Identification of a major causative agent of human cercarial dermatitis, Trichobilharzia franki (Muller and Kimmig 1994), in southern England and its evolutionary relationships with other European populations.

Background Trichobilharzia is the most species rich and widely distributed genus of schistosomes and is known throughout Europe and North America as an agent of human cercarial dermatitis. The disease is caused by an acute allergic reaction in the skin that develops as a consequence of repeated contact with water containing schistosomatid cercariae. However, despite historical outbreaks of the disease, there are no published records of accurately identified Trichobilharzia species from the UK. Methods Two hundred Radix auricularia (L.) were sampled from a recreational fishing lake in Hampshire and emerging schistosomatid cercariae were collected for microscopy and DNA extraction. General morphological description of the cercariae was performed, alongside sequencing and phylogenetic analysis of the 28S ribosomal DNA for accurate species identification as well as comparisons of ITS1 in order to identify evolutionary affinities with other European populations. All molecular comparisons were performed using published sequences. Results The phylogenetic analysis of 28S sequences identified the cercariae as Trichobilharzia franki. Two unique British ITS1 haplotypes were identified which were most closely related to haplotypes of T. franki populations from France. Haplotype network analysis indicated the mixing of T. franki populations throughout Europe. It is suggested that parasite distribution is the probable result of the movement of migratory waterfowl. Conclusions This is the first accurate record of T. franki in the UK. The movement of T. franki with waterfowl could pose a considerable human health risk, as in mainland Europe, and signifies T. franki-associated human cercarial dermatitis as a re-emerging disease in the UK

Intestinal inflammation and increased intestinal permeability in Plasmodium chabaudi AS infected mice

Background: Gastrointestinal symptoms are commonly associated with acute Plasmodium spp infection. Malaria-associated enteritis may provide an opportunity for enteric pathogens to breach the intestinal mucosa, resulting in life-threatening systemic infections. Methods: To investigate whether intestinal pathology also occurs during infection with a murine model of mild and resolving malaria, C57BL/6J mice were inoculated with recently mosquito-transmitted Plasmodium chabaudi AS. At schizogony, intestinal tissues were collected for quantification and localisation of immune mediators and malaria parasites, by PCR and immunohistochemistry. Inflammatory proteins were measured in plasma and faeces and intestinal permeability was assessed by FITC-dextran translocation after oral administration. Results: Parasitaemia peaked at approx. 1.5% at day 9 and resolved by day 14, with mice experiencing significant and transient anaemia but no weight loss. Plasma IFNγ, TNFα and IL10 were significantly elevated during peak infection and quantitative RT-PCR of the intestine revealed a significant increase in transcripts for ifng and cxcl10. Histological analysis revealed parasites within blood vessels of both the submucosa and intestinal villi and evidence of mild crypt hyperplasia. In faeces, concentrations of the inflammatory marker lactoferrin were significantly raised on days 9 and 11 and FITC-dextran was detected in plasma on days 7 to 14. At day 11, plasma FITC-dextran concentration was significantly positively correlated with peripheral parasitemia and faecal lactoferrin concentration. Conclusions: In summary, using a relevant, attenuated model of malaria, we have found that acute infection is associated with intestinal inflammation and increased intestinal permeability. This model can now be used to explore the mechanisms of parasite-induced intestinal inflammation and to assess the impact of increased intestinal permeability on translocation of enteropathogens

miR-22 Forms a Regulatory Loop in PTEN/AKT Pathway and Modulates Signaling Kinetics

Background: The tumor suppressor PTEN (phosphatase and tensin homolog) is a lipid phosphatase that converts PIP3 into PIP2 and downregulates the kinase AKT and its proliferative and anti-apoptotic activities. The FoxO transcription factors are PTEN downstream effectors whose activity is negatively regulated by AKT-mediated phosphorylation. PTEN activity is frequently lost in many types of cancer, leading to increased cell survival and cell cycle progression. Principal Findings: Here we characterize the widely expressed miR-22 and report that miR-22 is a novel regulatory molecule in the PTEN/AKT pathway. miR-22 downregulates PTEN levels acting directly through a specific site on PTEN 39UTR. Interestingly, miR-22 itself is upregulated by AKT, suggesting that miR-22 forms a feed-forward circuit in this pathway. Timeresolved live imaging of AKT-dependent FoxO1 phosphorylation revealed that miR-22 accelerated AKT activity upon growth factor stimulation, and attenuated its down regulation by serum withdrawal. Conclusions: Our results suggest that miR-22 acts to fine-tune the dynamics of PTEN/AKT/FoxO1 pathway

Anti-Neuroinflammatory effects of the extract of Achillea fragrantissima

<p>Abstract</p> <p>Background</p> <p>The neuroinflammatory process plays a central role in the initiation and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, and involves the activation of brain microglial cells. During the neuroinflammatory process, microglial cells release proinflammatory mediators such as cytokines, matrix metalloproteinases (MMP), Reactive oxygen species (ROS) and nitric oxide (NO). In the present study, extracts from 66 different desert plants were tested for their effect on lipopolysaccharide (LPS) - induced production of NO by primary microglial cells. The extract of <it>Achillea fragrantissima </it>(<it>Af</it>)<it/>, which is a desert plant that has been used for many years in traditional medicine for the treatment of various diseases, was the most efficient extract, and was further studied for additional anti-neuroinflammatory effects in these cells.</p> <p>Methods</p> <p>In the present study, the ethanolic extract prepared from <it>Af </it>was tested for its anti-inflammatory effects on lipopolysaccharide (LPS)-activated primary cultures of brain microglial cells. The levels of the proinflammatory cytokines interleukin1β (IL-1β) and tumor necrosis factor-α (TNFα) secreted by the cells were determined by reverse transcriptase-PCR and Enzyme-linked immunosorbent assay (ELISA), respectively. NO levels secreted by the activate cells were measured using Griess reagent, ROS levels were measured by 2'7'-dichlorofluorescein diacetate (DCF-DA), MMP-9 activity was measured using gel zymography, and the protein levels of the proinflammatory enzymes cyclooxygenase-2 (COX-2) and induced nitric oxide synthase (iNOS) were measured by Western blot analysis. Cell viability was assessed using Lactate dehydrogenase (LDH) activity in the media conditioned by the cells or by the crystal violet cell staining.</p> <p>Results</p> <p>We have found that out of the 66 desert plants tested, the extract of <it>Af </it>was the most efficient extract and inhibited ~70% of the NO produced by the LPS-activated microglial cells, without affecting cell viability. In addition, this extract inhibited the LPS - elicited expression of the proinflammatory mediators IL-1β, TNFα, MMP-9, COX-2 and iNOS in these cells.</p> <p>Conclusions</p> <p>Thus, phytochemicals present in the <it>Af </it>extract could be beneficial in preventing/treating neurodegenerative diseases in which neuroinflammation is part of the pathophysiology.</p

Radiogenomic Mapping of Edema/Cellular Invasion MRI-Phenotypes in Glioblastoma Multiforme

Despite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM.Based on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution.The top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (P<0.001). High POSTN and low miR-219 expression were significantly associated with the mesenchymal GBM subtype (P<0.0001).Here, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM

Unravelling the riddle of Radix: DNA barcoding for species identification of freshwater snail intermediate hosts of zoonotic digeneans and estimating their inter-population evolutionary relationships

Radix spp. are intermediate host snails for digenean parasites of medical and veterinary importance. Within this genus, species differentiation using shell and internal organ morphology can result in erroneous species identification, causing problems when trying to understand the population biology of Radix. In the present study, DNA barcoding, using cox1 and ITS2 sequences, identified populations of Radix auricularia and Radix balthica from specimens originally morphologically identified as Radix peregra from the UK. Assessment of cox1 and ITS2 as species identification markers showed that, although both markers differentiated species, cox1 possessed greater molecular diversity and higher phylogenetic resolution. Cox1 also proved useful for gaining insights into the evolutionary relationships of Radix species populations. Phylogenetic analysis and haplotype networks of cox1 indicated that R. auricularia appeared to have invaded the UK several times; some haplotypes forming a distinct UK specific clade, whilst others are more akin to those found on mainland Europe. This was in contrast to relationships between R. balthica populations, which had low molecular diversity and no distinct UK specific haplotypes, suggesting recent and multiple invasions from mainland Europe. Molecular techniques therefore appear to be crucial for distinguishing Radix spp., particularly using cox1. This barcoding marker also enables the population biology of Radix spp. to be explored, and is invaluable for monitoring the epidemiology of fluke diseases especially in the light of emerging diseases and food security

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial.

Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength. INTRODUCTION: To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength. METHODS: In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated. RESULTS: Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p &lt; 0.01) and QCT (5.7%, p &lt; 0.0001). Between-treatment differences were significant for trabecular spine (p = 0.0017) [non-parametric test], trabecular trochanter (10.7%, p &lt; 0.0001), total hip (10.8%, p &lt; 0.0001), and compressive strength indices at femoral neck (8.6%, p = 0.0001), and trochanter (14.1%, p &lt; 0.0001). CONCLUSIONS: Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength