bluuebunny/crossref_metadata_2025 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

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

Purpose

Advances a positive view of ageing and the importance of planning a purposeful future.

Findings

Argues 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 implications

Highlights the need for employees and employers to change their views of retirement, and make the most of the talent available, whatever its age.

Originality/value

Fits 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

Purpose

Highlights 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/approach

Gives 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.

Findings

Demonstrates 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 implications

Demonstrates how the training helped to improve flexibility, company reputation and employee morale at Birse Civils (NW).

Originality/value

Contains much to interest employers in high‐risk sectors such as construction.
Creating inspirational leadership at Cheltenham & Gloucester
Authors: Dawson Michael
Published: June 2005

Purpose

Describes 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/approach

Is based on information gathered during interviews with C&G's director of HR and senior HR manager.

Findings

Reveals 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 implications

Shows 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/value

Provides 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

Purpose

Highlights the reasons for the move to HR partnering and the advantages it can bring.

Design/methodology/approach

Suggests 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.

Findings

Advances 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 implications

Offers practical advice and suggestions on judging readiness for partnering, and for putting the key requirements in place.

Originality/value

Helps 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

Aim

To assess dosing and determinants of the choice of statins among starters of statins.

Methods

Data 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.

Results

In 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.

Conclusions

Many 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

Aims

The influence of efavirenz on lopinavir pharmacokinetics was investigated using a population approach.

Methods

Forty‐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.

Results

A 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).

Conclusions

These 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

Aims

To provide additional quantification of the risk of flucloxacillin‐related liver disease and to describe time trends in flucloxacillin prescribing in the UK.

Methods

This 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.

Results

We 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.

Conclusions

Flucloxacillin 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

Aims

Drug‐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.

Methods

We 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.

Results

Heart 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.

Conclusions

Alteration 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

Aims

To determine whether bosentan decreases the plasma concentration of sildenafil in patients with pulmonary arterial hypertension.

Methods

Ten 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.

Results

Treatment 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).

Conclusions

Bosentan 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

Objective  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

Background  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

Objective  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

Objective 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.
Ambulatory blood pressure monitoring in patients with hyperthyroidism before and after control of thyroid function
Authors: Iglesias P. , Acosta M. , Sánchez R. , Fernández‐Reyes M. J. , Mon C. , Díez J. J.
Published: June 2005

Background and Objective Thyroid hormones have pronounced effects on the cardiovascular system. Thyrotoxicosis affects blood pressure (BP), modifying both diastolic (DBP) and systolic (SBP) pressures. There are no studies examining BP with ambulatory blood pressure monitoring (ABPM) in hyperthyroidism before and after control of thyroid function. Our aims were (1) to analyse ABPM in a group of normotensive hyperthyroid patients before and after normalizing circulating thyroid hormones and (2) to compare these results with those obtained in a group of euthyroid subjects.

Patients and Measurements We studied 20 normotensive hyperthyroid subjects [18 women; age (mean ± SEM) 49·0 ± 3·0 years] and 15 healthy subjects. Patients were evaluated by ABPM over 24 h, at diagnosis and after therapy (n = 18).

Results The average 24‐h, daytime and night‐time SBP was significantly greater in hyperthyroid patients than in controls with no significant differences in DBP. Circadian BP rhythm, estimated by the difference between mean values of SBP, DBP and mean BP during daytime and night‐time, was unchanged. The average 24‐h and daytime SBP significantly decreased after normalizing thyroid function in the 18 hyperthyroid evaluated patients. Daytime SBP and DBP were higher than night‐time values both before and after control of thyroid function. However, no differences in circadian BP rhythm were observed.

Conclusions Normotensive hyperthyroid patients exhibit higher ambulatory SBP throughout 24 h than normotensive euthyroid subjects. Control of hyperthyroidism decreases ambulatory SBP values. Mean nocturnal fall in BP is comparable in normotensive hyperthyroid patients and control subjects.
Clinical evidence that hyperinsulinaemia independent of gonadotropins stimulates ovarian growth
Authors: Musso Carla , Shawker Thomas , Cochran Elaine , Javor Edward D. , Young Janice , Gorden Phillip
Published: June 2005

Objective  Ovarian enlargement is a constant feature of syndromes of extreme insulin resistance. The objective of this study is to show the role of insulin on ovarian growth in the presence of low gonadotropin levels.

Patients  Seven young patients with syndromes of extreme insulin resistance (five with lipodystrophy, one with Type B syndrome and one with Rabson–Mendenhall syndrome) were studied.

