Susceptibility of hamsters to clostridium difficile isolates of differing toxinotype

Clostridium difficile is the most commonly associated cause of antibiotic associated disease (AAD), which caused ~21,000 cases of AAD in 2011 in the U.K. alone. The golden Syrian hamster model of CDI is an acute model displaying many of the clinical features of C. difficile disease. Using this model we characterised three clinical strains of C. difficile, all differing in toxinotype; CD1342 (PaLoc negative), M68 (toxinotype VIII) and BI-7 (toxinotype III). The naturally occurring non-toxic strain colonised all hamsters within 1-day post challenge (d.p.c.) with high-levels of spores being shed in the faeces of animals that appeared well throughout the entire experiment. However, some changes including increased neutrophil influx and unclotted red blood cells were observed at early time points despite the fact that the known C. difficile toxins (TcdA, TcdB and CDT) are absent from the genome. In contrast, hamsters challenged with strain M68 resulted in a 45% mortality rate, with those that survived challenge remaining highly colonised. It is currently unclear why some hamsters survive infection, as bacterial and toxin levels and histology scores were similar to those culled at a similar time-point. Hamsters challenged with strain BI-7 resulted in a rapid fatal infection in 100% of the hamsters approximately 26 hr post challenge. Severe caecal pathology, including transmural neutrophil infiltrates and extensive submucosal damage correlated with high levels of toxin measured in gut filtrates ex vivo. These data describes the infection kinetics and disease outcomes of 3 clinical C. difficile isolates differing in toxin carriage and provides additional insights to the role of each toxin in disease progression

Corporate tax: what do stakeholders expect?

Motivated by the ongoing controversy surrounding corporate tax, this article presents a study that explores stakeholder expectations of corporate tax in the context of UK business. We conduct a qualitative analysis of in-depth interviews with representatives of community groups (NGOs/think tanks and special interest groups), as well as interviews with those representing business groups (business leaders and industry representatives). We then identify eight themes that together describe “what” companies need to do, “how” they need to do it, and “why” they need to do it, if they wish to appeal to a wide group of interested parties. We discuss our findings based on the corporate social responsibility literature and propose novel ways for community groups and business groups to connect on the topic of corporate tax, suggesting opportunities and themes for dialogue and potential steps to co-create solutions in a stakeholder society

Clostridium difficile infection.

Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis - the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota

Predominance and high antibiotic resistance of the emerging Clostridium difficile genotypes NAPCR1 and NAP9 in a Costa Rican hospital over a 2-year period without outbreaks

Clostridium difficile is the major causative agent of nosocomial antibiotic-associated diarrhea. In a 2009 outbreak of C. difficileassociated diarrhea that was recorded in a major Costa Rican hospital, the hypervirulent NAP1 strain (45%) predominated together with a local genotype variant (NAPCR1, 31%). Both strains were fluoroquinolone-resistant and the NAPCR1 genotype, in addition, was resistant to clindamycin and rifampicin. We now report on the genotypes and antibiotic susceptibilities of 68C. difficile isolates from a major Costa Rican hospital over a 2-year period without outbreaks. In contrast to our previous findings, no NAP1 strains were detected, and for the first time in a Costa Rican hospital, a significant fraction of the isolates were NAP9 strains (n = 14, 21%). The local NAPCR1 genotype remained prevalent (n = 18, 26%) and coexisted with 14 strains (21%) of classic hospital NAP types (NAP2, NAP4, and NAP6), eight new genotypes (12%), four environmental strains classified as NAP10 or NAP11 (6%), three strains without NAP designation (4%) and seven non-toxigenic strains (10%). All 68 strains were resistant to ciprofloxacin, 88% were resistant to clindamycin and 50% were resistant to moxifloxacin and rifampicin. Metronidazole and vancomycin susceptibilities were universal. The NAPCR1 and NAP9 strains, which have been associated with more severe clinical infections, were more resistant to antibiotics than the other strains. Altogether, our results confirm that the epidemiology of C. difficile infection is dynamic and that A−B+ strains from the NAP9 type are on the rise not only in the developed world. Moreover, our results reveal that the local NAPCR1 strains still circulate in the country without causing outbreaks but with equally high antibiotic-resistance rates and levelsUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Centro de Investigación en Enfermedades Tropicales (CIET)UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí

Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice.

Relapsing C. difficile disease in humans is linked to a pathological imbalance within the intestinal microbiota, termed dysbiosis, which remains poorly understood. We show that mice infected with epidemic C. difficile (genotype 027/BI) develop highly contagious, chronic intestinal disease and persistent dysbiosis characterized by a distinct, simplified microbiota containing opportunistic pathogens and altered metabolite production. Chronic C. difficile 027/BI infection was refractory to vancomycin treatment leading to relapsing disease. In contrast, treatment of C. difficile 027/BI infected mice with feces from healthy mice rapidly restored a diverse, healthy microbiota and resolved C. difficile disease and contagiousness. We used this model to identify a simple mixture of six phylogenetically diverse intestinal bacteria, including novel species, which can re-establish a health-associated microbiota and clear C. difficile 027/BI infection from mice. Thus, targeting a dysbiotic microbiota with a defined mixture of phylogenetically diverse bacteria can trigger major shifts in the microbial community structure that displaces C. difficile and, as a result, resolves disease and contagiousness. Further, we demonstrate a rational approach to harness the therapeutic potential of health-associated microbial communities to treat C. difficile disease and potentially other forms of intestinal dysbiosis

Ethics, Social Responsibility and Tax Aggressiveness. Can a Code of Ethics Absolve a Company?

The aim of the paper is to contribute to the debate on the relationship between ethics, socially responsible behaviour and tax aggressiveness through the analysis and discussion of a case study.The case presented in this paper concerns a famous Italian fashion house, well known all over the world, which in recent times was tried in court for a tax inversion operation. D&G Group was involved in a long legal trial, whose outcome has given rise to many discussions. The story definitely ended, and after the final trial the Group was judged innocent. However, this case raised a fervent debate that is still ongoing, and it gives the opportunity to discuss some important issues: What is the boundary between legality and ethics in tax behaviour? Can a company claim to adhere to ethical principles if it adopts aggressive tax practices? Can aggressive tax behaviours be acceptable from an ethical point of view?The case also opens questions related to the boundaries between the responsibilities of directors/managers and institutional responsibilities, at both national and supranational level

Board of director gender and corporate tax aggressiveness: An empirical analysis

This study examines the impact of board of director gender diversity on corporate tax aggressiveness. Based on a sample of 418 U.S. firms covering the 2006–2009 period (1672 firm-year observations), our ordinary least squares regression results show a negative and statistically significant association between female representation on the board and tax aggressiveness after controlling for endogeneity. Our results are consistent across several measures of tax aggressiveness and additional robustness checks

Novel therapeutic strategies for Clostridium difficile

Unal, Can/0000-0003-4710-9567WOS:000370162800001PubMed: 26565670Introduction: In recent years, Clostridium difficile has become the primary cause of antibiotic-associated diarrhea and pseudomembranous colitis, resulting in long and complicated hospital stays that represent a serious burden for patients as well as health care systems. Currently, conservative treatment of C. difficile infection (CDI) relies on the antibiotics vancomycin, metronidazole or fidaxomicin, or in case of multiple recurrences, fecal microbiota transplantation (FMT).Areas covered: The fast-spreading, epidemic nature of this pathogen urgently necessitates the search for alternative treatment strategies as well as antibiotic targets. Accordingly, in this review, we highlight the recent findings regarding virulence associated traits of C. difficile, evaluate their potential as alternative drug targets, and present current efforts in designing inhibitory compounds, with the aim of pointing out possibilities for future treatment strategies.Expert opinion: Increased attention on systematic analysis of the virulence mechanisms of C. difficile has already led to the identification of several alternative drug targets. In the future, applying state of the art omics' and the development of novel infection models that mimic the human gut, a highly complex ecological niche, will unveil the genomic and metabolic plasticity of this pathogen and will certainly help dealing with future challenges.Federal State of Lower Saxony, Niedersachsisches Vorab [VWZN2889]CM Unal and M Steinert were supported in this work by the Federal State of Lower Saxony, Niedersachsisches Vorab (VWZN2889). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed