Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis: comparison between private rheumatology practices and academic centers in a large observational cohort.

OBJECTIVE: To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. METHODS: We compared newly initiated TNF inhibition for axSpA in 363 patients enrolled in private practices with 100 patients recruited in 6 university hospitals within the Swiss Clinical Quality Management (SCQM) cohort. RESULTS: All patients had been treated with ≥ 1 nonsteroidal antiinflammatory drug and > 70% of patients had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 before anti-TNF agent initiation. The proportion of patients with nonradiographic axSpA (nr-axSpA) treated with TNF inhibitors was higher in hospitals versus private practices (30.4% vs 18.7%, p = 0.02). The burden of disease as assessed by patient-reported outcomes at baseline was slightly higher in the hospital setting. Mean levels (± SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 ± 1.0 vs 3.4 ± 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response at 1 year was reached for ankylosing spondylitis in 51.7% in private practices and 52.9% in university hospitals (p = 1.0) and for nr-axSpA in 27.5% versus 25.0%, respectively (p = 1.0). CONCLUSION: With the exception of a lower proportion of patients with nr-axSpA newly treated with anti-TNF agents in private practices in comparison to academic centers, adherence to ASAS treatment recommendations for TNF inhibition was equally high, and similar response rates to TNF blockers were achieved in both clinical settings.

Insulin Resistance as a Therapeutic Target for Chronic Kidney Disease.

Insulin resistance (IR) is a prevalent metabolic feature in chronic kidney disease (CKD). Postreceptor insulin-signaling defects have been observed in uremia. A decrease in the activity of phosphatidylinositol 3-kinase appears critical in the pathophysiology of CKD-associated IR. Lipotoxicity due to ectopic accumulation of lipid moieties has recently emerged as another mechanism by which CKD and/or associated metabolic disorders may lead to IR through impairment of various insulin-signaling molecules. Metabolic acidosis, anemia, excess of fat mass, inflammation, vitamin D deficiency, adipokine imbalance, physical inactivity, and the accumulation of nitrogenous compounds of uremia all contribute to CKD-associated IR. The clinical impacts of IR in this setting are numerous, including endothelial dysfunction, increased cardiovascular mortality, muscle wasting, and possibly initiation and progression of CKD. This is why IR may be a therapeutic target in the attempt to improve outcomes in CKD. General measures to improve IR are directed to counteract causal factors. The use of pharmaceutical agents such as inhibitors of the renin-angiotensin system may improve IR in hypertensive and CKD patients. Pioglitazone appears a safe and promising therapeutic agent to reduce IR and uremic-associated abnormalities. However, interventional studies are needed to test if the reduction and/or normalization of IR may actually improve outcomes in these patients.

Effects of antifolates - co-trimoxazole and pyrimethamine-sulfadoxine - on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria

Antimalarial drugs including the antifolate, pyrimethamine-sulfadoxine (PS), can modulate the prevalence and intensities of gametocytaemia following treatment of acute malaria infections. They may also directly influence the transmission and spread of drug insensitivity. Little is known of the effects of co-trimoxazole (Co-T), another antifolate antimalarial, on gametocytes in children with acute malaria infections. We compared the effects of Co-T and PS on the prevalence and intensities of gametocytaemia and gametocyte sex ratios in 102 children aged 0.5-12 years presenting with acute and uncomplicated falciparum malaria. Compared to pre-treatment, both drugs significantly increased gametocyte carriage post-initiation of treatment. However, gametocyte carriage was significantly lower on day 14 in those treated with Co-T than PS. Significant increase in gametocytaemia with time occurred in PS - but not Co-T-treated children. Kaplan-Meier survival curve of the cumulative probability of remaining gametocyte-free in children who were agametocytaemic at enrolment showed that by day 7 of follow up, children treated with PS had a significantly higher propensity to have developed gametocytes than in Co-T-treated children (Log-rank statistic 5.35, df = 1, P = 0.02). Gametocyte sex ratio changes were similar following treatment with both drugs. PS and Co-T treatment of acute malaria infections in children from this endemic area is associated with significant increases in prevalence and intensities of gametocytaemia but these effects are more marked in those treated with PS than Co-T.

Breastfeeding in the East Midlands: patterns, trends and data quality issues

Breastfeeding has important health benefits for both mother and child. Breastfed babies are less likely to report with gastric, respiratory and urinary tract infections and allergic diseases, while they are also less likely to become obese in later childhood. Improving breastfeeding initiation has become a national priority, and a national target has been set ̢?oto deliver an increase of two percentage points per annum in breastfeeding initiation rate, focusing especially on women from disadvantaged areas̢?. Despite improvements in data quality in previous years, it still remains difficult to construct an accurate and reliable picture of variations and trends in breastfeeding in the East Midlands. It is essential that nationally standardised data collection systems are put in place to enable effective and accurate monitoring and evaluation of breastfeeding status both at a local and national level.

The Eukaryotic Promoter Database EPD: the impact of in silico primer extension.

The Eukaryotic Promoter Database (EPD) is an annotated non-redundant collection of eukaryotic POL II promoters, experimentally defined by a transcription start site (TSS). There may be multiple promoter entries for a single gene. The underlying experimental evidence comes from journal articles and, starting from release 73, from 5' ESTs of full-length cDNA clones used for so-called in silico primer extension. Access to promoter sequences is provided by pointers to TSS positions in nucleotide sequence entries. The annotation part of an EPD entry includes a description of the type and source of the initiation site mapping data, links to other biological databases and bibliographic references. EPD is structured in a way that facilitates dynamic extraction of biologically meaningful promoter subsets for comparative sequence analysis. Web-based interfaces have been developed that enable the user to view EPD entries in different formats, to select and extract promoter sequences according to a variety of criteria and to navigate to related databases exploiting different cross-references. Tools for analysing sequence motifs around TSSs defined in EPD are provided by the signal search analysis server. EPD can be accessed at http://www.epd. isb-sib.ch.

Life history analysis of integrative and conjugative element activation in growing microcolonies of Pseudomonas.

Integrative and conjugative elements (ICE) are in some ways parasitic mobile DNA that propagate vertically through replication with the bacterial host chromosome but at low frequencies can excise and invade new recipient cells through conjugation and reintegration (horizontal propagation). The factors that contribute to successful horizontal propagation are not very well understood. Here, we study the influence of host cell life history on the initiation of transfer of a model ICE named ICEclc in bacteria of the genus Pseudomonas. We use time-lapse microscopy of growing and stationary-phase microcolonies of ICEclc bearing cells in combination with physiological staining and gene reporter analysis in stationary-phase suspended cells. We provide evidence that cell age and cell lineage are unlikely to play a role in the decision to initiate the ICEclc transfer program. In contrast, cells activating ICEclc show more often increased levels of reactive oxygen species and membrane damage than nonactivating cells, suggesting that some form of biochemical damage may make cells more prone to ICEclc induction. Finally, we find that ICEclc active cells appear spatially at random in a microcolony, which may have been a selective advantage for maximizing ICEclc horizontal transmission to new recipient species.

Characterization of chromosomal instability in murine colitis-associated colorectal cancer.

