bluuebunny/crossref_metadata_2025_split huggingface dataset:
A placebo‐controlled trial of exenatide twice‐daily added to thiazolidinediones alone or in combination with metformin
Authors: Liutkus J. , Rosas Guzman J. , Norwood P. , Pop L. , Northrup J. , Cao D. , Trautmann M. 
Published: October 2010

Aim: To test the hypothesis that glycaemic control with exenatide added to thiazolidinediones (TZDs) with or without metformin was superior to placebo. Methods: A 26‐week, multi‐country (Canada, Mexico, Romania, South Africa and the USA), randomized, double‐blind, placebo‐controlled study compared exenatide twice‐daily vs. placebo in 165 subjects suboptimally controlled with TZDs with or without metformin [HbA1c 8.2% (s.d. 0.9), fasting serum glucose 9.1 (2.6) mmol/l, body weight 93.9 (17.8) kg, diabetes duration 6.4 (4.3) years]. After a 2‐week, single‐blind, lead‐in period, subjects were randomly assigned (2 : 1) to add exenatide or placebo to current regimens. The primary endpoint was HbA1c change at endpoint (Week 26 or last‐observation‐carried‐forward). Results: Only 8 subjects were treated with concomitant TZD alone. Exenatide reduced HbA1c significantly more than placebo [−0.84% (s.e. 0.20) vs. −0.10% (0.23), treatment difference −0.74% (0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, −1.4 (s.e. 0.6) kg vs. placebo, −0.8 (0.7) kg, p = 0.176)]. Nearly 71% of subjects had both a reduction in HbA1c and body weight with exenatide compared with 54% with placebo. The most common adverse events (exenatide vs. placebo) were nausea (12% vs. 2%, p = 0.037), vomiting (8% vs. 0%, p = 0.031) and headache (4% vs. 4%). Confirmed (blood glucose <3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between groups. Conclusions: Exenatide added to TZDs alone or in combination with metformin significantly improved glycaemic control as determined by significant improvement in HbA1c without associated hypoglycaemia.
Internet‐based interventions for problem drinkers: From efficacy trials to implementation
Authors: CUNNINGHAM JOHN A. , KHADJESARI ZARNIE , BEWICK BRIDGETTE M. , RIPER HELEEN 
Published: October 2010

AbstractAims. Internet‐based interventions (IBIs) for problem drinkers have been in existence for over a decade. In that time, IBIs have increased in sophistication and there is the beginning of a solid research base suggesting their efficacy. A growing number of problem drinkers are using IBIs and attempts have been made to explore how IBIs can be integrated within primary care and other health‐care settings. This symposium provided an overview of IBIs for problem drinkers and highlighted some of the important issues in their development and implementation. Rationale. IBIs appear to be at a ‘cusp’ as technology and intervention practices are merged together in an attempt to provide better health care for problem drinkers. The timing of the 2009 International Network on Brief Interventions for Alcohol Problems Conference was ideal for a presentation and discussion of the role that IBIs play now that IBIs have started to shift into the mainstream of services for problem drinkers. Summary. The presentations in this symposium covered the ‘bench to bedside’ aspects of the development and evaluation of IBIs. They included a systematic review of the research to‐date in this field, a report on the results from a just completed randomised controlled trial, a report on an effectiveness trial of implementing IBIs in multiple university settings and a consideration of the cost‐effectiveness of IBIs.[Cunningham JA, Khadjesari Z, Bewick BM, Riper H. Internet‐based interventions for problem drinkers: From efficacy trials to implementation. Drug Alcohol Rev 2010;29;617–622]
Alcohol screening and brief intervention in primary care: Absence of evidence for efficacy in people with dependence or very heavy drinking
Authors: SAITZ RICHARD 
Published: October 2010

