Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.ResultsTwo hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.ConclusionDespite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives

EnvMine: A text-mining system for the automatic extraction of contextual information

<p>Abstract</p> <p>Background</p> <p>For ecological studies, it is crucial to count on adequate descriptions of the environments and samples being studied. Such a description must be done in terms of their physicochemical characteristics, allowing a direct comparison between different environments that would be difficult to do otherwise. Also the characterization must include the precise geographical location, to make possible the study of geographical distributions and biogeographical patterns. Currently, there is no schema for annotating these environmental features, and these data have to be extracted from textual sources (published articles). So far, this had to be performed by manual inspection of the corresponding documents. To facilitate this task, we have developed EnvMine, a set of text-mining tools devoted to retrieve contextual information (physicochemical variables and geographical locations) from textual sources of any kind.</p> <p>Results</p> <p>EnvMine is capable of retrieving the physicochemical variables cited in the text, by means of the accurate identification of their associated units of measurement. In this task, the system achieves a recall (percentage of items retrieved) of 92% with less than 1% error. Also a Bayesian classifier was tested for distinguishing parts of the text describing environmental characteristics from others dealing with, for instance, experimental settings.</p> <p>Regarding the identification of geographical locations, the system takes advantage of existing databases such as GeoNames to achieve 86% recall with 92% precision. The identification of a location includes also the determination of its exact coordinates (latitude and longitude), thus allowing the calculation of distance between the individual locations.</p> <p>Conclusion</p> <p>EnvMine is a very efficient method for extracting contextual information from different text sources, like published articles or web pages. This tool can help in determining the precise location and physicochemical variables of sampling sites, thus facilitating the performance of ecological analyses. EnvMine can also help in the development of standards for the annotation of environmental features.</p

The use of cystatin C to inhibit epithelial–mesenchymal transition and morphological transformation stimulated by transforming growth factor-β

INTRODUCTION: Transforming growth factor-β (TGF-β) is a potent suppressor of mammary epithelial cell (MEC) proliferation and is thus an inhibitor of mammary tumor formation. Malignant MECs typically evolve resistance to TGF-β-mediated growth arrest, enhancing their proliferation, invasion, and metastasis when stimulated by TGF-β. Recent findings suggest that therapeutics designed to antagonize TGF-β signaling may alleviate breast cancer progression, thereby improving the prognosis and treatment of breast cancer patients. We identified the cysteine protease inhibitor cystatin C (CystC) as a novel TGF-β type II receptor antagonist that inhibits TGF-β binding and signaling in normal and cancer cells. We hypothesized that the oncogenic activities of TGF-β, particularly its stimulation of mammary epithelial–mesenchymal transition (EMT), can be prevented by CystC. METHOD: Retroviral infection was used to constitutively express CystC or a CystC mutant impaired in its ability to inhibit cathepsin protease activity (namely Δ14CystC) in murine NMuMG MECs and in normal rat kidney (NRK) fibroblasts. The effect of recombinant CystC administration or CystC expression on TGF-β stimulation of NMuMG cell EMT in vitro was determined with immunofluorescence to monitor rearrangements of actin cytoskeletal architecture and E-cadherin expression. Soft-agar growth assays were performed to determine the effectiveness of CystC in preventing TGF-β stimulation of morphological transformation and anchorage-independent growth in NRK fibroblasts. Matrigel invasion assays were performed to determine the ability of CystC to inhibit NMuMG and NRK motility stimulated by TGF-β. RESULTS: CystC and Δ14CystC both inhibited NMuMG cell EMT and invasion stimulated by TGF-β by preventing actin cytoskeletal rearrangements and E-cadherin downregulation. Moreover, both CystC molecules completely antagonized TGF-β-mediated morphological transformation and anchorage-independent growth of NRK cells, and inhibited their invasion through synthetic basement membranes. Both CystC and Δ14CystC also inhibited TGF-β signaling in two tumorigenic human breast cancer cell lines. CONCLUSION: Our findings show that TGF-β stimulation of initiating metastatic events, including decreased cell polarization, reduced cell–cell contact, and elevated cell invasion and migration, are prevented by CystC treatment. Our findings also suggest that the future development of CystC or its peptide mimetics hold the potential to improve the therapeutic response of human breast cancers regulated by TGF-β

Comparative genomics of Escherichia coli isolated from patients with inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Inflammatory bowel disease (IBD) is used to describe a state of idiopathic, chronic inflammation of the gastrointestinal tract. The two main phenotypes of IBD are Crohn's disease (CD) and ulcerative colitis (UC). The major cause of IBD-associated mortality is colorectal cancer. Although both host-genetic and exogenous factors have been found to be involved, the aetiology of IBD is still not well understood. In this study we characterized thirteen <it>Escherichia coli </it>strains from patients with IBD by comparative genomic hybridization employing a microarray based on 31 sequenced <it>E. coli </it>genomes from a wide range of commensal and pathogenic isolates.</p> <p>Results</p> <p>The IBD isolates, obtained from patients with UC and CD, displayed remarkably heterogeneous genomic profiles with little or no evidence of group-specific determinants. No IBD-specific genes were evident when compared with the prototypic CD isolate, LF82, suggesting that the IBD-inducing effect of the strains is multifactorial. Several of the IBD isolates carried a number of extraintestinal pathogenic <it>E. coli </it>(ExPEC)-related virulence determinants such as the <it>pap</it>, <it>sfa</it>, <it>cdt </it>and <it>hly </it>genes. The isolates were also found to carry genes of ExPEC-associated genomic islands.</p> <p>Conclusions</p> <p>Combined, these data suggest that <it>E. coli </it>isolates obtained from UC and CD patients represents a heterogeneous population of strains, with genomic profiles that are indistinguishable to those of ExPEC isolates. Our findings indicate that IBD-induction from <it>E. coli </it>strains is multifactorial and that a range of gene products may be involved in triggering the disease.</p

