bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compilation of mRNA Polyadenylation Signals in Arabidopsis Revealed a New Signal Element and Potential Secondary Structures
Authors: Loke Johnny C. , Stahlberg Eric A. , Strenski David G. , Haas Brian J. , Wood Paul Chris , Li Qingshun Quinn 
Published: June 2005

Abstract
Using a novel program, SignalSleuth, and a database containing authenticated polyadenylation [poly(A)] sites, we analyzed the composition of mRNA poly(A) signals in Arabidopsis (Arabidopsis thaliana), and reevaluated previously described cis-elements within the 3′-untranslated (UTR) regions, including near upstream elements and far upstream elements. As predicted, there are absences of high-consensus signal patterns. The AAUAAA signal topped the near upstream elements patterns and was found within the predicted location to only approximately 10% of 3′-UTRs. More importantly, we identified a new set, named cleavage elements, of poly(A) signals flanking both sides of the cleavage site. These cis-elements were not previously revealed by conventional mutagenesis and are contemplated as a cluster of signals for cleavage site recognition. Moreover, a single-nucleotide profile scan on the 3′-UTR regions unveiled a distinct arrangement of alternate stretches of U and A nucleotides, which led to a prediction of the formation of secondary structures. Using an RNA secondary structure prediction program, mFold, we identified three main types of secondary structures on the sequences analyzed. Surprisingly, these observed secondary structures were all interrupted in previously constructed mutations in these regions. These results will enable us to revise the current model of plant poly(A) signals and to develop tools to predict 3′-ends for gene annotation.
Ageing – “Carpe diem” has no use‐by date
Authors: Rabey Gordon 
Published: June 2005

PurposeAdvances a positive view of ageing and the importance of planning a purposeful future.FindingsArgues the case for the introduction into the employment contract of a flexible retirement clause after an agreed period. Puts forward a five point WIIFM (what's in it for me?) index for comparing the options.Practical implicationsHighlights the need for employees and employers to change their views of retirement, and make the most of the talent available, whatever its age.Originality/valueFits the concept of “retirement” into the new regime of flexible and short‐term contracts.
Training hones the safety culture at Birse Civils Ltd
Authors: Mottram Caroline 
Published: June 2005

PurposeHighlights the improvement in the safety record of Birse Civils (NW) that resulted, at least in part, from a training program that won a regional training award in the most recent UK National Training Awards.Design/methodology/approachGives the inside story of what gave rise to the training “need”, how the training was developed, the numbers and grades of employee trained, and the outcomes of the training.FindingsDemonstrates that the four training programs described – site‐safety management, Construction Skills Certification Scheme, first‐aid training and “appointed person” training for lifting operations – have helped to bring about an almost unprecedented zero accident rate for the company.Practical implicationsDemonstrates how the training helped to improve flexibility, company reputation and employee morale at Birse Civils (NW).Originality/valueContains much to interest employers in high‐risk sectors such as construction.
Creating inspirational leadership at Cheltenham & Gloucester
Authors: Dawson Michael 
Published: June 2005

PurposeDescribes how an inspirational‐leadership program for senior managers at Cheltenham & Gloucester, one of the UK's largest mortgage lenders, is generating enthusiasm and energy within the business and helping the managers to get the best out of their teams, using more than just basic management techniques.Design/methodology/approachIs based on information gathered during interviews with C&G's director of HR and senior HR manager.FindingsReveals how the program, designed in close collaboration with development specialist Roffey Park, features six “forums”, which run over a 12‐month period, with each forum lasting one or two days. Recounts how the first five forums cover leadership and the leader's role during change, driving improvement, winning commitment (including the leader's use of communication), getting results and enhancing team effectiveness, while the final forum is a presentation by the participants on the results of a workplace assignment, undertaken as part of the learning. Describes the benefits that C&G has obtained by running the program.Practical implicationsShows that one of the key benefits of the program is that it brings together top managers from different parts of the organization, since organizers deliberately mix and match the cohort groups and ensure that the participants stay together for the whole program.Originality/valueProvides plenty to interest senior HR specialists who are keen to use senior management development to boost motivation and improve teamwork in their organizations.
Ready for HR partnering?
Authors: Goodge Peter 
Published: June 2005