Measurements  Baseline LH concentrations and luteinizing hormone releasing hormone (LHRH) tests were performed. Total testosterone, insulin and C‐peptide values were measured. Pelvic ultrasounds were performed.

Results  Four patients were prepubertal (age range 7–10 years old) and had prepubertal gonadotropin levels, and 2 of the 4 who were tested did not respond to LHRH (NIH 10 and RM‐PAL). Three patients were Tanner stage 4 (age range 13–17 years old) and had low gonadotropins that did not respond to LHRH stimulation test. All seven patients had marked hyperinsulinaemia and 6 of 7 had at least one enlarged ovary. Testosterone values were increased in 4 of 7 patients.

Conclusion  This represents the first example of the pathologic role of insulin to stimulate ovarian growth with low circulating gonadotropins. Thus, while ovarian growth and steroidogenesis are normally stimulated by gonadotropins at puberty, hyperinsulinaemia stimulates pathologic growth of the ovary and an androgenic steroid profile that is active at all ages. We suggest that these patients constitute a model to separate the effect of insulin from gonadotropin in stimulating ovarian growth and/or steroidogenesis.
Differentiated thyroid carcinoma with distant metastases at presentation: prognostic factors and outcome
Authors: Haq M. , Harmer C.
Published: June 2005

BackgroundDifferentiated thyroid cancer (DTC) presenting with distant metastases is uncommon. Prognostic factors that affect survival remain unclear.

AimTo evaluate factors influencing the survival of patients with DTC presenting with distant metastases.

MethodA retrospective study of 111 patients (62 F, 49 M) with DTC who presented with distant metastases (M1) treated at the Royal Marsden Hospital from 1940 to 2002.

ResultsThe median follow‐up of living patients was 3·9 years (0·3–48) with a 10‐year cause‐specific survival rate of 31%. Histology identified 46 papillary, 60 follicular and five Hürthle cell cancers. Sites of metastases comprised 54 lung (49%), 27 bone (24%), 21 multiple sites (19%) and nine with other single sites affected (8%). Near‐total, total or completion thyroidectomy was performed in 56% of patients, radioiodine ablation in 76% and radioiodine therapy in 67%. External beam radiotherapy was given to 12 patients and the same number received chemotherapy. Univariate analysis was performed with cause‐specific survival as the main outcome measure. Age over 70, poorly differentiated tumours and Hürthle cell cancers were associated with worse outcomes (P < 0·01). Patients with multiple organ metastases had a worse survival (P = 0·02). Radical surgery did not significantly improve outcome compared to more conservative forms of surgery (subtotal thyroidectomy, hemi‐thyroidectomy or lobectomy) but patients receiving radioiodine ablation and therapy had improved survival (P < 0·01). Multivariate analysis identified age over 70, poorly differentiated tumours and Hürthle cell variant to be the only independent factors associated with worse outcome (P < 0·01). Treatment in the 1991–2002 era was associated with an improved survival compared to all previous decades (P = 0·009).

ConclusionsPatients with DTC presenting with distant metastases have a worse outcome if aged over 70, have poorly differentiated tumours or have Hürthle cell variant. Despite their unfavourable prognosis, a dramatic improvement in survival was observed in the most recent era (1991–2002).
Seladin‐1/DHCR24 expression in normal ovary, ovarian epithelial and granulosa tumours
Authors: Fuller Peter J. , Alexiadis Maria , Jobling Tom , McNeilage Jane
Published: June 2005

Objective  The human DIMINUTO/DWARF1 homolog seladin‐1/DHCR24 has been recently reported to be up‐regulated in adrenocortical adenomas. Seladin‐1 expression has been reported in the normal ovary. Granulosa cell tumours of the ovary (GCT) as with adrenocortical adenomas arise from a steroidogenic tissue, respond to pituitary hormone stimulation and synthesize steroid hormones.

Design  To test the hypothesis that seladin‐1 may also have a role in the pathogenesis of GCT, we determined the expression of seladin‐1 in a cohort of GCT and in mucinous and serous cystadenocarcinomas and in normal ovary.

Measurements  Expression was determined by RT‐PCR using gene specific primers and probes combined with Southern blot analysis of the PCR products.

Results  Seladin‐1 expression was identified in the normal ovary, mucinous cystadenocarcinomas and serous cystadenocarcinomas of the ovary whereas no expression was observed in the GCT.

Conclusions  Based on our results, seladin‐1 is not expressed in the granulosa cells or at least not in those that give rise to GCT.
Molecular mechanism of ubiquitin recognition by GGA3 GAT domain
Authors: Kawasaki Masato , Shiba Tomoo , Shiba Yoko , Yamaguchi Yoshiki , Matsugaki Naohiro , Igarashi Noriyuki , Suzuki Mamoru , Kato Ryuichi , Kato Koichi , Nakayama Kazuhisa , Wakatsuki Soichi
Published: June 2005

GGA (Golgi‐localizing, γ‐adaptin ear domain homology, ARF‐binding) proteins, which constitute a family of clathrin coat adaptor proteins, have recently been shown to be involved in the ubiquitin‐dependent sorting of receptors, through the interaction between the C‐terminal three‐helix‐bundle of the GAT (GGA and Tom1) domain (C‐GAT) and ubiquitin. We report here the crystal structure of human GGA3 C‐GAT in complex with ubiquitin. A hydrophobic patch on C‐GAT helices α1 and α2 forms a binding site for the hydrophobic Ile44 surface of ubiquitin. Two distinct orientations of ubiquitin Arg42 determine the shape and the charge distribution of ubiquitin Ile44 surface, leading to two different binding modes. Biochemical and NMR data strongly suggest another hydrophobic binding site on C‐GAT helices α2 and α3, opposite to the first binding site, also binds ubiquitin although weakly. The double‐sided ubiquitin binding provides the GAT domain with higher efficiency in recognizing ubiquitinated receptors for lysosomal receptor degradation.
Activation of c‐Jun amino‐terminal kinase by GDNF induces G2/M cell cycle delay linked with actin reorganization
Authors: Fukuda Toshifumi , Asai Naoya , Enomoto Atsushi , Takahashi Masahide
Published: June 2005

It is well known that the cell cycle is controlled by several cyclin/cyclin‐dependent kinase (Cdk) complexes whose expression and phosphorylation states vary with orderly periodicity. During the cell cycle, activity of the cyclin/Cdk complexes can be regulated directly or indirectly by a number of molecules, including protein kinases and phosphatases, p53, and Cdk inhibitors. Here, we show that the addition of glial cell line‐derived neurotrophic factor (GDNF) induced G2/M cell cycle delay in human SK‐N‐MC neuroectodermal tumor cells that express RET tyrosine kinase, accompanying actin reorganization. Cell cycle delay at G2/M was characterized by accelerated and prolonged Cdc2 phosphorylation and stabilization of cyclin B1 and Wee1 kinase expression. Interestingly, we found that phosphorylation and/or expression of Cdc2, cyclinB1, and Wee1 was controlled by the Rac1/c‐Jun NH2‐terminal kinase (JNK) pathway. Immunohistochemical analysis suggested that the G2/M cell cycle delay may be necessary to prevent the mitotic progression of SK‐N‐MC cells with perturbed actin cytoskeletons.
Health literacy: concept analysis
Authors: Speros Carolyn
Published: June 2005

Aim.  This paper reports an analysis of the concept of health literacy in order to clarify its meaning, reduce ambiguities associated with references to it, and promote consistency in using the concept in nursing dialogue and research.

Background.  Health literacy is a relatively new concept in health promotion research. Only within the last decade have researchers identified the problems associated with health literacy, the role it plays in an individual's ability to comprehend health and self‐care information, and its relationship to health outcomes. Clarifying the concept is essential so that nurses develop an awareness of the phenomenon and its relationship to the outcomes of their communication and health education efforts.

Method.  The method used for this concept analysis was that of Walker and Avant (1995).

Findings.  Health literacy empowers people to act appropriately in new and changing health‐related circumstances through the use of advanced cognitive and social skills. The defining attributes of health literacy are reading and numeracy skills, comprehension, the capacity to use information in health care decision‐making, and successful functioning as a healthcare consumer. Antecedents of health literacy are literacy and a health‐related experience. Consequences of health literacy include improved self‐reported health status, lower health care costs, increased health knowledge, shorter hospitalizations, and less frequent use of health care services. Empirical referents of the concept are the Test of Functional Health Literacy in Adults and the health literacy component of the National Assessment of Adult Literacy.

Conclusions.  An analysis of the concept of health literacy enhances nurses’ ability to assess more accurately their clients’ levels of health literacy, thus identifying those at risk for misunderstanding health care instructions, shame associated with inadequate reading skills, and inability to adhere to health care recommendations.
Transforming the obstetric nursing workforce in NE Brazil through international collaboration
Authors: Girot Elizabeth A. , Enders Bertha Cruz , Wright Joyce
Published: June 2005

Aims.  This paper seeks to analyse the content, people and process of transformational change to introduce new ways of working for specialized obstetric nurses in northeast Brazil, and identify the lessons learned.

Background.  Countries across the globe are beginning to focus on improving the nursing workforce through new ways of working. High numbers of caesarean sections coupled with high indices of maternal mortality in northeast Brazil prompted the introduction of a British Council Higher Education Links scheme to work collaboratively to transform the role of the specialist obstetric nurse and introduce the principles of Safe Motherhood. The concept of a normal birth had not been widely accepted, with the birth process viewed as a medical condition requiring pharmaco‐therapeutic interventions rather than as a natural process.

Method.  Between 2000 and 2003, a more woman‐centred approach to childbirth was introduced through the local delivery of two in‐house education programmes and the qualification of 38 nurse‐midwives.

Discussion.  In spite of its slow progress, the success of the Higher Education collaboration has been recognized nationally, a new philosophy is guiding practice and new ways of working have been established.

Conclusion.  Lessons learned include the need to set achievable goals (content), respond to the emotional needs of those involved in the change (people) and make best use of reciprocal visits to rally the teams and sustain the focus for change (process). Although the Higher Education link is complete, funds are being sought for formal evaluation and dissemination. Overall, the process and outcomes of this collaboration suggest that to embrace such an opportunity to learn from each other can lead to real improvements in service and the lives of women.
Influence of policies on nursing practice in long‐term care environments for older people
Authors: Tolson Debbie , Maclaren William , Kiely Sian , Lowndes Andrew
Published: June 2005

Aim.  This paper reports a study exploring nurses’ awareness of, access to and use of policies within long‐term care environments for older people in Scotland.

Background.  The provision of the highest quality of nursing care for older people with continuing care needs is facilitated through a number of strategic mechanisms. These encompass regulatory systems, national and local policies and care guidance. Failure of practitioners to engage with the ‘policy context’ may compromise care standards.

Method.  This was a two‐stage investigation. A Delphi approach with 33 panel members was used to generate consensus as to the 10 most important current policies in this area of practice. A postal survey was undertaken with 2072 nurses to identify the practice impact of policies, including the 10 identified items.

Findings.  Identification of the 10 most important policies proved challenging for panel members. Initially they identified 137 policy items, which were reduced after clustering and two further rounds to 10 items (consensus agreement 57%). Completed questionnaires were returned by 986 (48%) nurses. A long list of problems limited access to policy information. Nurses reported little time to keep up to date, compounded by communication inefficiencies and limited access to the internet. Awareness of the 10 selected items ranged from 46 to 83% and clarity of the practice message was high (85–94%); however, the reported influence on practice varied, with 10–26% of respondents indicating no effect. Professional priorities did not coincide with the priorities of older people themselves.

Conclusion.  Nurses appear bewildered by the number and status of policy items. Current methods to provide nurses with information and keep them up to date were not ideal. Processes need to be developed that will engage nurses in policy and pursue closer alignment with the priorities of older people. Strategies are required to identify key policies and promote their implementation.
Day treatment programme for patients with eating disorders: randomized controlled trial
Authors: Kong Seongsook
Published: June 2005

Aim.  This paper reports a randomized controlled trial to compare the effects of day treatment programmes for patients with eating disorders with those of traditional outpatient treatment.

Background.  Eating disorders are common, especially in adolescents, and their worldwide prevalence is increasing. Treatment interventions for patients with eating disorders have traditionally been offered on an outpatient or inpatient basis, but the recent introduction of day hospital programmes offers the possibility of greater cost‐effectiveness and relapse‐prevention for this population.

Methods.  Volunteers from an outpatient clinic for eating disorders were randomly assigned either to a treatment group (n = 21), participating in a modified day treatment programme based on the Toronto Day Hospital Program, or to a control group (n = 22) receiving a traditional outpatient programme of interpersonal psychotherapy, cognitive behaviour therapy and pharmacotherapy. Data were collected from January to December 2002 using the Eating Disorder Examination, Eating Disorder Inventory‐2, Beck Depression Inventory, and Rosenberg Self‐Esteem Scale.

Results.  Participants in the day treatment programme showed significantly greater improvements on most psychological symptoms of the Eating Disorder Inventory‐2, frequency of binging and purging, body mass index, depression and self‐esteem scores than the control group. They also showed significant improvement in perfectionism, but the group difference was not significant.

