bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Teaching safe and effective prescribing in UK medical schools: a core curriculum for tomorrow's doctors
Authors: Maxwell Simon , Walley Tom
Published: June 2003

There is a pressing need for medical graduates to be fully prepared to take on the responsibilities of prescribing and to be able to respond to continual inevitable rapid changes in therapeutics. The curricula in UK medical schools were greatly influenced by Tomorrow's Doctors, published by the General Medical Council in 1993. This has recently been updated. While it highlights the management of disease and use of drugs as key learning objectives, it offers little specific guidance. In this document we expand on these broad statements, provide a view of how these learning objectives might be achieved, and identify the key elements of a core curriculum in prescribing and therapeutics.
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

Background  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

Aim  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

Objective  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

Background  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

Background  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

Objective  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.
A cluster analysis of road traffic‐related childhood knee injuries
Authors: Iakovakis I. , Dessypris N. , Dalamaga M. , Petridou E.
Published: June 2003

Background  Knee injuries represent an important category of road traffic injuries among children, and they are heterogeneous in their aetiology. The aims of this study were to estimate the incidence of road traffic childhood knee injuries in Greece by age and gender, point out their time, place and person co‐ordinates and identify clusters with distinct characteristics with a view to potential preventive interventions.

Methods  During a 3‐year period, 305 children with knee injuries resulting from a road traffic accident were identified among the 66 870 children with injuries recorded in the Emergency Department Injury Surveillance System (EDISS) of Greece. Using previously derived sampling ratios and national data on childhood population, incidence data by age and gender were estimated. Hierarchical analysis was undertaken for cluster identification.

Results  The incidence of road traffic knee injuries was 97.5 per 100 000 children–years. The incidence increased with age and was higher among boys than among girls. Most childhood knee injuries (50.2%) occur among pedestrians, and the majority (90.9%) of the children or their guardians admitted responsibility in crossing the road. Of the 31 children injured as car passengers, the vast majority (87.1%) were unrestrained, and a large fraction (38.7%) were front seat passengers. Two clusters were identified: the first consisted of younger children who resided mostly in the Athens area and suffered less serious knee injuries as pedestrians or car passengers during the colder months; the second consisted of older children, frequently tourists, who suffered more serious injuries as cyclists while vacationing.

Conclusions  Many of the children who suffered road traffic knee injuries as pedestrians admitted responsibility in road crossing, whereas a large proportion of children who were injured as car passengers were injured while improperly seated in the front and without seatbelt protection. Older children, frequently tourists, were at high risk of knee injuries while using motorcycles and bicycles.
Why do parents decide against immunization? The effect of health beliefs and health professionals
Authors: Smailbegovic M. S. , Laing G. J. , Bedford H.
Published: June 2003

Objectives  To explore the knowledge, attitudes and concerns with respect to immunization and vaccine‐preventable infections in parents whose children have not completed the recommended course of immunization.

Setting  Parents of children resident in the London Borough of Hackney.

Methods   Children born between 1 January 1999 and 15 February 1999 were identified from the child health database, and cases were defined as those who had defaulted for one or more primary immunization by 18 months of age. After validation of immunization status from health records, questionnaires were sent to parents. Ten respondents from this sample were interviewed.

Results   Questionnaires were sent to 129 parents of children identified as not completing the recommended immunization course. Nine questionnaires were returned ‘address unknown’, and 76 parents returned the completed questionnaire. The response rate from known residents was 76/110 (69%). Eight parents stated that their child had been immunized, leaving 68 questionnaires available for further analysis. Measles, mumps, rubella (MMR) and meningococcal C were most frequently omitted, usually because of concerns about vaccine safety. Twenty‐three out of 68 respondents perceived that having their child immunized with a particular vaccine was more risky than non‐immunization, particularly for MMR and meningococcal C vaccines. Those who agreed to be interviewed were notably concerned about the MMR vaccine, but not immunization in general. They perceived the information provided by health professionals to be poor.

Conclusions   The decision‐making process around childhood immunization is complex. Parents require information that is up to date, tailored to their individual needs and provided by health professionals who are well informed.
Recovery of T‐cell subsets after antiretroviral therapy in HIV‐infected children
Authors: Resino S. , Bellón J. Ma. , Gurbindo D. , León J. A. , Muñoz‐Fernández Ma. Á.
Published: June 2003

Background Variation of percentageCD4+ T cells may accurately reflects the kinetics of a comprehensive immune recovery independently of the antiretroviral (ART) regimen. To test this we have investigated the relationship among peripheral blood T‐cell subsets with the variation of percentageCD4+ T cells during follow up in 49 HIV‐infected children.

