bluuebunny/crossref_metadata_2025 huggingface dataset:
CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide
Authors: Bidstrup Tanja Busk , Bjørnsdottir Inga , Sidelmann Ulla Grove , Thomsen Mikael Søndergård , Hansen Kristian Tage
Published: August 2003

Aims  To identify the principal human cytochrome P450 (CYP) enzyme(s) responsible for the human in vitro biotransformation of repaglinide. Previous experiments have identified CYP3A4 as being mainly responsible for the in vitro metabolism of repaglinide, but the results of clinical investigations have suggested that more than one enzyme may be involved in repaglinide biotransformation.

Methods  [14C]‐Repaglinide was incubated with recombinant CYP and with human liver microsomes (HLM) from individual donors in the presence of inhibitory antibodies specific for individual CYP enzymes. Metabolites, measured by high‐performance liquid chromatography (HPLC) with on‐line radiochemical detection, were identified by liquid chromatography‐mass spectrophotometry (LC‐MS) and LC‐MS coupled on‐line to a nuclear magnetic resonance spectrometer (LC‐MS‐NMR).

Results  CYP3A4 and CYP2C8 were found to be responsible for the conversion of repaglinide into its two primary metabolites, M4 (resulting from hydroxylation on the piperidine ring system) and M1 (an aromatic amine). Specific inhibitory monoclonal antibodies against CYP3A4 and CYP2C8 significantly inhibited (> 71%) formation of M4 and M1 in HLM. In a panel of HLM from 12 individual donors formation of M4 and M1 varied from approximately 160–880 pmol min−1 mg−1 protein and from 100–1110 pmol min−1 mg−1 protein, respectively. The major metabolite generated by CYP2C8 was found to be M4. The rate of formation of this metabolite in HLM correlated significantly with paclitaxel 6α‐hydroxylation (rs = 0.80; P = 0.0029). Two other minor metabolites were also detected. One of them was M1 and the other was repaglinide hydroxylated on the isopropyl moiety (M0‐OH). The rate of formation of M4 in CYP2C8 SupersomesTM was 2.5 pmol min−1 pmol−1 CYP enzyme and only about 0.1 pmol min−1 pmol−1 CYP enzyme in CYP3A4 SupersomesTM. The major metabolite generated by CYP3A4 was M1. The rate of formation of this metabolite in HLM correlated significantly with testosterone 6β‐hydroxylation (rs = 0.90; P = 0.0002). Three other metabolites were identified, namely, M0‐OH, M2 (a dicarboxylic acid formed by oxidative opening of the piperidine ring) and M5. The rate of M1 formation in CYP3A4 SupersomesTM was 1.6 pmol min−1 pmol−1 CYP enzyme but in CYP2C8 Super‐somesTM it was only approximately 0.4 pmol min−1 pmol−1 CYP enzyme.

Conclusions  The results confirm an important role for both CYP3A4 and CYP2C8 in the human in vitro biotransformation of repaglinide. This dual CYP biotransformation may have consequences for the clinical pharmacokinetics and drug‐drug interactions involving repaglinide if one CYP pathway has sufficient capacity to compensate if the other is inhibited.
Haloperidol plasma concentration in Japanese psychiatric subjects with gene duplication of CYP2D6
Authors: Ohnuma Tohru , Shibata Nobuto , Matsubara Yoichiro , Arai Heii
Published: August 2003

Aims  The cytochrome P‐450 2D6 (CYP2D6) gene duplication/multiduplication producing an increase in enzyme activity, and the common Japanese mutation, CYP2D6*10A producing a decrease of enzyme activity were screened in a large number of Japanese psychiatric subjects (n = 111) in order to investigate whether these mutated alleles affected the plasma concentration of haloperidol.

Methods  Polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method was performed to identify the CYP2D6*10A and CYP2D6*2 genotypes in subjects who had been taking haloperidol. For the screening of duplicated active CYP2D6 gene, allele‐specific long PCR was performed. Plasma concentration of haloperidol was measured by the enzyme immunoassay, and expressed as ‘plasma concentration dose ratio’ to normalize individual differences.

Results  The plasma concentration–dose ratio showed large interindividual differences of approximately 18‐fold. PCR‐RFLP methods revealed that 29 (26.1%), 10 (9.0%), 39 (35.1%), 0 (0%), seven (6.3%) and 26 (23.4%) cases possessed the CYP2D6 genotypes *1/*1, *1/*2, *1/*10A, *2/*2, *2/*10A and *10 A/*10A, respectively. Six cases (5.4%) had duplicated CYP2D6 genes. There were no significant differences of plasma concentration–dose ratio between the groups classified by CYP2D6*10A and *2 genotypes (Kruskal–Wallis test; P = 0.37), even in those cases whose daily doses were lower than 20 mg (n = 90, P = 0.91). Subjects having duplicated genes (n = 6) did not show significant differences of plasma concentration–dose ratio by comparison with subjects who had no duplicated genes (Mann–Whitney U‐test; P = 0.80).

