Showing papers by "University of Leicester published in 2008"

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

Abstract: BACKGROUND: In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS: We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS: After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS: A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Rapid leukocyte migration by integrin-independent flowing and squeezing

Abstract: All metazoan cells carry transmembrane receptors of the integrin family, which couple the contractile force of the actomyosin cytoskeleton to the extracellular environment In agreement with this principle, rapidly migrating leukocytes use integrin-mediated adhesion when moving over two-dimensional surfaces As migration on two-dimensional substrates naturally overemphasizes the role of adhesion, the contribution of integrins during three-dimensional movement of leukocytes within tissues has remained controversial We studied the interplay between adhesive, contractile and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro We ablated all integrin heterodimers from murine leukocytes, and show here that functional integrins do not contribute to migration in three-dimensional environments Instead, these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge Myosin II-dependent contraction is only required on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus

The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease.

Abstract: Streptococcus pneumoniae is a Gram-positive bacterial pathogen that colonizes the mucosal surfaces of the host nasopharynx and upper airway. Through a combination of virulence-factor activity and an ability to evade the early components of the host immune response, this organism can spread from the upper respiratory tract to the sterile regions of the lower respiratory tract, which leads to pneumonia. In this Review, we describe how S. pneumoniae uses its armamentarium of virulence factors to colonize the upper and lower respiratory tracts of the host and cause disease.

ATP drives lamina propria T H 17 cell differentiation

Abstract: Interleukin (IL)-17-producing CD4(+) T lymphocytes (T(H)17 cells) constitute a subset of T-helper cells involved in host defence and several immune disorders. An intriguing feature of T(H)17 cells is their selective and constitutive presence in the intestinal lamina propria. Here we show that adenosine 5'-triphosphate (ATP) that can be derived from commensal bacteria activates a unique subset of lamina propria cells, CD70(high)CD11c(low) cells, leading to the differentiation of T(H)17 cells. Germ-free mice exhibit much lower concentrations of luminal ATP, accompanied by fewer lamina propria T(H)17 cells, compared to specific-pathogen-free mice. Systemic or rectal administration of ATP into these germ-free mice results in a marked increase in the number of lamina propria T(H)17 cells. A CD70(high)CD11c(low) subset of the lamina propria cells expresses T(H)17-prone molecules, such as IL-6, IL-23p19 and transforming-growth-factor-beta-activating integrin-alphaV and -beta8, in response to ATP stimulation, and preferentially induces T(H)17 differentiation of co-cultured naive CD4(+) T cells. The critical role of ATP is further underscored by the observation that administration of ATP exacerbates a T-cell-mediated colitis model with enhanced T(H)17 differentiation. These observations highlight the importance of commensal bacteria and ATP for T(H)17 differentiation in health and disease, and offer an explanation of why T(H)17 cells specifically present in the intestinal lamina propria.

Genome-wide association analysis identifies 20 loci that influence adult height

Abstract: Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

The Authentic Personality: A Theoretical and Empirical Conceptualization and the Development of the Authenticity Scale

Abstract: This article describes the development of a measure of dispositional authenticity and tests whether authenticity is related to well-being, as predicted by several counseling psychology perspectives. Scales were designed to measure a tripartite conception of authenticity, comprising self-alienation, authentic living, and accepting external influence, which was supported with exploratory factor analysis. Multi-group confirmatory factor analysis showed that the factor loadings were invariant across sample, ethnicity, and gender. The scale showed substantial discriminant validity from the Big Five personality traits, nonsignificant correlations with social desirability, and 2- and 4-week test-retest correlations ranging from r = .78 to .91. Each subscale was strongly related to self-esteem and aspects of both subjective and psychological well-being. This article provides the first direct test of several theoretical models that view authenticity as integral to well-being.

Definition, assessment and treatment of wheezing disorders in preschool children: An evidence-based approach

Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

An online repository of Swift/XRT light curves of GRBs.