AbstractIssues. Although screening and brief intervention (BI) in the primary‐care setting reduces unhealthy alcohol use, its efficacy among patients with dependence has not been established. This systematic review sought to determine whether evidence exists for BI efficacy among patients with alcohol dependence identified by screening in primary‐care settings. Approach. We included randomised controlled trials (RCTs) extracted from eight systematic reviews and electronic database searches published through September 2009. These RCTs compared outcomes among adults with unhealthy alcohol use identified by screening who received BI in a primary‐care setting with those who received no intervention. Key Findings. Sixteen RCTs, including 6839 patients, met the inclusion criteria. Of these, 14 excluded some or all persons with very heavy alcohol use or dependence; one in which 35% of 175 patients had dependence found no difference in an alcohol severity score between groups; and one in which 58% of 24 female patients had dependence showed no efficacy. Conclusion and Implications. Alcohol screening and BI has efficacy in primary care for patients with unhealthy alcohol use, but there is no evidence for efficacy among those with very heavy use or dependence. As alcohol screening identifies both dependent and non‐dependent unhealthy use, the absence of evidence for the efficacy of BI among primary‐care patients with screening‐identified alcohol dependence raises questions regarding the efficiency of screening and BI, particularly in settings where dependence is common. The finding also highlights the need to develop new approaches to help such patients, particularly if screening and BI are to be disseminated widely.[Saitz R. Alcohol screening and brief intervention in primary care: Absence of evidence for efficacy in people with dependence or very heavy drinking. Drug Alcohol Rev 2010;29;631–640]
NICE work if you can get it: Development of national guidance incorporating screening and brief intervention to prevent hazardous and harmful drinking in England
Authors: KANER EILEEN 
Published: October 2010

Abstract This paper describes the development of the first set of national guidance focused on the prevention of alcohol problems in England. These guidelines were produced by the National Institute for Health and Clinical Excellence (NICE) working with a multidisciplinary program development group of scientists, practitioners and lay members. In this work, screening and brief alcohol interventions represent a key element of a comprehensive public health strategy to prevent alcohol‐related risk and harm across the population. The first controlled trials of brief alcohol intervention were published in the mid to late 1980's and there are now around 60 published trials in this field. After 25 years of accumulated evidence in this field, brief alcohol interventions have yet to make a significant impact on routine clinical practice. While it is imperative to have good science to make the case for brief intervention delivery, this work is in vain if practitioners are unwilling or unable to use these interventions with their patients. Evidence from the alcohol field and other clinical areas indicates that national prioritisation of brief alcohol intervention activity, by a body, such as NICE, is likely to be a key driver of implementation by practitioners. This paper summarises a suite of complementary system‐level and practice recommendations, which were published by NICE in June 2010, and considers their likely impact on screening and brief alcohol in England.[Kaner E. NICE work if you can get it: Development of national guidance incorporating screening and brief intervention to prevent hazardous and harmful drinking in England. Drug Alcohol Rev 2010;29;589–595]
Grasping the thistle: The role of alcohol brief interventions in Scottish alcohol policy
Authors: GRAHAM LESLEY J. C. , MACKINNON DONNA 
Published: October 2010

AbstractIssue.Scotland has experienced a substantial rise in alcohol‐related harm, which is now one of the biggest public health challenges it faces.Approach.Alcohol problems in Scotland are described along with national alcohol policy response in addressing them. The role of a program of Alcohol Brief Interventions is discussed therein.Key Findings.In Scotland, considerable proportions of the population are drinking hazardously or harmfully, common across different age and socioeconomic groups. Rising consumption has been set in wider environmental changes with alcohol becoming more available and affordable. Scotland has had one of the fastest growing chronic liver disease mortality rates in the world at a time when rates in most of Western Europe are falling. Scotland's alcohol policy has an explicit aim to reduce population consumption and includes legislative measures to tackle price and availability. A national program to deliver Alcohol Brief Interventions for hazardous drinkers is a key plank of this wider strategy. A portfolio of studies will monitor and evaluate national policy and, through contribution analysis, describe the role Alcohol Brief Interventions play in reducing alcohol misuse.Implications.Effective alcohol policy recognises that determinants of health not only lie at individual level, but include wider social, environmental and economic factors. Scotland's policy is addressing these determinants with both population‐based and population‐targeted interventions.Conclusion.Scotland has a serious problem with alcohol. A comprehensive, evidence‐based, resourced alcohol policy is being implemented, which will need continual review to ensure it remains anchored in evidence while maintaining its ambition.[Graham LJC, MacKinnon D. Grasping the thistle: The role of alcohol brief interventions in Scottish alcohol policy.Drug Alcohol Rev2010;29;603–607]
Development of relational reasoning during adolescence
Authors: Dumontheil Iroise , Houlton Rachael , Christoff Kalina , Blakemore Sarah‐Jayne 
Published: October 2010