Conclusions  Gene duplication, and the common Japanese mutation CYP2D6*10A on CYP2D6 gene are not likely to be the main modulatory factors of plasma concentration of haloperidol in Japanese psychiatric subjects.
Pharmacodynamic characterization of the interaction between the glycoprotein IIb/IIIa inhibitor YM337 and unfractionated heparin and aspirin in humans
Authors: Graff Jochen , Klinkhardt Ute , Westrup Dagmar , Kirchmaier Carl M. , Breddin Hans Klaus , Harder Sebastian
Published: August 2003

Aims  To investigate the pharmacodynamic interaction of unfractionated heparin (UFH) and acetylic salicylic acid (ASA) on YM337, a monoclonal humanized antibody of the platelet GPIIb/IIIa receptor.

Methods  In a randomized, placebo‐controlled study three treatment groups each with six healthy volunteers received the following medication: group 1, ASA (3 days) + UFH + YM337 (placebo); group 2, ASA (placebo) + UFH (placebo) + YM337; group 3, ASA + UFH + YM337. Assessments were made over 24 h and included bleeding time (BT), ADP (20 µm)‐ and collagen (5 µg ml−1)‐induced platelet aggregation and PAC1 and CD62 expression measured by flow cytometry.

Results  In group 3 BT was prolonged to 35 [median, 16–45 min (1,3 quartile)] after UFH administration, increasing to 45 [median, 42–45 min (1,3 quartile)] after YM infusion (6 h). BT remained elevated to 26 [median, 14–45 min (1,3 quartile)] at 24 h, while groups 1 and 2 returned to normal values. Collagen‐induced aggregation was 73% [median, 70–80% (1,3 quartile)] under YM337 alone, 79% [median, 72–80% (1,3 quartile)] under ASA + UFH and reduced only in group 3 to 24% [median, 18–29% (1,3 quartile)]. In both groups receiving active YM337, PAC1 expression showed a reduction to < 20% after 6 h of infusion. CD62 expression was not significantly affected by any treatment.

Conclusion  UFH and YM337 have strong synergistic effects on BT, while coadministration of ASA strongly augments inhibitory effects of YM337 on collagen‐induced platelet aggregation.
The cardiovascular system in the ageing patient
Authors: Moore A. , Mangoni A. A. , Lyons D. , Jackson S. H. D.
Published: August 2003

The ageing process is associated with important changes in the responses of the cardiovascular system to pharmacological stimuli. They are not limited to the arterial system, involved in the modulation of cardiac afterload and vascular resistance, but they also involve the low‐resistance capacitance venous system and the heart. The main changes include loss of large artery compliance, dysfunction of some of the systems modulating resistance vessel tone, increased activity of the sympathetic nervous system, and reduced haemodynamic responses to inotropic agents. This review focuses on the effects of ageing on arterial and venous reactivity to drugs and hormones, the autonomic nervous system, and the cardiovascular responses to inotropic agents. Some of the age‐related changes might be at least partially reversible. This may have important therapeutic implications.
Clinical pharmacology of old age syndromes
Authors: Broadhurst C. , Wilson K. C. M. , Kinirons M. T. , Wagg A. , Dhesi J. K.
Published: August 2003

Several syndromes occur in old age. They are often associated with increased mortality and in all there is a paucity of basic and clinical research. The recent developments in the clinical pharmacology of three common syndromes of old age (delirium, urinary incontinence, and falls) are discussed along with directions for future research.
Is the increasing use of evidence‐based pharmacotherapy causing the renaissance of complementary medicine?
Authors: Vožeh Samuel
Published: August 2003

This brief commentary considers a possible hitherto infrequently discussed factor that might contribute to the increase in the use of complementary medicines: the difficulties of using placebo within the context of evidence‐based medicine, which represents the current standard for pharmacotherapy in most western culture countries. It discusses the possibility of placebo having a similar or better benefit–risk profile compared with an active compound in some diseases, and shows three examples in which this can be concluded from a clinical trial (insomnia, allergic rhinitis, irritable bowel disease). It is proposed that complementary medicine has under these circumstances taken the place of placebo therapy. By this, the commentary does not deny (and does not discuss) the possibility of an effect of complementary medicines other than the placebo effect. However, it recognizes that complementary medicine is open to the therapeutic application of the placebo effect by using a medicine with the claim that it has worked in similar situations and may work in the actual patient, without requiring hard data showing superiority to placebo. Physicians might be more open to the use of complementary medicines for indications in which the placebo effect is high, the conventional therapy carries a risk of side‐effects and the omission of treatment with a pharmacologically active compound does not result in irreversible damage. The regulators on their part should probably not require proof of effectiveness compared with placebo in controlled clinical trials. However, whenever used in this sense, the complementary medicine product must unequivocally demonstrate its safety with respect to both the ingredients and the pharmaceutical quality. This is unfortunately not always the case.
Tacrolimus dose requirement in renal transplant recipients is significantly higher when used in combination with corticosteroids
Authors: Hesselink Dennis A. , Ngyuen Hien , Wabbijn Marike , Gregoor Peter J. H. Smak , Steyerberg Ewout W. , Van Riemsdijk Iza C. , Weimar Willem , Van Gelder Teun
Published: August 2003

Aims  To evaluate the effect of corticosteroids on tacrolimus pharmacokinetics.