PurposeHighlights the reasons for the move to HR partnering and the advantages it can bring.Design/methodology/approachSuggests three essentials of successful HR partnering – understanding, resources and credibility. Explores each in some depth, and illustrates them with cases based on the experience of European companies.FindingsAdvances the view that there is no one best way to implement partnering; the HR model and its pace of introduction should be tailored to the organization.Practical implicationsOffers practical advice and suggestions on judging readiness for partnering, and for putting the key requirements in place.Originality/valueHelps readers to gauge their organizations’ readiness for partnering, and to avoid some of the pitfalls. Also proves valuable to organizations that have begun their partnering journey.
Suboptimal choices and dosing of statins at start of therapy
Authors: Mantel‐Teeuwisse Aukje K. , Klungel Olaf H. , Schalekamp Tom , Verschuren W. M. Monique , Porsius Arijan J. , De Boer Anthonius 
Published: June 2005

AimTo assess dosing and determinants of the choice of statins among starters of statins.MethodsData were obtained from the PHARMO database comprising pharmacy and linked hospital discharge records of approximately 300 000 subjects in the Netherlands. All new users of statins in 1998 were selected. Patient characteristics and drug regimens were compared between starters of different statins. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using polytomous logistic regression modelling, using the start of simvastatin therapy as reference category.ResultsIn 1998, 1738 patients started using simvastatin (41.1%), pravastatin (23.1%), fluvastatin (11.9%), atorvastatin (22.8%) or cerivastatin (1.0%). Compared with starters with simvastatin [mean dose 1.02 ± 0.39 defined daily doses (DDDs)], starters with pravastatin (1.27 ± 0.56 DDDs) and atorvastatin (1.43 ± 0.59 DDDs) received higher doses (P < 0.001), whereas users of fluvastatin (0.78 ± 0.37 DDDs) and cerivastatin (0.81 ± 0.30 DDDs) received lower doses (P < 0.001). Patients already using CYP3A4 inhibitors more frequently received fluvastatin (OR = 1.80; 95% CI 1.11, 2.94), metabolized by non‐CYP3A4 pathways, and atorvastatin (OR = 1.62; 95% CI 1.06, 2.47), which is metabolized by CYP3A4, than simvastatin. Statin doses were not adjusted when prescribed to patients using CYP3A4 inhibitors.ConclusionsMany patients starting statin therapy did not receive a statin of first choice. The coadministration of potentially interacting drugs may have led to a change in statin choice, but not in dosage lowering. These findings suggest that the quality of statin therapy could be improved.
Pharmacokinetic evidence for the induction of lopinavir metabolism by efavirenz
Authors: Dailly Eric , Allavena Clotilde , Raffi François , Jolliet Pascale 
Published: June 2005

AimsThe influence of efavirenz on lopinavir pharmacokinetics was investigated using a population approach.MethodsForty‐five HIV patients treated with lopinavir/ritonavir plus efavirenz (A) and 24 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (B) were studied.ResultsA relationship (P < 0.01) was established between the elimination rate constant of lopinavir (k10) and treatment with efavirenz. Mean k10 was higher in group A than in group B (0.3838 vs 0.2810 h−1) (P < 0.001, 95% confidence interval for difference between means 0.1004, 0.1052).ConclusionsThese results suggest that lopinavir metabolism is induced by efavirenz.
Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: Cohort study using data from the UK General Practice Research Database
Authors: Russmann Stefan , Kaye James A. , Jick Susan S. , Jick Hershel 
Published: June 2005

AimsTo provide additional quantification of the risk of flucloxacillin‐related liver disease and to describe time trends in flucloxacillin prescribing in the UK.MethodsThis was a cohort study using data from the UK General Practice Research Database. We identified patients with a first‐time prescription for flucloxacillin or, for comparison, oxytetracycline from 1992 to 2002 and cases who developed clinically documented cholestatic liver disease of uncertain origin after first‐time use of these drugs. We also determined the annual frequency of first‐time use of flucloxacillin from 1991 to 2000.ResultsWe identified 283 097 and 131 189 first‐time users of flucloxacillin and oxytetracycline, respectively. The risk of cholestatic liver disease per 100 000 first‐time users was 8.5 (95% CI 5.4, 12.6) in the 1–45 days and 1.8 (95% CI 0.6, 4.1) in the 46–90 days after starting flucloxacillin, and 0.8 (95% CI 0.02, 4.3) in the 1–45 days after starting oxytetracycline. The frequency of first‐time use of flucloxacillin remained stable between 1991 and 2000.ConclusionsFlucloxacillin is now established as an important cause of cholestatic liver disease. Warnings about the risk have not had an impact on prescribing practices in the UK, where it remains the predominantly prescribed antistaphylococcal oral antibiotic. This situation in the UK is in sharp contrast to regulatory actions and changes in prescribing habits in Australia after identification of the risk of cholestasis associated with flucloxacillin, and to the predominant use of the alternative drug dicloxacillin in the USA.
Investigation of the effects of physiological and vasodilation‐induced autonomic activation on the QTc Interval in healthy male subjects
Authors: Berger E. , Patel K. , Anwar S. , Davies W. , Sheridan D. J. 
Published: June 2005

AimsDrug‐induced prolongation of the QTc interval is an important marker for potential proarrhythmic action. Prolongation of the QTc interval results from alteration of the ionic currents that regulate cardiac repolarisation. Such effects may result from direct drug action or alternatively they could also occur indirectly by drug‐induced modulation of autonomic tone, which is known to regulate cardiac repolarization. This study examined the effects of physiological and drug‐induced autonomic activation on heart rate, QT and QTc intervals.MethodsWe studied 29 healthy male subjects aged 18–30 years. Electrocardiographs were recorded before and during autonomic activation induced by mental activation, standing, exercise and glyceryl trinitrate (GTN) (0.5 mg sublingual)‐induced vasodilation in the presence and absence of β‐blockade (atenolol 100 mg daily for 4 days). QT intervals were measured manually by electronic callipers and corrected using the Fridericia formula.ResultsHeart rates were significantly increased during mental arithmetic, standing, exercise and GTN and this effect was significantly attenuated by atenolol, except for mental activation. QTc intervals were significantly reduced on standing and exercise and this was significantly attenuated by atenolol during exercise. In contrast, GTN increased QTc intervals (Δ = 5.7 ms, confidence interval ± 3.2 ms, P < 0.005) and this was not attenuated by atenolol.ConclusionsAlteration in QTc intervals may result from physiological manoeuvres and vasodilation, interventions known to induce autonomic activation. We suggest that QTc prolongation due to GTN is indirectly mediated and unlikely to carry any proarrhythmic effect. Understanding whether drug‐induced QTc prolongation is directly or indirectly mediated may be important to determine any potential proarrhythmic risk.
Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension
Authors: Paul Gideon A. , Gibbs J Simon R. , Boobis Alan R. , Abbas Allifia , Wilkins Martin R. 
Published: June 2005

AimsTo determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension.MethodsTen patients (aged 39‐77 years) with pulmonary arterial hypertension in WHO functional class III received bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily for a second month. Sildenafil 100 mg was given as a single dose before starting bosentan (visit 1) and at the end of each month of bosentan treatment (visits 2 and 3). Sildenafil and its primary metabolite, desmethylsildenafil, were measured in plasma at 0 h and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h using liquid chromatography‐tandem mass spectrometry. Statistical analysis was by repeated measures anova, using log transformed data where appropriate.ResultsTreatment with bosentan 62.5 mg twice daily for 4 weeks was associated with a two‐fold increase in sildenafil clearance/F and a 50% decrease in the AUC (P < 0.001). Increasing the dose of bosentan to 125 mg twice daily led to a further increase in sildenafil oral clearance and decrease in the AUC (P < 0.001 vs. 62.5 mg bosentan). The ratio of AUC on bosentan treatment relative to that of visit 1 was 0.47 [95% confidence interval (CI) 0.36, 0.61] for visit 2 and 0.31 (95% CI 0.23, 0.41) for visit 3 (P < 0.001). Sildenafil Cmax fell from 759 ng ml−1 on visit 1 to 333 ng ml−1 on visit 3 (P < 0.01) and there was a significant decrease in the plasma half‐life of sildenafil on the higher bosentan dose (P < 0.05). The AUC and plasma half‐life of desmethylsildenafil was also decreased by bosentan in a dose‐dependent manner (P < 0.01).ConclusionsBosentan significantly decreases the plasma concentration of sildenafil when coadministered to patients with pulmonary hypertension.
Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD)
Authors: Turton James P. G. , Mehta Ameeta , Raza Jamal , Woods Kathryn S. , Tiulpakov Anatoly , Cassar Joseph , Chong Kling , Thomas Paul Q. , Eunice Marumudi , Ammini Ariachery C. , Bouloux Pierre M. , Starzyk Jerzy , Hindmarsh Peter C. , Dattani Mehul T. 
Published: June 2005

SummaryObjective  Mutations within the pituitary‐specific paired‐like homeobox gene PROP1 have been described in 50–100% of patients with familial combined pituitary hormone deficiency (CPHD). We screened a cohort of sporadic (n = 189) and familial (n = 44) patients with hypopituitarism (153 CPHD and 80 isolated hormone deficiencies) for mutations within the coding sequence of PROP1.Design and patients  Patients with congenital hypopituitarism were recruited from the London Centre for Paediatric Endocrinology as well as several national and international centres. The pituitary phenotype ranged from isolated growth hormone deficiency (IGHD) to panhypopituitarism. Clinical data, including endocrine and neuro‐radiological studies were obtained from patient records, and DNA was collected and screened for mutations within PROP1 using PCR and single‐stranded conformation polymorphism (SSCP) analysis. Positive results on SSCP were sequenced directly.Results  The prevalence of PROP1 mutations in unselected sporadic cases of hypopituitarism was lower (1·1%) than in familial cases (29·5%). PROP1 mutations can be associated with a highly variable phenotype, and both pituitary hypoplasia and pituitary hyperplasia. We describe the waxing and waning of a pituitary mass over 20 months in association with a PROP1 mutation that is predicted to lead to complete loss of function. Additionally, we have identified a possible founder mutation in CPHD patients from the Indian subcontinent.Conclusions  PROP1 mutations are rare in sporadic cases of CPHD, although the prevalence rises if there is a positive family history or if the patients are carefully selected with respect to the endocrine and neuroradiological phenotype. There is considerable phenotypic variability in families with the same mutation, indicating the role of other genetic or environmental factors on phenotypic expression. Finally, the pituitary enlargement that is observed in patients with PROP1 mutations can wax and wane in size before eventual involution.
Short‐term testosterone supplementation does not activate GH and IGF‐I production in postmenopausal women
Authors: Soares‐Welch Cacia , Mielke Kristi L. , Bowers Cyril Y. , Veldhuis Johannes D. 
Published: June 2005

SummaryBackground  Testosterone (Te), oestradiol, GH and IGF‐I concentrations fall in postmenopausal women.Objective  To test the effect of increased Te availability on impoverished GH/IGF‐I secretion in this context.Design/patients  Placebo (Pl) and a low vs. high dose of Te were administered transdermally for 7 days to each of 15 healthy older women (ages 48–81 years) in a randomized, double‐blind crossover design.Measurements  Frequent blood sampling, GHRP‐2 (Growth hormone releasing peptide‐2) infusion, and deconvolution analysis were used to assess GH secretion.Results  Graded Te supplementation increased serum Te concentrations (nmol/l) from 0·87 ± 0·06 [Pl] to 5 ± 1 [low] and 7·3 ± 1·6 [high] (P < 0·001), but did not affect: (i) pulsatile GH secretion (µg/l/12 h; conversion factor: 1 µg/l = 0·33 mU/l), 29 ± 7·2, 32 ± 5·6 and 27 ± 4·9; (ii) GH regularity (approximate entropy), 0·52 ± 0·05, 0·57 ± 0·05 and 0·56 ± 0·05; (iii) IGF‐I concentrations (µg/l; conversion factor: 1 µg/l = 0·131 nmol/l), 126 ± 13, 135 ± 15 and 141 ± 13; (iv) IGFBP‐3 (mg/l), 3·7 ± 0·2, 3·6 ± 0·1 and 3·7 ± 0·2; (v) IGFBP‐1 (µg/l), 41 ± 2·3, 44 ± 3·8 and 44 ± 3·2; and (vi) the mass of GH secreted (µg/l/3 h) after GHRP‐2 injection, 123 ± 27, 146 ± 32 and 147 ± 38.Conclusion  Up to 8‐fold elevation of Te concentrations for 1 week in postmenopausal women does not detectably amplify GH secretion or action, thus indicating that low androgen availability is not a proximate acute mediator of hyposomatotropism in postmenopausal individuals.
Endogenous oestrogens are related to cognition in healthy elderly women
Authors: Lebrun Corinne E. I. , Van Der Schouw Yvonne T. , De Jong Frank H. , Pols Huibert A. P. , Grobbee Diederick E. , Lamberts Steven W. J. 
Published: June 2005