Methods Children were divided into two groups according to the sign of slope percentageCD4+ T cell during follow up: Ps‐group (positive slope) and Ns‐group (negative percentageCD4 slope) indicative of immunological recovery or not, respectively. CD4+ and CD8+ T‐cell subset percentages were examined by three‐colour flow cytometry.

Results We found higher memory CD4+ and CD8+ T‐cell percentages in the Ns‐group than in the Ps‐group, and inversely, higher naive CD4+ and CD8+ T cells in the Ps‐group than in the Ns‐group. CD4+ and CD8+ subsets in the Ps‐group expressed higher levels of CD38+ and lower levels of HLA‐DR+ compared with the Ns‐group. We found a very strong positive correlation among the slope of percentageCD4+, CD4+ CD38+, whereas a negative correlation among the slope of percentageCD4+, the CD8+ CD28+ CD57+ and CD8+ CD57+ T‐cell subsets.

Conclusion Recovery of the CD4+ T‐cell percentage induced by ART reflects a reduction in the chronic immune activation and a measurable reconstitution of the immune system and depends on naive CD4+ T cells.
Fibrinogen, inflammation and concentric left ventricular hypertrophy in chronic renal failure
Authors: Zoccali C. , Benedetto F. A. , Mallamaci F. , Tripepi G. , Cutrupi S. , Parlongo S. , Malatino L. S. , Bonanno G. , Rapisarda F. , Fatuzzo P. , Seminara G. , Nicocia G. , Buemi M.
Published: June 2003

Background We investigated the relationship between fibrinogen and echocardiographic measurements of left ventricular (LV) geometry and LV function in a group of 192 patients with end stage renal disease (ESRD).

Results Patients in the third fibrinogen tertile had higher mean wall thickness (MWT), relative wall thickness (RWT) and left ventricular mass index (LVMI) and lower LV end diastolic diameter and LV ejection fraction than those in the other tertiles. On multivariate analysis fibrinogen resulted to be an independent correlate of MWT (P = 0·001) and RWT (P = 0·0001) and the first factor in rank explaining the variance in LV ejection fraction (P = 0·0001). Left ventricular concentric hypertrophy was more prevalent (P = 0·001) in patients in the third fibrinogen tertile (n = 35, 54%) than in those in the second (n = 24, 37%) and first (n = 13, 21%) tertiles. In a multiple logistic regression model patients in the third tertile of fibrinogen had a risk for left ventricular concentric hypertrophy that was 3·56 (95%CI: 1·56–8·14) fold higher than in those in the first tertile (P = 0·003).

Conclusions Elevated fibrinogen is independently associated with LV concentric hypertrophy and systolic dysfunction in ESRD patients. These relationships may contribute to the negative prognostic impact of elevated fibrinogen levels in ESRD.
Impaired cardiovagal and vasomotor responses to baroreceptor stimulation in type II diabetes mellitus
Authors: Sanya E. O. , Brown C. M. , Dütsch M. , Zikeli U. , Neundörfer B. , Hilz M. J.
Published: June 2003

Background In diabetic patients, impairment of the cardiovagal limb of the baroreflex has been well established. However, the role of sympathetic mediated baroreflex vasomotor control of the blood vessels is not well defined. We therefore assessed the vasomotor responses to sinusoidal baroreceptor stimulation in diabetic patients.

Materials and methods We studied 14 type II diabetic patients (age; 57 ± 7 years) and 18 healthy controls (age; 59 ± 11 years). Oscillatory neck suction was applied at 0·1 Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0·2 Hz to assess the effect of parasympathetic stimulation on the heart. Breathing was paced at 0·25 Hz. Spectral analysis was used to evaluate the oscillatory responses of RR‐interval and blood pressure.

Results The diabetic patients showed a significantly lower RR‐interval response (P < 0·05) to the 0·1 Hz neck suction (2·52 ± 0·50–3·62 ± 0·54 ln ms2) than the controls (4·23 ± 0·31–6·74 ± 0·36 ln ms2). The increase in power of 0·1 Hz systolic blood pressure oscillations during 0·1 Hz suction was also significantly smaller (P < 0·05) in the diabetics (1·17 ± 0·44–1·69 ± 0·44 mmHg2) than in the controls (1·60 ± 0·29 mmHg2−5·87 ± 1·25 mmHg2). The magnitude of the peak of the 0·2 Hz oscillation in the RR‐interval in response to 0·2 Hz neck stimulation was significantly greater (P < 0·05) in the controls (3·42 ± 0·46 ln ms2) than in the diabetics (1·58 ± 0·44 ln ms2).

Conclusion In addition to cardiovagal dysfunction, baroreflex‐mediated sympathetic modulation of the blood vessels is impaired in type II diabetic patients.
Decreased cortisol production in male type 1 diabetic patients
Authors: Kerstens M. N. , Luik P. T. , Van Der Kleij F. G. H. , Boonstra A. H. , Breukelman H. , Sluiter W. J. , Navis G. J. , Dullaart R. P. F.
Published: June 2003

Background It is unclear whether cortisol production and the 11βHSD‐mediated cortisol to cortisone interconversion are different between type 1 diabetic patients and healthy subjects.

Materials and methods Fourteen male, nonobese, normotensive type 1 diabetic patients without severe complications (HbA1c < 8·5%) were studied twice during a daily sodium intake of 50 and 200 mmol, and were then compared with 14 individually matched healthy subjects. Cortisol production was assessed by the sum of urinary cortisol metabolite excretion. Urinary ratios of (tetrahydrocortisol + allo‐tetrahydrocortisol)/tetrahydro‐cortisone [(THF + allo‐THF)/THE] and of free cortisol/free cortisone [UFF/UFE] were determined as parameters of 11βHSD activity.

Results Sum of urinary cortisol metabolite excretion during low‐ and high‐salt diet was 7·4 ± 2·5 vs. 7·7 ± 2·3 nmol min−1 m−2 (NS) in diabetic patients and 9·7 ± 2·1 vs. 11·2 ± 4·1 nmol min−1 m−2 (NS) in healthy subjects, respectively (P < 0·05 vs. healthy subjects at both diets). The allo‐THF excretion and allo‐THF/THF ratios were lower in the diabetic than in the healthy males during both diets (P < 0·05). Urinary (THF + alloTHF)/THE and UFF/UFE were similar in both groups and remained unchanged after salt loading.

Conclusions The sum of urinary cortisol metabolite excretion as a measure of cortisol production is lower in nonobese, normotensive type 1 diabetic males with adequate glycaemic control and without severe complications, irrespective of sodium intake. We suggest that this is at least in part as result of diminished 5α reductase activity, resulting in a decreased cortisol metabolic clearance. In type 1 diabetic and in healthy males, the 11βHSD setpoint is not affected by physiological variations in sodium intake.
Numbers of colony‐forming progenitors in patients with systemic mastocytosis: potential diagnostic implications and comparison with myeloproliferative disorders
Authors: Jordan J.‐H. , Jäger E. , Sperr W. R. , Schwarzinger I. , Födinger M. , Fritsche‐Polanz R. , Öhler L. , Geissler K. , Valent P.
Published: June 2003

Background An increase in colony‐forming progenitor cells (CFU) is typically seen in myeloproliferative disorders (MPD). Systemic mastocytosis (SM) is a haemopoietic neoplasm involving myeloid progenitors similar to MPD. In the present study, we measured the levels of peripheral blood (pb) and bone marrow (bm) CFU in patients with different categories of SM, and compared them with those obtained in MPD patients and healthy controls.

Materials and methods Numbers of CFU (CFU‐GM, BFU‐E, CFU‐GEMM) were measured in a colony assay in 25 patients with SM [indolent SM (ISM), n = 15; smouldering SM (SSM), n = 3; SM with an associated haematologic clonal non‐mast cell lineage disease (SM‐AHNMD), n = 5; aggressive SM (ASM), n = 1; mast cell leukaemia (MCL), n = 1] and 37 with MPD [chronic myeloid leukaemia (CML), n = 10; polycythemia vera (PV), n = 8; essential thrombocytosis (ET), n = 9; idiopathic myelofibrosis (IMF), n = 10].