Methods  In a randomized trial, kidney transplant recipients were treated with tacrolimus and mycophenolate mofetil with either daclizumab (n = 31) or 3 months of prednisone (n = 34). Tacrolimus dose‐adjusted predose concentrations (C0) at month 1–6 were compared between both groups and within the corticosteroid group before and after prednisone withdrawal.

Results  At month 1 the tacrolimus dose‐adjusted C0 in the corticosteroid group was 83 ± 8 vs 119 ± 17 ng ml−1 mg−1 kg−1 in the daclizumab group. The tacrolimus dose‐adjusted C0 within the corticosteroid group at month 1 and 2 was 42% and 29% lower compared with month 4 (P < 0.001).

Conclusions  A higher tacrolimus dose is required to reach target concentrations when used in combination with corticosteroids.
Identification of a novel splice‐site mutation in the CYP1A2 gene
Authors: Allorge Delphine , Chevalier Dany , Lo‐Guidice Jean‐Marc , Cauffiez Christelle , Suard Françoise , Baumann Pierre , Eap Chin B. , Broly Franck
Published: August 2003

Aims  To identify the molecular basis for a low CYP1A2 metabolic status, as determined by a caffeine phenotyping test, in a 71‐year‐old, nonsmoking, Caucasian woman who presented with very high clozapine concentrations despite being administered a standard dose of the drug.

Methods  The nucleotide sequence of the 7 exons, exon‐intron boundaries and 5′‐flanking region of the CYP1A2 gene was analysed by direct sequencing.

Results  Only one heterozygous point mutation was identified in the donor splice site of intron 6 (3534G > A) of CYP1A2. This mutation could cause abnormal RNA splicing and therefore lead to a truncated nonfunctional enzyme. No other carrier of this mutation was identified in a population of 100 unrelated healthy Caucasians.

Conclusions  This is the first report of a splice‐site mutation affecting the CYP1A2 gene. This polymorphism is a likely explanation for the low CYP1A2 activity associated with high clozapine concentrations in this patient.
Allele and genotype frequency of CYP2C19 in a Tamilian population
Authors: Adithan C. , Gerard N. , Vasu S. , Rosemary J. , Shashindran C. H. , Krishnamoorthy R.
Published: August 2003

Aims  To investigate the frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 alleles and CYP2C19 genotypes in a Tamilian population.

Methods  The study was conducted in 112 unrelated healthy human volunteers. DNA was extracted from leucocytes and analyzed by the PCR‐RFLP protocol. The PCR product was digested with restriction enzymes (SmaI and BamH1) and then separated electrophoretically using polyacrylamide gel.

Results  The frequencies of the CYP2C19*1, *2 and *3 alleles were 0.598 [95% confidence interval (CI) 0.507, 0.689], 0.379 (95% CI, 0.350,0.407) and 0.022 (95% CI −0.005, 0.049), respectively. The distribution of CYP2C19*1/*1,*1/*2, *1/*3, *2/*2 and *2/*3 genotypes were 0.295 (95% CI, 0.210, 0.379), 0.580 (95% CI, 0.488, 0.671), 0.027 (95% CI −0.003, 0.057), 0.080 (95% CI 0.030, 0.130) and 0.018 (95% CI −0.006, 0.042), respectively.

Conclusions  The distribution of CYP2C19*1/*1 in the Tamilian population is lower than that in Caucasians, Africans and the North Indian population. The CYP2C19*1/*2 is significantly higher in Tamilians when compared with other populations. The CYP2C19*1/*3 allele, which was not reported in the North Indian and Caucasian populations has been identified in 2.7% of the Tamilian population.
The effect of ketoconazole and diltiazem on oestrogen metabolism in postmenopausal women after single dose oestradiol treatment
Authors: Annas Anita , Carlström Kjell , Alván Gunnar , AL‐Shurbaji Ayman
Published: August 2003

Aims  The effect of the CYP3A4 inhibitors ketoconazole and diltiazem on the pharmacokinetics of oestrone was studied in six healthy postmenopausal women after treatment with a single oral dose of oestradiol.

