Showing papers by "Cardiff University published in 2007"

How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology

Abstract: Diastolic heart failure (DHF) currently accounts for more than 50% of all heart failure patients. DHF is also referred to as heart failure with normal left ventricular (LV) ejection fraction (HFNEF) to indicate that HFNEF could be a precursor of heart failure with reduced LVEF. Because of improved cardiac imaging and because of widespread clinical use of plasma levels of natriuretic peptides, diagnostic criteria for HFNEF needed to be updated. The diagnosis of HFNEF requires the following conditions to be satisfied: (i) signs or symptoms of heart failure; (ii) normal or mildly abnormal systolic LV function; (iii) evidence of diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an LVEF > 50% and an LV end-diastolic volume index (LVEDVI) 16 mmHg or mean pulmonary capillary wedge pressure >12 mmHg) or non-invasively by tissue Doppler (TD) (E/E' > 15). If TD yields an E/E' ratio suggestive of diastolic LV dysfunction (15 > E/E' > 8), additional non-invasive investigations are required for diagnostic evidence of diastolic LV dysfunction. These can consist of blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV mass index or left atrial volume index, electrocardiographic evidence of atrial fibrillation, or plasma levels of natriuretic peptides. If plasma levels of natriuretic peptides are elevated, diagnostic evidence of diastolic LV dysfunction also requires additional non-invasive investigations such as TD, blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV mass index or left atrial volume index, or electrocardiographic evidence of atrial fibrillation. A similar strategy with focus on a high negative predictive value of successive investigations is proposed for the exclusion of HFNEF in patients with breathlessness and no signs of congestion. The updated strategies for the diagnosis and exclusion of HFNEF are useful not only for individual patient management but also for patient recruitment in future clinical trials exploring therapies for HFNEF.

The UKIRT Infrared Deep Sky Survey (UKIDSS)

Abstract: Final published version including significant revisions. Twenty four pages, fourteen figures. Original version April 2006; final version published in MNRAS August 2007

NEW DEBATE International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care

Abstract: INTRODUCTION: The purpose of the present study was to review existing population surveys on the prevalence of infertilityandproportionofcouplesseekingmedicalhelpforfertilityproblems.METHODS:Populationsurveys,reporting the prevalence of infertility and proportion of couples seeking help in more and less developed countries, were reviewed. RESULTS: Estimates on the prevalence of infertility came from 25 population surveys sampling 172 413 women. The 12-month prevalence rate ranged from 3.5% to 16.7% in more developed nations and from 6.9% to 9.3% in less-developed nations, with an estimated overall median prevalence of 9%. In 17 studies sampling 6410 women, the proportion of couples seeking medial care was, on average, 56.1% (range 42–76.3%) in more developed countries and 51.2% (range 27–74.1%) in less developed countries. The proportion of people actually receiving care was substantially less, 22.4%. Based on these estimates and on the current world population, 72.4 million women are currently infertile; of these, 40.5 million are currently seeking infertility medical care. CONCLUSIONS: The current evidence indicates a 9% prevalence of infertility (of 12 months) with 56% of couples seeking medical care. These estimates are lower than those typically cited and are remarkably similar between more and less developed countries.

International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care

Abstract: INTRODUCTION The purpose of the present study was to review existing population surveys on the prevalence of infertility and proportion of couples seeking medical help for fertility problems. METHODS Population surveys, reporting the prevalence of infertility and proportion of couples seeking help in more and less developed countries, were reviewed. RESULTS Estimates on the prevalence of infertility came from 25 population surveys sampling 172 413 women. The 12-month prevalence rate ranged from 3.5% to 16.7% in more developed nations and from 6.9% to 9.3% in less-developed nations, with an estimated overall median prevalence of 9%. In 17 studies sampling 6410 women, the proportion of couples seeking medial care was, on average, 56.1% (range 42–76.3%) in more developed countries and 51.2% (range 27–74.1%) in less developed countries. The proportion of people actually receiving care was substantially less, 22.4%. Based on these estimates and on the current world population, 72.4 million women are currently infertile; of these, 40.5 million are currently seeking infertility medical care. CONCLUSIONS The current evidence indicates a 9% prevalence of infertility (of 12 months) with 56% of couples seeking medical care. These estimates are lower than those typically cited and are remarkably similar between more and less developed countries.

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.

