Development of a case formulation model for individuals who have viewed, distributed, and/or shared child sexual exploitation material

Increases in the number of arrests of individuals who download or distribute Child Sexual Exploitation Material (CSEM) have highlighted a need to further understand the offending pathways of this offender group. This article describes the development of an aetiological model specific to CSEM offending. Individuals who had viewed, distributed and/or shared CSEM (n = 20) were interviewed regarding their life and sexual history, relationships, substance use, offending details, and circumstances leading to their CSEM offending, resulting in seven superordinate themes: Developmental Context, Individual Propensities (risk-related and risk-protective) and Psychological Vulnerabilities, Personal Circumstances, Permission-Giving Thoughts, Internet Environment and Behaviour, Evaluation of Consequences for the Individual, and Desistance. These themes were combined into a case formulation tool specific for CSEM offending behaviour, with the aim of providing systematic guidance for assessment and treatment providers

Tumor Susceptibility Gene 101 (TSG101) Is a Novel Binding-Partner for the Class II Rab11-FIPs

The Rab11-FIPs (Rab11-family interacting proteins; henceforth, FIPs) are a family of Rab11a/Rab11b/Rab25 GTPase effector proteins implicated in an assortment of intracellular trafficking processes. Through proteomic screening, we have identified TSG101 (tumor susceptibility gene 101), a component of the ESCRT-I (endosomal sorting complex required for transport) complex, as a novel FIP4-binding protein, which we find can also bind FIP3. We show that α-helical coiled-coil regions of both TSG101 and FIP4 mediate the interaction with the cognate protein, and that point mutations in the coiled-coil regions of both TSG101 and FIP4 abrogate the interaction. We find that expression of TSG101 and FIP4 mutants cause cytokinesis defects, but that the TSG101-FIP4 interaction is not required for localisation of TSG101 to the midbody/Flemming body during abscission. Together, these data suggest functional overlap between Rab11-controlled processes and components of the ESCRT pathway

Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction – MiHeart/AMI study

Background: Myocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls. Methods: A sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 x 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum). Implications: Many phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required.Brazilian Ministry of Science and Technology (MCT)/The Financing Agency for Studies and Projects (FINEP

Short-term consumption of a high-fat diet increases host susceptibility to Listeria monocytogenes infection

peer-reviewedBackground A westernized diet comprising a high caloric intake from animal fats is known to influence the development of pathological inflammatory conditions. However, there has been relatively little focus upon the implications of such diets for the progression of infectious disease. Here, we investigated the influence of a high-fat (HF) diet upon parameters that influence Listeria monocytogenes infection in mice. Results We determined that short-term administration of a HF diet increases the number of goblet cells, a known binding site for the pathogen, in the gut and also induces profound changes to the microbiota and promotes a pro-inflammatory gene expression profile in the host. Host physiological changes were concordant with significantly increased susceptibility to oral L. monocytogenes infection in mice fed a HF diet relative to low fat (LF)- or chow-fed animals. Prior to Listeria infection, short-term consumption of HF diet elevated levels of Firmicutes including Coprococcus, Butyricicoccus, Turicibacter and Clostridium XIVa species. During active infection with L. monocytogenes, microbiota changes were further exaggerated but host inflammatory responses were significantly downregulated relative to Listeria-infected LF- or chow-fed groups, suggestive of a profound tempering of the host response influenced by infection in the context of a HF diet. The effects of diet were seen beyond the gut, as a HF diet also increased the sensitivity of mice to systemic infection and altered gene expression profiles in the liver. Conclusions We adopted a systems approach to identify the effects of HF diet upon L. monocytogenes infection through analysis of host responses and microbiota changes (both pre- and post-infection). Overall, the results indicate that short-term consumption of a westernized diet has the capacity to significantly alter host susceptibility to L. monocytogenes infection concomitant with changes to the host physiological landscape. The findings suggest that diet should be a consideration when developing models that reflect human infectious disease.This research was funded by the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie grant agreement No. 641984, through funding of the List_MAPS consortium. We also acknowledge funding and support from Science Foundation Ireland (SFI) in the form of a center grant (APC Microbiome Ireland grant SFI/12/RC/2273)

