase 2^®is a dietary supplement derived from the common white kidney bean (Phaseolus vulgaris). Phase 2 has been shown to inhibit alpha-amylase, the complex carbohydrate digesting enzyme, in vitro. The inhibition of alpha-amylase may result in the lowering of the effective Glycemic Index (GI) of certain foods. The objective of this study was to determine whether the addition of Phase 2 would lower the GI of a commercially available high glycemic food (white bread).</p> <p>Methods</p> <p>An open-label 6-arm crossover study was conducted with 13 randomized subjects. Standardized GI testing was performed on white bread with and without the addition of Phase 2 in capsule and powder form, each in dosages of 1500 mg, 2000 mg, and 3000 mg. Statistical analysis was performed by one-way ANOVA of all seven treatment groups using unadjusted multiple comparisons (t tests) to the white bread control.</p> <p>Results</p> <p>For the capsule formulation, the 1500 mg dose had no effect on the GI and the 2000 mg and 3000 mg capsule doses caused insignificant reductions in GI. For the powder, the 1500 mg and 2000 mg doses caused insignificant reductions in the GI, and the 3000 mg dose had a significant effect (-20.23 or 34.11%, p = 0.023)</p> <p>Conclusion</p> <p>Phase 2 white bean extract appears to be a novel and potentially effective method for reducing the GI of existing foods without modifying their ingredient profile.</p> <p>Trial Registration</p> <p>Trial Registration: ISRCTN50347345</p