Endomicroscopic and transcriptomic analysis of impaired barrier function and malabsorption in environmental enteropathy

Introduction: Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods: We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results: CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions: Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE

Comparison of hospital charge prediction models for gastric cancer patients: neural network vs. decision tree models

<p>Abstract</p> <p>Background</p> <p>In recent years, artificial neural network is advocated in modeling complex multivariable relationships due to its ability of fault tolerance; while decision tree of data mining technique was recommended because of its richness of classification arithmetic rules and appeal of visibility. The aim of our research was to compare the performance of ANN and decision tree models in predicting hospital charges on gastric cancer patients.</p> <p>Methods</p> <p>Data about hospital charges on 1008 gastric cancer patients and related demographic information were collected from the First Affiliated Hospital of Anhui Medical University from 2005 to 2007 and preprocessed firstly to select pertinent input variables. Then artificial neural network (ANN) and decision tree models, using same hospital charge output variable and same input variables, were applied to compare the predictive abilities in terms of mean absolute errors and linear correlation coefficients for the training and test datasets. The transfer function in ANN model was sigmoid with 1 hidden layer and three hidden nodes.</p> <p>Results</p> <p>After preprocess of the data, 12 variables were selected and used as input variables in two types of models. For both the training dataset and the test dataset, mean absolute errors of ANN model were lower than those of decision tree model (1819.197 vs. 2782.423, 1162.279 vs. 3424.608) and linear correlation coefficients of the former model were higher than those of the latter (0.955 vs. 0.866, 0.987 vs. 0.806). The predictive ability and adaptive capacity of ANN model were better than those of decision tree model.</p> <p>Conclusion</p> <p>ANN model performed better in predicting hospital charges of gastric cancer patients of China than did decision tree model.</p

Genetic testing in professional football: perspectives of key stakeholders

Purpose: Genetic research in football is currently in it’s infancy but is growing rapidly. However, the practical application of genetic testing in football and the views concerning its use are unknown. Thus, the purpose of this study was to assess the current practical application of genetic testing in professional football and provide an insight into the perspectives of key stakeholders (i.e., coaches, practitioners, players). Methods: In total, 122 participants completed an online anonymous survey. This consisted of 21 multiple choice and Likert scale questions, with the option of providing an explanation for each response. Results: Findings revealed genetic testing is rarely utilised by key stakeholders (10%) or their respective organisations (14%). However, three quarters (75%) had the opinion that genetic testing will have great utility in the future. The majority (72%) believed genetic testing should be used for athlete development and injury risk, whilst 35% believed that genetic testing should be utilised for talent identification purposes. However, most key stakeholders viewed their own (89%) and their colleagues’ (79%) knowledge related to genetic testing as insufficient; mainly due to ineffective current communication methods (91%). Most believed educational workshops are required (71%), whilst nearly all (91%) were interested in developing their expertise on the utility of genetic testing. Conclusion: Genetic testing is rarely used within professional football, although key stakeholders anticipate that it will be utilised more in the future. As such, educational support may prove valuable in improving key stakeholder knowledge and the practical application of genetic testing in professional football

Genetic variations between youth and professional development phase english academy football players

The purpose of this study was to examine differences in the genotype frequency distribution of thirty-three single nucleotide variants (SNVs) between youth development phase (YDP) and professional development phase (PDP) academy football players. One hundred and sixty-six male football players from two Category 1 and Category 3 English academies were examined within their specific age phase: YDP (n = 92; aged 13.84 ± 1.63 years) and PDP (n = 74; aged 18.09 ± 1.51 years). Fisher’s exact tests were used to compare individual genotype frequencies, whereas unweighted and weighted total genotype scores (TGS; TWGS) were computed to assess differences in polygenic profiles. In isolation, the IL6 (rs1800795) G allele was overrepresented in PDP players (90.5%) compared to YDP players (77.2%; p = 0.023), whereby PDP players had nearly three times the odds of possessing a G allele (OR = 2.83, 95% CI: 1.13–7.09). The TGS (p = 0.001) and TWGS (p < 0.001) were significant, but poor, in distinguishing YDP and PDP players (AUC = 0.643–0.694), with PDP players exhibiting an overall more power-orientated polygenic profile. If validated in larger independent youth football cohorts, these findings may have important implications for future studies examining genetic associations in youth football