Methods  Plasma oestrone concentrations were measured following the administration of 1) oestradiol, 2) oestradiol and ketoconazole and 3) oestradiol and diltiazem.

Results  Treatment with ketoconazole increased the AUC of oestrone (+ 4029 nmol l−1 h; 95% CI on the difference: 1588, 6471) and its Cmax (+ 306 nmol l−1; 95% CI on the difference: 117, 496). The AUC and Cmax of oestrone tended to increase on treatment with diltiazem although this did not reach the level of statistical significance.

Conclusions  The small increase in the plasma concentrations of oestrone formed from 17β‐oestradiol during co‐administration with ketoconazole is unlikely to be clinically significant.
The clinical pharmacology of ageing
Authors: Swift C. G.
Published: August 2003

The ageing of populations and individuals continues to be as vital, yet to some extent as neglected, a topic in pharmacology and therapeutics as was first realised about 30 years ago. In parallel with the realisation of the predicted demographic shifts in both the developed and developing world, there have since been major developments in the basic biological concepts of ageing, in the physiology of ageing, in the study of pathogenetic mechanisms underlying a variety of age‐associated disorders and syndromes, and in the evidence base for therapeutic intervention in elderly patient populations. These all present new challenges both in the practical delivery of effective medical care and in clinical and biological research. The scale of prescribing for an ageing population has continued to rise as anticipated. Whether there has now been any improvement in the quality or rationality of prescribing, or in the previously demonstrated unacceptable level of susceptibility to adverse drug reactions in the (now expanded) older patient population is largely unknown. We urgently need to find out using up‐to‐date research methods. National and international guidelines for drug development and regulation have more recently been followed by broader policy inititiatives on prescribing for older people, but the impact of these on standards of medication use and on clinical outcome remains to be seen. A new series in this journal on the clinical pharmacology of ageing is timely. The required focus and framework for research have often tended in the past to emerge as afterthoughts behind the merely disease specific, and it is to be hoped that a sequential review of some of the key topics may help to re‐ignite a more sound and less short‐sighted agenda than previously.
Diagnostic methods for Helicobacter pylori detection and eradication
Authors: Goddard A. F. , Logan R. P. H.
Published: August 2003

Helicobacter pylori
is the principal cause of peptic ulcer disease and an important risk factor for the development of gastric cancer. The efficacy of 1 week triple therapies, which often have eradication rates of>90%, is undermined by poor patient compliance and bacterial antimicrobial resistance. The development of new anti‐H. pylori therapies presents enormous challenges to clinical pharmacologists, not only in the identification of novel targets, but also in ensuring adequate drug delivery to the unique gastric mucus niche of H. pylori. Animal models of H. pylori infection have been developed but their clinical validity has yet to be established. Vaccination, to prevent or treat infection, has been demonstrated in animal models, but human studies have not been so encouraging.
Factors affecting family‐centred service delivery for children with disabilities
Authors: Law M. , Hanna S. , King G. , Hurley P. , King S. , Kertoy M. , Rosenbaum P.
Published: August 2003

Background  The provision of family‐centred services (FCS) emphasizes a partnership between parents and service providers so that families are involved in every aspect of services for their child. There is evidence that providing FCS is associated with improvements in parents’ satisfaction with services, decreased parental stress, and positive child outcomes.

Methods  The purpose of this study was to examine factors that are most important in determining parent perceptions of the family centredness of care and parent satisfaction with service. A cross‐sectional survey was completed by 494 parents, 324 service providers, and 15 CEOs from 16 organizations delivering children's rehabilitation services. Analyses were completed using a structural equation modelling approach.

Results  Survey return rates ranged from 77 to 94%. Findings indicate that the principal determinants of parent satisfaction with services are the family‐centred culture at the organization and parent perceptions of FCS. Parent satisfaction with services was also influenced by the number of places where services were received and the number of health and development problems experienced by their child.

Conclusion  Parent satisfaction with services is strongly influenced by the perception that services are more family centred, fewer places where services were received and fewer health and development problems for their child. Ways in which organizations can improve satisfaction through carrying out family‐centred behaviours are discussed.
Social patterning and prediction of parent‐reported behaviour problems at 3 years in a cohort study
Authors: Spencer N. , Coe C.
Published: August 2003

Objective  To study the determinants of parent‐reported behaviour problems at 3 years and the value of behaviour problems reported at 8 and 18 months as predictors of behaviour at 3 years

Study design  A whole year birth cohort

Setting  Coventry

Main outcomes  Parent‐reported behaviour problems at 3 years

Participants A total of 2580 infants were enrolled into the Coventry Cohort Study at the birth visit by their family health visitor. Data on parent‐reported behaviour at all three ages (8 months, 18 months and 3 years) were available on 775 infants.