Results In the patients with MPD, elevated numbers of pb CFU were detected in all groups when compared with healthy controls (P < 0·05). In most of the patients with ISM, circulating CFU levels (CFU‐GM, BFU‐E, and CFU‐GEMM) were within the normal range. In SSM, pb CFU‐GM levels were normal in two patients, and elevated in a third patient. In the ‘SM‐AHNMD‐group’, CFU levels were found to reflect the nature of the AHNMD: in SM with concomitant acute myeloid leukaemia (SM‐AML, n = 2), the levels of CFU were low or undetectable, whereas in SM with chronic myelomonocytic leukaemia (SM‐CMML, n = 2), elevated numbers of pb CFU‐GM were found.

Conclusion The numbers of CFU are normal in patients with ISM, but elevated in some patients with SSM and SM‐CMML. An elevated CFU level in SM should raise the suspicion of an associated MPD (CMML) or smouldering SM, a novel SM‐subtype that shares several features with MPD and sometimes progresses to an overt SM‐MPD.
Measurement of the soluble angiopoietin receptor tie‐2 in patients with coronary artery disease: development and application of an immunoassay
Authors: Chung N. A. Y. , Makin A. J. , Lip G. Y. H.
Published: June 2003

Background The angiopoietin family has emerged as a group of crucial growth factors to normal angiogenesis. They are essential to the development of the mature vessel wall and interact with the endothelium via endothelial cell‐specific tyrosine kinase receptors, tie‐1 and tie‐2. The role of the tie‐2 receptor has been extensively examined in neovascularization associated with malignancy, but little is known about the role it may play in atherosclerosis, a condition whose pathophysiology also involves angiogenesis. Soluble tie‐2 has been detected in the plasma of healthy controls, but this has yet to be applied to patients in the clinical setting.

Materials and methods We developed an ELISA to detect plasma tie‐2 levels and applied these to a clinical setting. The intra‐ and interassay coefficients of variation for the assay were 4·7% and 9·6%, respectively. We then measured levels of tie‐2, vascular endothelial growth factor (VEGF), another factor associated with angiogenesis, and the soluble VEGF receptor Flt‐1 (sFlt‐1) in 75 patients with coronary artery disease [25 with acute myocardial infarction (AMI), 25 with acute coronary syndromes (ACS) and 25 with stable angina] and 25 healthy controls.

Results Median [IQR, interquartile range] levels of tie‐2 were significantly higher in the coronary artery disease patients (AMI 12 [10–17] ng mL−1, ACS 10 [9–14] ng mL−1, stable angina 9 [3–11] ng mL−1) when compared with the controls (7·5 [7–9] ng mL−1P = 0·004). As expected, levels of VEGF and sFlt were significantly different from those in the healthy controls (P = 0·011 and P < 0·001, respectively). Significant correlations were found between levels of tie‐2 and VEGF (Spearman r = 0·59, P < 0·001), tie‐2 and sFlt‐1 (r = 0·45, P < 0·001) and VEGF and sFlt‐1 (r = 0·56, P < 0·001) in the whole study group.

Conclusion We suggest that tie‐2 may be potentially used as a marker of angiogenesis in atherosclerosis and may help elucidate the role of the angiopoietin/tie‐2 system in atherogenesis.
Effects of rosiglitazone and linoleic acid on human preadipocyte differentiation
Authors: Hutley L. J. , Newell F. M. , Joyner J. M. , Suchting S. J. , Herington A. C. , Cameron D. P. , Prins J. B.
Published: June 2003

Background Peroxisome proliferator activated receptor gamma (PPARγ) is a ligand‐activated transcription factor known to be central to both adipose tissue development and insulin action. Growth of adipose tissue requires differentiation of preadipocytes with acquisition of specific cellular functions including insulin sensitivity, leptin secretion and the capacity to store triglyceride. Dietary fatty acids and members of the thiazolidinedione class of compounds have been reported to influence adipogenesis at the transcriptional level. Here, we compare the effects of a dietary fatty acid, linoleic acid, and a thiazolidinedione, rosiglitazone, on biochemical and functional aspects of human preadipocyte differentiation in vitro.

Materials and methods Human omental and subcutaneous preadipocytes were subcultured 2–3 times and subsequently differentiated for 21 days in the presence of either linoleic acid or rosiglitazone. Differentiation was assessed using a number of biochemical and functional parameters.