AbstractBACKGROUND: Patients suffering from ulcerative colitis (UC) bear an increased risk for colorectal cancer. Due to the sparsity of colitis-associated cancer (CAC) and the long duration between UC initiation and overt carcinoma, elucidating mechanisms of inflammation-associated carcinogenesis in the gut is particularly challenging. Adequate murine models are thus highly desirable. For human CACs a high frequency of chromosomal instability (CIN) reflected by aneuploidy could be shown, exceeding that of sporadic carcinomas. The aim of this study was to analyze mouse models of CAC with regard to CIN. Additionally, protein expression of p53, beta-catenin and Ki67 was measured to further characterize murine tumor development in comparison to UC-associated carcinogenesis in men.METHODS: The AOM/DSS model (n = 23) and IL-10(-/-) mice (n = 8) were applied to monitor malignancy development via endoscopy and to analyze premalignant and malignant stages of CACs. CIN was assessed using DNA-image cytometry. Protein expression of p53, beta-catenin and Ki67 was evaluated by immunohistochemistry. The degree of inflammation was analyzed by histology and paralleled to local interferon-γ release.RESULTS: CIN was detected in 81.25% of all murine CACs induced by AOM/DSS, while all carcinomas that arose in IL-10(-/-) mice were chromosomally stable. Beta-catenin expression was strongly membranous in IL-10(-/-) mice, while 87.50% of AOM/DSS-induced tumors showed cytoplasmatic and/or nuclear translocation of beta-catenin. p53 expression was high in both models and Ki67 staining revealed higher proliferation of IL-10(-/-)-induced CACs.CONCLUSIONS: AOM/DSS-colitis, but not IL-10(-/-) mice, could provide a powerful murine model to mechanistically investigate CIN in colitis-associated carcinogenesis.PMID: 21799775 [PubMed - in process] PMCID: PMC3142131Free PMC Article

Impact of previous virological treatment failures and adherence on the outcome of antiretroviral therapy in 2007.

BACKGROUND: Combination antiretroviral treatment (cART) has been very successful, especially among selected patients in clinical trials. The aim of this study was to describe outcomes of cART on the population level in a large national cohort. METHODS: Characteristics of participants of the Swiss HIV Cohort Study on stable cART at two semiannual visits in 2007 were analyzed with respect to era of treatment initiation, number of previous virologically failed regimens and self reported adherence. Starting ART in the mono/dual era before HIV-1 RNA assays became available was counted as one failed regimen. Logistic regression was used to identify risk factors for virological failure between the two consecutive visits. RESULTS: Of 4541 patients 31.2% and 68.8% had initiated therapy in the mono/dual and cART era, respectively, and been on treatment for a median of 11.7 vs. 5.7 years. At visit 1 in 2007, the mean number of previous failed regimens was 3.2 vs. 0.5 and the viral load was undetectable (<50 copies/ml) in 84.6% vs. 89.1% of the participants, respectively. Adjusted odds ratios of a detectable viral load at visit 2 for participants from the mono/dual era with a history of 2 and 3, 4, >4 previous failures compared to 1 were 0.9 (95% CI 0.4-1.7), 0.8 (0.4-1.6), 1.6 (0.8-3.2), 3.3 (1.7-6.6) respectively, and 2.3 (1.1-4.8) for >2 missed cART doses during the last month, compared to perfect adherence. From the cART era, odds ratios with a history of 1, 2 and >2 previous failures compared to none were 1.8 (95% CI 1.3-2.5), 2.8 (1.7-4.5) and 7.8 (4.5-13.5), respectively, and 2.8 (1.6-4.8) for >2 missed cART doses during the last month, compared to perfect adherence. CONCLUSIONS: A higher number of previous virologically failed regimens, and imperfect adherence to therapy were independent predictors of imminent virological failure.

Debris flow hazard modelling on medium scale: Valtellina di Tirano, Italy

Debris flow hazard modelling at medium (regional) scale has been subject of various studies in recent years. In this study, hazard zonation was carried out, incorporating information about debris flow initiation probability (spatial and temporal), and the delimitation of the potential runout areas. Debris flow hazard zonation was carried out in the area of the Consortium of Mountain Municipalities of Valtellina di Tirano (Central Alps, Italy). The complexity of the phenomenon, the scale of the study, the variability of local conditioning factors, and the lacking data limited the use of process-based models for the runout zone delimitation. Firstly, a map of hazard initiation probabilities was prepared for the study area, based on the available susceptibility zoning information, and the analysis of two sets of aerial photographs for the temporal probability estimation. Afterwards, the hazard initiation map was used as one of the inputs for an empirical GIS-based model (Flow-R), developed at the University of Lausanne (Switzerland). An estimation of the debris flow magnitude was neglected as the main aim of the analysis was to prepare a debris flow hazard map at medium scale. A digital elevation model, with a 10 m resolution, was used together with landuse, geology and debris flow hazard initiation maps as inputs of the Flow-R model to restrict potential areas within each hazard initiation probability class to locations where debris flows are most likely to initiate. Afterwards, runout areas were calculated using multiple flow direction and energy based algorithms. Maximum probable runout zones were calibrated using documented past events and aerial photographs. Finally, two debris flow hazard maps were prepared. The first simply delimits five hazard zones, while the second incorporates the information about debris flow spreading direction probabilities, showing areas more likely to be affected by future debris flows. Limitations of the modelling arise mainly from the models applied and analysis scale, which are neglecting local controlling factors of debris flow hazard. The presented approach of debris flow hazard analysis, associating automatic detection of the source areas and a simple assessment of the debris flow spreading, provided results for consequent hazard and risk studies. However, for the validation and transferability of the parameters and results to other study areas, more testing is needed.