Evolutionary and biomedical insights from the rhesus macaque genome

Abstract: The rhesus macaque (Macaca mulatta) is an abundant primate species that diverged from the ancestors of Homo sapiens about 25 million years ago. Because they are genetically and physiologically similar to humans, rhesus monkeys are the most widely used nonhuman primate in basic and applied biomedical research. We determined the genome sequence of an Indian-origin Macaca mulatta female and compared the data with chimpanzees and humans to reveal the structure of ancestral primate genomes and to identify evidence for positive selection and lineage-specific expansions and contractions of gene families. A comparison of sequences from individual animals was used to investigate their underlying genetic diversity. The complete description of the macaque genome blueprint enhances the utility of this animal model for biomedical research and improves our understanding of the basic biology of the species.

The Amount of Recycled Crust in Sources of Mantle-Derived Melts

Abstract: Plate tectonic processes introduce basaltic crust (as eclogite) into the peridotitic mantle. The proportions of these two sources in mantle melts are poorly understood. Silica-rich melts formed from eclogite react with peridotite, converting it to olivine-free pyroxenite. Partial melts of this hybrid pyroxenite are higher in nickel and silicon but poorer in manganese, calcium, and magnesium than melts of peridotite. Olivine phenocrysts' compositions record these differences and were used to quantify the contributions of pyroxenite-derived melts in mid-ocean ridge basalts (10 to 30%), ocean island and continental basalts (many >60%), and komatiites (20 to 30%). These results imply involvement of 2 to 20% (up to 28%) of recycled crust in mantle melting.

Patients with hippocampal amnesia cannot imagine new experiences

Abstract: Amnesic patients have a well established deficit in remembering their past experiences. Surprisingly, however, the question as to whether such patients can imagine new experiences has not been formally addressed to our knowledge. We tested whether a group of amnesic patients with primary damage to the hippocampus bilaterally could construct new imagined experiences in response to short verbal cues that outlined a range of simple commonplace scenarios. Our results revealed that patients were markedly impaired relative to matched control subjects at imagining new experiences. Moreover, we identified a possible source for this deficit. The patients' imagined experiences lacked spatial coherence, consisting instead of fragmented images in the absence of a holistic representation of the environmental setting. The hippocampus, therefore, may make a critical contribution to the creation of new experiences by providing the spatial context into which the disparate elements of an experience can be bound. Given how closely imagined experiences match episodic memories, the absence of this function mediated by the hippocampus, may also fundamentally affect the ability to vividly re-experience the past.

Motivational Interviewing in Health Care: Helping Patients Change Behavior

Abstract: Behavior change is a critical part of effective health care. The final decision to become healthier, however, is that of the patient and not the practitioner. Anyone who has treated patients knows ...

Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes

Abstract: Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysacchari...

What are the characteristics of patients with severe, symptomatic, mitral regurgitation who are denied surgery?

Abstract: Aim To identify the proportion and characteristics of patients with severe symptomatic mitral regurgita tion (MR) who are denied surgery. Methods and results In the Euro Heart Survey on valvular heart disease, 396 patients had severe symptomatic MR as assessed by Doppler-echocardiography (grade >= 3/4) and New York Heart Association class 11 or greater. Patient characteristics were analysed according to the decision to operate or not. A decision not to operate was taken in 193 patients (49%). In multivariable analysis, decreased left ventricular ejection fraction (LVEF) [OR= 1.39 per 10% decrease, 95% CI (1.17-1.66), P = 0.0002], non-ischaemic aetiology [OR = 4.44, 95% CI (1.96-10.76), P = 0.0006], older age [OR = 1.40 per 10-year increase, 95% CI(1.15-1.72), P=0.001], increased Charlson comorbidity index [OR= 1.38 per 1 point increase, 95% CI (1.12-1.72), P = 0.004], and grade 3 MR [OR = 2.23, 95% CI (1.28-3.29), P = 0.005] were associated with the decision not to operate. One-year survival was 96.0 +/- 1.4% in patients with a positive decision for intervention vs. 89.5 +/- 2.3% in those with a negative decision (P = 0.02). Conclusion Surgery was denied in 49% of patients with severe symptomatic MR. Impaired LVEF, older age, and comorbidity were the most striking characteristics of patients who were denied surgery. The weight of age and LVEF in the decision do not seem justified according to current knowledge.

Style: Language Variation and Identity

Abstract: Style refers to ways of speaking - how speakers use the resource of language variation to make meaning in social encounters. This 2007 book develops a coherent theoretical approach to style in sociolinguistics, illustrated with copious examples. It explains how speakers project different social identities and create different social relationships through their style choices, and how speech-style and social context inter-relate. Style therefore refers to the wide range of strategic actions and performances that speakers engage in, to construct themselves and their social lives. Coupland draws on and integrates a wide variety of contemporary sociolinguistic research as well as his own extensive research in this field. The emphasis is on how social meanings are made locally, in specific relationships, genres, groups and cultures, and on studying language variation as part of the analysis of spoken discourse.