Abstract: Context. Swift data are revolutionising our understanding of Gamma Ray Bursts. Since bursts fade rapidly, it is desirable to create and disseminate accurate light curves rapidly. Aims. To provide the community with an online repository of X-ray light curves obtained with Swift. The light curves should be of the quality expected of published data, but automatically created and updated so as to be self-consistent and rapidly available. Methods. We have produced a suite of programs which automatically generates Swift/XRT light curves of GRBs. Effects of the damage to the CCD, automatic readout-mode switching and pile-up are appropriately handled, and the data are binned with variable bin durations, as necessary for a fading source. Results. The light curve repository website ⋆⋆ contains light curves, hardness ratios and deep images for every GRB which Swift’s XRT has observed. When new GRBs are detected, light curves are created and updated within minutes of the data arriving at the UK Swift Science Data Centre.

Transcatheter valve implantation for patients with aortic stenosis: a position statement from the European Association of Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

Abstract: Aims To critically review the available transcatheter aortic valve implantation techniques and their results, as well as propose recommendations for their use and development. Methods and results A committee of experts including European Association of Cardio-Thoracic Surgery and European Society of Cardiology representatives met to reach a consensus based on the analysis of the available data obtained with transcatheter aortic valve implantation and their own experience. The evidence suggests that this technique is feasible and provides haemodynamic and clinical improvement for up to 2 years in patients with severe symptomatic aortic stenosis at high risk or with contraindications for surgery. Questions remain mainly concerning safety and long-term durability, which have to be assessed. Surgeons and cardiologists working as a team should select candidates, perform the procedure, and assess the results. Today, the use of this technique should be restricted to high-risk patients or those with contraindications for surgery. However, this may be extended to lower risk patients if the initial promise holds to be true after careful evaluation. Conclusion Transcatheter aortic valve implantation is a promising technique, which may offer an alternative to conventional surgery for high-risk patients with aortic stenosis. Today, careful evaluation is needed to avoid the risk of uncontrolled diffusion.

Electrodeposition from Ionic Liquids

Abstract: PREFACE BASIC CONSIDERATIONS OF DEPOSITION IN IONIC LIQUIDS SYNTHESIS OF IONIC LIQUIDS AlCl3 Based First Generation Ionic Liquids Air and Water Stable Ionic Liquids Deep Eutectic Solvents PHYSICOCHEMICAL PROPERTIES OF IONIC LIQUIDS ELECTRODEPOSITION OF METALS Metal Deposition in AlCl3 Based Ionic Liquids Metal Deposition in Air and Water Stable Ionic Liquids Metal Deposition in Deep Eutectic Solvents Troublesome Aspects ELECTRODEPOSITION OF ALLOYS ELECTRODEPOSITION OF SEMICONDUCTORS ELECTRODEPOSITION OF CONDUCTING POLYMERS ELECTRODEPOSITION OF NANOCRYSTALLINE METALS AND ALLOYS ELECTRODEPOSITION ON THE NANOSCALE PLASMA ELECTROCHEMISTRY TECHNICAL ASPECTS Counter Electrode Reactions / Metal Dissolution Reference Electrodes Upscaling Recycling Impurities SURFACE PRETREATMENT / ELECTROPOLISHING PLATING PROTOCOLS FUTURE DIRECTIONS

Effectiveness of the diabetes education and self management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: cluster randomised controlled trial