Bad faith in All’s Well That Ends Well

All’s Well That Ends Well is a complicated and disturbing play that has a comic ending, but which seems anything but a comedy with a forced marriage based on bed-trickery between the reluctant Bertram and the feisty and witty Helena. Unsurprisingly, audiences have tended to side with Helena and the play has been classified as a “problem comedy” ever since William Lawrence identified this particular group of Shakespeare plays nearly a century ago. I want to argue in this essay that the play might better be classified as an “equivocation” play alongside Macbeth, Othello, and Troilus and Cressida and that the anxieties about fidelity, honesty and truthfulness in marriage need to be read in terms of the fear of religious tolerance/intolerance which dominated religious politics in the early years of James’s reign before the passing of the Oath of Allegiance (1606). The play is notable for its interest in chop logic, which the clown in particular displays throughout the play, a counterpoint to the arguments of Bertram and Helena who want very different things, but who are bound together as future husband and wife. Although the language of treason and treachery is used throughout, the play is less interested in answering the question of how far one can trust a stranger within than the issue of how far one can accommodate the needs of others. This article is published as part of a collection to commemorate the 400th anniversary of William Shakespeare’s death

Role of SNX16 in the Dynamics of Tubulo-Cisternal Membrane Domains of Late Endosomes

In this paper, we report that the PX domain-containing protein SNX16, a member of the sorting nexin family, is associated with late endosome membranes. We find that SNX16 is selectively enriched on tubulo-cisternal elements of this membrane system, whose highly dynamic properties and formation depend on intact microtubules. By contrast, SNX16 was not found on vacuolar elements that typically contain LBPA, and thus presumably correspond to multivesicular endosomes. We conclude that SNX16, together with its partner phosphoinositide, define a highly dynamic subset of late endosomal membranes, supporting the notion that late endosomes are organized in distinct morphological and functional regions. Our data also indicate that SNX16 is involved in tubule formation and cholesterol transport as well as trafficking of the tetraspanin CD81, suggesting that the protein plays a role in the regulation of late endosome membrane dynamics

Host Genes Related to Paneth Cells and Xenobiotic Metabolism Are Associated with Shifts in Human Ileum-Associated Microbial Composition

The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn’s disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD). Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R) and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3–V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA) support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions

Understanding the Role of the Josephin Domain in the PolyUb Binding and Cleavage Properties of Ataxin-3

Ataxin-3, the disease protein in the neurodegenerative disorder Spinocerebellar Ataxia Type 3 or Machado Joseph disease, is a cysteine protease implicated in the ubiquitin proteasome pathway. It contains multiple ubiquitin binding sites through which it anchors polyubiquitin chains of different linkages that are then cleaved by the N-terminal catalytic (Josephin) domain. The properties of the ubiquitin interacting motifs (UIMs) in the C-terminus of ataxin-3 are well established. Very little is known, however, about how two recently identified ubiquitin-binding sites in the Josephin domain contribute to ubiquitin chain binding and cleavage. In the current study, we sought to define the specific contribution of the Josephin domain to the catalytic properties of ataxin-3 and assess how the topology and affinity of these binding sites modulate ataxin-3 activity. Using NMR we modeled the structure of diUb/Josephin complexes and showed that linkage preferences are imposed by the topology of the two binding sites. Enzymatic studies further helped us to determine a precise hierarchy between the sites. We establish that the structure of Josephin dictates specificity for K48-linked chains. Site 1, which is close to the active site, is indispensable for cleavage. Our studies open the way to understand better the cellular function of ataxin-3 and its link to pathology

Targeting medication non-adherence behavior in selected autoimmune diseases: a systematic approach to digital health program development

Background 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn’s Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. Objective Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. Methods Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn’s Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. Results Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient-centric approaches (67%). Conclusions This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns

Non-Adherence in Patients on Peritoneal Dialysis: A Systematic Review

Background: It has been increasingly recognized that non-adherence is an important factor that determines the outcome of peritoneal dialysis (PD) therapy. There is therefore a need to establish the levels of non-adherence to different aspects of the PD regimen (dialysis procedures, medications, and dietary/fluid restrictions). Methods: A systematic review of peer-reviewed literature was performed in PubMed, PsycINFO and CINAHL databases using PRISMA guidelines in May 2013. Publications on non-adherence in PD were selected by two reviewers independently according to predefined inclusion and exclusion criteria. Relevant data on patient characteristics, measures, rates and factors associated with non-adherence were extracted. The quality of studies was also evaluated independently by two reviewers according to a revised version of the Effective Public Health Practice Project assessment tool. Results: The search retrieved 204 studies, of which a total of 25 studies met inclusion criteria. Reported rates of nonadherence varied across studies: 2.6 1353% for dialysis exchanges, 3.9 1385% for medication, and 14.4 1367% for diet/fluid restrictions. Methodological differences in measurement and definition of non-adherence underlie the observed variation. Factors associated with non-adherence that showed a degree of consistency were mostly socio-demographical, such as age, employment status, ethnicity, sex, and time period on PD treatment. Conclusion: Non-adherence to different dimensions of the dialysis regimen appears to be prevalent in PD patients. There is a need for further, high-quality research to explore these factors in more detail, with the aim of informing intervention designs to facilitate adherence in this patient populatio