Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants

BACKGROUND:Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants. METHODOLOGY/PRINCIPAL FINDINGS:By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes. CONCLUSIONS/SIGNIFICANCE:These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing

It's in the loop: shared sub-surface foot kinematics in birds and other dinosaurs shed light on a new dimension of fossil track diversity

The feet of ground-dwelling birds retain many features of their dinosaurian ancestry. Experiments with living species offer insights into the complex interplay among anatomy, kinematics and substrate during the formation of Mesozoic footprints. However, a key aspect of the track-making process, sub-surface foot movement, is hindered by substrate opacity. Here, we use biplanar X-rays to image guineafowl walking through radiolucent substrates of different consistency (solid, dry granular, firm to semi-liquid muds). Despite substantial kinematic variation, the foot consistently moves in a looping pattern below ground. As the foot sinks and then withdraws, the claws of the three main toes create entry and exit paths in different locations. Sampling these paths at incremental horizons captures two-dimensional features just as fossil tracks do, allowing depth-based zones to be characterized by the presence and relative position of digit impressions. Examination of deep, penetrative tracks from the Early Jurassic confirms that bipeds had an equivalent looping response to soft substrates approximately 200 Ma. Our integration of extant and extinct evidence demonstrates the influence of substrate properties on sinking depth and sub-surface foot motion, both of which are significant sources of track variation in the fossil record of dinosaurs

Observed Reductions in Schistosoma mansoni Transmission from Large-Scale Administration of Praziquantel in Uganda: A Mathematical Modelling Study

To date schistosomiasis control programmes based on chemotherapy have largely aimed at controlling morbidity in treated individuals rather than at suppressing transmission. In this study, a mathematical modelling approach was used to estimate reductions in the rate of Schistosoma mansoni reinfection following annual mass drug administration (MDA) with praziquantel in Uganda over four years (2003-2006). In doing this we aim to elucidate the benefits of MDA in reducing community transmission.Age-structured models were fitted to a longitudinal cohort followed up across successive rounds of annual treatment for four years (Baseline: 2003, TREATMENT: 2004-2006; n = 1,764). Instead of modelling contamination, infection and immunity processes separately, these functions were combined in order to estimate a composite force of infection (FOI), i.e., the rate of parasite acquisition by hosts.MDA achieved substantial and statistically significant reductions in the FOI following one round of treatment in areas of low baseline infection intensity, and following two rounds in areas with high and medium intensities. In all areas, the FOI remained suppressed following a third round of treatment.This study represents one of the first attempts to monitor reductions in the FOI within a large-scale MDA schistosomiasis morbidity control programme in sub-Saharan Africa. The results indicate that the Schistosomiasis Control Initiative, as a model for other MDA programmes, is likely exerting a significant ancillary impact on reducing transmission within the community, and may provide health benefits to those who do not receive treatment. The results obtained will have implications for evaluating the cost-effectiveness of schistosomiasis control programmes and the design of monitoring and evaluation approaches in general

Ethics takes time, but not that long

© 2007 Hansson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Scalar and vector Slepian functions, spherical signal estimation and spectral analysis

It is a well-known fact that mathematical functions that are timelimited (or spacelimited) cannot be simultaneously bandlimited (in frequency). Yet the finite precision of measurement and computation unavoidably bandlimits our observation and modeling scientific data, and we often only have access to, or are only interested in, a study area that is temporally or spatially bounded. In the geosciences we may be interested in spectrally modeling a time series defined only on a certain interval, or we may want to characterize a specific geographical area observed using an effectively bandlimited measurement device. It is clear that analyzing and representing scientific data of this kind will be facilitated if a basis of functions can be found that are "spatiospectrally" concentrated, i.e. "localized" in both domains at the same time. Here, we give a theoretical overview of one particular approach to this "concentration" problem, as originally proposed for time series by Slepian and coworkers, in the 1960s. We show how this framework leads to practical algorithms and statistically performant methods for the analysis of signals and their power spectra in one and two dimensions, and, particularly for applications in the geosciences, for scalar and vectorial signals defined on the surface of a unit sphere.Comment: Submitted to the 2nd Edition of the Handbook of Geomathematics, edited by Willi Freeden, Zuhair M. Nashed and Thomas Sonar, and to be published by Springer Verlag. This is a slightly modified but expanded version of the paper arxiv:0909.5368 that appeared in the 1st Edition of the Handbook, when it was called: Slepian functions and their use in signal estimation and spectral analysi

