Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

<p>Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.</p> <p>Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.</p> <p>Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.</p&gt

Uneven focal shoe deterioration in Tourette syndrome.

A 31-year-old single man (AB) sought neuropsychiatric consultation for treatment-resistant motor and vocal tics. He described himself expressing a total of 24 different tics, mainly facial twitches (eye blinking, raising eyebrows, mouth opening, lips licking, stereotyped grimacing) and inappropriate utterances (grunting, throat clearing, sniffing), since the age of 7. There appeared to be no family history of tic disorder. He reported occasional utterance of swear words in contextually inappropriate situations (coprolalia), and the urge to copy other people’s movements (echopraxia). Other tic-associated symptoms included self-injurious behaviours and forced touching of objects. A.B. met both DSM-IV-tr and ICD-10 criteria for Tourette syndrome, and also DSM-IV-tr criteria for attention deficit hyperactivity disorder (combined type) in childhood

Living and Dying at the Portus Romae

This paper presents the first results of research into plant, animal, and human remains from Portus, the maritime port of Imperial Rome, in order to examine the diet and geographical origins of its inhabitants between the second and sixth century AD. Comparisons with evidence from the excavation and ceramic analysis show clear changes throughout the period, with shifts in diet and patterns of foods import that can be related to the commercial and political changes following the breakdown of Roman of the Mediterranean

Infected erythrocyte-derived extracellular vesicles alter vascular function via regulatory Ago2-miRNA complexes in malaria

Malaria remains one of the greatest public health challenges worldwide, particularly in sub-Saharan Africa. The clinical outcome of individuals infected with Plasmodium falciparum parasites depends on many factors including host systemic inflammatory responses, parasite sequestration in tissues and vascular dysfunction. Production of pro-inflammatory cytokines and chemokines promotes endothelial activation as well as recruitment and infiltration of inflammatory cells, which in turn triggers further endothelial cell activation and parasite sequestration. Inflammatory responses are triggered in part by bioactive parasite products such as hemozoin and infected red blood cell-derived extracellular vesicles (iRBC-derived EVs). Here we demonstrate that such EVs contain functional miRNA-Argonaute 2 complexes that are derived from the host RBC. Moreover, we show that EVs are efficiently internalized by endothelial cells, where the miRNA-Argonaute 2 complexes modulate target gene expression and barrier properties. Altogether, these findings provide a mechanistic link between EVs and vascular dysfunction during malaria infection

Strong but opposing effects of associational resistance and susceptibility on defense phenotype in an African savanna plant

The susceptibility of plants to herbivores can be strongly influenced by the identity, morphology and palatability of neighboring plants. While the defensive traits of neighbors often determine the mechanism and strength of associational resistance and susceptibility, the effect of neighbors on plant defense phenotype remains poorly understood. We used field surveys and a prickle-removal experiment in a semi-arid Kenyan savanna to evaluate the efficacy of physical defenses against large mammalian herbivores in a common understory plant, Solanum campylacanthum. We then quantified the respective effects of spinescent Acacia trees and short-statured grasses on browsing damage and prickle density in S. campylacanthum. We paired measurements of prickle density beneath and outside tree canopies with long-term herbivore-exclusion experiments to evaluate whether associational resistance reduced defense investment by decreasing browsing damage. Likewise, we compared defense phenotype within and outside pre-existing and experimentally created clearings to determine whether grass neighbors increased defense investment via associational susceptibility. Removing prickles increased the frequency of browsing by ~25%, and surveys of herbivory damage on defended leaves suggested that herbivores tended to avoid prickles. As predicted, associational resistance and susceptibility had opposing effects on plant phenotype: individuals growing beneath Acacia canopies (or, analogously, within large-herbivore exclosures) had a significantly lower proportion of their leaves browsed and produced ~ 70–80% fewer prickles than those outside refuges, whereas plants in grass-dominated clearings were more heavily browsed and produced nearly twice as many prickles as plants outside clearings. Our results demonstrate that associational resistance and susceptibility have strong, but opposing, effects on plant defense phenotype, and that variable herbivore damage is a major source of intraspecific variation in defense phenotype in this system

The potential health impact of restricting less-healthy food and beverage advertising on UK television between 05.30 and 21.00 hours: A modelling study