SummaryObjective  To investigate whether levels of endogenous hormones, in particular circulating oestrogens and SHBG, are associated with cognition in healthy postmenopausal women.Design  Cross‐sectional study.Patients  Four hundred and two healthy postmenopausal women aged 50–74 years between 8 and 30 years after menopause, none taking oestrogen.Measurements  Serum concentration of oestradiol, oestrone, and sex hormone binding globulin (SHBG) determined by immunoassay. Cognition assessed using the mini‐mental state examination questionnaire (MMSE).Results  In this group, 149 individuals had a MMSE score < 27, while only 89 individuals had a MMSE score < 26, indicating a relatively healthy population with regard to cognitive ability. Cognition decreased with age, time since menopause and blood pressure, and was better with higher age at menopause. Serum oestrogens and SHBG levels were not related to age, age at menopause, or time since menopause, and oestrogen levels were positively associated with blood pressure. After adjustment for mean arterial pressure and SHBG, the frequency of mild cognitive impairment decreased significantly with higher oestradiol and oestrone serum levels [ORs Q5 vs. Q1: 0·41 (95% CI 0·20–0·84) and 0·51 (95% CI 0·20–0·99) for oestradiol and oestrone, respectively].Conclusions  Postmenopausal women with higher remaining circulating oestradiol levels appear less likely to suffer from cognitive impairment. This effect is independent of age at menopause, time since menopause and BMI. These findings support the hypothesis that endogenous oestrogens may protect against cognitive decline with ageing.
Severe hypoleptinaemia associated with insulin resistance in patients with common variable immunodeficiency
Authors: Ferraroni Natasha Rebouças , Geloneze Bruno , Mansour Eli , Perroud Ana Paula , Muscelli Elza O. , Tambascia Marcos , De Lima Zollner Ricardo , Velloso Licio Augusto 
Published: June 2005

SummaryObjective Common variable immunodeficiency (CVI) is a primary immunodeficiency syndrome characterized by impaired production of antibodies and recurrent infections. Delay in diagnosis leads to metabolic wastage and low body weight. Leptin, a hormone produced by white adipose tissue, modulates insulin action by signal transduction cross‐talk and by direct action on pancreatic beta‐cells. We hypothesized that patients with CVI might present a defective regulation of leptin production and insulin resistance.Patients Thirteen CVI patients (39 ± 11 years) under gammaglobulin replacement were evaluated in parallel with 13 gender‐, age‐, body weight‐ and body mass index (BMI)‐matched healthy voluntaries, and with data from two large population series, the Bruneck and the Hoorn Studies.Measurements Serum leptin and insulin levels, homeostasis model assessment – insulin resistance (HOMA‐IR), body composition, haematological, biochemical and immunoglobulin measurements were obtained. Data were analysed by a one‐way analysis of variance (anova) and by Pearson's rank analysis. The institutional ethics committee approved the study, and informed consent was obtained from patients and controls.Results No differences were found between CVI and the control group when comparing gender distribution, age, body weight, BMI, waist/hip ratio, relative body fat and fasting glucose levels. Leptin levels were lower (P < 0·05) in CVI patients than in controls and lower than fasting leptin levels detected in a large population study. CVI patients’ serum leptin levels did not correlate with BMI (r = 0·074, P = 0·8) and their high HOMA‐IR indicated insulin resistance.Conclusions CVI patients are relatively hypoleptinaemic and insulin resistant, and their serum leptin levels are not correlated to their BMI.