Results Omental and subcutaneous preadipocytes differentiated in the presence of linoleic acid showed marked cytoplasmic triacylglycerol accumulation however, no biochemical markers of differentiation (LPL expression, G3PDH gene expression and enzyme activity and leptin expression or secretion) were detected. In contrast, treatment of these cells with rosiglitazone induced full biochemical differentiation as judged by all markers assessed, despite comparatively little lipid accumulation. The rosiglitazone effects were subcutaneous depot‐specific. Cells treated with linoleic acid showed decreased glucose uptake cf rosiglitazone‐treated cells. A luciferase reporter assay demonstrated that rosiglitazone potently activates h‐peroxisome proliferator activated receptor gamma while linoleic acid had no effect.

Conclusions These studies demonstrate that (a) human preadipocytes have the potential to accumulate triacylglycerol irrespective of their stage of biochemical differentiation; (b) while omental preadipocytes are refractory to biochemical differentiation in vitro, they are able to accumulate triacylglycerol; and (c) rosiglitazone and linoleic acid may exert their effects via different biochemical pathways.
Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin
Authors: IJzerman R. G. , De Jongh R. T. , Beijk M. A. M. , Van Weissenbruch M. M. , Delemarre‐van de Waal H. A. , Serné E. H. , Stehouwer C. D. A.
Published: June 2003

Background To investigate whether microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function, we investigated skin microvascular function in individuals with increased coronary heart disease (CHD) risk.

Materials and methods Forty‐six healthy White individuals aged 30–70 years were studied. Coronary heart disease risk was assessed with the use of the CHD risk score according to the Framingham Heart Study, which is based on the risk factors age, blood pressure, cigarette smoking, total cholesterol, HDL cholesterol and diabetes. Endothelium‐dependent and ‐independent vasodilation in skin were evaluated with laser Doppler after iontophoresis of acetylcholine and sodium nitroprusside. Videomicroscopy was used to measure recruitment of skin capillaries after arterial occlusion.

Results Coronary heart disease risk score (i.e. the 10‐year probability of CHD) varied from 1–37%. Microvascular function decreased with increasing quartiles of CHD risk (for acetylcholine‐mediated vasodilation: 687, 585, 420 and 326%, P = 0·002; for nitroprusside‐mediated vasodilation: 776, 582, 513 and 366%, P = 0·02; for capillary recruitment: 49·9, 44·6, 27·2 and 26·7%, P = 0·001). These trends were similar in men and women (P for interaction > 0·2) and independent of body mass index.

Conclusions Increased CHD risk is associated with an impaired endothelium‐dependent vasodilatation and capillary recruitment in skin, suggesting that microvascular function in skin is a valid model to study the relationships between cardiovascular risk factors and microvascular function.
Low mast cell density in the human duodenal mucosa from chronic inflammatory duodenal bowel disorders is associated with defective villous architecture
Authors: Crivellato E. , Finato N. , Isola M. , Ribatti D. , Beltrami C. A.
Published: June 2003

Background Mast cells (MC) have recently been implicated in the processes of tissue homeostasis, remodeling and repair.

Design In this study, the total and tryptase‐reactive mast cell populations were quantified in the duodenal mucosa of 27 subjects suffering from chronic inflammatory bowel disorders. Mast cell density was both related to the general villous architecture (normal or defective) and to the microvascular density in the duodenal mucosa.

Results Total mast cell and tryptase‐positive mast cell subpopulation densities were found to be significantly reduced in the samples with defective villous architecture in comparison with those exhibiting a normal villous profile. In these last samples, a relevant proportion of mucosal mast cells exhibited ultrastructural features of secretory activity, in particular piecemeal degranulation. Finally, no correlation was established between microvascular density and tryptase activity, as it has been previously demonstrated in other pathological conditions.

Conclusions Overall, these findings indicate a significant correlation between mast cell density and the duodenal mucosal architecture.
Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease
Authors: Jonasson T. F. , Hedner T. , Hultberg B. , Öhlin H.
Published: June 2003

Background Elevated plasma total homocysteine appears to be related to endothelial dysfunction and impaired nitric oxide production. We aimed to investigate [1] whether elevated levels of plasma total homocysteine are associated with high plasma levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, and [2] whether reduction of plasma total homocysteine levels by folate and vitamin B supplementation lowers plasma concentration of asymmetric dimethylarginine.

Materials and methods Sixty patients with ischaemic heart disease and with plasma total homocysteine levels of 15·0 µmol L−1 were randomized to open therapy with folic acid, pyridoxine and cyancobalamin for 3 months (n = 30) or to no treatment (n = 30). Samples were also obtained from 34 patients with plasma total homocysteine levels of 8·0 µmol L−1 on admission.