Results  Living in rented accommodation [adjusted OR 2.38 (95% CI 1.36, 4.21); OR, odds ratio; CI, confidence intervals] and living in a smoking household [adjusted OR 2.47 (95% CI 1.53, 3.99)] were independently associated with parent‐reported behaviour problems at 3 years after controlling for other sociodemographic variables in logistic regression. The risk of behaviour problems at 3 years was increased in those reporting behaviour problems at 8 months [OR 3.77 (95% CI 1.73, 8.20)] and 18 months [OR 5.84 (95% CI 3.34, 10.23)] after adjustment for sociodemographic variables and other health problems. Behaviour at 8 months as a predictor of behaviour at 3 years had a sensitivity of 13.9%, a specificity of 95.7%, a positive predictive value of 32.6%, and positive and negative likelihood ratios of 3.23 and 0.90. For behaviour at 18 months, the sensitivity was 35.6%, the specificity 92.9%, the positive predictive value 42.9%, and positive and negative likelihood ratios 5.01 and 0.69.

Conclusions  Parent‐reported behaviour problems at 8 and 18 months are highly specific but not particularly sensitive as predictors of behaviour problems at 3 years. Assuming the availability of an effective early intervention, use of a question such as that in the Warwick Child Health and Morbidity Profile at 8 and 18 months will identify, respectively, 21% and 36% of children at risk of parent‐reported behaviour problems at 3 years.
Intentional communicative behaviours of Turkish‐speaking children with normal and delayed language development
Authors: Topbaş S. , Maviş İ. , Erbaş D.
Published: August 2003

Background  Language profiles may predict whether children with slower language development will catch up to their peers by overcoming this transient phenomenon or will be at risk for persistent language disorders. The research of the last decade has focused on this topic. Some researchers have emphasized the significance of developing communicative intentions, which provide a potential predictor of later language competence. In Turkey, children with slower language development may not be diagnosed partly because of the lack of sufficient standardized assessment/evaluation tools, educational and therapeutic media, and qualified speech‐language therapists. In devising appropriate evaluation instruments, it is necessary to examine cross‐linguistic variation in early language acquisition. The purpose of this study therefore is to observe, describe and assess early communicative behaviours of 15–36 months old Turkish‐speaking children by using a functional communicative approach.

Methods  The research was designed within a qualitative‐descriptive paradigm, involving qualitative data collection, observation and data analysis procedures. A total of 16 children, eight typically developing and eight language delayed, served as subjects. The classification system used in this study for coding children's communicative intentions was mostly based upon a system used by Dore (1977). Each variable was referred to as one of three intentional categories: regulating behaviours (request for object, request for action and protest), social interaction (direct attention, greeting and acknowledgement) and joint attention (comment/statement, asking for information and responding). A non‐parametric Mann–Whitney U‐test was carried out to verify the descriptive measures in comparing the delayed and normal group performance.

Results  As expected, the mode of expressing communicative intentions varied as a function of age for both groups. Children with normal language development were observed to express intentions within the category of joint attention more frequently whereas the children with delayed language expressed intentions related to the variables of regulating behaviours and social interaction.
Use of an interactive game to increase food acceptance – a pilot study
Authors: Gillis L.
Published: August 2003

Background  Techniques to improve food selection in healthy children with long standing food refusal are limited. The use of educational games has been successful in getting children to increase knowledge in healthy eating, but it is uncertain whether this translates into behaviour change. Therefore the purpose of this study was to test the use of an interactive food game to increase food acceptance in healthy‐weight school‐age children with chronic food refusal.

Methods  Children attended an outpatient clinic and played an interactive game with a therapist and one parent during which non‐preferred foods were consumed. Weekly recording of food consumption occurred with diet analysis by a Registered Dietitian three times during a 1‐year time span.

Results  The children increased their repertoire of foods and had a more balanced intake. The changes in intake were incorporated into their daily meal patterns in the home setting and were maintained for 1 year.

Conclusions  An interactive food game is a successful tool for increasing food variety in healthy children with chronic food refusal. As this report included only three subjects, the results will be used for subsequent work on this topic.
A clinical evaluation of ophthalmic assessment in children with sensori‐neural deafness
Authors: Guy R. , Nicholson J. , Pannu S. S. , Holden R.
Published: August 2003

Background  Since 1991, children with sensori‐neural deafness and their families within Southern Derbyshire have been supported by a multiagency approach to their diagnosis and management.

Results  One hundred and twenty‐two children were seen at the Child Development Centre for an holistic assessment, and 110 of these children have had an ophthalmic assessment, of whom 48 (43.6%) were found to have ophthalmic abnormalities. These included 43 children (39.1%) with refractive errors, ranging from mild to severe. Of 82 children with uncomplicated deafness, 26 (31.7%) had refractive errors. The prevalence of ophthalmic problems was higher than the prevalence in hearing school children in the literature and in local pre‐school children. There were six cases of Usher syndrome. Twenty‐one children had more than one eye defect. The findings indicate that deaf and hearing impaired children are two to three times more likely to develop ophthalmic abnormalities than their hearing peers, which makes early detection of paramount importance. An important local outcome has been the establishment of guidelines for ophthalmic assessment to include assessment of vision and screening for Usher syndrome by electro‐physiological testing at aged 7 years and above. Screening has been completed to date in 78 children with congenital sensori‐neural deafness.

Conclusions  Sensitive and efficient ophthalmic assessment and management are essential for all deaf and hearing impaired children and national guidelines need to be established for both assessment of vision and screening for Usher syndrome, based on further evaluated research.
Black South African children's understanding of health and illness: colds, chicken pox, broken arms and AIDS
Authors: Peltzer K. , Promtussananon S.
Published: August 2003

Purpose  To examine the understanding of both health and illness (colds, broken arms, chicken pox, AIDS) in the same black South African children

Method  The sample included 60 children (30 were 5‐year‐olds and 30 were 9‐year‐olds) selected by simple random sampling from a rural primary school. They were interviewed, using a semi‐structured interview schedule, about their understanding of health issues and their exposure to learning about health or sickness.

Results  Differences across age in children's expressed understanding of health and illnesses were found. The 9‐year‐olds were more likely to give objective signs of chicken pox and AIDS than the 5‐year‐olds. They also knew more about objective symptoms of colds, chicken pox and AIDS, and were more likely to mention non‐observable signs of colds and broken arms. Although there were no differences between the two age groups regarding ‘knowing’ strategies for avoiding illnesses, the older children had a more accurate knowledge about preventive measures than the younger children. The understanding of AIDS followed the same developmental sequence reported for children's understanding of general physical illness.

Conclusion  The results have implications for the creation of developmentally appropriate and effective health and AIDS education curricula for primary and elementary grades.
Risk‐taking sexual behaviour and self‐reported depression in middle adolescence – a school‐based survey
Authors: Kosunen E. , Kaltiala‐Heino R. , Rimpelä M. , Laippala P.
Published: August 2003

Background Early sexual activity has been widely studied in the context of pregnancies, substance use and antisocial behaviour, but the aspects of psychosexual health have received less attention.

Aim To study the associations of early sexual activity and self‐reported depression.

Setting A school survey in Finland in 1999 and 2000 in the eighth and ninth grades.

Methods Adolescents with experience of sexual intercourse were studied (11 793 girls and 10 443 boys, mean age 15.5 years). Scores of 8 or more in the Beck Depression Inventory were regarded as indicative of self‐reported depression. Associations with sexual behaviour variables were analysed using logistic regression models.

Results In both genders, self‐reported depression increased in proportion to the number of sexual partners and with the non‐use of contraception. A higher number of coital experiences correlated with depression only among boys. Adjusting for age and age at menarche/oigarche did not affect the associations detected. In stepwise logistic regression, an increasing number of partners increased the risk for self‐reported depression [for boys with at least five partners odds ratio (OR) 2.5, 95% confidence intervals (CI) 2.2–3.0, and for girls OR 2.7, 95% CI 2.3–3.2]. Boys and girls who did not use contraception showed roughly twice as high a risk as contraceptive users. However, girls with five or more coital experiences had a significantly lower risk for depression compared to girls with only one sexual intercourse.

Conclusions Multiple sexual partners and non‐use of contraception may reflect a depressive disorder in both genders. While adolescent health service providers should be aware of the risk for depression among sexually active adolescents, the sexual health of depressed adolescents also warrants special attention.
PPARγ and metabolism: insights from the study of human genetic variants
Authors: Gurnell Mark
Published: August 2003

Diabetes, obesity, atherosclerosis and cancer are the principal contributors to morbidity and mortality in Western society. Emerging evidence indicates that a nuclear receptor, the peroxisome proliferator‐activated receptor γ (PPARγ), plays a role in these pathological processes. Furthermore, modulation of receptor action in these diseases may be of therapeutic value, as exemplified by the recent introduction of the thiazolidinediones, a novel class of insulin‐sensitizing agent for the treatment of type 2 diabetes mellitus. The availability of such high‐affinity ligands has facilitated the study of signalling pathways through which PPARγ regulates metabolic processes; these analyses have been complemented by the study of human subjects harbouring (naturally occurring) mutations and polymorphisms within the receptor. The latter have provided unique genetic evidence for a link between PPARγ and mammalian glucose homeostasis, lipid metabolism and regulation of fat mass. This review highlights recent studies which have advanced our understanding of the pivotal role that this receptor plays in metabolism, with particular reference to the consequences of inherited variation in the human receptor gene.
Presence of magnetic resonance imaging abnormalities of the hypothalamic–pituitary axis is a significant determinant of the first 3 years growth response to human growth hormone treatment in prepubertal children with nonacquired growth hormone deficiency
Authors: Zenaty Delphine , Garel Catherine , Limoni Costanzo , Czernichow Paul , Léger Juliane
Published: August 2003

objective The factors influencing the highly variable growth response to GH treatment in GH‐deficient children are not fully understood. Despite a real benefit with GH treatment in term of growth response, most of these patients attain a mean adult height below their target height and the strategy to optimise final height has to be improved. The aim of this study was to investigate whether the presence of congenital abnormalities of the hypothalamic–pituitary axis on magnetic resonance imaging (MRI) could be a determinant of the growth response in nonacquired prepubertal GH‐deficient children, and to identify which pretreatment variables most significantly affect the first 3 years growth response to human GH (hGH) therapy.

patients and methods The growth response to hGH treatment (0·55 ± 0·1 IU/kg/week) was evaluated in 69 prepubertal children with nonacquired GH deficiency, according to the absence (group A: chronological age = 4·8 ± 2·4 years, n= 37) or the presence (group B: chronological age = 3·4 ± 2·7 years, n= 32) of developmental abnormalities on cerebral magnetic imaging and, after controlling for GH dose, age, height, height velocity (SDS) and body mass index at start of treatment, maximum stimulated GH peak concentration, GH deficiency type (isolated vs. multiple deficiency), parental height, size at birth and sex.

results After 3 years of treatment, the mean height gain was significantly higher in patients of group B vs. group A (2·2 ± 1·3 vs. 1·6 ± 1 SDS; P < 0·05). In a multiple regression analysis, age (r2 = 0·19, negatively correlated), pretreatment height velocity (r2 = 0·11, negatively correlated), GH dose (r2 = 0·05, positively correlated) and presence of magnetic resonance imaging developmental abnormalities (r2 = 0·05, positively correlated) were found to significantly explain 40% of the variability in growth response.

conclusions The detection of congenital abnormalities in the hypothalamic–pituitary area on MRI is more important than the level of maximum stimulated GH to predict the growth response to hGH treatment in prepubertal nonacquired GH‐deficient children. Although the persistence of GH deficiency remains to be confirmed during follow‐up by reassessment of GH secretion in isolated GH‐deficient patients with normal MRI findings, further studies are needed to evaluate whether an increased hGH dose in these patients could improve long‐term growth response.
Insulin resistance and β‐cell dysfunction in normoglycaemic European women with a history of gestational diabetes
Authors: Kousta Eleni , Lawrence Natasha J. , Godsland Ian F. , Penny Anna , Anyaoku Victor , Millauer Barbara A. , Cela Ester , Johnston Desmond G. , Robinson Stephen , McCarthy Mark I.
Published: August 2003

objective Women with previous gestational diabetes (GDM) are at increased risk of subsequent type 2 diabetes. To characterize early metabolic abnormalities associated with this increased risk, we studied normoglycaemic women with a history of GDM.

patients and measurements We performed an insulin‐modified, frequently sampled intravenous glucose tolerance test (FSIVGTT) in 34 normoglycaemic European women with previous GDM and 44 European control women, deriving measures of insulin sensitivity, glucose effectiveness, glucose disappearance rate and acute insulin response to glucose.

results Post‐GDM women were more obese than controls [body mass index (BMI), geometric mean (95% confidence interval); 25·3 kg/m2 (23·8–27·1 kg/m2) vs. 23·1 kg/m2 (21·9–24·3 kg/m2), P = 0·03]. Evidence of insulin resistance was provided by their lower insulin sensitivity as measured by FSIVGTT [0·6 × 10−4/min/pmol/l (0·3–1·2 × 10−4/min/pmol/l) vs. 1·5 × 10−4/min/pmol/l (1·2–1·8 × 10−4/min/pmol/l), P = 0·01] and by homeostatic model assessment [72% (49–107%) vs. 153% (113–206%), P = 0·004]; and by their higher fasting triglycerides [1·0 mmol/l (0·7–1·5 mmol/l) vs. 0·7 mmol/l (0·6–0·8 mmol/l), P = 0·001]. Though there was no difference between groups in fasting NEFA levels, acute NEFA suppression was diminished in the post‐GDM group (P = 0·01). Concomitant β‐cell dysfunction in the post‐GDM women was revealed by their lower disposition index [0·05/min (0·02–0·10/min) vs. 0·11/min (0·09–0·14/min), P = 0·02] compared to controls. The differences in insulin sensitivity, but not those of β‐cell function, were partly, though not completely, attributable to differences in regional and total adiposity.