Abstract: Objective To evaluate the effectiveness of a structured group education programme on biomedical, psychosocial, and lifestyle measures in people with newly diagnosed type 2 diabetes Design Multicentre cluster randomised controlled trial in primary care with randomisation at practice level Setting 207 general practices in 13 primary care sites in the United Kingdom Participants 824 adults (55% men, mean age 595 years) Intervention A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care Main outcome measures Haemoglobin A 1c levels, blood pressure, weight, blood lipid levels, smoking status, physical activity, quality of life, beliefs about illness, depression, and emotional impact of diabetes at baseline and up to 12 months Main results Haemoglobin A 1c levels at 12 months had decreased by 149% in the intervention group compared with 121% in the control group After adjusting for baseline and cluster, the difference was not significant: 005% (95% confidence interval −010% to 020%) The intervention group showed a greater weight loss: −298 kg (95% confidence interval −354 to −241) compared with 186 kg (−244 to −128), P=0027 at 12 months The odds of not smoking were 356 (95% confidence interval 111 to 1145), P=0033 higher in the intervention group at 12 months The intervention group showed significantly greater changes in illness belief scores (P=0001); directions of change were positive indicating greater understanding of diabetes The intervention group had a lower depression score at 12 months: mean difference was −050 (95% confidence interval −096 to −004); P=0032 A positive association was found between change in perceived personal responsibility and weight loss at 12 months (β=012; P=0008) Conclusion A structured group education programme for patients with newly diagnosed type 2 diabetes resulted in greater improvements in weight loss and smoking cessation and positive improvements in beliefs about illness but no difference in haemoglobin A 1c levels up to 12 months after diagnosis Trial registration Current Controlled Trials ISRCTN17844016

Psoriasis is associated with increased beta-defensin genomic copy number.

Abstract: Psoriasis is a common inflammatory skin disease with a strong genetic component. We analyzed the genomic copy number polymorphism of the beta-defensin region on human chromosome 8 in 179 Dutch individuals with psoriasis and 272 controls and in 319 German individuals with psoriasis and 305 controls. Comparisons in both cohorts showed a significant association between higher genomic copy number for beta-defensin genes and risk of psoriasis.

MIPAS: an instrument for atmospheric and climate research

Abstract: MIPAS, the Michelson Interferometer for Pas- sive Atmospheric Sounding, is a mid-infrared emission spectrometer which is part of the core payload of ENVISAT. It is a limb sounder, i.e. it scans across the horizon detecting atmospheric spectral radiances which are inverted to verti- cal temperature, trace species and cloud distributions. These data can be used for scientific investigations in various re- search fields including dynamics and chemistry in the alti- tude region between upper troposphere and lower thermo- sphere. The instrument is a well calibrated and characterized Fourier transform spectrometer which is able to detect many trace constituents simultaneously. The different concepts of retrieval methods are described including multi-target and two-dimensional retrievals. Operationally generated data sets consist of temperature, H2O, O3, CH4, N2O, HNO3, and NO2 profiles. Measurement errors are investigated in de- tail and random and systematic errors are specified. The re- sults are validated by independent instrumentation which has been operated at ground stations or aboard balloon gondolas and aircraft. Intercomparisons of MIPAS measurements with other satellite data have been carried out, too. As a result, it

The UKIDSS galactic plane survey

Abstract: 'The definitive version is available at www.blackwell-synergy.com .' Copyright Blackwell Publishing DOI: 10.1111/j.1365-2966.2008.13924.x

An extremely luminous X-ray outburst at the birth of a supernova

Abstract: Massive stars end their short lives in spectacular explosions—supernovae—that synthesize new elements and drive galaxy evolution. Historically, supernovae were discovered mainly through their 'delayed' optical light (some days after the burst of neutrinos that marks the actual event), preventing observations in the first moments following the explosion. As a result, the progenitors of some supernovae and the events leading up to their violent demise remain intensely debated. Here we report the serendipitous discovery of a supernova at the time of the explosion, marked by an extremely luminous X-ray outburst. We attribute the outburst to the 'break-out' of the supernova shock wave from the progenitor star, and show that the inferred rate of such events agrees with that of all core-collapse supernovae. We predict that future wide-field X-ray surveys will catch each year hundreds of supernovae in the act of exploding.

Recent developments in meta‐analysis

Abstract: The art and science of meta-analysis, the combination of results from multiple independent studies, is now more than a century old. In the last 30 years, however, as the need for medical research and clinical practice to be based on the totality of relevant and sound evidence has been increasingly recognized, the impact of meta-analysis has grown enormously. In this paper, we review highlights of recent developments in meta-analysis in medical research. We outline in particular how emphasis has been placed on (i) heterogeneity and random-effects analyses; (ii) special consideration in different areas of application; (iii) assessing bias within and across studies; and (iv) extension of ideas to complex evidence synthesis. We conclude the paper with some remarks on ongoing challenges and possible directions for the future.

Broadband observations of the naked-eye gamma-ray burst GRB 080319B

Abstract: Long-duration gamma-ray bursts (GRBs) release copious amounts of energy across the entire electromagnetic spectrum, and so provide a window into the process of black hole formation from the collapse of massive stars Previous early optical observations of even the most exceptional GRBs (990123 and 030329) lacked both the temporal resolution to probe the optical flash in detail and the accuracy needed to trace the transition from the prompt emission within the outflow to external shocks caused by interaction with the progenitor environment Here we report observations of the extraordinarily bright prompt optical and gamma-ray emission of GRB 080319B that provide diagnostics within seconds of its formation, followed by broadband observations of the afterglow decay that continued for weeks We show that the prompt emission stems from a single physical region, implying an extremely relativistic outflow that propagates within the narrow inner core of a two-component jet

Sliding mode observers: a survey

Abstract: Sliding mode observers have unique properties, in that the ability to generate a sliding motion on the error between the measured plant output and the output of the observer ensures that a sliding mode observer produces a set of state estimates that are precisely commensurate with the actual output of the plant. It is also the case that analysis of the average value of the applied observer injection signal, the so-called equivalent injection signal, contains useful information about the mismatch between the model used to define the observer and the actual plant. These unique properties, coupled with the fact that the discontinuous injection signals which were perceived as problematic for many control applications have no disadvantages for software-based observer frameworks, have generated a ground swell of interest in sliding mode observer methods in recent years. This article presents an overview of both linear and non-linear sliding mode observer paradigms. The use of the equivalent injection signal in problems relating to fault detection and condition monitoring is demonstrated. A number of application specific results are also described. The literature in the area is presented and qualified in the context of continuing developments in the broad areas of the theory and application of sliding mode observers.

Depression screening and patient outcomes in cardiovascular care : a systematic review

Abstract: Context Several practice guidelines recommend that depression be evaluated and treated in patients with cardiovascular disease, but the potential benefits of this are unclear. Objective To evaluate the potential benefits of depression screening in patients with cardiovascular disease by assessing (1) the accuracy of depression screening instruments; (2) the effect of depression treatment on depression and cardiac outcomes; and (3) the effect of screening on depression and cardiac outcomes in patients in cardiovascular care settings. Data sources MEDLINE, PsycINFO, CINAHL, EMBASE, ISI, SCOPUS, and Cochrane databases from inception to May 1, 2008; manual journal searches; reference list reviews; and citation tracking of included articles. Study selection We included articles in any language about patients in cardiovascular care settings that (1) compared a screening instrument to a valid major depressive disorder criterion standard; (2) compared depression treatment with placebo or usual care in a randomized controlled trial; or (3) assessed the effect of screening on depression identification and treatment rates, depression, or cardiac outcomes. Data extraction Methodological characteristics and outcomes were extracted by 2 investigators. Results We identified 11 studies about screening accuracy, 6 depression treatment trials, but no studies that evaluated the effects of screening on depression or cardiovascular outcomes. In studies that tested depression screening instruments using a priori-defined cutoff scores, sensitivity ranged from 39% to 100% (median, 84%) and specificity ranged from 58% to 94% (median, 79%). Depression treatment with medication or cognitive behavioral therapy resulted in modest reductions in depressive symptoms (effect size, 0.20-0.38; r(2), 1%-4%). There was no evidence that depression treatment improved cardiac outcomes. Among patients with depression and history of myocardial infarction in the ENRICHD trial, there was no difference in event-free survival between participants treated with cognitive behavioral therapy supplemented by an antidepressant vs usual care (75.5% vs 74.7%, respectively). Conclusions Depression treatment with medication or cognitive behavioral therapy in patients with cardiovascular disease is associated with modest improvement in depressive symptoms but no improvement in cardiac outcomes. No clinical trials have assessed whether screening for depression improves depressive symptoms or cardiac outcomes in patients with cardiovascular disease.

