Effects of dietary antioxidants and environmental stressors on immune function and condition in Lithobates (Rana) sylvaticus.

The negative effects of abiotic and biotic stressors on animal condition, physiology, behaviour, and fitness have become increasingly recognized, making it critical to understand how these may be mitigated, such as through diet. When consumed, dietary antioxidants (secondary metabolites produced by plants) provide protection from oxidative damage that can result from exposure to stressors. We examined the effects of dietary antioxidants (ß-carotene and vitamin E) on the ability of Lithobates sylvaticus (wood frog) tadpoles to overcome the detrimental effects imposed by two common environmental stressors - exposure to the herbicide atrazine or infection by a pathogenic helminth parasite (Echinostoma trivolvis). Tadpoles which were fed high concentrations of either vitamin E or ß-carotene had a greater immune response compared to those given trace diets of either compound as measured by circulating white blood cells and a phytohemaglutination assay (PHA). Similarly, tadpoles in the herbicide and parasitism treatments that were given trace antioxidant diets had significant weight loss, whereas those consuming high levels of vitamin E or ß-carotene did not. Our results suggest that dietary antioxidants, specifically ß-carotene and vitamin E, have a positive effect on tadpole immune systems and overall condition that likely allows them to better cope with natural stressors, with potential implications for their foraging behaviour.

Increased intestinal epithelial cell turnover and intestinal motility in Gymnophalloides seoi-infected C57BL/6 mice.

The changing patterns of goblet cell hyperplasia, intestinal epithelial cell turnover, and intestinal motility were studied in ICR and C57BL/6 mice infected with Gymnophalloides seoi (Digenea: Gymnophallidae). Whereas ICR mice retained G. seoi worms until day 7 post-infection (PI), C57BL/6 mice showed a rapid worm expulsion within day 3 PI. Immunosuppression with Depo-Medrol significantly delayed the worm expulsion in C57BL/6 mice. Goblet cell counts were increased in both strains of mice, peaking at day 1 PI in C57BL/6 mice and slowly increasing until day 7 PI in ICR mice. In C57BL/6 mice infected with G. seoi, newly proliferating intestinal epithelial cells were remarkably increased in the crypt, and the increase was the highest at day 1 PI. However, in ICR mice, newly proliferating intestinal epithelial cells increased slowly from day 1 to day 7 PI. Intestinal motility was increased in G. seoi-infected mice, and its chronological pattern was highly correlated with the worm load in both strains of mice. Meanwhile, immunosuppression of C57BL/6 mice abrogated the goblet cell proliferation, reduced the epithelial cell proliferation, and suppressed the intestinal motility. Goblet cell hyperplasia, increased intestinal epithelial cell turnover, and increased intestinal motility should be important mucosal defense mechanisms in G. seoi-infected C57BL/6 mice.

Control of macrophage activation and function by PPARs.

Abstract: Macrophages, a key component of the innate defense against pathogens, participate in the initiation and resolution of inflammation, and in the maintenance of tissues. These diverse and at times antithetical functions of macrophages are executed via distinct activation states, ranging from classical to alternative to deactivation. Because the dysregulation of macrophage activation is pathogenically linked to various metabolic, inflammatory and immune disorders, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. Here, the mechanisms by which peroxisome proliferator-activated receptors (PPARs) transcriptionally regulate macrophage activation in health and disease states, including obesity, insulin resistance and cardiovascular disease, are reviewed.

When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions.

Helminth secretomes comprise many potential immunomodulators. The molecular and functional diversity of these entities and their importance at the host-parasite interface have been increasingly recognized. It is now common to hypothesize that parasite-derived molecules (PDMs) are essential mediators used by parasites to establish and remain in their hosts. Suppression of PDM release has been reported for two anthelmintic drug classes, the benzimidazoles and macrocyclic lactones, the mechanisms of action of which remain incompletely resolved. We propose that bringing together recent insights from different streams of parasitology research, for example, immunoparasitology and pharmacology, will stimulate the development of new ways to alter the host-parasite interface in the search for novel anthelmintic strategies.

Integration of Management Strategies for Skin-Related Neglected Tropical Diseases.

The concept of skin neglected tropical diseases has been widely adopted into the policy and strategy of various organizations, governments, nongovernmental organizations, and health agencies. By pooling information and resources across different diseases, whose primary manifestations affect the skin, it is possible to deliver integrated surveillance and control programs and promote advocacy and reduction of disability and stigma. A further key part of the skin neglected tropical diseases program is the development and validation of training methods for front-line health workers. Networks that allow those involved in this work to share and compare expertise are being developed through various organizations.

Eosinophils in health and disease: the LIAR hypothesis.

Discussions of eosinophils are often descriptions of end-stage effector cells with destructive capabilities mediated predominantly by released cytotoxic cationic granule proteins. Moreover, eosinophils in the medical literature are invariably associated with the pathologies linked with helminth infections or allergic diseases such as asthma. This has led to an almost fatalist view of eosinophil effector functions and associated therapeutic strategies targeting these cells that would make even William of Ockham proud - eosinophil effector functions have physiological consequences that increase patient morbidity/mortality and 'the only good eosinophils are dead eosinophils'. Unfortunately, the strengths of dogmas are also their greatest weaknesses. Namely, while the repetitive proclamation of dogmatic concepts by authoritative sources (i.e. reviews, meeting proceedings, textbooks, etc.) builds consensus within the medical community and lower the entropies surrounding difficult issues, they often ignore not easily explained details and place diminished importance on alternative hypotheses. The goal of this perspective is twofold: (i) we will review recent observations regarding eosinophils and their activities as well as reinterpret earlier data as part of the synthesis of a new paradigm. In this paradigm, we hypothesize that eosinophils accumulate at unique sites in response to cell turnover or in response to local stem cell activity(ies). We further suggest that this accumulation is part of one or more mechanisms regulating tissue homeostasis. Specifically, instead of immune cells exclusively mediating innate host defence, we suggest that accumulating tissue eosinophils are actually regulators of Local Immunity And/or Remodeling/Repair in both health and disease - the LIAR hypothesis; (ii) we want to be inflammatory (pun intended!) and challenge the currently common perspective of eosinophils as destructive end-stage effector cells. Our hope is to create more questions than we answer and provoke everyone to spend countless hours simply to prove us wrong!

Neuroimmunomodulation during infectious diseases: mechanisms, causes and consequences for the host.

In this special issue of Neuroimmunomodulation, the reader will find reviewed some of the hottest topics in the field of neuroendocrine-immune interactions, with emphasis on infectious diseases. For instance, the role that immunoendocrine alterations have during human tuberculosis, a chronic infectious disease, is discussed, and it is concluded that these immunoendocrine interactions may play a detrimental role during the disease, in terms of the development of protective immune responses, control of tissue damage and metabolic disorders. Also, the role that neuroimmunomodulation plays in parasitic diseases is presented, and emphasizes the importance of the host-parasite neuroimmunoendocrine network during helminth infection. Moreover, the influence of beta-androstenes on resistance to viral and bacterial infections is discussed, as well as the impact of infectious diseases upon neuroendocrine circuits. Also, the reader will find contributions to the study of sex hormones and modulation of immunity against leishmaniasis, as well as recent work on the immune mechanisms associated with resistance or susceptibility to parasitic diseases during pregnancy. We hope that our readers will find the first ever special issue devoted to neuroimmunomodulation and infectious diseases fascinating and enticing.

Neuroimmunoendocrine modulation in the host by helminth parasites: a novel form of host-parasite coevolution?

Helminth parasites have evolved diverse molecular mechanisms that facilitate their establishment, growth and reproduction inside an immunologically hostile environment. Thus, the physiological interactions during the course of the immune response to helminths are complex. Infection induces antigen-specific recognition by the immune system, which is consequently charged with the responsibility of marshalling the appropriate effector responses necessary to destroy the parasite, or at the very least inhibit its progression. Obviously, the immune system should accomplish this task while minimizing collateral damage to the host. As our understanding of the neuroendocrine system grows, it has become increasingly clear that this complex network of neurotransmitters, hormones, and cytokines plays an important role in mediating immunity. Helminths present an especially complex relationship between pathogen and these physiological systems, with hormonally dependent host factors such as sex and age correlated with parasite success. On top of the effect that this particular type of parasites may have on the invaded host, recent experimental evidence suggests that helminth parasites not only actively evade immune response, but are also able to exploit the hormonal microenvironment within their host to favor their establishment, growth and reproduction. This complex strategy of host-parasite relationship is much better exemplified by two helminth parasites: the trematode Schistosoma mansoni and the cestode Taenia crassiceps that respond to adrenal steroids and sexual steroids, respectively. Understanding how the host endocrine system can under certain circumstances favor the establishment of a parasitic infection opens interesting perspectives into the host-parasite relationship field.

Helicobacter pylori, helminth infections and growth: a cross-sectional study in a high prevalence population.