Classification of Altered Volcanic Island Arc Rocks using Immobile Trace Elements: Development of the Th–Co Discrimination Diagram

Abstract: Many diagrams conventionally used to classify igneous rocks utilize mobile elements, which commonly renders them unreliable for classifying rocks from the geological record.The K2O^SiO2 diagram, used to subdivide volcanic arc rocks into rock type (basalts, basaltic andesites, andesites, dacites and rhyolites) and volcanic series (tholeiitic, calc-alkaline, high-K calc-alkaline and shoshonitic), is particularly susceptible to the effects of alteration.However, by usingTh as a proxy for K2O and Co as a proxy for SiO2 it is possible to construct a topologically similar diagram that performs the same task but is more robust for weathered and metamorphosed rocks. This study uses 41000 carefully filtered Tertiary^Recent island arc samples to construct aTh^Co classification diagram. A‘testing set’comprising data not used in constructing the diagram indicates a classification success rate of c. 80%.When applied to some hydrothermally altered, then tropically weathered Cretaceous volcanic arc lavas from Jamaica, the diagramdemonstrates the presence ofa tholeiitic volcanic arc series dominated by intermediate^acid lavas overlain by a calc-alkaline series dominated by basic lavas.

Gene conversion: mechanisms, evolution and human disease

Abstract: Gene conversion, one of the two mechanisms of homologous recombination, involves the unidirectional transfer of genetic material from a 'donor' sequence to a highly homologous 'acceptor'. Considerable progress has been made in understanding the molecular mechanisms that underlie gene conversion, its formative role in human genome evolution and its implications for human inherited disease. Here we assess current thinking about how gene conversion occurs, explore the key part it has played in fashioning extant human genes, and carry out a meta-analysis of gene-conversion events that are known to have caused human genetic disease.

Stable Magnesium(I) Compounds with Mg-Mg Bonds

Abstract: The chemistry of the group 2 metals (beryllium, magnesium, calcium, strontium, and barium) is dominated by the +2 oxidation state. Here, we report the reductions of two magnesium(II) iodide complexes with potassium metal in toluene, leading to thermally stable magnesium(I) compounds, (L)MgMg(L) (where L is [(Ar)NC(NPri2)N(Ar)]- or {[(Ar)NC(Me)]2CH}-, Ar is 2,6-diisopropylphenyl, Me is methyl, and Pri is isopropyl) in moderate yields. The results of x-ray crystallographic and theoretical studies are consistent with central Mg2+(2) units that have single, covalent magnesium-magnesium bonding interactions with 2.8508 +/- 0.0012 (standard deviation) and 2.8457 +/- 0.0008 angstrom bond lengths, respectively, and predominantly ionic interactions with the anionic ligands (L).

The use of computer technology in university teaching and learning: a critical perspective

Abstract: Despite huge efforts to position information and communication technology (ICT) as a central tenet of university teaching and learning, the fact remains that many university students and faculty make only limited formal academic use of computer technology. Whilst this is usually attributed to a variety of operational deficits on the part of students, faculty, and universities, this paper considers the wider social relations underpinning the relatively modest use of technology in higher education. The paper explores how university use of computer technology is shaped into marginalized and curtailed positions by a variety of actors. From the ‘writing’ of ICT at a national policy level through to the marginalization of ICT within the lived ‘student experience’, a consistent theme emerges where computer technology use is constructed in limited, linear, and rigid terms far removed from the creative, productive, and empowering uses which are often celebrated by educational technologists. In the light of such constraints, the paper considers how these dominant constructions of a peripheral and limited use of ICT may be challenged by the higher education community. In particular, it concludes by reflecting on current critical thinking about how educational technologists can foster a more expansive and empowered use of computer technology within university settings.

IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells

Abstract: Epstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12 have been reported to form a heterodimeric hematopoietin in human and mouse. We have constructed a heterodimeric protein covalently linking EBI3 and p35, to form a novel cytokine whichwe nowcall IL-35. The Fc fusion protein of IL-35 induced proliferation of murine CD4+CD25+ and CD4+CD25– T cells when stimulated with immobilized anti- CD3 and anti-CD28 antibodies in vitro. The IL-35-expanded CD4+CD25+ T cell population expressed Foxp3 and produced elevated levels of IL-10, whereas the IL-35- induced CD4+CD25– T cells produced IFN-c but not IL-4. The in vitro expanded CD4+CD25+ T cells retained their suppressive functions against CD4+CD25– effector cells. Furthermore, when cultured with soluble anti-CD3 antibody and antigenpresenting cells, IL-35 suppressed the proliferation of CD4+CD25– effector cells. Moreover, IL-35 inhibited the differentiation of Th17 cells in vitro. In vivo, IL-35 effectively attenuated established collagen-induced arthritis in mice, with concomitant suppression of IL-17 production but enhanced IFN-c synthesis. Thus, IL-35 is a novel anti-inflammatory cytokine suppressing the immune response through the expansion of regulatory T cells and suppression of Th17 cell development.

