Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study

Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation

Approaches in biotechnological applications of natural polymers

Natural polymers, such as gums and mucilage, are biocompatible, cheap, easily available and non-toxic materials of native origin. These polymers are increasingly preferred over synthetic materials for industrial applications due to their intrinsic properties, as well as they are considered alternative sources of raw materials since they present characteristics of sustainability, biodegradability and biosafety. As definition, gums and mucilages are polysaccharides or complex carbohydrates consisting of one or more monosaccharides or their derivatives linked in bewildering variety of linkages and structures. Natural gums are considered polysaccharides naturally occurring in varieties of plant seeds and exudates, tree or shrub exudates, seaweed extracts, fungi, bacteria, and animal sources. Water-soluble gums, also known as hydrocolloids, are considered exudates and are pathological products; therefore, they do not form a part of cell wall. On the other hand, mucilages are part of cell and physiological products. It is important to highlight that gums represent the largest amounts of polymer materials derived from plants. Gums have enormously large and broad applications in both food and non-food industries, being commonly used as thickening, binding, emulsifying, suspending, stabilizing agents and matrices for drug release in pharmaceutical and cosmetic industries. In the food industry, their gelling properties and the ability to mold edible films and coatings are extensively studied. The use of gums depends on the intrinsic properties that they provide, often at costs below those of synthetic polymers. For upgrading the value of gums, they are being processed into various forms, including the most recent nanomaterials, for various biotechnological applications. Thus, the main natural polymers including galactomannans, cellulose, chitin, agar, carrageenan, alginate, cashew gum, pectin and starch, in addition to the current researches about them are reviewed in this article.. }To the Conselho Nacional de Desenvolvimento Cientfíico e Tecnológico (CNPq) for fellowships (LCBBC and MGCC) and the Coordenação de Aperfeiçoamento de Pessoal de Nvíel Superior (CAPES) (PBSA). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462) and COMPETE 2020 (POCI-01-0145-FEDER-006684) (JAT)

Advances in estimation by the item sum technique using auxiliary information in complex surveys

To collect sensitive data, survey statisticians have designed many strategies to reduce nonresponse rates and social desirability response bias. In recent years, the item count technique (ICT) has gained considerable popularity and credibility as an alternative mode of indirect questioning survey, and several variants of this technique have been proposed as new needs and challenges arise. The item sum technique (IST), which was introduced by Chaudhuri and Christofides (2013) and Trappmann et al. (2014), is one such variant, used to estimate the mean of a sensitive quantitative variable. In this approach, sampled units are asked to respond to a two-list of items containing a sensitive question related to the study variable and various innocuous, nonsensitive, questions. To the best of our knowledge, very few theoretical and applied papers have addressed the IST. In this article, therefore, we present certain methodological advances as a contribution to appraising the use of the IST in real-world surveys. In particular, we employ a generic sampling design to examine the problem of how to improve the estimates of the sensitive mean when auxiliary information on the population under study is available and is used at the design and estimation stages. A Horvitz-Thompson type estimator and a calibration type estimator are proposed and their efficiency is evaluated by means of an extensive simulation study. Using simulation experiments, we show that estimates obtained by the IST are nearly equivalent to those obtained using “true data” and that in general they outperform the estimates provided by a competitive randomized response method. Moreover, the variance estimation may be considered satisfactory. These results open up new perspectives for academics, researchers and survey practitioners, and could justify the use of the IST as a valid alternative to traditional direct questioning survey modes.Ministerio de Economía y Competitividad of SpainMinisterio de Educacion, Cultura y Deporteproject PRIN-SURWE

Somatostatin Receptor 1 and 5 Double Knockout Mice Mimic Neurochemical Changes of Huntington's Disease Transgenic Mice

Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD). However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5). and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease

Expansion and Characterization of Human Melanoma Tumor-Infiltrating Lymphocytes (TILs)