AIM: Helicobacter pylori (H. pylori) infection is usually acquired in childhood and may adversely affect growth, although data are inconsistent. This study investigated growth parameters in a paediatric cohort with a high prevalence of H. pylori and helminth infection. METHODS: A cross-sectional study of African refugee children (<16 years) recruited at their initial health assessment following resettlement in Australia. Detailed demographic, infection and anthropometric data were obtained. H. pylori infection was diagnosed by monoclonal faecal antigen enzyme immunoassay testing (MFAT). Growth restriction was defined as children with any anthropometric measures below the fifth centile for age and gender. RESULTS: H. pylori infection was detected in 149/182 (81.9%). Children with H. pylori infection were older (mean 8.5 years, standard deviation (SD) 4.2 years vs. 5.8 years, SD 4.5 years, p < 0.001). No gender differences were observed. After adjustment for age, H. pylori did not adversely affect body mass index or other anthropometric measurements. Helminth infections were common (41.8%) but not associated with reduced growth or with H. pylori infection. CONCLUSION: H. pylori and helminth infections are prevalent in African refugee children but neither is associated with growth restriction. Longitudinal growth velocity studies are necessary to identify any long-term consequences of H. pylori on childhood growth.

Clinical evaluation for morbidity associated with soil-transmitted helminth infection in school-age children on Pemba Island, Tanzania.

BACKGROUND: More than 1.5 billion people are infected with soil-transmitted helminths (Ascaris lumbricoides, hookworm, Strongyloides stercoralis, and Trichuris trichiura), causing an estimated global burden in excess of 3 million disability-adjusted life years. However, the relationship between soil-transmitted helminth infection, adverse health consequences, and beneficial effects of deworming are not well understood. METHODOLOGY: We pursued a detailed longitudinal clinical evaluation of school-age children to evaluate morbidity associated with soil-transmitted helminth infection and responses to treatment. This exploratory study was embedded into a randomized controlled trial. Overall, 434 children, aged 7-14 years, underwent a detailed medical history, physical examination, stool microscopy for soil-transmitted helminths, and hemoglobin (Hb) measurement at baseline. Medical history and stool examination were repeated at 3 and 18 weeks posttreatment. Additionally, Hb measurement was performed at the 18-week treatment follow-up. Logistic regression was employed to assess clinical factors associated with soil-transmitted helminth infection at baseline, and longitudinal data analysis to examine change in health outcomes following treatment over time. PRINCIPAL FINDINGS: All enrolled children were infected with T. trichiura, and randomized into four different treatment interventions. None of the medical history, physical examination, and laboratory (i.e., Hb) findings were associated with A. lumbricoides, hookworm, or S. stercoralis infection at baseline. A composite of physical exam findings for anemia, including pallor of the conjunctiva, nail beds, and palmar creases predicted lower Hb values (-3.8 g/dl, 95% confidence interval (CI): -6.9, -0.6 g/dl). When examining longitudinal trends, we did not find improvements to Hb or face Wong-Baker Likert scale among children with soil-transmitted helminth infection compared to those without infection, although there was a slight trend toward improving Hb values after treating hookworm infection. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates the challenges of measuring morbidity in the context of soil-transmitted helminth infection and treatment, thus confirming the mainly subtle morbidity effects of infection.

Anaemia in pregnancy.

BACKGROUND: Anaemia in pregnancy is a common medical condition managed by general practitioners (GPs) in Australia. OBJECTIVE: The aim of this article is to raise awareness of anaemia that occurs in pregnancy, understand its increasing complexities with an expanding migrant population, identify at-risk groups and promote appropriate management. DISCUSSION: With anaemia reportedly occurring in 25% of women in pregnancy and GPs managing the majority of preconception and early pregnancy care, it is important to have a sound understanding of the aetiology, risks and management options. While iron deficiency anaemia is most commonly seen, a more complex understanding in regard to other causes and haemoglobinopathy screening is required.

Helminth extracellular vesicles in host-parasite interactions.

Extracellular vesicles (EVs) have been characterized from many species of parasitic helminths, and recent experimental evidence supports important functions for their cargo in host-parasite relationships as immunomodulatory mediators. Here we summarize available data on the effects of parasite-derived EVs, including their protein and/or small RNA contents, on their hosts.

Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma.

During helminth infection and allergic asthma, naive CD4+ T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo.

Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm.