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.

Myc deletion rescues Apc deficiency in the small intestine

Abstract: The APC gene encodes the adenomatous polyposis coli tumour suppressor protein, germline mutation of which characterizes familial adenomatous polyposis (FAP), an autosomal intestinal cancer syndrome. Inactivation of APC is also recognized as the key early event in the development of sporadic colorectal cancers and its loss results in constitutive activity of the b-catenin–Tcf4 transcription complex. The proto-oncogene c-MYC has been identified as a target of the Wnt pathway in colorectal cancer cells in vitro, in normal crypts in vivo and in intestinal epithelial cells acutely transformed on in vivo deletion of the APC gene; however, the significance of this is unclear. Therefore, to elucidate the role Myc has in the intestine after Apc loss, we have simultaneously deleted both Apc and Myc in the adult murine small intestine. Here we show that loss of Myc rescued the phenotypes of perturbed differentiation, migration, proliferation and apoptosis, which occur on deletion of Apc. Remarkably, this rescue occurred in the presence of high levels of nuclear b-catenin. Array analysis revealed that Myc is required for the majority of Wnt target gene activation following Apc loss. These data establishMycas the criticalmediator of the early stages of neoplasia following Apc loss.

Acquisition and voxelwise analysis of multi-subject diffusion data with Tract-Based Spatial Statistics

Abstract: There is much interest in using magnetic resonance diffusion imaging to provide information on anatomical connectivity in the brain by measuring the diffusion of water in white matter tracts. Among the measures, the most commonly derived from diffusion data is fractional anisotropy (FA), which quantifies local tract directionality and integrity. Many multi-subject imaging studies are using FA images to localize brain changes related to development, degeneration and disease. In a recent paper, we presented a new approach, tract-based spatial statistics (TBSS), which aims to solve crucial issues of cross-subject data alignment, allowing localized cross-subject statistical analysis. This works by transforming the data from the centers of the tracts that are consistent across a study's subjects into a common space. In this protocol, we describe the MRI data acquisition and analysis protocols required for TBSS studies of localized change in brain connectivity across multiple subjects.

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.

Human Tumor-Derived Exosomes Selectively Impair Lymphocyte Responses to Interleukin-2

Abstract: Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion.

A survey of genetic human cortical gene expression.

Abstract: It is widely assumed that genetic differences in gene expression underpin much of the difference among individuals and many of the quantitative traits of interest to geneticists. Despite this, there has been little work on genetic variability in human gene expression and almost none in the human brain, because tools for assessing this genetic variability have not been available. Now, with whole-genome SNP genotyping arrays and whole-transcriptome expression arrays, such experiments have become feasible. We have carried out whole-genome genotyping and expression analysis on a series of 193 neuropathologically normal human brain samples using the Affymetrix GeneChip Human Mapping 500K Array Set and Illumina HumanRefseq-8 Expression BeadChip platforms. Here we present data showing that 58% of the transcriptome is cortically expressed in at least 5% of our samples and that of these cortically expressed transcripts, 21% have expression profiles that correlate with their genotype. These genetic-expression effects should be useful in determining the underlying biology of associations with common diseases of the human brain and in guiding the analysis of the genomic regions involved in the control of normal gene expression.

The role of fluorine in medicinal chemistry

Abstract: The small and highly electronegative fluorine atom can play a remarkable role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can enhance a number of pharmacokinetic and physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the exquisitely sensitive technique of Positron Emission Tomography (PET) imaging. This short review aims to bring together these various aspects of the use of fluorine in medicinal chemistry applications, citing selected examples from across a variety of therapeutic and diagnostic settings. The increasingly routine incorporation of fluorine atom(s) into drug candidates suggests a bright future for fluorine in drug discovery and development. A major challenge moving forward will be how and where to install fluorine in a rational sense to best optimise molecular properties.

Technology acceptance: a meta‐analysis of the TAM: Part 1

Abstract: Purpose – This paper is the first of two concerned with a meta-analysis of the technology acceptance model (TAM). This part aims to present a narrative literature review of 145 papers published on the TAM. Design/methodology/approach – The approach takes the form of a literature review of 145 papers on the TAM. Findings – The review identifies TAM as a basis for identifying gaps and providing guidelines for implementation of management and the conduct of future research. Originality/value – The paper presents a comprehensive literature review and a rigorous meta-analysis to progress towards a unified view of the TAM.