BACKGROUND: Restrictions on the advertising of less-healthy foods and beverages is seen as one measure to tackle childhood obesity and is under active consideration by the UK government. Whilst evidence increasingly links this advertising to excess calorie intake, understanding of the potential impact of advertising restrictions on population health is limited. METHODS AND FINDINGS: We used a proportional multi-state life table model to estimate the health impact of prohibiting the advertising of food and beverages high in fat, sugar, and salt (HFSS) from 05.30 hours to 21.00 hours (5:30 AM to 9:00 PM) on television in the UK. We used the following data to parameterise the model: children's exposure to HFSS advertising from AC Nielsen and Broadcasters' Audience Research Board (2015); effect of less-healthy food advertising on acute caloric intake in children from a published meta-analysis; population numbers and all-cause mortality rates from the Human Mortality Database for the UK (2015); body mass index distribution from the Health Survey for England (2016); disability weights for estimating disability-adjusted life years (DALYs) from the Global Burden of Disease Study; and healthcare costs from NHS England programme budgeting data. The main outcome measures were change in the percentage of the children (aged 5-17 years) with obesity defined using the International Obesity Task Force cut-points, and change in health status (DALYs). Monte Carlo analyses was used to estimate 95% uncertainty intervals (UIs). We estimate that if all HFSS advertising between 05.30 hours and 21.00 hours was withdrawn, UK children (n = 13,729,000), would see on average 1.5 fewer HFSS adverts per day and decrease caloric intake by 9.1 kcal (95% UI 0.5-17.7 kcal), which would reduce the number of children (aged 5-17 years) with obesity by 4.6% (95% UI 1.4%-9.5%) and with overweight (including obesity) by 3.6% (95% UI 1.1%-7.4%) This is equivalent to 40,000 (95% UI 12,000-81,000) fewer UK children with obesity, and 120,000 (95% UI 34,000-240,000) fewer with overweight. For children alive in 2015 (n = 13,729,000), this would avert 240,000 (95% UI 65,000-530,000) DALYs across their lifetime (i.e., followed from 2015 through to death), and result in a health-related net monetary benefit of £7.4 billion (95% UI £2.0 billion-£16 billion) to society. Under a scenario where all HFSS advertising is displaced to after 21.00 hours, rather than withdrawn, we estimate that the benefits would be reduced by around two-thirds. This is a modelling study and subject to uncertainty; we cannot fully and accurately account for all of the factors that would affect the impact of this policy if implemented. Whilst randomised trials show that children exposed to less-healthy food advertising consume more calories, there is uncertainty about the nature of the dose-response relationship between HFSS advertising and calorie intake. CONCLUSIONS: Our results show that HFSS television advertising restrictions between 05.30 hours and 21.00 hours in the UK could make a meaningful contribution to reducing childhood obesity. We estimate that the impact on childhood obesity of this policy may be reduced by around two-thirds if adverts are displaced to after 21.00 hours rather than being withdrawn

Impact of fractional excretion of sodium on a single morning void urine collection as an estimate of 24-hour urine sodium.

The standard for assessing dietary sodium intake is to measure 24-hour urine sodium. On average, 93% of daily sodium intake is excreted over 24-hours. Expense and difficulties in obtaining complete 24-hour collections have led to the measurement of sodium concentration in spot and single-void urine samples, using predictive equations to estimate 24-hour urine sodium. Although multiple predictive equations have been developed, in addition to having an average bias, all the equations overestimate 24-hour sodium at lower levels of 24-hour sodium and underestimate 24-hour urine sodium at higher levels of 24-hour sodium. One of the least biased estimating equations is the INTERSALT equation, which incorporates a spot urine creatinine concentration. The authors hypothesized that differential fractional excretion of sodium (FeNa)(derived from a morning void collection) relative to creatinine would impact on the accuracy of the INTERSALT equation in estimating 24-hour urine sodium. In a prospective study of 139 adults aged 65 years and over, three sequential morning void and 24-hour urine samples were examined. There was a significant correlation between increasing FENa and the difference between estimated and measured 24-hours urine sodium (r = 0.358, P < .01). In the lowest quartile of FENa, the INTERSALT equation overestimated 24-hour urine sodium, but underestimated 24-hour urine sodium with greater magnitude in each of the subsequent quartiles of FENa. Differential excretion of sodium relative to creatinine, potentially impacted by renal blood flow and hydration, among other factors, affected the accuracy of the INTERSALT equation. Additional research may refine the INTERSALT and other predictive equations to increase their accuracy

miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. © 2013 Lino Cardenas et al

Effectiveness of Mechanisms and Models of Coordination between Organizations, Agencies and Bodies Providing or Financing Health Services in Humanitarian Crises: A Systematic Review.

BACKGROUND: Effective coordination between organizations, agencies and bodies providing or financing health services in humanitarian crises is required to ensure efficiency of services, avoid duplication, and improve equity. The objective of this review was to assess how, during and after humanitarian crises, different mechanisms and models of coordination between organizations, agencies and bodies providing or financing health services compare in terms of access to health services and health outcomes. METHODS: We registered a protocol for this review in PROSPERO International prospective register of systematic reviews under number PROSPERO2014:CRD42014009267. Eligible studies included randomized and nonrandomized designs, process evaluations and qualitative methods. We electronically searched Medline, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and the WHO Global Health Library and websites of relevant organizations. We followed standard systematic review methodology for the selection, data abstraction, and risk of bias assessment. We assessed the quality of evidence using the GRADE approach. RESULTS: Of 14,309 identified citations from databases and organizations' websites, we identified four eligible studies. Two studies used mixed-methods, one used quantitative methods, and one used qualitative methods. The available evidence suggests that information coordination between bodies providing health services in humanitarian crises settings may be effective in improving health systems inputs. There is additional evidence suggesting that management/directive coordination such as the cluster model may improve health system inputs in addition to access to health services. None of the included studies assessed coordination through common representation and framework coordination. The evidence was judged to be of very low quality. CONCLUSION: This systematic review provides evidence of possible effectiveness of information coordination and management/directive coordination between organizations, agencies and bodies providing or financing health services in humanitarian crises. Our findings can inform the research agenda and highlight the need for improving conduct and reporting of research in this field