Listeria monocytogenes Internalin B Activates Junctional Endocytosis to Accelerate Intestinal Invasion

Listeria monocytogenes (Lm) uses InlA to invade the tips of the intestinal villi, a location at which cell extrusion generates a transient defect in epithelial polarity that exposes the receptor for InlA, E-cadherin, on the cell surface. As the dying cell is removed from the epithelium, the surrounding cells reorganize to form a multicellular junction (MCJ) that Lm exploits to find its basolateral receptor and invade. By examining individual infected villi using 3D-confocal imaging, we uncovered a novel role for the second major invasin, InlB, during invasion of the intestine. We infected mice intragastrically with isogenic strains of Lm that express or lack InlB and that have a modified InlA capable of binding murine E-cadherin and found that Lm lacking InlB invade the same number of villi but have decreased numbers of bacteria within each infected villus tip. We studied the mechanism of InlB action at the MCJs of polarized MDCK monolayers and find that InlB does not act as an adhesin, but instead accelerates bacterial internalization after attachment. InlB locally activates its receptor, c-Met, and increases endocytosis of junctional components, including E-cadherin. We show that MCJs are naturally more endocytic than other sites of the apical membrane, that endocytosis and Lm invasion of MCJs depends on functional dynamin, and that c-Met activation by soluble InlB or hepatocyte growth factor (HGF) increases MCJ endocytosis. Also, in vivo, InlB applied through the intestinal lumen increases endocytosis at the villus tips. Our findings demonstrate a two-step mechanism of synergy between Lm's invasins: InlA provides the specificity of Lm adhesion to MCJs at the villus tips and InlB locally activates c-Met to accelerate junctional endocytosis and bacterial invasion of the intestine

Constitutive Activation of PrfA Tilts the Balance of Listeria monocytogenes Fitness Towards Life within the Host versus Environmental Survival

PrfA is a key regulator of Listeria monocytogenes pathogenesis and induces the expression of multiple virulence factors within the infected host. PrfA is post-translationally regulated such that the protein becomes activated upon bacterial entry into the cell cytosol. The signal that triggers PrfA activation remains unknown, however mutations have been identified (prfA* mutations) that lock the protein into a high activity state. In this report we examine the consequences of constitutive PrfA activation on L. monocytogenes fitness both in vitro and in vivo. Whereas prfA* mutants were hyper-virulent during animal infection, the mutants were compromised for fitness in broth culture and under conditions of stress. Broth culture prfA*-associated fitness defects were alleviated when glycerol was provided as the principal carbon source; under these conditions prfA* mutants exhibited a competitive advantage over wild type strains. Glycerol and other three carbon sugars have been reported to serve as primary carbon sources for L. monocytogenes during cytosolic growth, thus prfA* mutants are metabolically-primed for replication within eukaryotic cells. These results indicate the critical need for environment-appropriate regulation of PrfA activity to enable L. monocytogenes to optimize bacterial fitness inside and outside of host cells

Cell tracking in cardiac repair: what to image and how to image

Stem cell therapies hold the great promise and interest for cardiac regeneration among scientists, clinicians and patients. However, advancement and distillation of a standard treatment regimen are not yet finalised. Into this breach step recent developments in the imaging biosciences. Thus far, these technical and protocol refinements have played a critical role not only in the evaluation of the recovery of cardiac function but also in providing important insights into the mechanism of action of stem cells. Molecular imaging, in its many forms, has rapidly become a necessary tool for the validation and optimisation of stem cell engrafting strategies in preclinical studies. These include a suite of radionuclide, magnetic resonance and optical imaging strategies to evaluate non-invasively the fate of transplanted cells. In this review, we highlight the state-of-the-art of the various imaging techniques for cardiac stem cell presenting the strengths and limitations of each approach, with a particular focus on clinical applicability