Results Plasma asymmetric dimethylarginine concentrations in patients with elevated total homocysteine levels were not significantly higher (0·68 ± 0·19 µmol L−1) than in patients with low total homocysteine levels (0·61 ± 0·10 µmol L−1; P = 0·08). Plasma asymmetric dimethylarginine level in the vitamin supplemented group was 0·65 ± 0·12 µmol L−1 before, and 0·64 ± 0·12 µmol L−1 after 3 months of vitamin supplementation (NS). Plasma asymmetric dimethylarginine levels were correlated with serum cystatin C levels (P < 0·001).

Conclusion A nonsignificant trend to increased plasma levels of asymmetric dimethylarginine in patients with high plasma total homocysteine levels may be explained by concomitant subtle renal dysfunction. Substantial reduction of plasma total homocysteine did not affect the level of plasma asymmetric dimethylarginine.
Immune activation and degradation of tryptophan in coronary heart disease
Authors: Wirleitner B. , Rudzite V. , Neurauter G. , Murr C. , Kalnins U. , Erglis A. , Trusinskis K. , Fuchs D.
Published: June 2003

Background Inflammation and immune activation appear to be important in the pathogenesis of coronary heart disease (CHD). Cytokine interferon‐γ, which is released during cell‐mediated immune responses, induces indoleamine (2,3)‐dioxygenase (IDO), an enzyme degrading tryptophan to kynurenine. Therefore, immune stimulation is commonly associated with an increased kynurenine to tryptophan ratio (kyn trp−1) indicative for activated indoleamine (2,3)‐dioxygenase and a measurable decline of tryptophan.

Methods Blood concentrations of kynurenine and free tryptophan and the kynurenine to tryptophan ratio were examined in 35 patients with coronary heart disease verified by coronary angiography and compared with healthy controls. Patients were observed before percutaneus transluminal coronary angioplasty (21 patients: one with artery disease, nine with 2‐ or 3‐artery disease, and five with restenosis).

Results and conclusions Decreased tryptophan concentrations were found in a significant proportion of coronary heart disease patients and coincided with increased kyn trp−1 and also with increased neopterin concentrations, indicating an activated cellular immune response. We conclude that in coronary heart disease immune activation is associated with an increased rate of tryptophan degradation and thereby lowered tryptophan levels. Results may provide a basis for a better understanding of the pathogenesis of mood disturbances and depression in coronary heart disease patients.
Impaired vasodilator responses to atrial natriuretic peptide in essential hypertension
Authors: Bulut D. , Potthast R. , Hanefeld C. , Schulz T. , Kuhn M. , Mügge A.
Published: June 2003

Background Atrial natriuretic peptide (ANP) has vasodilating and diuretic/natriuretic properties, both of which contribute to lower blood pressure. These effects are mediated by binding of ANP to a cell‐surface receptor [type A guanylyl cyclase (GC‐A)]. It has been demonstrated by studies in monogenetic mouse models that the ANP/GC‐A system participates in the maintenance of blood pressure homeostasis.

Methods In male patients with essential hypertension (EH; n = 36) as the only cardiovascular risk factor and normotensive controls (n = 12), blood flow was measured in the forearm circulation in response to i.a. infusion of synthetic human ANP, acetylcholine, orciprenaline, and sodium nitroprusside by strain‐gauge venous plethysmography. In blood samples, cyclic guanosine′5‐monophosphate (cGMP) and ANP concentrations were measured at resting conditions and during exogenous ANP infusion. In 200 patients with EH, genomic DNA was screened for an inhibitory deletion mutation of the GC‐A gene, which has been recently linked to EH in a Japanese cohort.

Results The vasodilatations in response to ANP and acetylcholine were impaired in the forearm circulation of patients with EH, whereas the responses to orciprenaline and nitroprusside were preserved. Plasma ANP and cGMP concentrations were increased in the patients with EH both at resting conditions and during ANP infusion; the resting plasma cGMP levels correlated significantly with the plasma ANP levels (r = 0·68). A specific deletion mutation of the GC‐A gene did not account for the diminished relaxant effects of ANP in our study population.

Conclusions The vascular ANP/GC‐A pathway is altered in patients with EH, in addition to the known defects on the nitric oxide/cGMP pathway. Attenuation of the vasodilative responses to ANP suggests impaired receptor or postreceptor responsiveness of GC‐A. It is possible that this dysfunction participates in the pathomechanism of EH.