Conclusion.  Nurses in day treatment programmes can play various and important roles establishing a therapeutic alliance between patient and carer in the initial period of treatment. In addition, the cognitive and behavioural work that is vital to a patient's recovery, that is, dealing with food issues, weight issues and self‐esteem, is most effectively provided by a nurse therapist who maintains an empathic involvement with the patient.
Producing the magnum opus: a metaphor for nephrology nursing expertise acquisition
Authors: Bonner Ann , Greenwood Jennifer
Published: June 2005

Aim. This paper elucidates the nature of metaphor and the conditions necessary to its use as an analytic device in qualitative research, and describes how the use of metaphor assisted in the analytic processes of a grounded theory study of nephrology nursing expertise.

Background. The use of metaphor is pervasive in everyday thought, language and action. It is an important means for the comprehension and management of everyday life, and makes challenging or problematic concepts easier to explain. Metaphors are also pervasive in quantitative and qualitative research for the same reason. In both everyday life and in research, their use may be implicit or explicit.

Methods. The study using grounded theory methodology took place in one renal unit in New South Wales, Australia between 1999 and 2000 and included six non‐expert and 11 expert nurses. It involved simultaneous data collection and analysis using participant observation, semi‐structured interviews and review of nursing documentation.

Findings. A three stage skills‐acquisitive process was identified in which an orchestral metaphor was used to explain the relationships between stages and to satisfactorily capture the data coded within each stage.

Conclusion. Metaphors create images, clarify and add depth to meanings and, if used appropriately and explicitly in qualitative research, can capture data at highly conceptual levels. Metaphors also assist in explaining the relationship between findings in a clear and coherent manner.
Discourse analysis: towards an understanding of its place in nursing
Authors: Crowe Marie
Published: June 2005

Aim.  This paper describes how discourse analysis, and in particular critical discourse analysis, can be used in nursing research, and provides an example to illustrate the techniques involved.

Background.  Discourse analysis has risen to prominence in the 1980s and 1990s in disciplines such as the social sciences, literary theory and cultural studies and is increasingly used in nursing. This paper investigates discourse analysis as a useful methodology for conducting nursing research. Effective clinical reasoning relies on employing several different kinds of knowledge and research that draw on different perspectives, methodologies and techniques to generate breadth of knowledge and depth of understanding of clinical practices and patients’ experiences of those practices.

Discussion.  The steps in a discourse analysis include: choosing the text, and identifying the explicit purpose of the text, the processes used for claiming authority connections to other discourses, construction of major concepts, processes of naming and categorizing, construction of subject positions, construction of reality and social relations and implications for the practice of nursing. The limitations of discourse analysis, its relationship to other qualitative approaches and questions for evaluating the rigour of research using discourse analysis are also explored. The example of discourse analysis shows how a text influences the practice of nursing by shaping knowledge, values and beliefs.

Conclusion.  Discourse analysis can make a contribution to the development of nursing knowledge by providing a research strategy to examine dominant discourses that influence nursing practice.
Graduated compression stockings as prophylaxis for flight‐related venous thrombosis: systematic literature review
Authors: Hsieh Hsiu‐Fang , Lee Feng‐Ping
Published: June 2005

Aim.  This paper reports a systematic review whose objective was to evaluate the effectiveness of graduated compression stockings as prophylaxis for flight‐related venous thrombosis, including deep vein thrombosis and superficial venous thrombosis, after air travel in the general population.

Background.  Despite the extended history of the use of graduated compression stockings, their application to prevent flight‐related thrombosis was not explored until flight‐related thrombosis was perceived as a preventable illness. Even now, their effectiveness in preventing flight‐related thrombosis remains unresolved.

Methods.  Generic terms including stocking/s, sock/s, or hosiery/hosieries were used to search a variety of electronic databases. Based on the selection criteria, decisions regarding inclusion and exclusion of primary studies were made. Using a meta‐analysis software program, relative risk for the incidence of deep vein thrombosis, superficial venous thrombosis, and intention‐to‐treat analysis was calculated.

Results.  A total of nine randomized controlled trials were included. In the treatment group, two of 1237 participants developed deep vein thrombosis in comparison with 46 of 1245 in the control group. The weighted relative risk for deep vein thrombosis was 0·08, with fixed 95% confidence interval 0·03–0·23. In the treatment group, four of 826 participants developed superficial venous thrombosis in comparison with seven of 823 in the control group. The weighted relative risk for superficial venous thrombosis was 0·67. with fixed 95% confidence interval 0·24–1·87 (non‐significant difference). Using intention‐to‐treat analysis, the risk for participants in the treatment group was 0·53 times as great as that for those in the control group.

Conclusions.  This review demonstrates the effectiveness of medium compression pressure, below‐knee graduated compression stockings in preventing flight‐related deep vein thrombosis but not superficial venous thrombosis in low‐medium‐ or high‐risk participants.