bluuebunny/crossref_metadata_2025_split huggingface dataset:
CYP3A5 phenotype‐genotype correlations in a British population
Authors: King Barry P. , Leathart Julian B. S. , Mutch Elaine , Williams Faith M. , Daly Ann K. 
Published: June 2003

Aims  To develop a polymerase chain reaction (PCR)‐restriction fragment length polymorphism (RFLP)‐based assay to genotype for hepatic CYP3A5 expression and to use this assay to study a British population.Methods  CYP3A5‐specific PCR primers were designed with one including a base‐pair mismatch to create a RsaI site in samples positive for A6986 (CYP3A5*1 allele). Following PCR and RsaI digestion, different band patterns on electrophoresis were predicted for individuals positive for CYP3A5 (CYP3A5*1 allele) compared with those who do not express the gene (CYP3A5*3 homozygotes). The assay was validated by DNA sequencing. DNA samples from a human liver bank consisting of 22 livers whose CYP3A5 expression had been determined by immunoblotting and a group of random individuals (n = 100) from the North‐east of England were genotyped by the new assay.Results  In the liver bank, five out of 22 samples expressed CYP3A5 at significant levels (>20 pmol mg−1 protein) and were found to have the genotype CYP3A5*1/CYP3A5*3 by the PCR‐RFLP assay. All other liver DNA samples were CYP3A5*3 homozygotes. In the group of 100 random individuals, 13 had the genotype CYP3A5*1/CYP3A5*3 and all others were CYP3A5*3 homozygotes, predicting that 13% (95% confidence interval (CI) 6%, 20%) would show significant hepatic CYP3A5 expression. The frequency for the CYP3A5*1 allele was 0.065 (95% CI 0.032, 0.097).Conclusions  We have developed a simple assay for the detection of the CYP3A5*1/CYP3A5*3 alleles and shown that in a British population their frequency is similar to that reported previously. We have also shown a good correlation between hepatic CYP3A5 expression and genotype for a British Caucasian liver bank.
Polymorphic hydroxylation of perhexiline in vitro
Authors: Sørensen L. B. , Sørensen R. N. , Miners J. O. , Somogyi A. A. , Grgurinovich N. , Birkett D. J. 
Published: June 2003

Aims  The aims of this study were to examine the in vitro enzyme kinetics and CYP isoform selectivity of perhexiline monohydroxylation using human liver microsomes.Methods  Conversion of rac‐perhexiline to monohydroxyperhexiline by human liver microsomes was assessed using a high‐performance liquid chromatography assay with precolumn derivatization to measure the formation rate of the product. Isoform selective inhibitors were used to define the CYP isoform profile of perhexiline monohydroxylation.Results  The rate of perhexiline monohydroxylation with microsomes from 20 livers varied 50‐fold. The activity in 18 phenotypic perhexiline extensive metabolizer (PEM) livers varied about five‐fold. The apparent Km was 3.3 ± 1.5 µm, the Vmax was 9.1 ± 3.1 pmol min−1 mg−1 microsomal protein and the in vitro intrinsic clearance (Vmax/Km) was 2.9 ± 0.5 µl min−1 mg−1 microsomal protein in the extensive metabolizer livers. The corresponding values in the poor metabolizer livers were: apparent Km 124 ± 141 µm; Vmax 1.4 ± 0.6 pmol min−1 mg−1 microsomal protein; and intrinsic clearance 0.026 µl min−1 mg−1 microsomal protein. Quinidine almost completely inhibited perhexiline monohydroxylation activity, but inhibitors selective for other CYP isoforms had little effect.Conclusions  Perhexiline monohydroxylation is almost exclusively catalysed by CYP2D6 with activities being about 100‐fold lower in CYP2D6 poor metabolizers than in extensive metabolizers. The in vitro data predict the in vivo saturable metabolism and pharmacogenetics of perhexiline.
Influence of age on the enantiomeric disposition of ibuprofen in healthy volunteers
Authors: Tan Soo Choon , Patel Bhavesh K. , Jackson Stephen H. D. , Swift Cameron G. , Hutt Andrew J. 
Published: June 2003