AbstractNon‐linear changes in behaviour and in brain activity during adolescent development have been reported in a variety of cognitive tasks. These developmental changes are often interpreted as being a consequence of changes in brain structure, including non‐linear changes in grey matter volumes, which occur during adolescence. However, very few studies have attempted to combine behavioural, functional and structural data. This multi‐method approach is the one we took in the current study, which was designed to investigate developmental changes in behaviour and brain activity during relational reasoning, the simultaneous integration of multiple relations. We used a relational reasoning task known to recruit rostrolateral prefrontal cortex (RLPFC), a region that undergoes substantial structural changes during adolescence. The task was administered to female participants in a behavioural (N = 178, 7–27 years) and an fMRI study (N = 37, 11–30 years). Non‐linear changes in accuracy were observed, with poorer performance during mid‐adolescence. fMRI and VBM results revealed a complex picture of linear and possibly non‐linear changes with age. Performance and structural changes partly accounted for changes with age in RLPFC and medial superior frontal gyrus activity but not for a decrease in activation in the anterior insula/frontal operculum between mid‐adolescence and adulthood. These functional changes might instead reflect the maturation of neurocognitive strategies.
Assessing Similarity of DNA profiles
Authors: Hepworth Graham , Gordon Ian 
Published: October 2010

SummaryThe genetic similarity of strains of a pathogen can be assessed by using a matrix of dissimilarities that is derived from bands in their DNA profile which are present or absent. The dependence between elements of the dissimilarity matrix, if not accounted for, results in underestimation of the variance in comparisons between groups of strains which are differentiated according to the possession of an attribute. We examine a previously proposed statistic for determining whether a group of strains is more similar than expected. We show the limitations of this statistic and propose a new statistic which better addresses the hypotheses that are usually considered in this field of study. The statistic proposed is based on similarity between strains within the group of interest and with those outside. This statistic also needs to account for the dependence in the raw data, and we use the correlation between elements of the dissimilarity matrix to investigate how this dependence affects the underestimation of the variance. Using examples involving the pathogenic yeast Candida, we show how permutation tests can be applied to the differentiation of groups of strains.
Geochemical and isotopic characterization of volcanic and geothermal fluids discharged from the Ecuadorian volcanic arc
Authors: INGUAGGIATO S. , HIDALGO S. , BEATE B. , BOURQUIN J. 
Published: October 2010