Caucasian Infants Scan Own- and Other-Race Faces Differently

Young infants are known to prefer own-race faces to other race faces and recognize own-race faces better than other-race faces. However, it is entirely unclear as to whether infants also attend to different parts of own- and other-race faces differently, which may provide an important clue as to how and why the own-race face recognition advantage emerges so early. The present study used eye tracking methodology to investigate whether 6- to 10-month-old Caucasian infants (N = 37) have differential scanning patterns for dynamically displayed own- and other-race faces. We found that even though infants spent a similar amount of time looking at own- and other-race faces, with increased age, infants increasingly looked longer at the eyes of own-race faces and less at the mouths of own-race faces. These findings suggest experience-based tuning of the infant's face processing system to optimally process own-race faces that are different in physiognomy from other-race faces. In addition, the present results, taken together with recent own- and other-race eye tracking findings with infants and adults, provide strong support for an enculturation hypothesis that East Asians and Westerners may be socialized to scan faces differently due to each culture's conventions regarding mutual gaze during interpersonal communication

Opinion: hazards faced by macromolecules when confined to thin aqueous films

Samples prepared for single-particle electron cryo-microscopy (cryo-EM) necessarily have a very high surface-to-volume ratio during the short period of time between thinning and vitrification. During this time, there is an obvious risk that macromolecules of interest may adsorb to the air-water interface with a preferred orientation, or that they may even become partially or fully unfolded at the interface. In addition, adsorption of macromolecules to an air-water interface may occur even before thinning. This paper addresses the question whether currently used methods of sample preparation might be improved if one could avoid such interfacial interactions. One possible way to do so might be to preemptively form a surfactant monolayer over the air-water interfaces, to serve as a structure-friendly slide and coverslip. An alternative is to immobilize particles of interest by binding them to some type of support film, which-to continue using the analogy-thus serves as a slide. In this case, the goal is not only to prevent the particles of interest from diffusing into contact with the air-water interface but also to increase the number of particles seen in each image. In this direction, it is natural to think of developing various types of affinity grids as structure-friendly alternatives to thin carbon films. Perhaps ironically, if precautions are not taken against adsorption of particles to air-water interfaces, sacrificial monolayers of denatured protein may take the roles of slide, coverslip, or even both

Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2

<p>Abstract</p> <p>Background</p> <p>The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses.</p> <p>Methods</p> <p>Subjects with stage II (≥ 6 +LN), III, or stage IV breast cancerwith > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact.</p> <p>Results</p> <p>All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6–6.7 years of follow-up.</p> <p>Conclusion</p> <p>Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00005956</p

Common risk factor approach to address socioeconomic inequality in the oral health of preschool children – a prospective cohort study

Background: Dental caries remains the most prevalent chronic condition in children and a major contributor to poor general health. There is ample evidence of a skewed distribution of oral health, with a small proportion of children in the population bearing the majority of the burden of the disease. This minority group is comprised disproportionately of socioeconomically disadvantaged children. An in-depth longitudinal study is needed to better understand the determinants of child oral health, in order to support effective evidence-based policies and interventions in improving child oral health. The aim of the Study of Mothers’ and Infants’ Life Events Affecting Oral Health (SMILE) project is to identify and evaluate the relative importance and timing of critical factors that shape the oral health of young children and then to seek to evaluate those factors in their inter-relationship with socioeconomic influences.Methods/Design: This investigation will apply an observational prospective study design to a cohort ofsocioeconomically-diverse South Australian newborns and their mothers, intensively following these dyads as the children grow to toddler age. Mothers of newborn children will be invited to participate in the study in the early post-partum period. At enrolment, data will be collected on parental socioeconomic status, mothers’ general and dental health conditions, details of the pregnancy, infant feeding practice and parental health behaviours and practices. Data on diet and feeding practices, oral health behaviours and practices, and dental visiting patterns will be collected at 3, 6, 12 and 24 months of age. When children turn 24-30 months, the children and their mothers/primary care givers will be invited to an oral examination to record oral health status. Anthropometric assessment will also be conducted.Discussion: This prospective cohort study will examine a wide range of determinants influencing child oral health and related general conditions such as overweight. It will lead to the evaluation of the inter-relationship among main influences and their relative effect on child oral health. The study findings will provide high level evidence of pathways through which socio-environmental factors impact child oral health. It will also provide an opportunity to examine the relationship between oral health and childhood overweight.Discussion: This prospective cohort study will examine a wide range of determinants influencing child oral health and related general conditions such as overweight. It will lead to the evaluation of the inter-relationship among main influences and their relative effect on child oral health. The study findings will provide high level evidence of pathways through which socio-environmental factors impact child oral health. It will also provide an to examine the relationship between oral health and childhood overweight

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe