Celiac disease (CD) is an autoimmune disorder of the small intestine which is triggered by dietary gluten in genetically predisposed (HLA-DQ2/DQ8 positive) individuals. Only a fraction of HLA-DQ2/DQ8 positive individuals develop CD indicating that other factors have a role in the disorder. Several studies have addressed intestinal microbiota aberrancies in pediatric CD, but the results are inconsistent. Previously, we demonstrated that pediatric CD patients have lower duodenal expression of TLR2 and higher expression of TLR9 as compared to healthy controls (HC) indicating that microbiota may have a role in CD.
We used bacterial phylogenetic microarray to comprehensively profile the microbiota in duodenal biopsies of CD (n = 10) and HC (n = 9) children. The expression of selected mucosa-associated genes was assessed by qRT-PCR in CD and HC children and in treated CD adults (T-CD, n = 6) on gluten free diet.
The overall composition, diversity and the estimated microbe associated molecular pattern (MAMP) content of microbiota were comparable between CD and HC, but a sub-population profile comprising eight genus-like bacterial groups was found to differ significantly between HC and CD. In HC, increased TLR2 expression was positively correlated with the expression of tight junction protein ZO-1. In CD and T-CD, the expression of IL-10, IFN-g and CXCR6 were higher as co5mpared to HC.
The results suggest that microbiota and altered expression of mucosal receptors have a role in CD. In CD subjects, the increased expression of IL-10 and IFN-g may have partly resulted from the increased TLR9 expression and signaling.
Celiac disease (CD) is a common chronic immune-mediated, inflammatory disorder of the small intestine induced by intolerance to gluten-containing dietary products [1, 2]. When a CD patient consumes gluten, an inflammatory cascade occurs in the small intestinal mucosa, eventually resulting in an active disease that is characterized by villous atrophy, crypt hyperplasia and increased numbers of lymphocytes in the lamina propria [1, 3]. Untreated CD is manifested by gastrointestinal symptoms, malabsorption and even malnutrition [1, 3] and also by extra-intestinal symptoms such as dermititis herpetiformis (skin rash) in some individuals . Both genetic predisposition and environmental factors are considered to be involved in the development of CD . Individuals who carry the alleles human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 have an increased risk of developing the disease, but only less than one tenth of them eventually get CD, indicating that other genetic factors and/or environmental factors are also important in the pathogenesis . Recently, 13 new CD risk loci were identified, bringing the number of known CD loci to 40 and giving a refined picture of the genetic risk of CD . Most of these loci contain candidate genes of immunological function, but the pathways leading from genetic predisposition to an affected person are poorly understood [6, 7]. The intestinal microbiota is a major dictator of the antigen milieu of enterocytes, and it may have a role in the CD pathogenesis.
Gut colonization starts immediately after birth, and considerable microbiota maturation takes place during the first years of life followed by a gradual microbiota succession until young adulthood [8–10]. A balanced commensal microbiota contributes to the physiological development of the gut and the maturation of the immune system; thereby, alterations in the intestinal microbiota could play a role in the onset of different diseases, including CD [3, 11]. Increased bacterial diversity and changes in several bacterial groups in the microbiota of pediatric CD patients have been reported in several studies [12–16]. However, other recent studies have failed to show major microbiota differences between children with and without CD [17–19]. Two recent studies have addressed the microbiota in infants with a genetic predisposition to CD [4, 11]. Both of these reported the microbiota of predisposed infants to be different from that of non-predisposed, but while Sellitto et al. reported a reduction or lack of Bacteroides in predisposed infants , De Palma et al. found that Bacteroides fragilis and staphylococci were increased and bifidobacteria were reduced in genetically susceptible infants . Although the idea that the microbiota is involved in the etiology of CD has been addressed in numerous studies, the results on specific CD-associated microbiota changes remain inconclusive.
Recently, we demonstrated that pediatric CD patients have decreased duodenal expression of Toll-like receptor 2 (TLR2) and the negative regulator of Toll-receptor signaling (Tollip), and increased expression of TLR9 and interleukin 8 (IL-8), which is a marker of intestinal inflammation . TLRs are a family of pattern recognition receptors, which recognize conserved microbe-associated motifs such as lipopolysaccharides (LPS, ligand for TLR4), lipoproteins and lipoteichoeic acids (LTA, ligand for TLR2), flagellin (TLR5) and nucleic acid motifs (TLR3, 7 and 9). Intestinal epithelial homeostasis is dependent on the activation of TLRs at adequate levels in order to keep defense against microbes balanced and to avoid an excessive inflammatory response to gut commensals [20, 21]. Further, TLR signaling is known to affect epithelial barrier function by having a bearing on the expression of tight junction proteins, mucus protein mucin 2 and antimicrobial peptides such as RegIII-γ [20, 21]. Thus, our previous results suggested that microbiota may play a role in the etiology of CD, but we were unable to reveal aberrancies in the duodenal mucosal microbiota of pediatric CD by targeting selected bacterial groups by quantitative PCR (qPCR) .
The objectives of the present study were to comprehensively characterize the total duodenal mucosal microbiota and to re-evaluate the possible microbiota differences in pediatric CD patients and healthy controls by using a high-throughput bacterial phylogenetic microarray (HITChip). Further, the expression of nine mucosa-associated genes, IL-10, interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), a tight junction protein zonula occludens-1 (ZO-1), a gap junction protein connexin-43 (Cx43), a mucus protein mucin 2 (MUC2), an antimicrobial peptide RegIIIγ, a chemokine CXCL16 and its receptor CXCR6 were measured by using a quantitative reverse transcription-PCR (qRT-PCR).
Duodenal biopsy samples were collected from 20 Finnish children and 6 Finnish adults: 10 children with newly diagnosed CD (median age 9.5 ± 4.1 y; 3-14 y, 4 males and 6 females) before the implementation of gluten-free diet (GFD), 10 healthy control (HC) children (median age 8.5 ± 3.8 y; 4-16y, 4 males and 6 females) with gastrointestinal complaints or other reasons for esophagogastroduodenoscopy (abdominal pain - 4 patients, gastroesophageal reflux disease – 2 patients, growth retardation – 2 patients esophagitis -1 patient, achalasia – 1 patient) and 6 adults (median age 46 ± 11.4 y; 30-60 y) with CD who had been on a GFD at least for a year (treated CD, T-CD). All HC and T-CD subjects had both negative celiac serology and normal small intestinal mucosa (Marsh 0 lesions), while CD patients had both positive celiac serology markers (anti-tissue transglutaminase antibodies and/or anti-endomysium antibodies) and villous atrophy and crypt hyperplasia (Marsh III lesions) in duodenal biopsy. The study subjects were the same as in our previous study  and the same DNA and RNA preparations were used in this study. The DNA and RNA extraction and purification protocols were described in detail earlier .
Gene expression assays were performed using comparative Ct (threshold cycle)-method with ABI 7300 Real Time PCR System. (Applied Biosystems/Life Technologies Corporation, Carlsbad, CA). Taqman Gene Expression Assays (Applied Biosystems) used in analyses were: IL-10, assay ID: Hs00174086_m1; IFN-g, assay ID: Hs00174143_m1; TNF-α assay ID: Hs00174128; ZO-1, assay ID: Hs01551861_m1; Cx43, assay ID: Hs00748445_s1; MUC2, assay ID: Hs03005103_g1; RegIIIγ, assay ID: Hs01595405_m1; CXCL16, assay ID: Hs00222859_m1; CXCR6, assay ID: Hs01890898_s1. Gene expression assays were performed according to kit's protocol. Reactions were run in three replicates in a total volume of 20 μl or 50 μl with 25 ng of cDNA in each. Thermal cycler conditions used were 1) 50°C for 2 min, 2) 95°C for 10 min, 3) 95°C for 15 sec, 4) 60°C for 1 min. Steps 3 and 4 were repeated 40 times. Gene expression of 18S rRNA was used as an endogenous control (a house-keeping gene) to normalize the gene expression. Negative control and Universe Human Reference RNA (Agilent Technologies, Santa Clara, CA) as a control RNA were included in every PCR run. Results were analyzed with RQ-Study program (Applied Biosystems) to receive Ct values for all samples. The relative expression of genes was then calculated as described in detail previously .
The microbiota was analyzed with the bacterial phylogenetic microarray –the HITChip (Human Intestinal Tract Chip) [22–24]. This microarray consists of over 4 800 oligonucleotide probes targeting the V1 and V6 hypervariable regions of the 16S rRNA gene of 1038 intestinal phylotypes [22–24]. It allows a comprehensive and high-resolution analysis of the microbiota composition at different taxonomic levels. Genus-like level (L2) taxa correspond to bacteria having 90% or higher similarity in their 16S rRNA gene, whereas L1 taxa correspond to a phylum-like level .
The HITChip measurements were performed as previously described [22–24]. In brief, amplification of 16S rRNA gene was carried out from 100-200 ng of DNA with primer T7 prom-Bact-27 F and Bact-1369R , followed by in vitro transcription, dye labeling, fragmentation, and hybridization, as described earlier . The arrays were scanned with Agilent DNA Microarray Scanner G2505C (Agilent, USA) and the intensity values for each image were extracted from the generated images using Agilent Extraction Software, version 10.7.3.1. Normalization and quality control of HITChip array data were performed with scripts in R statistical software, as described earlier [22, 24, 26]. The technical replicates having a Pearson correlation over 0.94 were selected for further analysis and the replicates were averaged. The between sample normalization was carried out with min-max algorithm [27, 28]. Signal intensity threshold was applied to reduce experimental and possible cross-hybridization noise, as described previously .
The relative content of selected MAMPs was estimated from the HITChip profiles summarizing the abundance of Gram-positive, Gram–negative or flagellated genus-like bacterial groups. The abundance of Gram-positive bacteria is assumed to reflect the load of LTA, i.e. TLR2 ligands, the abundance of Gram-negative bacteria the load of LPS i.e. TLR4 ligands, and the abundance of flagellated bacteria the load of TLR5 ligands. The general GC% of the microbiome was estimated based on the genomic GC-content of representative species from each of the genus-like group (Additional file 1: Table S1), weighted by the relative abundance of each of these groups in the total microbiota. The GC% is taken to reflect the load of unmethylated CpG motifs, i.e. TLR9 ligands, as a high GC content of a bacterial genome correlates with a higher number of CpG motifs in the genome (Kant R, de Vos WM, Palva A, Satokari R, unpublished results) [29, 30].
The data analysis was performed in R version 2.15.1 (R Development CT 2012). The sum of signal intensities for probes targeting a genus-like group was used as a quantitative measure of the abundance of the group in a sample . When computing the signal at higher level taxa, the probe intensities were divided by the number of known target phylotypes per probe. The signal intensity above threshold was log10-transformed.
The diversity of the microbial profiles was computed by Simpson's reciprocal index of diversity (1/D) and Shannon indices on probe-level data [31, 32]. Principal component analysis (PCA) and Redundancy analysis (RDA) [33, 34] were computed using R packages 'stats' and 'vegan'. The significance of separation in RDA was assessed with a permutation test  using 50000 permutations.
Bacterial groups that are associated with the health status were selected with 9-fold cross-validation (CV). The data was split into 9 subsets (folds) of equal size with stratification such that both CD and HC samples were present in all folds. In the CV procedure, eight subsets were used for training, and one subset in turn was left out for testing. Within each CV fold, six random forests were learned to predict the study group using a set of bacteria, selected by: i) choosing the 2, 4, 6, 8, or 10 bacteria having smallest p-values from two-sample t-test carried out within the training set, or ii) selecting the bacterial groups with high mean decrease in gini score from random forest using all bacteria . The prediction error of the random forests was then estimated with the test data. The feature selection method with lowest prediction error rate from cross-validation (that is, 8 bacteria with smallest p-values) was then applied for the full data, and its prediction error was estimated with 9-fold cross validation. Significance of the prediction was tested with permutation test using 10,000 permutations.
Differentially present bacterial groups were analyzed with Student's t-test assuming two tailed distribution . False discovery rate (FDR) correction of p-values was carried out using Benjamini-Hochberg (BH) correction . The average relative abundance of each phylum- or genus-like group was estimated by first calculating the percentage of signal intensity within each sample, and then computing the average of percentage of signal intensities within CD and HC groups.
For relative gene expression, the normality of the data was tested by Shapiro-Wilk normality test function. When normality assumption applied, ANOVA and Tukey Honest Significant Differences post-hoc analysis was carried out. If the data residuals differed significantly from normality, Kruskal-Wallis and associated posthoc analysis were carried out . For all analyses, FDR corrected p-values below 0.05 were considered significant. The correlations between bacterial groups, gene expressions and MAMP content were estimated by Spearman coefficient, followed by FDR correction (BH) of p-value.
The study was accepted by the ethical committee of the Hospital District of Southwest Finland. Written informed consent was obtained from all of the study patients or their parents. Pediatric T-CD subjects could not be included as a control group in the study, because in Finland follow-up biopsies are not taken from children if celiac serology turns negative within two years after the implementation of GFD.
HITChip microbiota profiles were obtained from 10 CD subjects (4 males and 6 females) and 9 healthy controls (HC, median age 9 ± 4.1 years, 4 males and 5 females) (no significant difference in median age, one HC was not included due to a low reproducibility of HITChip profile, Additional file 2: Table S2).
At the bacterial phylum-like level, representatives from 13 groups were detected in the duodenal mucosa of the pediatric subjects (Table 1). The phylum-like level microbiota profiles were found to be individual-specific with large inter-individual variation (Figure 1). Proteobacteria, Bacilli and Bacteroidetes were found to be the major bacterial groups in the duodenal mucosa of both CD and HC (Figure 2). Proteobacteria and Bacilli constituted each approximately one third of the community while Bacteroidetes amounted to around 14% (Figure 2). There were no significant differences in the abundance of bacterial phylum-like groups between CD and HC. Similarly, the bacterial diversity was comparable between the HC and CD groups (Figure 3).
*Relative abundance of the total microbiota (mean ± standard deviation). No statistically significant differences in the abundance of individual genus-like bacterial groups between HC and CD.
cl cluster, uncult uncultured, Gram + Gram positive bacteria, Gram- Gram negative bacteria, high-GC% bacteria genomic GC% content is more than 58%, Y motile/flagellated, N non-motile/non-flagellated, Y/N motility variable (50% of the group were taken to be flagellated).
Composition of the duodenal mucosa-associated microbiota in healthy control (HC and celiac disease (CD) children. Relative proportions of bacterial phylum-like groups of the total microbiota are depicted for each individual (HC1-HC9 and CD1-CD10).
Relative proportion of phylum-like groups in the duodenal microbiota of celiac disease (CD, white columns) and healthy control children (HC, grey columns). Mean and standard error are shown for HC (n = 9) and CD (n = 10) groups.
Duodenal microbiota diversity in healthy control (HC, n = 9) and celiac disease (CD, n = 10) children. The dominant/common species richness and evenness was assessed by Simpson Reciprocal (1/D) and overall species richness and evenness was assessed by Shannon Indices. Boxplot shows 25th to 75th percentile, with a line at median.
Altogether 65 genus-like groups were detected in the duodenal biopsies (Table 1). HC and CD shared the same predominant genus-like groups, whose average proportion was above 5% of the total signal. The predominant groups were Sutterella wadsworthensis et rel., Streptococcus mitis et rel., Aquabacterium, Streptococcus bovis et rel., Streptococcus intermedius et rel., and Prevotella melaninogenica et rel. (Table 1). Among these, the most abundant bacterial groups in both HC and CD were Sutterella wadsworthensis et rel. and Streptococcus mitis et rel., both with an average abundance of 14 to 19% (Table 1). No single genus-like bacterial group abundance differed significantly between HC and CD (Table 1).
The general MAMP content was estimated based on the microbiota profiles (Table 1). No significant difference between the abundance of Gram-positive or Gram-negative bacteria carrying LTA or LPS respectively was found, nor in the abundance of potentially flagellated bacteria between HC and CD. Thus, the ligand load for TLR2, 4 and 5 seems comparable between HC and CD. In addition, the average GC% content of the total microbiota and the relative abundance of high-GC% bacteria (genomic GC% > 58%) were comparable between the groups suggesting a similar load of unmethylated CpG motifs, which are ligands for the TLR9.
In PCA and RDA plots, HC vs. CD subjects did not cluster separately, showing that the groups do not differ in terms of the total microbiota profile (Additional file 3: Figure S1, Additional file 4: Figure S2). Moreover, as already mentioned above, no single genus-like bacterial group's abundance differed significantly between HC and CD (Table 1).
Further analysis was performed with random forests using feature selection as preprocessing step, where the best method was chosen from six candidates using cross-validation. The aim was to identify a possible health status-related bacterial sub-population within the total microbiota. The feature selection method resulting in lowest cross-validated prediction error was to choose a set of eight genus-like bacteria having lowest p-values from t-test (Figure 4). Thus, although no single genus-like group individually differed significantly between HC and CD, a random forest learned with a profile of selected eight genus-like groups predicted the health status with error rate of 31.6%. This is significantly better than random guess, having a median error rate of 53%, and 95% confidence intervals of [32%, 74%].
Sub-profile of the duodenal microbiota separating celiac disease (CD) and healthy control (HC) children. A) Eight HITChip genus-like level bacterial groups selected with random forest and cross-validation showing higher abundance in either HC (5 groups) or CD (3 groups). The error rate of random forest is 31.6%, whereas 95% confidence intervals for random assignment are [32%, 74%]. B) The profile of eight bacterial groups separates healthy control children (HC) and celiac disease children (CD) in redundancy analysis (RDA). p-value obtained by permutation test (50000 permutations) is 0.050.
As can be seen from Table 1, P. melaninogenica et rel. has a relative abundance of 5.3% and 6.5% in HC and CD, respectively and it is among the predominant genus-like groups contributing to the separation between HC and CD. Also Haemophilus ssp. and Serratia ssp. had relatively higher abundance in CD, whereas the other five bacterial groups were higher in HC, see Table 1.
The gene expression levels of ZO-1, CXCL16, CXCR6, IL-10, IFN-γ, TNF-α, Cx43, MUC2, and RegIIIγ in duodenal biopsies were assessed by relative quantitative reverse transcription-PCR in the HC and CD children. Biopsies from six T-CD adults were included for comparison, because biopsies from T-CD children were not available (see ethical considerations above). The expression of ZO-1, CXCL16, CXCR6 could be assessed only from 8 HC and 9 CD subjects, because RNA of some of the samples did not suffice after the other qRT-PCR analysis (Figures 5 and 6).
The relative expression of zonula occludens 1 (ZO-1) (A) and the scatterplot of ZO-1 and TLR2 expressions (B) in duodenal biopsies. A) Expression of ZO-1 in duodenal biopsies of healthy control children (HC, n = 8), celiac disease children (CD, n = 9) and treated celiac disease adults (T-CD, n = 6). The relative gene expression of ZO-1 is significantly between CD and T-CD (*p < 0.05). Boxplot shows 25th to 75th percentile with a line at median and the whiskers represent interquartile range. Samples, which are outside 1.5 times the interquartile range above the upper quartile (3rd quartile) and below the lower quartile (1st quartile) are denoted by circles. B) The scatterplot of relative expression of ZO-1 and TLR2 in duodenal biopsies of HC. The relationship between ZO-1 and TLR2 expressions is estimated by linear regression, and indicated by dashed line. The effect of slope is significant (p = 0.02), having coefficient of determination (R2) of 0.63.
The relative expression of CXCL6 (A) and CXCR16 (B) in duodenal biopsies of healthy control children (HC, n = 8), celiac disease children (CD, n = 9) and treated celiac adults (T-CD, n = 6). Boxplot shows 25th to 75th percentile with a line at median and the whisker represents interquartile range. Samples, which are outside 1.5 times the interquartile range above the upper quartile (3rd quartile) and below the lower quartile (1st quartile) are denoted by circles. A) The difference in CXCR6 expression between HC and CD or T-CD is statistically significant (*p < 0.05). B) CXCL16 expression shows no significant differences between the groups.
The gene expression of ZO-1 was decreased in CD as compared to T-CD (Figure 5). The expression of CXCR6 was higher in CD and T-CD as compared to HC (Figure 6A). The expressions of IL-10 and IFN-γ were higher, whereas the ratio of IL-10 to IFN-γ was significantly reduced in both CD and T-CD as compared to HC (Figure 7). The gene expressions of TNF-α, Cx43, MUC2, RegIIIγ (Table A2), and CXCL16 (Figure 6B) were found to be comparable between the groups.
The relative expression of interleukin-10 (IL-10) (A), interferon gamma (IFNγ) (B) and IL-10 to IFNγ mRNA ratio (C) in duodenal biopsies of healthy control children (HC, n = 10), celiac disease children (CD, n = 10) and treated celiac adults (T-CD, n = 6). Boxplot shows 25th to 75th percentile with a line at median and the whisker represents interquartile range. Samples which are outside 1.5 times the interquartile range above the upper quartile (3rd quartile) and below the lower quartile (1st quartile) are denoted by circles. A) IL-10 expression is significantly different between HC and CD. B) IFNγ expression is significantly different between HC and CD or T-CD. C) The ratio of IL-10/IFNγ expression is significantly different between HC and CD or T-CD. The significance between study groups: *p < 0.05.
When correlating of TLR2 expression  with the expression of proteins related to the physical barrier function or the production of antimicrobial peptides (Cx43, ZO-1, MUC2 and RegIIIγ), the ZO-1 expression correlated positively with the TLR2 expression in the HC group (p = 0.03, rho = 0.88). The expression of Cx43 negatively correlated with the relative abundance of bacteria related to Solobacterium moorei (previously Bulleidia moorei) et rel. (p = 0.03, rho = -0.82). No other correlations were found between the relative abundance of genus-like groups or the estimated MAMP content of the microbiota and the gene expressions (data not shown).
Human small intestine, especially duodenum, is a distinctive environment for microbial life because of the excretion of digestive enzymes and bile, and it harbors a microbiota that is different from the one in the large intestine . The HITChip analysis showed that representatives of the genus Streptococcus constitute 29% and 32% of the total duodenal microbiota in HC and CD subjects, respectively, and that the signal obtained for all Bacilli (phylum-like group) predominantly resulted from streptococci. This is in line with the previous findings [39, 40]. In addition to Bacilli, Proteobacteria, Bacteroidetes and Clostridium cluster XIVa were found to be the most abundant phylum-like groups in the duodenum. These bacteria have previously been found to be dominant groups in the ileum, distal duodenum and proximal jejunum [17, 39, 41] and in the duodenum . Interestingly, within Proteobacteria a single most abundant genus-like group was found to be Sutterella wadsworthensis et rel. both in CD and HC subjects, which suggests that it belongs to the normal duodenal microbiota. Similarly, Mukhopadhya et al. detected S. wadsworthensis with an equally high frequency of 84 to 86% in the colonic biopsies of healthy adults (n = 64) or ulcerative colitis patients (n = 69), showing that the species belongs to the normal microbiota of intestinal mucosa and is unlikely to have a role in IBD . Genus Aquabacterium belonging to the Proteobacteria also had a relatively high abundance (~9.5%, prevalence 100% in both CD and HC) in the duodenum of both groups of children. Previously, Aquabacterium has been detected in human colonic mucosal biopsy , but to our knowledge, this is the first time that Aquabacterium has been described as an abundant inhabitant of the human small intestine.
In the PCA and RDA analysis, HC and CD subjects did not cluster separately. Furthermore, none of the 65 genus-like bacterial groups was found to be significantly different in abundance between HC and CD. Thus, the overall duodenal microbiota composition seems comparable between HC and CD, which is in line with the results obtained by Ou et al  and Nistal et al  using small intestinal biopsies. Moreover, the bacterial diversity was also found to be comparable between the study groups. Previously, bacterial diversity assessed by PCR-T/DGGE has been observed to be increased in children with CD [13, 16]. It is noteworthy that PCR-D/TGGE analysis detects only the most abundant bacteria and therefore may strongly underestimate microbiota diversity in complex communities. Our results from high-throughput microbiota profiling, like the results by Nistal et al , give a more in depth view of the duodenal microbiota regarding the bacterial groups inhabiting duodenal mucosa and the overall diversity. In addition, several studies have found differences in specific bacterial groups between HC and CD [12, 14, 15, 44]. The most consistent findings from these studies were that children with CD have increased counts of Bacteroides and reduced counts of bifidobacteria either in feces or duodenal epithelium [12, 14, 15] which were not found to differ between CD and HC in this study.
As the overall microbiota profile, diversity or individual genus-like groups did not show a significant difference between HC and CD, random forest was used to explore whether a sub-population bacterial profile could be associated with the health status. A profile of eight bacterial groups was found to distinguish HC from CD. The abundance of Prevotella melaninogenica, and the total abundance of Prevotella spp (Table 1) were found to be higher in CD, which is in line with the results of Ou et al. Haemophilus et rel. were also found to be enriched, although insignificantly as an individual bacterial group, in CD children by Nistal et al. . Serratia spp. was also found to be present in higher abundance in CD. The phylogenetic microarray targets mainly S. marcescens, which is considered as an opportunistic pathogen able to cause invasive infections (sepsis, meningitis, pneumonitis) in neonates [45, 46]. These bacteria may impair the intestinal integrity, but their possible role in CD remains to be elucidated.
In the distinctive profile detected by random forest, P. oralis, R. bromii, P. cinnamivorans, Proteus and C. stercorarium groups are increased in the HC group. R. bromii is of particular interest, because it acts as key species for fiber/resistant starch degradation in the intestine  feeding butyrate producing bacteria including P. cinnamivorans. Butyrate is a major source of energy to the enterocytes and acts as a regulator of gene expression, inflammation and differentiation in host cells . Previously, R. bromii has been detected at increased level in healthy subjects as compared to Crohn's disease patients , indicating its potential role for benefiting the gut mucosal homeostasis.
Finally, it should be taken into account that the highly individual-specific microbiota-profiles may have a strong impact on the results within small study groups. Moreover, children in the HC group had healthy duodenal mucosa, but had gastrointestinal complaints or other reasons for gastroscopy and the possibility of microbiota alterations in these children as compared to children devoid of any symptoms can´t be excluded. Therefore, the profile comprising eight genus-like bacterial groups, which showed significant difference between CD and HC should be verified in future studies.
Similar average proportion of Gram-positive and Gram-negative bacteria, which are the carriers of LTA and LPS, respectively, was found in CD and HC. Our previous findings from the same cohort showed that the expression of TLR2 is higher in HC . As the LTA content is comparable between HC and CD, the net signaling through TLR2 is presumably higher in HC. In vitro, TLR2 stimulation of intestinal epithelial cells (IECs) has been shown to increase Cx43 synthesis, the apical reorganization of ZO-1 and trans-epithelial resistance, which reflects the strength of tight junctions between IECs and barrier function [51–53]. Although no significant difference was found in the expression ZO-1 and Cx43 between HC and CD, the expression of ZO-1 was significantly lower in CD as compared to T-CD. Moreover, there was a significant positive correlation between the expressions of ZO-1 and TLR2 in HC further supporting earlier findings, which demonstrated more permeable epithelial barrier in CD as compared to HC due to the decreased expression of tight junction proteins . Negative correlation was found between the abundance of S. moorei et rel. and the expression of Cx43. Previously this bacterium has been associated with oral cavity diseases  and its possible down-regulatory effect of Cx43 may facilitate invasion and colonization. In CD, however, S. moorei et rel. seems to be irrelevant as it was found to be as abundantly present in HC and CD.
CXCL16 has been shown to function as a scavenger receptor in antigen-presenting cells where it mediates adhesion and phagocytosis of both Gram-positive and Gram-negative bacteria . In addition, it works as a chemokine for CXCR6-expressing cells such as natural killer T cells and T helper 1 (Th1) - polarized CD4 T cells . Since both microbiota alterations and Th1-polarized inflammation have been linked to the pathogenesis of celiac disease, we decided to evaluate the expression of both CXCL16 and its receptor CXCR6 in this study. We found that the expression of cytokine CXCL16 was found to be comparable in CD and HC and T-CD, whereas the expression of its receptor CXCR6 was higher in CD and T-CD as compared to HC. CXCL16 has dual functions as a transmembrane adhesion molecule and a soluble chemokine . Both the membrane-bound form of CXCL16 and its receptor CXCR6 have been found to be expressed not only by dendritic cells/macrophages and T cells respectively, but also by IECs [58–60]. Previously, increased intestinal CXCL16 expression has been observed in the colonic biopsies of Crohn´s disease patients due to immune cell infiltration . In this study, an increased expression of CXCR6 was not only observed in the inflamed mucosa of CD but also in T-CD without immune cell infiltration suggesting an altered expression in epithelial cells. However, increased expression of CXCR6 in mucosa associated immune cells cannot be excluded when studying whole biopsies with different cell types. Diegelmann et al observed that in vitro stimulation of CXCR6 activates several distinct signaling pathways in IECs and they suggested that the CXCL16-CXCR6 chemokine-receptor system contributes to the integrity of epithelium and the regulation of mucosal innate and adaptive immune systems . To our knowledge our data report for the first time an increased duodenal expression of CXCR6 in CD subjects in whom it may have an important role in the mucosal immunity.
The average genomic GC content (GC%) of the total microbiota and the proportion of high-GC% bacteria was found to be comparable between the HC and CD groups. High GC content of a bacterial genome correlates with a higher number of potentially immunostimulatory CpG motifs in the genome (Kant R, de Vos WM, Palva A, Satokari R, unpublished results) [29, 30] and thus, the GC% was taken to reflect the load of TLR9 ligands in the microbiota. Consequently, HC and CD are likely to harbor similar load of TLR9 ligands. Our previous results from the same cohort showed that the expression of TLR9 in duodenum is higher in CD . Thus, the signaling through TLR9 is presumably higher in CD as compared to HC due to the equally high load of TLR9 ligands and higher expression of TLR9. In immune cells, TLR9 stimulation is known to trigger Th1 type immune responses [61–63]. Further, a recent in vitro study demonstrated that apical TLR9 stimulation of IECs leads to an increased expression of IFN-γ and IL-10, but not TNF-α from peripheral blood mononuclear cells (PBMCs) on the basolateral side . In CD patients, increased mucosal expression of IL-10 and IFN-γ is well documented and has been associated with the activity of gliadin-reactive T-cells upon the gluten/gliadin stimulation either in vivo or in vitro[65–69]. We found that the expression of IL-10 and IFN-γ in the duodenal mucosa was increased not only in CD but also in T-CD with gluten-free diet, suggesting for an additional gluten/gliadin-independent route of stimulation. Similarly to previous studies [65, 68, 69], TNF-α expression was found to be unaffected in CD and T-CD as compared to HC. The ratio of IL-10 to IFN-γ transcripts was strongly reduced in both CD and T-CD as compared to HC suggesting that although IL-10 expression was also increased there is a significant inclination towards a Th1 response both in untreated and treated CD. Since both CD and T-CD had increased expression of TLR9 , we hypothesize that the increased TLR9 signaling in the small intestine may contribute to the persistent activation of Th1 (IFN-γ) signaling pathway markers in the small intestine found in CD children despite gluten-free diet treatment . Due to the limitations in studying whole biopsies with different cell types we cannot conclude which of the proposed signaling routes i.e. the direct TLR9 stimulation of immune cells or the stimulation of IECs with subsequent triggering of immune cells would possibly encompass more into the observed cytokine profile.
Our results suggest that intestinal microbiota and host-microbe cross-talk play a role in the CD. While the overall microbiota composition in the duodenal mucosa was comparable between the CD and healthy children, a sub-population profile comprising eight genus-like bacterial groups was found to differ significantly between the study groups. The sub-population of bacteria has potentially a specific role in e.g. maintaining gut homeostasis in the healthy individuals or in compromising the epithelial function in CD. Secondly, these and our previous results from the same cohort  suggest that altered expression of mucosal receptors and epithelial host-microbe cross-talk have a role in CD. We hypothesize that increased TLR9 signaling in the duodenum may contribute to the Th1 response (increased IFN-γ) found in the small intestinal mucosa of CD subjects even after the implementation of GFD.
Riikka Lankinen is acknowledged for technical assistance. The financial support from the Academy of Finland (grant nr. 138902), the Finnish Medical Foundation, the Paediatric Research Foundation, the Hospital District of Southwest Finland, the Finnish Coeliac Society, and the Center of Excellence in Microbial Food Safety (CoE-MiFoSa) research program of the Academy of Finland are gratefully acknowledged.
Study concept and design: MK, WdV, RS; collection of clinical samples: MK, HL; acquisition of data: JC, MK, HH, HL, RS; analysis and interpretation of data: JC, MK, HH, JS, RS; statistical analysis: JC, JS; drafting of the manuscript: JC, MK, RS; critical reading and revision of the manuscript: JC, MK, AP, WdV, JS, RS; obtained funding: MK, AP, RS; administrative: MK, AP, RS; study supervision: MK, JS, RS. All authors read and approved the final version for publication.


text:
Your data is safe with EMDESK
Enterprise class security, access controls, and action logs that provide peace of mind.
Enterprise-grade security
EMDESK understands that your projects contain personal, restricted, or classified data that is core to your organization's activity and competitive advantage.
Security and confidentiality are our highest priority. EMDESK is designed from the ground up with security in mind. We put enterprise class security measures in place with strong technical, logical, and legal precautions to protect your data from loss or unauthorized access. We make sure your data is safe and secure by providing multiple layers of protection as well as controls that enable you to meet your security needs.
After the evaluation by the project management team of the Fraunhofer EU-Network and the Fraunhofer SIT (Institute for Secure Information Technology) EMDESK clearly convinced us, also because of its usability. It also fulfils the strict data-protection standards of the Fraunhofer Gesellschaft.
Maximilian Steiert
EU Project Officer, Headquarter of the Fraunhofer-Gesellschaft (Germany)
Developed and hosted in Germany
EMDESK is built exclusively by our employees with proven experience and reliability who are located in our headquarters in Germany. The production systems and customer data is stored in secure data centres with Open Telekom Cloud (OTC) in Germany.
To ensure the highest infrastructure security, EMDESK is hosted with the Open Telekom Cloud (OTC) – one of the most secure and modern cloud data centres in the world. OTC infrastructure is operated in Deutsche Telekom's highly secure twin-core data centres in Magdeburg and Biere, Germany, as well as data backup. All services are strictly regulated and are regularly checked and certified by independent institutions, in order to meet the latest security and data protection requirements (TISAX, Trusted Cloud, ISO 14001, ISO 22301, ISO 9001, ISO 20000, ISO 27001, ISO 27017, ISO 27018, CSA Star Level 2, TÜV Trusted Cloud Service, TCDP version 1.0). For more information, visit: https://open-telekom-cloud.com/en/security/data-centers
Ferri Abolhassan, Director of T-Systems' IT Division responsible for Telekom Security says that "Companies find what they are looking for in Biere: the highest level of security and reliability coupled with strict Germany data protection – an unbeatable combination."
OTC's data processing is strictly regulated by the German data protection act and compliant with GDPR which is certified in accordance with the Trusted Cloud Data Protection Profile (TCDP) 1.0. For more information, visit: https://open-telekom-cloud.com/en/security/data-protection-and-compliance
OTC Security Page
Data segregation & confidentiality
The production systems, the database and the network are physically and logically separated from the enterprise infrastructure. In addition, we separate customer accounts logically at the data layer.
There are strict security policies for employees' access. Access to customer data is only a last resort option, strictly controlled and logged, technically and legally limited to a handful of employees to ensure appropriate customer support under strict confidentiality conditions and supervision of senior management.
To connect to our production infrastructure, employees must use secure authentication that is identity-based and restricted based on employee role using a least-privilege approach.
Our employees are trained on data protection and legally obliged to non-disclosure. When evaluating access levels, the security workgroup takes into account employee experience levels, responsibilities, and internal risk assessments.
Software development security
The software architecture and release cycle is designed to protect against security breaches. EMDESK uses a version control system to track changes to our code base. Changes to the architecture and code must follow the internal coding principles, security policies, and industry's best practices for security. Changes are pushed to a staging server for thorough review and withstand numerous manual/automated tests before being released into production. At regular intervals we conduct source code reviews by our development advisory team.
Releases are typically deployed outside typical European business hours during a planned downtime period. Urgent changes can be made available on demand (e.g. a security patch).
Each user in EMDESK has a unique account with a verified business email address. EMDESK forces users to set account passwords validated against password policies with high security criteria, including complexity, reuse, and expiration requirements. Passwords are hashed and salted in accordance with industry best practice. 2-Factor Authentication is available as an additional security measure to protect EMDESK accounts. User sessions and IP addresses are individually tracked and can be individually audited or revoked by their user. We have a maximum session duration configured.
Precise access control
Client administrators and managers administer user provisioning on their account, and have the option to control access through precise and cascading permission system. This allows admins to control each user's or user group's access throughout the project, while allowing project managers to further delineate permissions.
Project participation is limited to users invited to the project by a user with sufficient permissions, and range from full administrative privileges for that project, read/edit/manage permissions per section or element to read-only access.
EMDESK protects all data in transit or at rest using industry standard Transport Layer Security (TLS) and AES encryption. AES encryption is used for the transmission of any customer data between our datacenter locations, as well as between our data centres and end user devices. User files uploaded to EMDESK servers are automatically encrypted with AES 256 using per-file keys. These encryption keys are stored in a secure key vault, which is a separate database decoupled from the file storage layer.
Data redundancy, backup, and recovery
EMDESK's data protection model provides near real-time database replication to ensure that customer data is both secure and available on redundant and geographically distributed servers in Germany. The exchange of data between them runs via their own network, separate from the internet.
A full backup is performed daily, encrypted, and stored in an environment separate from the primary servers to ensure fault tolerance. In an emergency, customer data from the past can be restored. Even in the unlikely event of multiple server failures, major disruptions, or disasters, we can recover the entire production system from our disaster recovery site, which includes a live updated standby database system.
Action traceability, content, and document recovery
The Activity Tracker logs all updates and actions along the entire project lifecycle with all details, user identity, and timestamps. This gives you control and traceability at all times.
If a user deletes project items, files, folders from the work space, EMDESK puts them into a separate recycle bin. Client administrators and managers can safely recover deleted items from the project's recycle bin for 120 days after deletion.
With built-in document versioning, EMDESK saves a history of all previous versions of files, and allows you to restore them for up to 30 days. Unlimited version history is available on per-document basis.
Privacy and GDPR compliant
EMDESK is committed and obligated by European and German law to protect the privacy of users and their data. The EU's General Data Protection Regulation (GDPR) and the German federal data protection act (BDSG) force organizations based in Germany and the EU, but also those outside of the EU processing the personal data of people residing in the EU, to comply with these regulations. These legislations give users greater security, transparency, and control of their personal data online – a principle we couldn't agree more with.
We have certified our services, for which we act as data processor, under GDPR / BDSG. We have established processes to ensure that we respect your right to erasure, rectification, data portability, information and to be forgotten or restriction. We have a personal data registry that is maintained, pursuant to Article 30 of the GDPR. This lists out the type of personal data, where the personal data is stored, maintained, and processed, any data flow, who the responsible party is, and the retention times. For more information, see our Privacy Policy.
Availability and reliability (99.9% uptime)
We strive to ensure availability of more than 99.9% across all services, with all scheduled maintenance taking place outside typical European business hours. Over the years of continuous operation, EMDESK has reached or exceeded 99.9% uptime. Most updates and maintenance of production systems require no downtime. Production systems are hosted in the Open Telekom Cloud (OTC) and we operate multiple redundant systems that are resistant to any single point of failure. OTC can guarantee permanent data availability of up to 99.999 percent, which corresponds to Tier 3+ security. We publish the availability, which is tracked by external monitoring.
OTC Zero Outage
Application performance and safety are monitored around the clock by our in-house operations team. We test for intruders and attacks. We implement an Intrusion Detection System (IDS) with alarms to warn of suspicious activity. System and network logs are sent off-site to help respond to incidents and analyse root causes. We monitor all common vulnerabilities and exposures (CVEs) for our environment and typically patch critical vulnerabilities within 24 hours. To detect security vulnerabilities, EMDESK uses a combination of automated scanning, penetration testing, and third-party security research.
We have a proven track record and trusted customers for over a decade. Through years of successful and growing business since 2008 with over thousands of users and organizations, including hundreds with long-term subscriptions, we are committed and financially secure to delivering our services over the next decade.
We understand that you may have specific concerns that are not addressed on this page and we encourage you to contact us if you have any questions about EMDESK's security and compliance procedures. Please note that EMDESK is committed to the continuous improvement of its security practices and the information on this page is subject to change.

redpajama_set_name: RedPajamaCommonCrawl


text:
Men in Trees: ABC Cancels Anne Heche Drama
by Trevor Kimball, May 5, 2008
After being ping-ponged around the ABC schedule for two years, the network has cancelled the series about Marin (Anne Heche) and the residents of Elmo, Alaska. In retrospect, the writing's been on the wall for awhile.
When Men in Trees premiered in the fall of 2006, it attracted a respectable number of viewers. Unfortunately, the show never seemed to be a priority for the network — possibly because it's not produced by ABC's in-house production company. Though its viewership was slowly growing, the TV show's first season was cut short due to ABC's scheduling of October Road (which is produced by ABC Studios). Instead of airing all 22 episodes, the network opted to air just 17 and added the remaining five episodes to the series' season two order, in preparation for a possible writers strike.
When the writers strike hit in November 2007, it was expected that Men in Trees would benefit from the lack of original scripted programming on network television. That never seemed to happen and the series was put on hiatus in December. It returned once the strike was over in February and ABC cut Men in Trees' second season order to 19 episodes, including the five from season one.
There series is on hiatus once again and isn't scheduled to return until after the May sweeps period is finished — a sure sign that a network has lost faith in a series. ABC sent tapes of both Men in Trees and October Road to Lifetime to see if they'd be interested in taking on either series. They weren't.
To little surprise, series creator Jenny Bicks was informed of the Men in Trees cancellation last week. She lamented to TV Guide, "I wish the show had not been moved six times and put onto two long hiatuses. No show could survive that."
She says, "I am really proud of the work we did on MIT… A huge thank you to our supportive fans."
On the positive side, Bicks realized that the series might not be back for season three and the cast and crew did some extra filming. As a result, an alternative ending for this season's finale was filmed to serve as a series finale.
Men in Trees is scheduled to return to ABC on May 28th. If the network lets it remain in that Wednesday night timeslot for three episodes, the series finale should air on June 11, 2008. Based on the network's track record with this show, it's hard to say if that will actually happen. Stay tuned!
More about: Men in Trees
Where Are They Now? Some Greenroom Chatter for February 15, 2009
Where Are They Now? Some Greenroom Chatter for November 19, 2008
Where Are They Now? Some Greenroom Chatter for October 13, 2008
2007-2008 Season Cancellations: TV Series Finale Podcast #41
ABC Announces Their 2008-09 Schedule. Who's Been Cancelled?
TV News Briefs: X-Files, Millennium, Vegas, Scrubs, Men in Trees, The Shield and Friday Night Lights
Where Are They Now? Green Room Chatter for March 27, 2008
ABC Renews Nine Shows for 2008-2009, What About the Rest?
Where Are They Now? Green Room Chatter for December 21, 2007
Where Are They Now? Some Green Room Chatter for September 18, 2007
2007 Cancelled Shows: ABC Cuts Some Beloved Series
Series Updates, My $.02 on Studio 60: TV Series Finale Podcast #26
Cancellations and Renewals: TV Series Finale Podcast #25
Men in Trees: What Happened to ABC's Anne Heche Drama?
2006-07 Shows: ABC Renews 14, What About the Rest?
Just want to put the word out again. This show is great. I am still in love with this place called Elmo. Even now in 2015 there is not much good on TV. I basically not watching TV at all because it is always the same sh** like Grey's Anatomy…(stopped watching it years ago) or the forensic crap. Can't believe that they never filmed season 3. Just finished watching "Men in Trees" (season 1 & 2) again after watching it in 2008. First time I watched it in Germany. But unfortunately they always moved the show around to late hours.… Read more »
Reply to Yvonne
Hey,none of the tv stations here air good to very often. If something is good, you can be sure they'll give it a stupid 10pm or later, time slot, then run the scheduled episode late, cancel it, or move it to different day, to ensure viewers can't find it, then say it wasn't popular! ….can't watch what we can't find! I loved Men in Trees, and still rematch the measly 6 episodes that we're all I could find when aired ( I recorded them!). I HATE all the reality shows ( networks love them b/c cheap to make and make… Read more »
I ABSOLUTELY loved this series.. and keep checking to see if there any updates as to when.. I am also on the waiting list / wish list to purchase the original series.. BUT still to no avail…
Come now.. Bring it to South Africa, we definitely seem to be your biggest fans!!
Men in Trees is one of the best shows ever!!!!! We need good holesome shows Like Mein in Trees
Bring it back and please the public!! I am from South Africa and loved the snow and mountains!!
Ag please man, finish a good job.
man oh man, why do they always do this? good shows getting scrapped, which are so out there & different from everything else & that appeal to both sexes….but oh no…don't do something smarter than the rest of the TV "gurus" to stay ahead of the pack & show some guts, but play sheep & follow their lead.
Bring it back – its different, out there & gives viewers a choice. Its also great to watch. Bring it back, please. Show a little bit of individuality & flair!
August 6, 2010 6:27 am
i want men in trees to return – they havew been showing series 1 & 2 again here in SA its a great series – bring on series 3!!!
Reply to susan
What is wrong with ABC! Men In Trees was one of the best shows ever. Too many sit-coms, police shows and what do you want to buy now! I'm sick to death of all that crape. I always looked forward to this show. Made me want to live there in that laid back life. Love, Love, loved it!
I am so disappointed that MIT has been cancelled/axed…..it was such a great show…so very different from anything else we've seen lately. The writing was witty and the actors had become friends over the 2 seasons. I feel as if we have all just been left in the air…right when things were beginning to get interesting. Please reconsider this decision to end such a great series…I already miss it! I am from Australia.
uchey
I live in Nigeria ,and DSTV just aired te s1 and s2 of the Men In Trees,from the first show to the last i was hooked.it was beautiful. You could relate the series ,it meant something,taught you something and in every episode,there was something that happened that you could relate to your self.all this cancellation ,hope it isnt true ,i need the s3 please ;pretty please.
I totally agree with Anonymous. All that is aired are those crummy police, lawyer, hospital dramas, and crazy housewives. I have enough drama in my life. I enjoyed watching Men In Trees. It truly was different from the other programs, and something I looked forward to viewing. I wish it would find its way back.
I really enjoyed this show. I'm sick to death of forensic medicine police dramas. I don't even watch the shows – being subjected to the commercials for their programs is enough. This just had great characters interacting with on another. I also thought the commentary thoughtful. I hope it makes a comeback.
Men in Trees was so much fun to watch!!!! I to want this show BACK why do they cancel all the good shows????
I can't believe there's not gonna be a 3rd season!!! It's a brilliant show!!! It's sooooo different from the rest!! We got the first season played last summer in Spain and the pity is they didn't give it a chance and scheduled it on tuesday's, two episodes, on a channel with little audience. I want it back!!!!
I agree completely, I am still waiting to hear news that MIT is back on. I'm also waiting for them to sell seasons 1 & 2 in the stores cause I can't make myself watch the junk they play now!
C.J. Phoenix
I have really missed this show. I really got into the characters and the scenes were really beautiful. I always made sure I was home in time to watch "my show"! It truly could have gone on much longer had it not been for some poor planning on some other people's parts…I would love to see a resurrection of this show!!! And add some more relationship writing into it – I think people actually learned some things from this show!!!
December 17, 2009 11:14 am
How can we get them to bring back MIT? I love that show, my husband even liked it!
I've been away due to a military deployment and returned with the expectation of the show returning. Color me surprised as I kept on waiting to see the commercials announcing the return of the newest season. Finally went searching for some information. I got hooked on MIT and it is definitely aggravating when the networks continually cancel a show that I look forward to so much.


Closed-end funds (CEFs) offer a unique investment opportunity due to several structural features and special market dynamics. While open-end funds create and destroy shares in response to investor demand enabling subscriptions and redemptions at net asset value (NAV) CEFs instead have a fixed number of shares, giving CEF managers additional flexibility to add value.
Purchasing shares of an individual CEF at a discount to its NAV offers both elevated income levels and price appreciation potential relative to identically positioned open-end peers. In this paper we look at how systematic management of a portfolio of CEFs may capture elevated income and total returns by exploiting inconsistent pricing of CEFs within and across various asset classes.
Neither entirely active nor passive, Parametric's Dividend Income Strategy seeks outperformance via a transparent, rules-based portfolio that emphasizes diversification instead of return forecasts. In this paper, organized as a set of frequently asked questions, we explain traditional income-investing approaches and how our strategy differs.


text:
How did Marlows Ropes Perform on the Clipper Round the World Yacht Race 2017-18?
November 2, 2018 | posted by Jon Mitchell
It's a question, we all would like to know and in this informative Technical film, Marlow Ropes inspects and tests the ropes that made the 47,000 nautical miles around the Globe on the 2017-18 edition of the Clipper Round the World Yacht Race. The fleet of Clipper yachts were fully rigged using mostly D2 Racing, our superior Cruiser/Racer line, great for halyards, sheets and control lines, thanks to it's Dyneema SK78 core, this rope is capable of extremely high breakloads and proves itself to be more than capable of circumnavigating the globe. The fleet also used D12 Max running rigging which used Dyneema SK99 and is used in lashings, strops, cascades and wire.
In this interesting rig inspection and break-testing technical film, Marlow's David Mossman meets with Clipper's Head of Maintenance, Simon Johnston to look at the ropes on the fleet following their return from the race finish at Liverpool, pointing out some interesting cases of ware, and increasingly, a lack of. The film then follows Marlow's Technical Manager, Paul Dyer, back in the testing facility where they break a D12 Max Forestay Strop and D2 Racing Runner to test the amount of residual strength in the rope .
Find out how they fared in one of the world's toughest races, whether the ropes could do the same job all over again and what this means for everyday sailors using Marlow's superior cruiser/racer rope series.
Take a look back at the 2017-18 Clipper Race in Marlow's Clipper News hub
Marlow Launches Leisure Marine New Product Line-Up for 2018-19
Marlow Collaborates with DSM Dyneema on Road to Racing Victory


On during May 1 - 3 at Darling Harbour, Sydney, CeBIT includes an exhibition, keynote addresses, conference streams and forums focus on topics covering communications, government and commerce. The Exhibition spans four halls at the Sydney Convention and Exhibition Centre.
Keynote addresses and conferences are a valuable resource for IT professionals. Speakers include Mitchell Baker, Mozilla CEO, Dave Girouard, Google's vice president and general manager, enterprise and Jim Steele, Salesforce.com president.
Sony had a range of business projectors on hand, including the VPL-EX4 (shown on the middle row, left), boasting 2100 ANSI lumens and three seperate LCD panels for red, green and blue colours. The VPL-EX4 is available now, priced at AU$1,895.
Also on display, was Sony's IPELA IP-networked videoconferencing products. Local customers include the University of Queensland and Seven Network.
Sony also took the opportunity to spruik the benefits of Blu-Ray as a storage medium. The BWU100A internal IDE burner (AU$1,099) and VGNAR38G Blu-Ray- equipped notebook took centre stage at Sony's booth.
ELO digital demonstrated its range of document management products including ELOprofessional, ELOenterprise.
Panasonic's monstrous 103-inch plasma, being touted as the largest available to date, overshadowed the rest of their stand. The plasma display is designed for business use in areas such as TV production, digital signage, exhibitions and private theatres and is priced to suit. If you have a spare AU$105,000 it can be yours!
Panasonic's Toughbooks also made an appearance. The CF-19 (shown above) is a new shock, spill and dust resistant notebook. Priced from AU$6,099, it can survive a 90cm drop, Panasonic claims, has a battery life of 8 hours and a 10.4-inch anti-reflective screen.
Motion Computing offers mobile devices for specialised fields such as healthcare, manufacturing and hospitality, displayed two new devices. First announced in February, the C5 mobile clinical assistant (shown above with charging dock) has been co-developed with Intel for use by health professionals. Shipping in May, it's priced at AU$3,399.
The LE1700, available now, is the company's latest tablet PC. It sports a Core 2 Duo processor, Windows Vista and support for up to 4GB of RAM. Pricing is yet to be confirmed.
According to Motion Computing, the C5 is "the first highly sealed, fully disinfectable computer".
It combines several features aimed to improve clinician's workflow including "a built-in barcode and RFID reader for patient identification and supply, specimen and medication administration verification, a built-in camera and a fingerprint reader to improve security and simplify clinician authentication."
Customer relationship management provider, salesforce.com's president, Jim Steele, gave a keynote address on Tuesday, entitled "The Business Web".
Security vendor Grisoft was promoting the latest release of AVG, version 7.5. Products being promoted for businesses includes Anti-Malware, Internet Security and Anti-Virus, File Server and e-mail server software for Linux and FreeBSD.
Not to be outdone, open-source vendors including Red Hat made a splash. Red Hat Enterprise Linux 5 was released Down Under on March 14.
IBM's Mary Ann Fisher, linux program executive, public sector, presented at the CeBIT e-Government Forum on the use of open-source in government.
BitDefender had popcorn and "human firewalls" on hand for all delegates.
Web conferencing vendor, WebEx's visually contrasting stand complete with bouncy balls and a giant overhead inflated balloon.
CSIRO featured local-grown technical innovations at their stand, including an impressive looking underwater exploration vehicle. Sadly the organisation's air guitar shirt didn't make an appearance.
Symbol, purchased by Motorola earlier this year, had a range of devices aimed at field sales support. Staff manning the stand demonstrated the durability of ruggedised devices by hitting them against the bench and throwing them in the air.
Their latest device, the MC35, is a ruggardised Windows Mobile 5-based PDA (referred to as an EDA -- enterprise digital assistant). The handheld has in-built GPS capabilities, Wi-Fi, bluetooth and a camera. Pricing starts at AU$800.
No tour of the CeBIT Australia 2007 expo would be complete without a visit to the CNET Networks Australia stand. If you're lucky you might find ZDNet Australia journalists such as Munir Kotadia (centre) publishing stories from the event. Nick Gibson, assistant editor for our sister site Builder AU (left) and video editor Matt Oxley (right) were also working furiously at the event.
ZDNet Australia is presenting, in conjunction with CeBIT, the 2007 Emerging Technology Innovation Award on Wednesday. The award, open exclusively to CeBIT exhibitors, recognises technical achievements that have made an impact in the last 18 months.
Google's search appliances also made an appearance. The rack-mountable Mini Search Appliance, shown here, allows businesses to index and search up to 100,000 internal documents in more than 220 different file formats, including HTML, PDF and Microsoft Office file types.
Its big brother, the Google Search Appliance, can search up to 500,000 documents and starts at AU$74,486 (ex. GST).
Google's vice president for enterprise, Dave Girouard, presented at CeBIT Australia 2007, on May 1.
CeBIT Australia is on again for 2007 with hundreds of IT products and services on display in addition to the conference, keynotes and forums. Join us as we take a photo tour of the exhibition halls.


Clay have been used by cultures throughout history for their nutrients and to help rid the body of toxins. Many animals will also turn to eating dirt and clay to help remove poisons from their systems or during times of illness or distress. In recent times, healing clay have once again been gaining popularity for internal and external detoxification, and with good reason. Most associate clay treatments with either a facial or body mask, but clay has a variety of other health properties. Selecting the right one depends mainly on the needs of your skin/health.


New AEW Signee Fenix Apparently Injured At AAW Event In Texas - Wrestling Inc.
Fenix apparently was injured at tonight's AAW show in Texas. Fenix appeared to have been going for a springboard cutter and then landed awkwardly.
After the move, Fenix grabbed his head. The match ended quickly after, as AR Fox got in the ring and was immediately pinned by Penta. Fenix was then stretchered to the back. It is not yet known how serious the injury is. We will post any updates as they become available.
Fenix and Pentagon appeared at Thursday's AEW "Double or Nothing" Ticket Party and attacked the Young Bucks. Fenix and Pentagon are currently still signed to Lucha Underground, but can work dates with other promotions. They are slated to face The Young Bucks at "Double Or Nothing" over Memorial Day weekend.
It was just announced tonight that Fenix would be teaming with Pentagon Jr. to face Rob Van Dam and Sabu in the main event for Impact Wrestling's "United We Stand" on April 4th at the Rahway Rec Center in Rahway, New Jersey.


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Bupa's Care Plus launches global int'l health range in Brazil
Helen Burggraf
13 December 2017 •
Care Plus, the Brazil-based health insurance arm of Bupa, is introducing a new, "global" range of international private medical insurance to the Brazilian market, which it says is a first for that country.
The launch of the Master International range is being done in collaboration with two other established names in global healthcare – Blue Cross Blue Shield in the US, and Bupa's own international business outside of the US – Care Plus said in a statement.
It said the "unique-to-market" new range would offer businesses in Brazil "a significant talent attraction and retention tool", as it will enable them to offer their employees healthcare coverage "around the world", not just in their home market.
Founded in Brazil 25 years ago by its chief executive, Roberto Laganá (pictured), Care Plus was acquired by the UK-based, globally-focused Bupa towards the end of last year. At the time Bupa said the deal would enable it to expand its operations in Latin America.
It provides health insurance plans to more than 400 Brazilian companies, giving it around 100,000 clients in Brazil. In addition to basic health insurance, Care Plus offers its clients dental plans, occupational health and prevention products.
'We listened to our customers'
Care Plus founder and CEO Laganá said the Master International range had been conceived and engineered in response to a demand from the marketplace.
"Our clients and brokers have stated the need for a product offering coverage to globally-minded and globally-mobile customers," he explained.
"We've listened to them."
In its statement announcing the launch of the Master International range, Care Plus noted that the new range will be made available to existing Care Plus clients in Brazil who currently are subscribed to its Master I plan, as well as to new customers with compatible plans, and to "an additional 2,000 new customers" by the end of 2018.
Bupa was founded in the UK in 1947 by the coming together of a number of provident associations and hospital contributory schemes, was initially known as the British United Provident Association although, as it says in a history on its website, it "was never actually a provident association itself". By July 1948 it says it had 38,000 customers "and an 80% share of the private health insurance market" in the UK.
It remains privately held, and has expanded from health insurance in the UK to include privately-run Bupa hospitals, as well as internationally, so that it's now one of the world's largest providers of health insurance and healthcare, looking after more than 27 million people across the globe.
In addition to London and Brighton in the UK, it has offices in Miami, Copenhagen, Dubai (in partnership with Oman Insurance Co), and Hong Kong, as well as regional offices in Mainland China, Singapore, Egypt, Mexico, the Dominican Republic, Bolivia, Brazil, Panama, Guatemala, Ecuador, and – since the acquisition of Care Plus – Brazil.
international private medical insurance
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Back and Forth MK x Jonas Blue x Becky Hill Download 'Back and Forth' on iTunes
Ed Sheeran Home
Ed Sheeran Confirms New EP Collaboration With His "Favourite" Artist
5 January 2012, 19:18 | Updated: 5 January 2012, 19:22
The 'A Team' singer is currently working on a brand new EP which will see him collaborating with an unknown recording artist.
Ed Sheeran has revealed that his current recording project is for a new EP collaboration with his favourite artist.
The 'Lego House' singer has teased his secret project for the past few days while working in a recording studio in Los Angeles.
"The project is a collaboration EP with one of my favourite artists," Ed tweeted earlier today (5th January). "It was an honour to work with them, the tracks sound great.
"In the end we had 10 hours to make this new EP project due to delayed planes. But there's 3 tunes done, can't wait for you to hear them.
Ed added: "Some of the most interesting music I've made in a while."
The 'A Team' singer also tweeted the phrase "The Slumdon Bridge", potentially hinting at a track or EP title.
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ICE removes 2 violent criminal aliens wanted in El Salvador
ALEXANDRIA, La. — Two Salvadoran nationals wanted on murder and rape charges in their home country were removed from the United States Wednesday by officers with U.S. Immigration and Customs Enforcement's (ICE) Enforcement and Removal Operations (ERO) to face charges.
Salvadoran law enforcement authorities issued an arrest warrant in November 2010 for Oscar Giovanni Castro, 32. He is wanted in El Salvador for allegedly murdering an individual Dec. 9, 2004. They also issued an arrest warrant in December 2009 for Jose Mario Solis, 28. He is wanted in El Salvador for allegedly raping a child or disabled person.
"ICE will continue to focus its enforcement operations on identifying, arresting and removing dangerous criminals who pose the greatest risk to our communities," said Trey Lund, field office director for ERO New Orleans.
Lund oversees a five-state area of operations to include Louisiana, Alabama, Arkansas, Mississippi and Tennessee.
"This removal is the result of the diligent work on the part of our officers, law enforcement partners and chief counsel. It is a successful day when another dangerous criminal is removed from our communities," said ERO Washington Field Office Director M. Yvonne Evans.
ERO initially took Castro into custody in the District of Columbia.
Castro and Solis were removed via a charter flight Wednesday from Alexandria to San Salvador, El Salvador, via ICE Air Operations. From there, ICE officers transferred both individuals into Salvadoran law enforcement custody. Since 2006 ICE Air Operations, headquartered in Kansas City, Mo., has supported ERO by providing mass air transportation and removal coordination services to ERO field offices nationwide. Staffed by ERO officers, these air charters enable the agency to repatriate large groups of deportees in an efficient, expeditious and humane manner.
These most recent repatriations are another example of expanded bi-national cooperation to identify, arrest and repatriate Salvadoran criminal suspects who have fled to the United States to avoid prosecution. ICE officers work closely with the Policía Nacional Civil (PNC), the Salvadoran National Interpol Office and Salvadoran immigration as part of this effort.
In fiscal year 2013, ICE returned 160 criminals with active arrest warrants from the PNC to El Salvador via ICE removal flights. Many of those arrested were accused of homicide-related charges or other violent crimes.
Since Oct. 1, 2009, ERO has removed more than 645 foreign fugitives from the United States who were sought in their native countries for serious crimes, including kidnapping, rape and murder. ERO works with ICE's Homeland Security Investigations Office of International Affairs, foreign consular offices in the United States and Interpol to identify foreign fugitives illegally present in the country.


3 Mini Haunts. Photo-Ops. Endless Scares.
Mortem Manor has taken over Old Town, Kissimmee!
This seasonal event will put you in the Halloween spirit. With 3 mini haunted houses, photo-ops and scare actors running the property the haunt at old town will leave you screaming for more! This seasonal event runs select days thru early November and is located in the South Lot in Old Town Kissimmee, just minutes from the major parks!
Tickets start at just $7.


Yesterday I took a step that has been months in the making: I announced a start date for my new podcast. In less than a week, on December 7, the first of 10 initial episodes (and 10 shorter bonus episodes) of the Sweet Valley Diaries podcast will be available for public consumption. I'm thrilled, excited, even a little nervous. But above all, I feel content: I think my friends and I have done a good job with the show, and even if not a soul ever listens to it, I had so much fun making it that I kind of want to invent some fake podcasts just to trick people I like into having highly direct, interview-style conversations around a table with me.
I wrote about the launch date yesterday on the Sweet Valley Diaries blog, and I've included the body of that post below. But I think of this blog as a place where I tell true stories about myself and muse about the creative process, so let me give you a glimpse into this whole "setting a release date" thing: I've been trying to do it since September.
Every month, I make a plan – goals I have and tasks I want to accomplish. (For example, since today is the 1st of December, I've been sneaking new-month planning time in between loads of laundry.) At the very start of a new month, those four-plus weeks stretch out as wide and slow as a mid-afternoon cat. It's easy for me to imagine I'll have "plenty of time" to accomplish a long list of somewhat complex goals, and I rarely bother to break those steps down into smaller steps, because my goals sheet only has so many slots and I want to be able to fill them all up with amazing, unrealistic future accomplishments! Even though I kept writing "set podcast release schedule" and "set and announce premiere date" as monthly goals, first in September, then in October…it just wasn't quite happening.
I wanted to set a release date, but I didn't have all my guests scheduled. I wanted to set a release date, but it was taking me hours and hours to edit episode one. I wanted to set a release date but I was still planning my bonus content. I wanted to set a release date, but I have never made a podcast myself before and there were so many unknowns.
One think I knew for sure? A release date was a deadline, and I never miss a deadline. In this case in fact, a release date was more like a series of deadlines, because I want to make sure and get a new episode out on each successive Thursday (Thursday, Dec 7, was the day I finally landed on; very few of the shows I listen to release on Thursday, and "7" is a go-to number for one of Sweet Valley's main characters, Jessica Wakefield). As soon as I made the call, the next 20 weeks of my life were to be deadline-ified.
You may have heard that a deadline is a strategy (perhaps from Gretchen Rubin, who would no doubt recognize me as an Obliger). For me, it's such an effective strategy that I was a little afraid of it. I had to be ready. Or at least ready enough. And call it first-of-the-month optimism, but I think I am.
VERY BIG NEWS: It's Almost Podcasting Time!
Sweet Valley High. It's been an interest bordering on an obsession, and getting dangerously reminiscent of an "area of expertise" in the years since this blog was born.
But I've developed a side passion: podcasts.
Like my love of SVH, my podcast passion has been a long time in the making (the very first podcasts were coming on to the scene around the same time as The Diaries first began!). And I'm beyond thrilled to finally announce that, over the past few months, I've been working hard to merge these two passions together, like the hottest couple in school, making out at Miller's Point in broad daylight.
One week from today, on December 7, The first episode of the Sweet Valley Diaries Podcast will launch on all your favorite podcasting platforms. I know that Sweet Valley fans are my target demo, but the entire show is designed to do something I have never been quite able to achieve with the blog: to let non-die hards (or even total Sweet Valley neophytes) get a glimpse of the beautiful, absurd, dark perfection that is Sweet Valley High.


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Why Quit Victoria backs vaping..
Why Quit Victoria backs vaping regulation that's split the federal government
Quit Victoria has backed new vaping regulations that has divided the federal government.
There's a crack down on liquid nicotine, with a $220,000 fine for those who do it from July.
It's sparked an internal revolt within the Coalition.
Some MPs believe the "onerous regulatory requirements" will ultimately lead to people smoking cigarettes again.
Dr Sarah White, director of Quit Victoria, told Neil Mitchell vaping was "not a silver bullet" to stop smoking.
"This why it's sensible to put this regulation in place, because what it does is still provide an avenue for people to access e-cigarettes under the supervision of a medical practitioner, but it prevents them from becoming a recreational product that has the potential to get people addicted, or even keep them addicted to nicotine," she said.
"We simply still don't know what those long-term health harms are."
Click PLAY below to hear more on 3AW Mornings
PIC: Getty (iStock)


A hugely impressive and incredibly unique, 3 bedroom upper conversion of a fully restored Victorian villa known as 'Cruachan', with City views, private garden and parking, in the heart of Rutherglen close to a variety of excellent amenities.
Croftview enjoys an enviable position on the much sought after Glenorchard Road. The property has been extended and improved by the present owners and now offers generous accommodation, ideal for family life and entertaining. EPC - D.
A well presented upper cottage flat in the popular Scotstounhill area of Glasgow's West End situated within easy travelling distance of all amenities and Glasgow City Centre.
***RARELY AVAILABLE*** FIVE BEDROOM DETACHED VILLA with DRIVEWAY, INTEGRAL GARAGE, DOWNSTAIRS WC, UTILITY, DINING KITCHEN & CONSERVATORY right beside St Kenneth's & Kirktonholme Primary Schools & walking distance to Village, train station and Town Centre.
An impeccably well-presented 3 bedroom detached villa occupying a generous garden plot within this lovely Bellway Homes development just off Carmunnock Road. EPC-C.
A superb family home in a superb school catchment area located at the head of a cul-de-sac and commanding an elevated position, this detached villa occupies a generous plot which would provide scope for future extension if required.
Kelvin Valley Properties are delighted to present to the market this immaculately presented and seldom available 4 bedroom detached villa in sought after Auchinvole Crescent in Kilsyth. These properties seldom come onto the market and this one has recently had a new kitchen and bathroom installed.
Seldom available, a well presented four bedroom detached villa, located in popular setting and set within generous mature garden grounds, close to local amenities and services.


DC Water is soliciting offers for Request for Proposal (RFP) Number: 15-PR-CFO-01 for External Audit Services. This is an Open Market Procurement with Preference Points for Certified Local Business Enterprises and Local Small Business Enterprises. The RFP will be available Wednesday, November 5, 2014, 2:00 P.M. EST, at DC Water, Department of Procurement, at 5000 Overlook Avenue, SW, Room 200, Washington, DC 20032. Firms may download a copy from website www.dcwater.com or request a copy from Sandra Smith, Acting Procurement Manager, at Sandra.smith@dcwater.com or on 202-787-2697. The Proposal Closing Date and Time is, Friday, December 5, 2014, 2:00 P.M. EST.


On August 8, Mr Biti first resisted arrest at the Chirundu Border Post arguing that he was protected by International law since he had already crossed the Zambezi River and was in the process of applying for Asylum from Zambia. Then, after an interview with Mr Biti the Zambian authorities at the border refused to hand him over stating that they wanted to consult with their superiors in Lusaka, since Biti had indicated that he was running away from political persecution. Zambia's Minister of Information and Broadcasting Services and Chief Government Spokesperson, Dora Siliya has said that her government denied asylum to Tendai Biti because there is no threat to the lives of citizens in Zimbabwe. She also said that the country was stable and that the elections had been declared free and fair by SADC. In addition, she added that Mr Biti has been handed back to the Zimbabwean authorities and not deported because he was not in Zambia illegally but he had been denied entry into the country and was being held at the boarder pending consultations.
The Applicant seeks leave to apply for judicial review pursuant to Order 53 of the Rules of the Supreme Court 1999 Edition. Having perused the ex-parte summons for judicial review and the affidavit in support of the same I allocate the matter to Judge P Yangailo. In the meantime the applicant is to remain in the custody of Zambian Immigration officers who will facilitate his appearance before Judge Yangailo at the High Court in Lusaka at 8:00 hours on the 9th day of August, 2018 for the application for leave to be heard.
…the grounds under which he would want to seek asylum are not meritorious. So basically he has not been arrested, all we are doing is keeping him in safe custody and waiting for the Zimbabwean authority to help him get back to Harare. The grounds do not merit asylum. He is not in danger. He is only going to answer charges to legitimate courts of law.
an authorised officer shall not refuse a refugee a permit under this section if the officer has reason to believe that the refusal of a permit will necessitate the return of the refugee to the territory from which he entered Zambia and that the refugee may be tried, or detained or restricted or punished without trial, for an offence of a political character after arrival in that territory or is likely to be the subject of physical attack in that territory.
The section, however, provides further that 'such authorised officer may in his discretion and without assigning any reason refuse to issue a permit'. This section is most likely what the Zambian authorities relied on to summarily deny Mr Biti asylum. Moreover, Section 17 of the same Act stipulates that "[n]o act or thing done or omitted to be done by any authorised officer or other person shall, if the act or omission was done or omitted bona fide while acting in the execution of his duty under this Act, subject him personally to any liability, action, claim or demand whatsoever." So, the Officers may also use of the concept of bona fide to justify their rejections.
Strangely, however, Justice Chawatama did not mention the 2017 Refugees Act, now in force in the country. Section 11(4) of the Refugee Act guarantees the rights of asylum-seekers stipulating that "a person who applies for recognition as a refugee under this section […] has the right to remain in Zambia— (a) until that person is recognised as a refugee; or (b) where the application for recognition as a refugee is rejected, until that person has had an opportunity to exhaust that person's right of appeal under section 15" (right to appeal that does not seem to have been afforded Mr Biti). On the other side, as Mr Biti seemed to have sympathised with the Zambian oppositions, the Government of Zambia could have considered him as threat to the national security and the public order, according to section 23.3 of the 2017 Act. However, it seems that Mr Biti's claim was generally considered not deserving any refugee status without any further explanations.
Thus, the decision of the Zambian authorities, has been at least incomplete given that the explanations provided to Mr Biti were not complete. Moreover, given that section 23.1 of the Act prohibits returning a person to a country where they may be subjected to persecution based on political opinion, Mr Biti should not have been returned to Zimbabwe, at least without the completion of the judicial process. Mr Biti was arrested and then freed on bail on his return to Zimbabwe.
Thus, even though the Zambian authorities could make use of their discretion given by several domestic legal instruments to try to justify the rejection of the claim made by Mr Biti, they certainly should have granted him the right to appeal the decision, which he was not granted. It is also clear that Mr Biti was charged with crimes related to political opinion and therefore should not have been returned to Zimbabwe, where the political situation is still uncertain, even if President Mnangagwa twitted that it was thanks to him that Mr Biti was finally released because, in his words, '[a]t such a crucial time in the history of the new Zimbabwe, nothing is more important than unity, peace and dialogue'.
Dr Cristiano d'Orsi is a Research Fellow and Lecturer at the South African Research Chair in International Law (SARCIL), University of Johannesburg. He was previously a Research Fellow and Lecturer at the Centre for Human Rights, Faculty of Law, University of Pretoria in South Africa. His expertise mainly deals with the legal protection of the people "on the move" (asylum-seekers, refugees, migrants, IDPs) in Africa. Another field of its interests includes the protection of the socio-economic rights. Cristiano holds a PhD in International Relations (International Law) from the Graduate Institute of International and Development Studies in Geneva (Switzerland).


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Q: Importing data from a webpage written in script (seajs) to Excel I would like to ask about how can we get the data from an HTML which is using JavaScript to show data in a table.
http://www.oanda.com/currency/historical-rates/
I need to extract various kinds of currency exchange rates from the site - from USD to other currency and vice versa. I tried to use the Get External Data > From Web function in Excel, but the website may protect these kind of queries, so I cannot get the table I want (error message saying the currency ex rate I'm looking for does not exist). Because I need to input the original currency and target currency in the website, I cannot get the table without inputting the org and target currency. This is the only recognize site the company uses, so I have to stick with this site.
Everyday I need to convert up to 2k times, is there any VBA for me to use so that I could run the code to auto extracting the exchange rates?

A: This will get the last 60 days and output to a csv file on your desktop. You can change the "USD" part of the URL as required.
Sub GetRates()

    Dim myURL As String, sFilename As String
    Dim WinHttpReq As Object, oStream As Object

    myURL = "http://www.oanda.com/currency/historical-rates/download?quote_currency=USD&end_date=" & Format(Now(), "yyyy-m-d") & "&period=daily&display=absolute&rate=0&data_range=d60&price=bid&view=graph&base_currency_0=CAD&download=csv"
    sFilename = Environ$("USERPROFILE") & "\Desktop\rates.csv"

    Set WinHttpReq = CreateObject("Microsoft.XMLHTTP")
    WinHttpReq.Open "GET", myURL, False
    WinHttpReq.Send

    myURL = WinHttpReq.ResponseBody

    If WinHttpReq.Status = 200 Then
        Set oStream = CreateObject("ADODB.Stream")
        oStream.Open
        oStream.Type = 1
        oStream.Write WinHttpReq.ResponseBody
        oStream.SaveToFile sFilename, 2
       oStream.Close
    End If

End Sub

A: thank you very much @S O!  because i'm new to code, i made some adjustment to your code to get various type of currency pair exchange rate.
i saved org currency list in col A and target currency list in col B.
below is the code i use:
Sub GetRates()

Dim myURL As String, sFilename As String
Dim WinHttpReq As Object, oStream As Object
Dim i As Long, lastrow As Long

With ActiveSheet
lastrow = Sheet1.Range("A" & .Rows.Count).End(xlUp).Row
For i = 2 To lastrow

myURL = "http://www.oanda.com/currency/historical-rates/download?quote_currency=" & Sheet1.Range("A" & i).Value & "&end_date=" & Format(Now(), "yyyy-m-d") & "&period=daily&display=absolute&rate=0&data_range=d60&price=bid&view=graph&base_currency_0=" & Sheet1.Range("B" & i).Value & "&download=csv"
sFilename = Environ$("USERPROFILE") & "\Desktop\" & Sheet1.Range("A" & i).Value & Sheet1.Range("B" & i).Value & ".csv"

Set WinHttpReq = CreateObject("Microsoft.XMLHTTP")
WinHttpReq.Open "GET", myURL, False
WinHttpReq.Send

myURL = WinHttpReq.ResponseBody

If WinHttpReq.Status = 200 Then
    Set oStream = CreateObject("ADODB.Stream")
    oStream.Open
    oStream.Type = 1
    oStream.Write WinHttpReq.ResponseBody
    oStream.SaveToFile sFilename, 2
   oStream.Close
End If

Next i
End With

End Sub

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