Entre l'exemple et l'expérience: de la transmission par la famille d'une tradition à celle d'un ethos religieux

(Résumé de l'ouvrage) Les textes rassemblés dans cet ouvrage proposent diverses approches du phénomène religieux contemporain. Ils en montrent le caractère "flottant", les frontières incertaines. Ils font découvrir de nouveaux lieux vers lesquels s'oriente aujourd'hui une certaine quête de sens et de sacré. Ils pistent les dérives des grandes religions traditionnelles occidentales et les tentatives qu'entreprennent celles-ci pour freiner l'abandon qu'elles enregistrent ou - pire- l'indifférence qu'elle suscitent. Récusant tout autant "la mort de Dieu" que " le retour du religieux", les auteurs soulignent tous la complexité croissante de ce qu'on appelle couramment le religieux.

Terms of Reference for Project: Review of AHP Support for Children with Statements of Special Educational Needs in Special Schools and Mainstream Education

This is the Terms of Reference for the review of Allied Health Professional (AHP) support for children/young people with statements of special educational needs.It outlines expectations of the review and should be read in conjunction with the Project Initiation Document (PID) for Phase 1of the review, the Terms of Reference for the Project Board and the Engagement Plan for phase 1.

Transcriptional regulation of RNA polymerase III in mammalian cells

L'ARN Polymérase III (Pol III) transcrit un ensemble de petits ARN non traduits impliqués dans des processus cellulaires tels que la biosynthèse des protéines, la maturation des ARNs ou le contrôle transcriptionnel. De ce fait, la Pol III joue un rôle important dans la régulation de la croissance et la prolifération cellulaire. L'initiation de la transcription par la Pol III nécessite l'interaction entre des facteurs de transcription et le complexe de la Pol III lui-même. Un sous- complexe de la Pol III, composé de 3 sous-unités, HsRPC3, HsRPC6 et HsRPC7 sert d'intermédiaire dans cette interaction. Dans cette étude, nous avons caractérisé une nouvelle sous-unité de la Pol III, HsRPC7-Like, homologue à HsRPC7. Nous avons montré que ces deux homologues se trouvent spécifiquement chez les vertébrés. Ils proviennent d'un ancêtre commun qui, après duplication il y a 600 millions d'années, a donné naissance à ces deux paralogues. Dans les cellules humaines, deux formes de Pol III coexistent : l'une contientt HsRPC7, l'autre HsRPC7-Like. Nous avons localisé, à l'échelle du génome entier, la présence de ces deux formes de Pol III dans des cellules humaines et dans le foie de souris. Les deux sous-unités ont démontré des caractéristiques identiques, suggérant qu'elles possèdent des fonctions similaires. Cependant, nous avons analysé les motifs d'expression des gènes codant pour RPC7 et RPC7-Like dans des lignées cellulaires dans des conditions variées telles que la concentration de sérum et la densité cellulaire, ainsi que les motifs d'expression dans le foie de souris et des cellules d'hépatocarcinome de souris. Nos résultats suggèrent que l'expression de ces deux sous-untiés varie en fonction de l'activité de prolifération de la cellule. - RNA polymerase III (Pol III) transcribes a set of genes coding for short untranslated RNAs involved in essential cellular processes as for example protein biosynthesis, RNA maturation, and transcriptional control. Thereby Pol III plays an important role in regulating cell growth and proliferation. Initiation of Pol III transcription requires interactions between transcription factors and the Pol III core complex. A Pol III sub-complex composed of three subunits, HsRPC3, HsRPC6, and HsRPC7 mediates this interaction. In this study, we have characterized a new Pol III subunit, HsRPC7-Like, an homologue of HsRPC7. We have shown that these two homologues are specific to vertebrates and originate from an ancestor gene that duplicated 600 mio years ago to give birth to two paralogues. In human cells, two forms of Pol III coexist, one containing HsRPC7 and the other HsRPC7-Like. We have localized, genome-wide, these two Pol III forms in human cells and mouse liver. Both subunits were found on all types of Pol III genes, suggesting that they share similar function. However, we analysed the expression patterns of the RPC7 and RPC7-Like coding genes under various conditions of serum concentration and cell density in different cell lines, as well as expression patterns in mouse liver and mouse hepatocarcinoma cells. Our results suggest that the expression of these two subunits varies with the proliferation rate of the cell.

