Intestinal Damage Determines the Inflammatory Response and Early Complications in Patients Receiving Conditioning for a Stem Cell Transplantation

Contains fulltext : 87954.pdf (publisher's version ) (Open Access)BACKGROUND: Stem cell transplantation (SCT) is still complicated by the occurrence of fever and inflammatory complications attributed to neutropenia and subsequent infectious complications. The role of mucosal barrier injury (MBI) of the intestinal tract therein has received little attention. METHODS: We performed a retrospective analysis in 163 SCT recipients of which data had been collected prospectively on intestinal damage (citrulline), inflammation (C-reactive protein), and neutrophil count. Six different conditioning regimens were studied; 5 myeloablative (MA) and 1 non-myeloablative (NMA). Linear mixed model multivariate and AUC analyses were used to define the role of intestinal damage in post-SCT inflammation. We also studied the relationship between the degree of intestinal damage and the occurrence of early post-SCT complications. RESULTS: In the 5 MA regimen there was a striking pattern of inflammatory response that coincided with the occurrence of severe intestinal damage. This contrasted with a modest inflammatory response seen in the NMA regimen in which intestinal damage was limited. With linear mixed model analysis the degree of intestinal damage was shown the most important determinant of the inflammatory response, and both neutropenia and bacteremia had only a minor impact. AUC analysis revealed a strong correlation between citrulline and CRP (Pearson correlation r = 0.96). Intestinal damage was associated with the occurrence of bacteremia and acute lung injury, and influenced the kinetics of acute graft-versus-host disease. CONCLUSION: The degree of intestinal damage after myeloablative conditioning appeared to be the most important determined the inflammatory response following SCT, and was associated with inflammatory complications. Studies should explore ways to ameliorate cytotoxic therapy-induced intestinal damage in order to reduce complications associated with myeloablative conditioning therapy

Evaluating genetic markers and neurobiochemical analytes for fluoxetine response using a panel of mouse inbred strains

RationaleIdentification of biomarkers that establish diagnosis or treatment response is critical to the advancement of research and management of patients with depression.ObjectiveOur goal was to identify biomarkers that can potentially assess fluoxetine response and risk to poor treatment outcome.MethodsWe measured behavior, gene expression, and the levels of 36 neurobiochemical analytes across a panel of genetically diverse mouse inbred lines after chronic treatment with water or fluoxetine.ResultsGlyoxylase 1 (GLO1) and guanine nucleotide-binding protein 1 (GNB1) mostly account for baseline anxiety-like and depressive-like behavior, indicating a common biological link between depression and anxiety. Fluoxetine-induced biochemical alterations discriminated positive responders, while baseline neurobiochemical differences differentiated negative responders (p < 0.006). Results show that glial fibrillary acidic protein, S100 beta protein, GLO1, and histone deacetylase 5 contributed most to fluoxetine response. These proteins are linked within a cellular growth/proliferation pathway, suggesting the involvement of cellular genesis in fluoxetine response. Furthermore, a candidate genetic locus that associates with baseline depressive-like behavior contains a gene that encodes for cellular proliferation/adhesion molecule (Cadm1), supporting a genetic basis for the role of neuro/gliogenesis in depression.ConclusionWe provided a comprehensive analysis of behavioral, neurobiochemical, and transcriptome data across 30 mouse inbred strains that has not been accomplished before. We identified biomarkers that influence fluoxetine response, which, altogether, implicate the importance of cellular genesis in fluoxetine treatment. More broadly, this approach can be used to assess a wide range of drug response phenotypes that are challenging to address in human samples.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2574-z) contains supplementary material, which is available to authorized users

The changing epidemiology of oral cancer: definitions, trends, and risk factors

Objective This review has three objectives, namely: (i) to discuss how oral cancer is and ought to be defined and recorded; (ii) to present up-to-date data on the incidence burden of the disease in the four countries of the UK, and review recent analyses of trends in the disease; and (iii) to summarise recent evidence on risk factors of the disease. Methods Cancer definitions were clarified by the International Classification of Diseases accounting for anatomical and aetiological differences; descriptive epidemiology included international / UK literature review and information requests for incidence data from the UK cancer registries (2000-2016); analytical epidemiology focused on reviewing the findings of the International Head and Neck Cancer Epidemiology (INHANCE) consortium, which has pooled data from multiple case-control studies providing the best estimates of risk factors. Results Emerging evidence of the role played by risk factors in different anatomical sites means that oral cavity cancer and oropharynx cancer should be considered distinct disease entities – and a standardised attribution of anatomical subsites will be helpful in ensuring consistency in how data are presented. In 2016, over 3,700 people were diagnosed with oral cavity cancer and over 3,500 people were diagnosed with oropharyngeal cancer in the UK. Incidence of oropharyngeal cancer is rapidly rising across the UK. Rates of oral cavity cancer are higher in Northern Ireland and higher still (and relatively stable) in Scotland, but rising in England and Wales. INHANCE data show that while the consumption of alcohol and tobacco are the prime risk factors for oral cavity and oropharyngeal cancers, they provide greater certainty in the preventive benefits of reducing these risk factors. The role played by other factors such as low socioeconomic status, genetics, oral health, and human papillomavirus (only for oropharyngeal cancer) have become clearer. Conclusions This epidemiology provides a strong foundation for designing and managing both population and individual oral cavity and oropharyngeal cancer control strategies

Bandwidth selection for kernel density estimation: a review of fully automatic selectors

On the one hand, kernel density estimation has become a common tool for empirical studies in any research area. This goes hand in hand with the fact that this kind of estimator is now provided by many software packages. On the other hand, since about three decades the discussion on bandwidth selection has been going on. Although a good part of the discussion is about nonparametric regression, this parameter choice is by no means less problematic for density estimation. This becomes obvious when reading empirical studies in which practitioners have made use of kernel densities. New contributions typically provide simulations only to show that the own selector outperforms some of the existing methods. We review existing methods and compare them on a set of designs that exhibit few bumps and exponentially falling tails. We concentrate on small and moderate sample sizes because for large ones the differences between consistent methods are often negligible, at least for practitioners. As a byproduct we find that a mixture of simple plug-in and cross-validation methods produces bandwidths with a quite stable performance

A roadmap for research on identity in the information society

As research into identity in the information society gets into its stride, with contributions from many scholarly disciplines such as technology, social sciences, the humanities and the law, a moment of intellectual stocktaking seems appropriate. This article seeks to provide a roadmap of research currently undertaken in the field of identity and identity management showing how the area is developing and how disparate contributions relate to each other. Five different perspectives are proposed through which work in the identity field can be seen: tensions, themes, application areas, research focus and disciplinary approaches and taken together they provide a comprehensive overview of the intellectual territory currently being tilled by academia on this subject. This attempt at a coherent overview is offered in the spirit of debate and discussion, and the authors invite criticism, development and improvement. Another purpose of this paper is to provide an introduction to the range and type of research that the new journal Identity in the Information Society will publish, giving researchers working in the field a clearer idea of the scope of multidisciplinary study that is envisaged