Aims
To determine the influence of age on the enantioselective disposition of ibuprofen in humans.
Methods
Healthy young (n = 16; aged 20–36 years) and elderly (n = 16; aged 66–84 years) volunteers were given a 400‐mg oral dose of racemic ibuprofen, and blood and urine samples were collected for 24 h post drug administration. Serum concentrations, total and free, and urinary excretion of both enantiomers of ibuprofen together with the urinary excretion of the stereoisomers of the two major metabolites of the drug, both free and conjugated, were determined by high‐performance liquid chromatography.
Results
Ageing had little effect on the distribution and metabolism of R‐ibuprofen, unbound clearance of the R‐enantiomer via inversion being approximately two‐fold that via noninversion mechanisms in both age groups. In contrast, the free fraction of S‐ibuprofen was significantly greater [33%; young 0.48 ± 0.10%; elderly 0.64 ± 0.20%] mean difference −0.16; 95% confidence interval (CI) −0.05, −0.27; P < 0.01; and the unbound clearance of the drug enantiomer was significantly lower (28%; young 15.9 ± 2.2 l min−1; elderly 11.5 ± 4.1 l min−1; mean difference 4.4; 95% CI 2.12, 6.68; P < 0.001) in the elderly. The metabolite formation clearances of S‐ibuprofen via glucuronidation, and oxidation at the 2‐ and 3‐ positions of the isobutyl side chain decreased by 24, 28 and 30%, respectively, in the elderly compared with the young, the differences between the two age groups being significant in each case (P < 0.05).
Conclusions
Following administration of racemic ibuprofen age‐associated stereoselective alterations in drug disposition have been observed, with the elderly having increased free concentrations and lower unbound clearance of the S‐enantiomer in comparison with the young. In contrast, the handling of the R‐enantiomer is essentially unaltered with age. The results of this study indicate that the elderly have an increased exposure to the active ibuprofen enantiomer and thus some caution may be required when using this drug in this age group.
Chronotherapy of high‐dose active vitamin D3 in haemodialysis patients with secondary hyperparathyroidsm: a repeated dosing study
Authors: Tsuruoka Shuichi , Wakaumi Michi , Sugimoto Koichi , Saito Tetsuo , Fujimura Akio 
Published: June 2003

Aims  Renal osteodystrophy is the major complication in patients with end‐stage renal failure. Oral or intravenous vitamin D3 (D3) is given to these patients, but severe hypercalcaemia sometimes interrupts this therapy. This study was undertaken to determine whether the effectiveness and safety of D3 also depend on its dosing time during a repeated treatment.Methods  A higher dose (3 µg) was given orally to 13 haemodialysis patients at 08.00 h or 20.00 h for 12 months by a randomized, cross‐over design.Results  Three patients were withdrawn due to severe hypercalcaemia after switching from 08.00 h to 20.00 h dosings. The elevation in serum calcium concentration was significantly (P < 0.001) greater during the 08.00 h dosing in the remaining ten patients. Mean serum Ca concentration after the trial was 10.92 (95% confidence interval (CI) 10.79, 11.06) and 9.55 mg dl−1 (95% CI 9.30, 9.71) by 08.00 h and 20.00 h dosing, respectively. On the other hand, the suppression of the elevated serum parathyroid hormone (PTH) and subsequent increment in bone density were significantly greater during the 08.00 h dosing. Mean PTH concentration after the trial was 414 (95% CI 360, 475) and 220 pg ml−1 (95% CI 202, 249) by 08.00 h and 20.00 h dosing, respectively (P = 0.02). Mean increment of bone density after the trial was 22 (95% CI 8, 32) and 57 g cm−3 (95% CI 43, 83) by 08.00 h and 20.00 h dosing, respectively (P = 0.04).Conclusion  These results indicate that a higher dose of oral D3 is more effective and safe after dosing at evening in patients with renal osteodystrophy.
A proof of concept study to evaluate putative benefits of montelukast in moderate persistent asthmatics
Authors: Currie Graeme P. , Lee Daniel K. C. , Dempsey Owen J. , Fowler Stephen J. , Cowan Louise M. , Lipworth Brian J. 
Published: June 2003

Aims  Whether chronic dosing with montelukast confers benefit in patients with moderate to severe asthma remains to be fully established. A proof of concept study was performed evaluating putative benefits with montelukast in moderate persistent asthmatics who were taken off inhaled corticosteroids (ICS) and switched to salmeterol. The latter was done to dissociate the effects of montelukast from ICS.Methods  Twenty moderate to severe persistent asthmatics completed a randomized double‐blind crossover study. Subjects received montelukast 10 mg daily or placebo for 2 weeks each. This was preceded by a  2‐week run‐in when ICS were discontinued and salmeterol started, and used on a regular basis throughout the study. Measurements were made after run‐in and after both randomized treatments.Results  There were no significant sequence effects for responses as to whether placebo or montelukast were given first or second. Methacholine PD20 values after run‐in, first and second placebo were 63 µg, 60 µg and 64 µg, respectively (corresponding to 2, 4 and 6 weeks of ICS washout, respectively). Lung function deteriorated pre vs post run‐in, which was significant (P < 0.05) for FEF25‐75 % predicted. Montelukast conferred significant (P < 0.05) improvements as change from post run‐in compared with placebo in methacholine PD20, FEV1 % predicted, FEF25‐75 % predicted, diurnal peak expiratory flow, symptoms and salbutamol use. For the primary outcome of methacholine PD20, this amounted to a 1.6‐fold difference (95% CI 1.1, 2.5).Conclusions  In moderate persistent asthmatics switched from taking ICS to salmeterol alone, adding montelukast conferred significant benefits on all parameters of asthma control. Further studies are indicated to evaluate whether montelukast exhibits additive effects to ICS/long‐acting β2‐adrenoceptor agonist combination inhalers upon clinically important outcomes.
Choosing a safe place to cross the road: the relationship between attention and identification of safe and dangerous road‐crossing sites
Authors: Tabibi Z. , Pfeffer K. 
Published: June 2003

AbstractBackground  Safe pedestrian behaviour relies on cognitive skills, including the ability to focus attention on the traffic environment and ignore irrelevant stimuli. An important pedestrian skill that young children find difficult is the ability to find a safe place to cross the road. The aim of this study was to examine the relationship between attention and children's ability to identify safe and dangerous road‐crossing sites.Methods  Participants were 95 children (aged 6.5 years, 8.6 years and 10.4 years) and 33 adults. Ability to identify safe and dangerous road‐crossing sites was assessed using computer presentations of five safe and five dangerous sites. Attention was assessed using the Stroop test for resistance to interference. Correlations were calculated between Stroop test measures and pedestrian task measures (accuracy and speed of identifying safe and dangerous road‐crossing sites) for each age group separately.Results  The ability to identify safe and dangerous road‐crossing sites and the ability to resist interference increased with age. Significant correlations were observed between identification of safe and dangerous road‐crossing sites and performance on the Stroop test for children but not for adults.Discussion  The results indicated that attention is required for identifying road‐crossing sites quickly and accurately, especially for younger children. Road safety training programmes for children may need to take into account the development of children's attention.
A 12‐month follow‐up of preschool children investigating the natural history of speech and language delay
Authors: Roulstone S. , Peters T. J. , Glogowska M. , Enderby P. 
Published: June 2003

AbstractAim  The aim of this paper is to examine the natural history of early speech and language delay in preschool children over a 12‐month period.Methods  The study reports data on 69 children under the age of 3.5 years who were referred for speech and language therapy because of early speech and language delay. The children were monitored over a 12‐month period but received no direct intervention during that time. Assessment of their comprehension, expressive language and their phonology took place at baseline and again at 6 and 12 months after baseline.Results  The results show a general picture of improvement, although there was considerable individual variation. By the end of the 12 months, two‐thirds of the children were still eligible on the study intake criteria. Therapist's rating of a child's functional communication at the outset was a significant predictor of the child's outcome at the end of the 12‐month period.Discussion  The paper discusses the appropriateness of a ‘monitoring’ approach to the management of early language delay and highlights the need to consider the social issues and views of parents as well as the severity of a child's difficulties.
Sustained performance and regulation of effort in clinical and non‐clinical hyperactive children
Authors: Berlin L. , Bohlin G. , Nyberg L. , Janols L.‐O. 
Published: June 2003

AbstractObjective  To study sustained performance and its relation to regulation of effort among four different groups of children: two clinical subgroups of children diagnosed with attention‐deficit hyperactivity disorder (ADHD) – one with and one without comorbid oppositional defiant disorder (ODD); a control sample of children without a diagnosis of ADHD but with parental reports of hyperactivity; and a normal control sample.Methods  Sustained performance was studied (n= 64) using a choice reaction time task with long interstimulus intervals, and hyperactive behaviour and regulation of effort was rated throughout the task.Results  The clinical sample differed from the normal controls regarding all measures of overall, but not initial, performance. When studying performance over time, the ADHD group was shown to differ from the normal controls with regard to omissions, mean reaction time and regulation of effort. No significant differences were found between the ADHD children with or without comorbid ODD. The non‐clinical hyperactive children differed from the normal controls with regard to reaction time, initially and overall, and regulation of effort overall.Conclusions  Deficits in sustained performance among ADHD children appear to be evident when long interstimulus intervals are used, and these deficits are related to poor regulation of effort. Further, the observed differences between ADHD children and normal controls do not appear to be a result of comorbid conduct problems. The non‐clinical hyperactive children were more similar to the control group than to the ADHD group.
Promoting mental health and emotional well‐being among children and youth: a role for community child health?
Authors: Alperstein G. , Raman S. 
Published: June 2003

Introduction‘Teenage suicides double as the future crumbles’ with collapse of the economy in Argentina (Arie 2002). Schizophrenia ‘linked to racism’, a study reveals among ethnic minorities in London (Boydell et al. 2001).The promotion of emotional well‐being focuses on improving environments (social, physical, economic) that affect emotional well‐being and enhancing the ‘coping’ capacity of communities as well as individuals (Wood & Wise 1997). What improvements in the ‘environment’ are required, and how does one ‘enhance coping’ in order to promote emotional well‐being? What is the role of those working in community child health in promoting mental health and emotional well‐being?Most of the research on the determinants of the health and well‐being of populations have focused on physical health problems, particularly mortality and life expectancy (Marmot & Wilkinson 1999). There is less research on the ‘upstream’ (socioeconomic) determinants of mental health problems, and even less on emotional well‐being and enhancing ‘coping’ or promoting resilience. Examples of upstream determinants of mental health problems include good evidence linking the prevalence of mental health problems of children and young people to income, educational status and family structure (Sawyer et al. 2001). Male youth suicide has been linked to such upstream determinants as relative unemployment rates. Suicide has increased with increasing ratio of youth to overall unemployment rates (Morrell et al. 2001). A significantly higher risk of suicide in Australia over the past century was shown to be associated with conservative governments compared with social democratic government tenures (Page et al. 2002).
Attitudes and practices regarding circumcision in Turkey
Authors: Şahin F. , Beyazova U. , Aktürk A. 
Published: June 2003