AbstractThe Ecuadorian Quaternary volcanic arc is characterized by about 60 volcanoes many of which are active or potentially active. This volcanic activity is the result of the subduction processes of the Nazca Plate beneath the north‐western part of South America. The geochemical signature of the discharged fluids from these volcanic systems gives an important contribution to the comprehension of the subduction processes in the South‐American region. In this work, we present the first systematic geochemical characterization of discharged fluids from the entire Ecuadorian volcanic arc on the basis of the chemical and isotopic composition of 56 samples of thermal and cold waters, as well as 32 dissolved and 27 bubbling gases collected from north to south across the arc. The isotopic composition of waters reveals a mainly meteoric origin, while the chemistry of the dissolved gases is characterized by He and CO2 contents, 2–3 orders of magnitude higher than the air saturated water values, which implies very active gas–water interaction processes with deep fluids. Moreover, both dissolved and bubbling gases’ isotopic signature shows a wide compositional range, with helium ranging between 0.1 and 7.12 R/Ra and carbon ranging from −1.75 to −10.50‰δ13C(TDIC). Such isotopic features may be related to the presence of at least two distinct end‐member sources: the mantle and the crust. Finally, this geochemical study clearly reveals the two distinct geographic parts of the arc, showing different isotopic characteristics of fluids for the Quaternary active volcanism, (north of 2°S), and for the inactive arc, (south of 2°S).
Gas geochemistry related to wellhead production data to investigate physical reservoir phenomena in geothermal reservoirs: application at Cerro Prieto IV (Mexico)
Authors: BARRAGÁN R. M. , ARELLANO V. M. , RODRÍGUEZ M. H. , PÉREZ A. , SEGOVIA N. 
Published: October 2010

AbstractThe chemical composition of the steam discharged by wells at the Cerro Prieto IV (CP IV) sector of the Cerro Prieto (Mexico) geothermal field was used to estimate important reservoir parameters such as steam fractions at the entrance of the wells (also called ‘excess steam’) and volumetric liquid saturations in the reservoir. The results were analyzed together with chemical and wellhead production data over a time interval to investigate physical phenomena in the reservoir fluid induced by exploitation practices. For starting conditions, the reservoir temperatures at CP IV sector were estimated to be between 270 and 320°C; relatively high reservoir liquid saturations (>0.9) were estimated at the northwest and at the center of the sector, while at the southeast moderate liquid saturations (<0.2) were found. The main reservoir physical processes included (i) moderate boiling with enthalpy increases to values consistently lower than that for the steam (2676 kJ kg−1) and with preferential flow of steam to the wells in the periphery of CP IV, (except toward the north), (ii) the entry of shallower, cooler waters into the reservoir at the center of the CP IV sector; and (iii) widespread boiling with high‐temperature steam condensation in the south and east of the sector. In some CP IV wells, separated entries for pre‐existent reservoir steam and reservoir liquid were identified. According to the analysis of 2005 data, relatively high temperatures (>300°C), high reservoir steam fractions (>0.4), and relatively low volumetric liquid saturations (<0.2) were estimated for fluids entering wells located along the southeast of CP IV. However, at the center of the sector the inflow of cooler waters moving down through the Fault H system was inferred to occur and was related to exploitation.
Co‐operative signalling through DP1 and DP2 prostanoid receptors is required to enhance leukotriene C4 synthesis induced by prostaglandin D2 in eosinophils
Authors: Mesquita‐Santos FP , Bakker‐Abreu I , Luna‐Gomes T , Bozza PT , Diaz BL , Bandeira‐Melo C 
Published: October 2010

BACKGROUND AND PURPOSE Prostaglandin (PG) D2 has emerged as a key mediator of allergic inflammatory pathologies and, particularly, PGD2 induces leukotriene (LT) C4 secretion from eosinophils. Here, we have characterized how PGD2 signals to induce LTC4 synthesis in eosinophils.EXPERIMENTAL APPROACH Antagonists and agonists of DP1 and DP2 prostanoid receptors were used in a model of PGD2‐induced eosinophilic inflammation in vivo and with PGD2‐stimulated human eosinophils in vitro, to identify PGD2 receptor(s) mediating LTC4 secretion. The signalling pathways involved were also investigated.KEY RESULTS In vivo and in vitro assays with receptor antagonists showed that PGD2‐triggered cysteinyl‐LT (cysLT) secretion depends on the activation of both DP1 and DP2 receptors. DP1 and DP2 receptor agonists elicited cysLTs production only after simultaneous activation of both receptors. In eosinophils, LTC4 synthesis, but not LTC4 transport/export, was activated by PGD2 receptor stimulation, and lipid bodies (lipid droplets) were the intracellular compartments of DP1/DP2 receptor‐driven LTC4 synthesis. Although not sufficient to trigger LTC4 synthesis by itself, DP1 receptor activation, signalling through protein kinase A, did activate the biogenesis of eosinophil lipid bodies, a process crucial for PGD2‐induced LTC4 synthesis. Similarly, concurrent DP2 receptor activation used Pertussis toxin‐sensitive and calcium‐dependent signalling pathways to achieve effective PGD2‐induced LTC4 synthesis.CONCLUSIONS AND IMPLICATIONS Based on pivotal roles of cysLTs in allergic inflammatory pathogenesis and the collaborative interaction between PGD2 receptors described here, our data suggest that both DP1 and DP2 receptor antagonists might be attractive candidates for anti‐allergic therapies.LINKED ARTICLE This article is commented on by Mackay and Stewart, pp. 1671–1673 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01236.x
Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations
Authors: Jones RL , Woodward DF , Wang JW , Clark RL 
Published: October 2010

