Showing papers by "University of Birmingham published in 2007"

Proposed minimum reporting standards for chemical analysis

Abstract: There is a general consensus that supports the need for standardized reporting of metadata or information describing large-scale metabolomics and other functional genomics data sets. Reporting of standard metadata provides a biological and empirical context for the data, facilitates experimental replication, and enables the re-interrogation and comparison of data by others. Accordingly, the Metabolomics Standards Initiative is building a general consensus concerning the minimum reporting standards for metabolomics experiments of which the Chemical Analysis Working Group (CAWG) is a member of this community effort. This article proposes the minimum reporting standards related to the chemical analysis aspects of metabolomics experiments including: sample preparation, experimental analysis, quality control, metabolite identification, and data pre-processing. These minimum standards currently focus mostly upon mass spectrometry and nuclear magnetic resonance spectroscopy due to the popularity of these techniques in metabolomics. However, additional input concerning other techniques is welcomed and can be provided via the CAWG on-line discussion forum at http://msi-workgroups.sourceforge.net/ or http://Msi-workgroups-feedback@lists.sourceforge.net. Further, community input related to this document can also be provided via this electronic forum.

Catalytic Carbophilic Activation: Catalysis by Platinum and Gold π Acids

Abstract: The ability of platinum and gold catalysts to effect powerful atom-economic transformations has led to a marked increase in their utilization. The quite remarkable correlation of their catalytic behavior with the available structural data, coordination chemistry, and organometallic reactivity patterns, including relativistic effects, allows the underlying principles of catalytic carbophilic activation by π acids to be formulated. The spectrum of reactivity extends beyond their utility as catalytic and benign alternatives to conventional stoichiometric π acids. The resulting reactivity profile allows this entire field of catalysis to be rationalized, and brings together the apparently disparate electrophilic metal carbene and nonclassical carbocation explanations. The advances in coupling, cycloisomerization, and structural reorganization—from the design of new transformations to the improvement to known reactions—are highlighted in this Review. The application of platinum- and gold-catalyzed transformations in natural product synthesis is also discussed.

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.

Abstract: The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up)

Beyond Engagement and Participation: User and Community Coproduction of Public Services

Abstract: In recent years, there has been a radical reinterpretation of the role of policy making and service delivery in the public domain. Policy making is no longer seen as a purely top-down process but rather as a negotiation among many interacting policy systems. Similarly, services are no longer simply delivered by professional and managerial staff in public agencies but are coproduced by users and their communities. Th is article presents a conceptual framework for understanding the emerging role of user and community coproduction and presents several case studies that illustrate how diff erent forms of coproduction have played out in practice. Traditional conceptions of service planning and management are now outdated and need to be revised to account for coproduction as an integrating mechanism and an incentive for resource mobilization — a potential that is still greatly underestimated. However, coproduction in the context of multipurpose, multistakeholder networks raises important public governance issues that have implications for public services reform.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry.

Abstract: Hepatitis C virus (HCV) is a leading cause of cirrhosis and liver cancer worldwide. A better understanding of the viral life cycle, including the mechanisms of entry into host cells, is needed to identify novel therapeutic targets. Although HCV entry requires the CD81 co-receptor, and other host molecules have been implicated, at least one factor critical to this process remains unknown (reviewed in refs 1-3). Using an iterative expression cloning approach we identified claudin-1 (CLDN1), a tight junction component that is highly expressed in the liver, as essential for HCV entry. CLDN1 is required for HCV infection of human hepatoma cell lines and is the first factor to confer susceptibility to HCV when ectopically expressed in non-hepatic cells. Discrete residues within the first extracellular loop (EL1) of CLDN1, but not protein interaction motifs in intracellular domains, are critical for HCV entry. Moreover, antibodies directed against an epitope inserted in the CLDN1 EL1 block HCV infection. The kinetics of this inhibition indicate that CLDN1 acts late in the entry process, after virus binding and interaction with the HCV co-receptor CD81. With CLDN1 we have identified a novel key factor for HCV entry and a new target for antiviral drug development.