AbstractBackground  In Turkey, circumcision is a necessity for boys to gain a masculine identity. In contrast to Western societies, where circumcision is performed in the neonatal period, it is performed at older ages in our population, and the timing may affect the psychosocial well‐being of males. The person who performs the operation, a physician or a traditional circumciser, may affect their health as well.Objective  To provide some information about the practice of circumcision in Turkey, such as timing, by whom and why it is performed in our country, and relation of their fathers’ past emotions about their own circumcision to this current practice.Methods  Questionnaires were filled out in face‐to‐face interviews with parents of 1235 male children under 16 years of age who attended well‐child clinics of Gazi University Hospital and 10 different primary health care centres throughout Ankara, Turkey.Results  Median age of circumcision was found to be 6 years. Only 14.8% of children were circumcised before 1 year of age. The main reasons for circumcision were religious and traditional. The medical benefits of the procedure outweighed the traditional reasons for only 15.2% of the families. The operation was carried out by a traditional circumciser in 13.3% of the children. Most of the fathers who could remember their own emotions about circumcision confessed that they had been frightened. They remembered the procedure as painful. Indeed, the mean age of their sons’ circumcision was close to their own circumcision age.Conclusions  Traditions still play an important role in the timing of circumcision and by whom and why it is performed in Turkey. Changing times and educational levels do not seem to affect the traditional approach to circumcision.
Predictors of a child's ability to use a visual analogue scale
Authors: Shields B. J. , Palermo T. M. , Powers J. D. , Grewe S. D. , Smith G. A. 
Published: June 2003

AbstractBackground  Visual analogue scales (VAS) are used to assess the strength of perceptions of both children and adults in many clinical and research settings. Although the VAS has been shown by some authors to be reliable for use by children aged 5 years and older, others have proposed that young children, generally ≤ 7 years of age, may not have the conceptual ability to use a VAS.Objective  To identify demographic and cognitive variables that would maximize the accuracy of predicting children's abilities to use a VAS.Methods  Forty kindergarten children performed a seriation task, used a VAS to perform a calibration task and completed the Block Design and Vocabulary subtests of the Wechsler Preschool and Primary Scale of Intelligence – Revised (WPPSI‐R). An estimated IQ was calculated from the WPPSI‐R subtest scores. Socioeconomic status was assessed using the Hollingshead Four Factor Index of Social Status. Logistic regression was used to determine the best predictive models. Sensitivity, specificity, negative predictive value, positive predictive value and accuracy were calculated for statistically significant predictive models.Main outcome measure  Successful completion of the calibration study by the child.Results  Only 42% of the subjects could use a VAS. The subject's age (≥ 5.6 years), combined with estimated IQ (≥ 100), was the best predictor of a child's ability to use a VAS (88% accuracy).Conclusion  The majority of kindergarten children in our study could not complete a VAS accurately. Cognitive ability, combined with chronological age, was the best predictor of a child's accurate use of a VAS, as determined by logistic regression. Paediatric researchers may need to consider alternative rating scales to measure perceptions in children under 7 years of age.
Children with a tracheostomy: experience of their carers in school
Authors: Smith J. C. , Williams J. , Gibbin K. P. 
Published: June 2003

AbstractObjective  Tracheostomies in children are increasingly performed for chronic medical conditions. There are no published studies reporting the experience of children with a tracheostomy in school. Such information would be valuable in planning the care and education of these children. The aims of this study were to identify those children with a tracheostomy in Nottinghamshire schools and determine the support they were receiving.Design, setting and participants  Questionnaire survey to families and school carers of 11 children with a tracheostomy.Results  All children of school age were in full‐time education (five mainstream, five special schools). One preschool child attended a Family Centre. Four had problems finding suitable carers, delaying return to school in three. Four parents were dissatisfied with aspects of the child's experience at school: two felt the teaching staff were unsupportive, one was unhappy with the care of the tracheostomy, and one had problems funding a carer. Ten out of 11 school carers were satisfied with their training; 10 would have liked regular update sessions. The amount of care required varied. Those with complex medical problems in a special school setting needed frequent care, and one had required admission to hospital from school. One child had time off school because of lack of carer availability. Those who were severely disabled had less time off school for ill health after the tracheostomy than before the tracheostomy.Conclusion  Children with tracheostomies can successfully and safely achieve full‐time education in both mainstream and special schools. A dedicated multidisciplinary team, including input from the parents, is essential to achieve this goal. Regular revision of skills and information sessions for the teaching staff would be beneficial.