The three main soil-transmitted helminth infections, ascariasis, trichuriasis, and hookworm, are common clinical disorders in man. The gastrointestinal tract of a child living in poverty in a less developed country is likely to be parasitised with at least one, and in many cases all three soil-transmitted helminths, with resultant impairments in physical, intellectual, and cognitive development. The benzimidazole anthelmintics, mebendazole and albendazole, are commonly used to remove these infections. The use of these drugs is not limited to treatment of symptomatic soil-transmitted helminth infections, but also for large-scale prevention of morbidity in children living in endemic areas. As a result of data showing improvements in child health and education after deworming, and the burden of disease attributed to soil-transmitted helminths, the worldwide community is awakening to the importance of these infections. Concerns about the sustainability of periodic deworming with benzimidazole anthelmintics and the emergence of resistance have prompted efforts to develop and test new control tools.

Measuring the Effect of Soil-Transmitted Helminth Infections on Cognitive Function in Children: Systematic Review and Critical Appraisal of Evidence.

Recently the role of soil-transmitted helminth (STH) infections in children's cognitive developmental impairment has been under scrutiny. We conducted a systematic review of the evidence for associations between STH infections and cognitive function of children using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. We aimed to identify the domains of cognitive function in three age strata (<24months, 24-59months and ≥60months) and critically appraise the general design protocol of the studies, with a focus on the cognitive function measurement tools used. A total of 42 papers fulfilled the inclusion criteria, including 10 studies from a recent Cochrane review. Our findings demonstrate variation in tested domains, lack of consistency in the use of measurement tools and analysis of results. Cognitive function measures in children aged under 59months have been mainly limited to domains of gross motor, fine motor and language skills, whereas in children aged 60months and above most studies tested domains such as memory and processing speed. Even within the same age group the results on the association between STH infections and measures of cognitive development were often conflicting. The current study highlights the need for methodological consensus in the use of measurement tools and data analysis protocols if the effect of STH infections on cognitive function domains in children is to be correctly established. This will be an imperative next step to generate conclusive evidence of the role of STH infections in cognitive development in children.

A Double-Blind Randomized Controlled Trial of Maternal Postpartum Deworming to Improve Infant Weight Gain in the Peruvian Amazon.

BACKGROUND: Nutritional interventions targeting the critical growth and development period before two years of age can have the greatest impact on health trajectories over the life course. Compelling evidence has demonstrated that interventions investing in maternal health in the first 1000 days of life are beneficial for both mothers and their children. One such potential intervention is deworming integrated into maternal postpartum care in areas where soil-transmitted helminth (STH) infections are endemic. METHODOLOGY/PRINCIPAL FINDINGS: From February to August 2014, 1010 mother-infant pairs were recruited into a trial aimed at assessing the effectiveness of maternal postpartum deworming on infant and maternal health outcomes. Following delivery, mothers were randomly assigned to receive either single-dose 400 mg albendazole or placebo. Participants were followed-up at 1 and 6 months postpartum. There was no statistically significant difference in mean weight gain between infants in the experimental and control groups (mean difference: -0.02; 95% CI: -0.1, 0.08) at 6 months of age. Further, deworming had no effect on measured infant morbidity indicators. However, ad hoc analyses restricted to mothers who tested positive for STHs at baseline suggest that infants of mothers in the experimental group had greater mean length gain in cm (mean difference: 0.8; 95% CI: 0.1, 1.4) and length-for-age z-score (mean difference: 0.5; 95% CI: 0.2, 0.8) at 6 months of age. CONCLUSIONS/SIGNIFICANCE: In a study population composed of both STH-infected and uninfected mothers, maternal postpartum deworming was insufficient to impact infant growth and morbidity indicators up to 6 months postpartum. Among STH-infected mothers, however, important improvements in infant length gain and length-for-age were observed. The benefits of maternal postpartum deworming should be further investigated in study populations having higher overall prevalences and intensities of STH infections and, in particular, where whipworm and hookworm infections are of public health concern. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01748929).

Intestinal parasites, growth and physical fitness of schoolchildren in poor neighbourhoods of Port Elizabeth, South Africa: a cross-sectional survey.