Educational outreach visits: effects on professional practice and health care outcomes

Abstract: Background Educational outreach visits (EOVs) have been identified as an intervention that may improve the practice of healthcare professionals. This type of face-to-face visit has been referred to as university-based educational detailing, academic detailing, and educational visiting. Objectives To assess the effects of EOVs on health professional practice or patient outcomes. Search methods For this update, we searched the Cochrane EPOC register to March 2007. In the original review, we searched multiple bibliographic databases including MEDLINE and CINAHL. Selection criteria Randomised trials of EOVs that reported an objective measure of professional performance or healthcare outcomes. An EOV was defined as a personal visit by a trained person to healthcare professionals in their own settings. Data collection and analysis Two reviewers independently extracted data and assessed study quality. We used bubble plots and box plots to visually inspect the data. We conducted both quantitative and qualitative analyses. We used meta-regression to examine potential sources of heterogeneity determined a priori. We hypothesised eight factors to explain variation across effect estimates. In our primary visual and statistical analyses, we included only studies with dichotomous outcomes, with baseline data and with low or moderate risk of bias, in which the intervention included an EOV and was compared to no intervention. Main results We included 69 studies involving more than 15,000 health professionals. Twenty-eight studies (34 comparisons) contributed to the calculation of the median and interquartile range for the main comparison. The median adjusted risk difference (RD) in compliance with desired practice was 5.6% (interquartile range 3.0% to 9.0%). The adjusted RDs were highly consistent for prescribing (median 4.8%, interquartile range 3.0% to 6.5% for 17 comparisons), but varied for other types of professional performance (median 6.0%, interquartile range 3.6% to 16.0% for 17 comparisons). Meta-regression was limited by the large number of potential explanatory factors (eight) with only 31 comparisons, and did not provide any compelling explanations for the observed variation in adjusted RDs. There were 18 comparisons with continuous outcomes, with a median adjusted relative improvement of 21% (interquartile range 11% to 41%). There were eight trials (12 comparisons) in which the intervention included an EOV and was compared to another type of intervention, usually audit and feedback. Interventions that included EOVs appeared to be slightly superior to audit and feedback. Only six studies evaluated different types of visits in head-to-head comparisons. When individual visits were compared to group visits (three trials), the results were mixed. Authors' conclusions EOVs alone or when combined with other interventions have effects on prescribing that are relatively consistent and small, but potentially important. Their effects on other types of professional performance vary from small to modest improvements, and it is not possible from this review to explain that variation.

The EUV Imaging Spectrometer for Hinode

Abstract: The EUV Imaging Spectrometer (EIS) on Hinode will observe solar corona and upper transition region emission lines in the wavelength ranges 170 – 210 A and 250 – 290 A. The line centroid positions and profile widths will allow plasma velocities and turbulent or non-thermal line broadenings to be measured. We will derive local plasma temperatures and densities from the line intensities. The spectra will allow accurate determination of differential emission measure and element abundances within a variety of corona and transition region structures. These powerful spectroscopic diagnostics will allow identification and characterization of magnetic reconnection and wave propagation processes in the upper solar atmosphere. We will also directly study the detailed evolution and heating of coronal loops. The EIS instrument incorporates a unique two element, normal incidence design. The optics are coated with optimized multilayer coatings. We have selected highly efficient, backside-illuminated, thinned CCDs. These design features result in an instrument that has significantly greater effective area than previous orbiting EUV spectrographs with typical active region 2 – 5 s exposure times in the brightest lines. EIS can scan a field of 6×8.5 arc min with spatial and velocity scales of 1 arc sec and 25 km s−1 per pixel. The instrument design, its absolute calibration, and performance are described in detail in this paper. EIS will be used along with the Solar Optical Telescope (SOT) and the X-ray Telescope (XRT) for a wide range of studies of the solar atmosphere.

The natural history of cervical HPV infection: unresolved issues.

Abstract: The identification of high-risk human papillomavirus (HPV) types as a necessary cause of cervical cancer offers the prospect of effective primary prevention and the possibility of improving the efficiency of cervical screening programmes. However, for these opportunities to be realized, a more complete understanding of the natural history of HPV infection, and its relationship to the development of epithelial abnormalities of the cervix, is required. We discuss areas of uncertainty, and their possible effect on disease prevention strategies.

Fluorescence analysis of dissolved organic matter in natural, waste and polluted waters—a review

Abstract: Dissolved organic matter (DOM) in aquatic systems originates from a range of sources. Some is allochthonous, transported from the surrounding landscape to the water body, and is derived from and influenced by the geology, land use and hydrology of its origin. Some is created in situ through microbial activity, which may provide an independent source of organic matter, or a recycling mechanism for that which has been transported into the water body. The relative contribution of each source depends upon the location and environmental conditions within and without the water body. Human activity is also a source of DOM, much of which is believed to be labile, which can enter the aquatic system through direct point discharges, diffuse leaching and aerial dispersal. Fluorescence spectroscopy can provide an excellent tool to source DOM fractions, and to monitor and understand DOM transformations in aquatic systems, as much DOM has an intrinsic fluorescence. In particular, recent advances in optical technology, enabling rapid investigation of shorter wavelengths, have enabled more detailed characterization of organic material and its reactions in water. In this article, we review the use of fluorescence spectroscopic techniques to measure the intrinsic fluorescence of organic matter and the application of fluorescent DOM analysis in marine waters, freshwaters and wastewaters. Copyright © 2007 John Wiley & Sons, Ltd.

‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease

Abstract: Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

Abstract: Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome- wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

Extracting semantic representations from word co-occurrence statistics: a computational study.

Abstract: The idea that at least some aspects of word meaning can be induced from patterns of word co-occurrence is becoming increasingly popular. However, there is less agreement about the precise computations involved, and the appropriate tests to distinguish between the various possibilities. It is important that the effect of the relevant design choices and parameter values are understood if psychological models using these methods are to be reliably evaluated and compared. In this article, we present a systematic exploration of the principal computational possibilities for formulating and validating representations of word meanings from word co-occurrence statistics. We find that, once we have identified the best procedures, a very simple approach is surprisingly successful and robust over a range of psychologically relevant evaluation measures.

Cellular responses to viral infection in humans: lessons from Epstein-Barr virus.

Abstract: Epstein-Barr virus (EBV) provides a useful model to study cellular immunity to a genetically stable, persistent human virus. Different sets of proteins expressed during EBV's lytic and cell transforming infections induce qualitatively different cellular immune responses. The factors governing immunodominance hierarchies and the biological effectiveness of these different responses are now being revealed. Analysis of infectious mononucleosis (IM), a clinical syndrome that can arise during primary EBV infection, has allowed the evolution of the responses to be tracked over time, giving an understanding of the immune response kinetics and of those determinants affecting selection into memory. Furthermore, following IM, expression of the receptor for the homeostatic cytokine IL-15 on NK and T cells is lost within these individuals. This experiment of nature provides a system to advance understanding of immunological homeostasis in humans, illustrating how data obtained from the study of EBV have wider significance to the immunological community.

Stochastic model checking

Abstract: This tutorial presents an overview of model checking for both discrete and continuous-time Markov chains (DTMCs and CTMCs). Model checking algorithms are given for verifying DTMCs and CTMCs against specifications written in probabilistic extensions of temporal logic, including quantitative properties with rewards. Example properties include the probability that a fault occurs and the expected number of faults in a given time period. We also describe the practical application of stochastic model checking with the probabilistic model checker PRISM by outlining the main features supported by PRISM and three real-world case studies: a probabilistic security protocol, dynamic power management and a biological pathway.

A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment†‡

Abstract: n this study, patients with acute myeloid leukemia or high-risk myelodysplastic syndrome who were unfit for intensive chemotherapy were randomized to receive either low-dose cytarabine (ara-C) or hydroxyurea with or without all-trans retinoic acid. The results indicted that low-dose ara-C was superior to best supportive care and hydroxyurea and may represent standard care against which new treatments are compared in this patient group.

EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis

Abstract: Objectives: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. Methods: An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. Results: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. Conclusions: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.

Reducing explicit and implicit outgroup prejudice via direct and extended contact: The mediating role of self-disclosure and intergroup anxiety.

Abstract: In 4 studies, the authors investigated mediators of the effect of cross-group friendship. In Study 1, cross-group friendship among White elementary school children predicted more positive explicit outgroup attitude toward South Asians, mediated by self-disclosure and intergroup anxiety. In Study 2, cross-group friendship and extended contact among White and South Asian high school students positively predicted explicit outgroup attitude, mediated by self-disclosure and intergroup anxiety. Study 3 replicated these findings in a larger independent sample. In all 3 studies, exposure to the outgroup positively predicted implicit outgroup attitude. Study 4 further showed that self-disclosure improved explicit outgroup attitude via empathy, importance of contact, and intergroup trust. The authors discuss the theoretical and practical implications of these findings, which argue for the inclusion of self-disclosure as a key component of social interventions to reduce prejudice.

CD1d–lipid-antigen recognition by the semi-invariant NKT T-cell receptor

Abstract: The CD1 family is a large cluster of non-polymorphic, major histocompatibility complex (MHC) class-I-like molecules that bind distinct lipid-based antigens that are recognized by T cells. The most studied group of T cells that interact with lipid antigens are natural killer T (NKT) cells, which characteristically express a semi-invariant T-cell receptor (NKT TCR) that specifically recognizes the CD1 family member, CD1d. NKT-cell-mediated recognition of the CD1d-antigen complex has been implicated in microbial immunity, tumour immunity, autoimmunity and allergy. Here we describe the structure of a human NKT TCR in complex with CD1d bound to the potent NKT-cell agonist alpha-galactosylceramide, the archetypal CD1d-restricted glycolipid. In contrast to T-cell receptor-peptide-antigen-MHC complexes, the NKT TCR docked parallel to, and at the extreme end of the CD1d-binding cleft, which enables a lock-and-key type interaction with the lipid antigen. The structure provides a basis for the interaction between the highly conserved NKT TCR alpha-chain and the CD1d-antigen complex that is typified in innate immunity, and also indicates how variability of the NKT TCR beta-chain can impact on recognition of other CD1d-antigen complexes. These findings provide direct insight into how a T-cell receptor recognizes a lipid-antigen-presenting molecule of the immune system.

Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

Abstract: OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals. DATA SOURCES Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed. REVIEW METHODS The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective. RESULTS Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses. CONCLUSIONS Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Abstract: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.

A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk

Abstract: To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).

Bacterial efflux pump inhibitors from natural sources

Abstract: The rapid spread of bacteria expressing multidrug resistance (MDR) has necessitated the discovery of new antibacterials and resistance-modifying agents. Since the initial discovery of bacterial efflux pumps in the 1980s, many have been characterized in community- and hospital-acquired Gram-positive and Gram-negative pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and, more recently, in mycobacteria. Efflux pumps are able to extrude structurally diverse compounds, including antibiotics used in a clinical setting; the latter are rendered therapeutically ineffective. Antibiotic resistance can develop rapidly through changes in the expression of efflux pumps, including changes to some antibiotics considered to be drugs of last resort. It is therefore imperative that new antibiotics, resistance-modifying agents and, more specifically, efflux pump inhibitors (EPIs) are characterized. The use of bacterial resistance modifiers such as EPIs could facilitate the re-introduction of therapeutically ineffective antibiotics back into clinical use such as ciprofloxacin and might even suppress the emergence of MDR strains. Here we review the literature on bacterial EPIs derived from natural sources, primarily those from plants. The resistance-modifying activities of many new chemical classes of EPIs warrant further studies to assess their potential as leads for clinical development.