Various immunotherapeutic strategies for cancer are aimed at augmenting the T cell response against tumor cells. Adoptive cell therapy (ACT), where T cells are manipulated ex vivo and subsequently re-infused in an autologous manner, has been performed using T cells from various sources. Some of the highest clinical response rates for metastatic melanoma have been reported in trials using tumor-infiltrating lymphocytes (TILs). These protocols still have room for improvement and furthermore are currently only performed at a limited number of institutions. The goal of this work was to develop TILs as a therapeutic product at our institution.TILs from 40 melanoma tissue specimens were expanded and characterized. Under optimized culture conditions, 72% of specimens yielded rapidly proliferating TILs as defined as at least one culture reaching ≥3×10(7) TILs within 4 weeks. Flow cytometric analyses showed that cultures were predominantly CD3+ T cells, with highly variable CD4+:CD8+ T cell ratios. In total, 148 independent bulk TIL cultures were assayed for tumor reactivity. Thirty-four percent (50/148) exhibited tumor reactivity based on IFN-γ production and/or cytotoxic activity. Thirteen percent (19/148) showed specific cytotoxic activity but not IFN-γ production and only 1% (2/148) showed specific IFN-γ production but not cytotoxic activity. Further expansion of TILs using a 14-day "rapid expansion protocol" (REP) is required to induce a 500- to 2000-fold expansion of TILs in order to generate sufficient numbers of cells for current ACT protocols. Thirty-eight consecutive test REPs were performed with an average 1865-fold expansion (+/- 1034-fold) after 14 days.TILs generally expanded efficiently and tumor reactivity could be detected in vitro. These preclinical data from melanoma TILs lay the groundwork for clinical trials of ACT

Factors Associated with Work Participation and Work Functioning in Depressed Workers: A Systematic Review

Background Depression is associated with negative work outcomes such as reduced work participation (WP) (e.g., sick leave duration, work status) and work functioning (WF) (e.g., loss of productivity, work limitations). For the development of evidence-based interventions to improve these work outcomes, factors predicting WP and WF have to be identified. Methods This paper presents a systematic literature review of studies identifying factors associated with WP and WF of currently depressed workers. Results A total of 30 studies were found that addressed factors associated with WP (N = 19) or WF (N = 11). For both outcomes, studies reported most often on the relationship with disorder-related factors, whereas personal factors and work-related factors were less frequently addressed. For WP, the following relationships were supported: strong evidence was found for the association between a long duration of the depressive episode and work disability. Moderate evidence was found for the associations between more severe types of depressive disorder, presence of co-morbid mental or physical disorders, older age, a history of previous sick leave, and work disability. For WF, severe depressive symptoms were associated with work limitations, and clinical improvement was related to work productivity (moderate evidence). Due to the cross-sectional nature of about half of the studies, only few true prospective associations could be identified. Conclusion Our study identifies gaps in knowledge regarding factors predictive of WP and WF in depressed workers and can be used for the design of future research and evidence-based interventions. We recommend undertaking more longitudinal studies to identify modifiable factors predictive of WP and WF, especially work-related and personal factors

Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: Findings from the MAL-ED birth cohort study

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. Background Dietary and illness factors affect risk of growth faltering; the role of enteropathogens is less clear. As part of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, we quantify the effects of enteropathogen infection, diarrhoea and diet on child growth. Methods Newborns were enrolled and followed until 24 months. Length and weight were assessed monthly. Illnesses and breastfeeding practices were documented biweekly; from 9 to 24 months, non-breast milk intakes were quantified monthly. Routinely collected non-diarrhoeal stools were analysed for a broad array of enteropathogens. A linear piecewise spline model was used to quantify associations of each factor with growth velocity in seven of eight MAL-ED sites; cumulative effects on attained size at 24 months were estimated for mean, low (10th percentile) and high (90th percentile) exposure levels. Additionally, the six most prevalent enteropathogens were evaluated for their effects on growth. results Diarrhoea did not have a statistically significant effect on growth. Children with high enteropathogen exposure were estimated to be 1.21±0.33 cm (p<0.001; 0.39 length for age (LAZ)) shorter and 0.08±0.15 kg (p=0.60; 0.08 weight-for-age (WAZ)) lighter at 24 months, on average, than children with low exposure. Campylobacter and enteroaggregativeEscherichia coli detections were associated with deficits of 0.83±0.33 and 0.85±0.31 cm in length (p=0.011 and 0.001) and 0.22±0.15 and 0.09±0.14 kg in weight (p=0.14 and 0.52), respectively. Children with low energy intakes and protein density were estimated to be 1.39±0.33 cm (p<0.001; 0.42 LAZ) shorter and 0.81±0.15 kg (p<0.001; 0.65 WAZ) lighter at 24 months than those with high intakes. conclusions Reducing enteropathogen burden and improving energy and protein density of complementary foods could reduce stunting