The Google generation: the information behaviour of the researcher of the future

Abstract: Purpose – This article is an edited version of a report commissioned by the British Library and JISC to identify how the specialist researchers of the future (those born after 1993) are likely to access and interact with digital resources in five to ten years' time. The purpose is to investigate the impact of digital transition on the information behaviour of the Google Generation and to guide library and information services to anticipate and react to any new or emerging behaviours in the most effective way.Design/methodology/approach – The study was virtually longitudinal and is based on a number of extensive reviews of related literature, survey data mining and a deep log analysis of a British Library and a JISC web site intended for younger people.Findings – The study shows that much of the impact of ICTs on the young has been overestimated. The study claims that although young people demonstrate an apparent ease and familiarity with computers, they rely heavily on search engines, view rather than rea...

Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions.

Abstract: Lesions of the common inflammatory skin disease psoriasis are characterized by epidermal hyperproliferation, leucocyte adhesion molecule expression and leucocyte infiltration. The local release of proinflammatory cytokines, such as TNF-alpha, may play an important role in the induction of these events. We have, therefore, analysed aqueous extracts of lesional and uninvolved (clinically normal) stratum corneum for the presence of TNF-alpha immunoreactivity and biological activity. TNF-alpha immunoreactivity and bioactivity were consistently higher in lesional compared with uninvolved samples. By using an anti-TNF-alpha neutralizing antibody it was demonstrated that the biological activity measured was due to the presence of TNF-alpha alone. Concentrations of soluble TNF receptors (p55 and p75) were also higher in lesional stratum corneum extracts, with the p55 form predominating. The plasma of psoriatic patients was also found to contain elevated concentrations of soluble p55 compared with normal controls. These results confirm the presence of immunoreactive TNF-alpha and, for the first time, conclusively demonstrate TNF-alpha biological activity and quantifiable concentrations of soluble TNF receptors (p55 and p75) in lesional psoriatic samples. TNF-alpha recovery from stratum corneum probably reflects synthesis in deeper, viable layers, where it is likely to exert its biological effects. Local and systemic release of soluble TNF receptors, in particular p55, may serve to regulate the effects of TNF-alpha in psoriasis.

Talin depletion reveals independence of initial cell spreading from integrin activation and traction

Abstract: Talins link integrins to the actin cytoskeleton and are important for cell spreading. Sheetz and colleagues show that talin is dispensable for initial cell spreading but it is required for sustained cell spreading and adhesion.

Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia

Abstract: Many common diseases are accompanied by disturbances in biochemical traits. Identifying the genetic determinants could provide novel insights into disease mechanisms and reveal avenues for developing new therapies. Here, we report a genome-wide association analysis for commonly measured serum and urine biochemical traits. As part of the WTCCC, 500,000 SNPs genome wide were genotyped in 1955 hypertensive individuals characterized for 25 serum and urine biochemical traits. For each trait, we assessed association with individual SNPs, adjusting for age, sex, and BMI. Lipid measurements were further examined in a meta-analysis of genome-wide data from a type 2 diabetes scan. The most promising associations were examined in two epidemiological cohorts. We discovered association between serum urate and SLC2A9, a glucose transporter (p = 2 × 10−15) and confirmed this in two independent cohorts, GRAPHIC study (p = 9 × 10−15) and TwinsUK (p = 8 × 10−19). The odds ratio for hyperuricaemia (defined as urate >0.4 mMol/l) is 1.89 (95% CI = 1.36–2.61) per copy of common allele. We also replicated many genes previously associated with serum lipids and found previously recognized association between LDL levels and SNPs close to genes encoding PSRC1 and CELSR2 (p = 1 × 10−7). The common allele was associated with a 6% increase in nonfasting serum LDL. This region showed increased association in the meta-analysis (p = 4 × 10−14). This finding provides a potential biological mechanism for the recent association of this same allele of the same SNP with increased risk of coronary disease.

A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes

Abstract: Aims/hypothesis This 52-week multinational, randomised, open-label, parallel-group, non-inferiority trial compared clinical outcomes following supplementation of oral glucose-lowering drugs with basal insulin analogues detemir and glargine in type 2 diabetic patients.