BACKGROUND AND PURPOSEThe highly lipophilic acyl‐sulphonamides L‐798106 and L‐826266 showed surprisingly slow antagonism of the prostanoid EP3receptor system in guinea‐pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated.EXPERIMENTAL APPROACHAntagonist selectivity was assessed using a panel of human recombinant prostanoid receptor‐fluorimetric imaging plate reader assays. Potencies/affinities and onset half‐times of agonists and antagonists were obtained on guinea‐pig‐isolated aorta and vas deferens.n‐Octanol‐water partition coefficients were predicted.KEY RESULTSL‐798106, L‐826266 and the less lipophilic congener (DG)‐3ap appear to behave as selective, competitive‐reversible EP3antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3and TP (thromboxane‐like) agonism on guinea‐pig aorta (above pEC50of 8.0) were associated with progressively longer onset half‐times; similar trends were found for TP and histamine H1antagonism above a pA2limit of 8.0. In contrast, L‐798106 (EP3), L‐826266 (EP3, TP) and the lipophilic H1antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)‐3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3system were overall much faster, although trends were similar.CONCLUSIONS AND IMPLICATIONSHigh affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3antagonists is discussed.
Interaction of diltiazem with an intracellularly accessible binding site on CaV1.2
Authors: Shabbir W , Beyl S , Timin EN , Schellmann D , Erker T , Hohaus A , Hockerman GH , Hering S 
Published: October 2010

BACKGROUND AND PURPOSEDiltiazem inhibits CaV1.2 channels and is widely used in clinical practice to treat cardiovascular diseases. Binding determinants for diltiazem are located on segments IIIS6, IVS6 and the selectivity filter of the pore forming α1subunit of CaV1.2. The aim of the present study was to clarify the location of the diltiazem binding site making use of its membrane‐impermeable quaternary derivative d‐cis‐diltiazem (qDil) and mutant α1subunits.EXPERIMENTAL APPROACHCaV1.2 composed of α1, α2‐δ and β2a subunits were expressed in tsA‐201 cells and barium currents through CaV1.2 channels were recorded using the patch clamp method in the whole cell configuration. qDil was synthesized and applied to the intracellular side (via the patch pipette) or to the extracellular side of the membrane (by bath perfusion).KEY RESULTSQuaternary derivative d‐cis‐diltiazem inhibited CaV1.2 when applied to the intracellular side of the membrane in a use‐dependent manner (59 ± 4% at 300 µM) and induced only a low level of tonic (non‐use‐dependent) block (16 ± 2% at 300 µM) when applied to the extracellular side of the membrane. Mutations in IIIS6 and IVS6 that have previously been shown to reduce the sensitivity of CaV1.2 to tertiary diltiazem also had reduced sensitivity to intracellularly applied qDil.CONCLUSION AND IMPLICATIONSThe data show that use‐dependent block of in CaV1.2 by diltiazem occurs by interaction with a binding site accessible via a hydrophilic route from the intracellular side of the membrane.