BACKGROUND: As traditional lifestyle and diets change with social and economic development, disadvantaged communities in low- and middle-income countries increasingly face a double burden of communicable and non-communicable diseases. We studied the relationship between physical fitness and infections with soil-transmitted helminths (STHs), intestinal protozoa and Helicobacter pylori among schoolchildren in Port Elizabeth, South Africa. METHODS: We conducted a cross-sectional survey among 1009 children, aged 9 to 12 years, from eight primary schools in socioeconomically disadvantaged neighbourhoods of Port Elizabeth. Physical fitness was determined using field-deployable tests of the Eurofit fitness test battery. Stool samples were analysed with the Kato-Katz thick smear technique to diagnose STHs and with rapid diagnostic tests (RDTs) to detect intestinal protozoa and H. pylori infections. Haemoglobin (Hb) levels were assessed and anthropometric indicators determined. RESULTS: Complete data were available for 934 children (92 %). In two schools, high STH prevalences were found (Ascaris lumbricoides 60 and 72 %; Trichuris trichiura 65 % each). For boys and girls co-infected with A. lumbricoides and T. trichiura (n = 155) the maximal oxygen uptake (VO2 max) was estimated to be 50.1 and 47.2 ml kg(-1) min(-1), compared to 51.5 and 47.4 ml kg(-1) min(-1) for their non-infected peers (n = 278), respectively. On average, children without helminth infections had greater body mass (P = 0.011), height (P = 0.009) and a higher body mass index (P = 0.024) and were less often stunted (P = 0.006), but not significantly less wasted compared to their peers with a single or dual species infection. Among 9-year-old boys, a negative correlation between helminth infections and VO2 max, grip strength and standing broad jump distance was observed (P = 0.038). The overall mean Hb level was 122.2 g l(-1). In the two schools with the highest prevalence of STHs the Hb means were 119.7 and 120.5 g l(-1), respectively. CONCLUSIONS: Intestinal parasite infections appear to have a small but significant negative effect on the physical fitness of infected children, as expressed by their maximal oxygen uptake. We observed a clear impact on anthropometric indicators.

Impact of parasitic infections and dietary intake on child growth in the schistosomiasis-endemic Dongting Lake Region, China.

The simultaneous impacts of parasitic infections and dietary intake on growth patterns were investigated for 427 children aged 10-13 years in the schistosomiasis-endemic Dongting Lake region of China. Height, weight, mid-upper arm circumference, and skinfold thicknesses (triceps, biceps, and subscapular) were measured, and eggs of Schistosoma japonicum, Ascaris lumbricoides, Trichuris trichiura, and Fasciolopsis buski in the collected stool samples of each subject were detected by Kato-Katz thick smear technique. Long-term dietary intake of each subject was assessed with a semiquantitative food frequency questionnaire. The results demonstrate that the study children were retarded in growth compared with the standards of Chinese rural children; among them, the girls were more frequently infected for S. japonicum and had lower intakes of protein and energy. Reduced height, weight, and mid-upper arm circumference were noted in children infected with S. japonicum, most severely in the girls with the least energy and protein intakes. Multiple stepwise regression analysis indicated that growth retardation was significantly and substantially associated with S. japonicum infection and lack of protein-energy intakes. For child health programs, regular schistosomiasis screening and treatment in schoolchildren needs to be complemented by health and nutrition education for both children and parents. Also, special attention should be paid to educating parents about the needs of girls.

Helminth infection and cognitive impairment among Filipino children.

The objective of this study was to examine the independent effect of infection with each of four helminths (Ascaris lumbricoides, Schistosoma japonicum, Necator americanus, and Trichuris trichiura) on cognitive function after adjusting for the potential confounders nutritional status, socioeconomic status (SES), hemoglobin, sex, and the presence of other helminthes. This cross-sectional study was carried out in a rural village in Leyte, The Philippines in 319 children 7-18 years old. Three stools were collected and read in duplicate by the Kato Katz method. Infection intensity was defined by World Health Organization criteria. Cognitive tests were culturally adapted and translated. Learning and memory cognitive domains were each defined by three subscales of the Wide Range Assessment of Memory and Learning, which had an inter-rater reliability >/= 0.92 and test-retest reliabilities ranging from 0.61 to 0.89. A household SES questionnaire was administered. A logistic regression model was used to quantify the association between performance in different cognitive domains (learning, memory, verbal fluency, and the Philippine Non-Verbal Intelligence Test) and helminth infections. After adjusting for age, sex, nutritional status, hemoglobin, and SES, S. japonicum infection was associated with poor performance on tests of learning (odds ratio [OR] = 3.04, 95% confidence interval [CI] = 1.1-6.9), A. lumbricoides infection was associated with poor performance on tests of memory (OR = 2.2, 95% CI = 1.04-4.7), and T. trichiura infection was associated with poor performance on tests of verbal fluency (OR = 4.5, 95% CI = 1.04-30). Helminth infection was associated with lower performance in three of the four cognitive domains examined in this study. These relationships remained after rigorous control for other helminths and important confounding covariates.