The Pathophysiology of Inhalational Brucellosis in Balb/c Mice

To characterize the clinical presentation and pathophysiology of inhalational brucellosis, Balb/c mice were challenged with Brucella melitensis 16M in a nose-only aerosol exposure chamber. A low dose of 1000 cfu/animal of B. melitensis resulted in 45% of mice with tissue burdens eight weeks post-challenge. The natural history of brucellosis in mice challenged by higher aerosol doses was examined by serial euthanizing mice over an eight week period. Higher challenge doses of 1.00E+05 and 5.00E+05 cfu resulted in positive blood cultures 14 days post-challenge and bacterial burdens were observed in the lung, liver and/or spleens 14 days post-challenge. In addition, the progression of brucellosis was similar between mice challenged by the intranasal and aerosol routes. The results from this study support the use of the Balb/c aerosol nose-only brucellosis mouse model for the evaluation of therapeutics against inhalational brucellosis

Twin births, sex of children and maternal risk of ovarian cancer: a cohort study in Norway

In a follow-up of 1 208 001 women aged 20–74 years, no significant association was found between twin births (112 cases) and risk, though those with twin girls had a non-significantly higher risk than those with singleton births; among the latter, those with girls only had a higher risk of endometrioid tumours (incidence rate ratio 1.35; 95% confidence interval 1.03–1.76, based on 475 cases) than women with boys only

Human Rhinovirus Infections in Rural Thailand: Epidemiological Evidence for Rhinovirus as Both Pathogen and Bystander

BACKGROUND: We describe human rhinovirus (HRV) detections in SaKaeo province, Thailand. METHODS: From September 1, 2003-August 31, 2005, we tested hospitalized patients with acute lower respiratory illness and outpatient controls without fever or respiratory symptoms for HRVs with polymerase chain reaction and molecularly-typed select HRVs. We compared HRV detection among hospitalized patients and controls and estimated enrollment adjusted incidence. RESULTS: HRVs were detected in 315 (16%) of 1919 hospitalized patients and 27 (9.6%) of 280 controls. Children had the highest frequency of HRV detections (hospitalized: <1 year: 29%, 1-4 year: 29%, ≥ 65 years: 9%; controls: <1 year: 24%, 1-4 year: 14%, ≥ 65 years: 2.8%). Enrollment adjusted hospitalized HRV detection rates were highest among persons aged <1 year (1038/100,000 persons/year), 1-4 years (457), and ≥ 65 years (71). All three HRV species were identified, HRV-A was the most common species in most age groups including children aged <1 year (61%) and all adult age groups. HRV-C was the most common species in the 1-4 year (51%) and 5-19 year age groups (54%). Compared to controls, hospitalized adults (≥ 19 years) and children were more likely to have HRV detections (odds ratio [OR]: 4.8, 95% confidence interval [CI]: 1.5, 15.8; OR: 2.0, CI: 1.2, 3.3, respectively) and hospitalized children were more likely to have HRV-A (OR 1.7, CI: 0.8, 3.5) or HVR-C (OR 2.7, CI: 1.2, 5.9) detection. CONCLUSIONS: HRV rates were high among hospitalized children and the elderly but asymptomatic children also had substantial HRV detection. HRV (all species), and HRV-A and HRV-C detections were epidemiologically-associated with hospitalized illness. Treatment or prevention modalities effective against HRV could reduce hospitalizations due to HRV in Thailand

Cancer risk in close relatives of women with early-onset breast cancer – a population-based incidence study

Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs 24.5) and for ovarian cancer (20 vs 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast–ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5–7.4) and especially brothers (29; 7.7–74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer. © 1999 Cancer Research Campaig