Extensive remodeling of DC function by rapid maturation-induced transcriptional silencing.

The activation, or maturation, of dendritic cells (DCs) is crucial for the initiation of adaptive T-cell mediated immune responses. Research on the molecular mechanisms implicated in DC maturation has focused primarily on inducible gene-expression events promoting the acquisition of new functions, such as cytokine production and enhanced T-cell-stimulatory capacity. In contrast, mechanisms that modulate DC function by inducing widespread gene-silencing remain poorly understood. Yet the termination of key functions is known to be critical for the function of activated DCs. Genome-wide analysis of activation-induced histone deacetylation, combined with genome-wide quantification of activation-induced silencing of nascent transcription, led us to identify a novel inducible transcriptional-repression pathway that makes major contributions to the DC-maturation process. This silencing response is a rapid primary event distinct from repression mechanisms known to operate at later stages of DC maturation. The repressed genes function in pivotal processes--including antigen-presentation, extracellular signal detection, intracellular signal transduction and lipid-mediator biosynthesis--underscoring the central contribution of the silencing mechanism to rapid reshaping of DC function. Interestingly, promoters of the repressed genes exhibit a surprisingly high frequency of PU.1-occupied sites, suggesting a novel role for this lineage-specific transcription factor in marking genes poised for inducible repression.

The role of triple infection with hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV) type-1 on CD4+ lymphocyte levels in the highly HIV infected population of North-Central Nigeria

We set out to determine the seroprevalence of hepatitis B and C among human immunodeficiency virus type-1 (HIV-1) infected individuals in North-Central Nigeria to define the influence of these infections on CD4+ lymphocytes cells among our patients as access to antiretroviral therapy improves across the Nigerian nation. The CD4+ values of 180 confirmed HIV-1 infected individuals were enumerated using a superior fluorescence-activated cell sorter system. These patients were tested for the presence of hepatitis B surface antigen and anti-hepatitis C virus (HCV) using third generation enzyme-linked immunosorbent assays. Fifty (27.8%) patients had active hepatitis B virus (HBV) infection while 33 (18.3%) tested positive for anti-HCV antibody. Of these infections, 110 (61.1%), 37 (20.6%), and 20 (11.1%) had HIV only, HBV/HIV-only, and HCV/HIV-only respectively. A HBV/HCV/HIV coinfection prevalence of 7.2% (13 patients) was recorded. Patients coinfected with HIV/HBV/HCV appeared to have lower CD4+ counts (mean = 107 cells/µl; AIDS defining) when compared to HBV/HIV-only (mean = 377 cells/µl), HCV/HIV-only (mean = 373 cells/µl) and patients with mono HIV infection (mean = 478 cells/µl). Coinfection with HBV or HCV is relatively common among HIV-infected patients in Nigeria and should be a big consideration in the initiation and choice of therapy.