conclusions European normoglycaemic women with previous GDM display both glucoregulatory and antilipolytic insulin resistance, reduced β‐cell function and dyslipidaemia. These metabolic abnormalities are likely to contribute to their increased risk of future type 2 diabetes.
Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3‐year follow‐up study
Authors: Pop Victor J. , Brouwers Evelien P. , Vader Huib L. , Vulsma Thomas , Van Baar Anneloes L. , De Vijlder Jan J.
Published: August 2003

objective To evaluate the impact of maternal hypothyroxinaemia during early gestation (fT4 below the lowest tenth percentile and TSH within the reference range: 0·15–2·0 mIU/l) on infant development, together with any subsequent changes in fT4 during gestation.

design A prospective 3‐year follow‐up study of pregnant women and their children up to the age of 2 years.

measurements Child development was assessed by means of the Bayley Scales of Infant Development in children of women with hypothyroxinaemia (fT4 below the tenth percentile at 12 weeks’ gestation) at 12 weeks’ gestation (cases), and in children of women with fT4 between the 50th and 90th percentiles at 12 weeks’ gestation, matched for parity and gravidity (controls). Maternal thyroid function (fT4 and TSH) was assessed at 12, 24 and 32 weeks’ gestation. The mental and motor function of 63 cases and 62 controls was compared at the age of 1 year, and of 57 cases and 58 controls at the age of 2 years.

results Children of women with hypothyroxinaemia at 12 weeks’ gestation had delayed mental and motor function compared to controls: 10 index points on the mental scale (95% CI: 4·5–15 points, P = 0·003) and eight on the motor scale at the age of 1 year (95% CI: 2·3–12·8 points, P = 0·02), as well as eight index points on the mental (95% CI: 4–12 points, P = 0·02), and 10 on the motor scale (95%CI: 6–16 points, P = 0·005) at the age of 2 years. Children of hypothyroxinaemic women in whom the fT4 concentration was increased at 24 and 32 weeks’ gestation had similar scores to controls, while in the controls, the developmental scores were not influenced by further declines in maternal fT4 at 24 and 32 weeks’ gestation.

conclusions Maternal hypothyroxinaemia during early gestation is an independent determinant of a delay in infant neurodevelopment. However, when fT4 concentrations increase during pregnancy in women who are hypothyroxinaemic during early gestation, infant development appears not to be adversely affected.
Epidemiological survey of thyroid volume and iodine intake in schoolchildren, postpartum women and neonates living in Ulaan Baatar
Authors: Fuse Yozen , Igari Tomoyuki , Yamada Chieri , Sakano Shoji , Ito Harumichi , Umenai Takusei , Irie Minoru
Published: August 2003

objective  Although endemic goiter had been recognized in most parts of the country, there are few available data on iodine‐deficiency disorders (IDDs) in Mongolia. This study aimed to characterize the current status of iodine deficiency in Ulaan Baatar, Mongolia's capital city.

design  Cross‐sectional, observational study designed and performed according to the surveillance methods for IDD prevalence recommended by WHO/UNICEF/ICCIDD.

subjects  A total of 505 schoolchildren aged 9–14 years (237 girls and 268 boys) and 138 mothers and their neonatal infants were selected to clinical and biochemical examination of the thyroid in 1996 and 1999.

measurements  The anthropometric measurements, thyroid volume determined by ultrasound, blood TSH and FT4 concentrations, urinary iodine concentration and iodine content of salt consumed in households.

results  Median thyroid volumes based on age were generally higher than those in iodine‐sufficient areas and comparative to those reported in mild iodine‐deficiency areas. Application of the updated WHO/ICCIDD reference values in iodine‐replete European schoolchildren to the Mongolian children aged 10–12 years resulted in a goiter prevalence of 43·3%. The median value of urinary iodine concentration was 152·5 µg/l (1·20 µmol/l) and 40·3% of children excreted iodine below 100 µg/l. Iodized salt (> 40 ppm) was consumed in 63·1% of households and in the children using noniodized salt their urinary iodine concentration was lower than those using ionized salt. In postpartum women, median thyroid volume and urinary iodine concentration were 11·3 ml and 107 µg/l (0·84 µmol/l), respectively, and 46% of women excreted less than 100 µg/l (0·79 µmol/l) of iodine. Of their neonates, 17·8% had elevated blood TSH levels (> 5 mU/l). In a 1999 survey, the goiter prevalence and ratio of low iodine excretion in schoolchildren decreased to 29·8% and 31·3%, respectively, while median urinary iodine concentration remain unchanged (160 µg/l; 1·26 µmol/l).

conclusion  The present study clearly indicates the presence of mild iodine deficiency in Mongolia. Enlarged thyroid gland and normal iodine excretion observed in schoolchildren living in Ulaan Baatar may result from the residual effects of iodine deficiency previously and presumably still exist in the city. Slight reduction in the rate of children with enlarged thyroid and low urinary iodine excretion after the onset of national iodinization programme suggests incomplete normalization of thyroid volume in children and that the correction of iodine deficiency is now in progress in Ulaan Baatar. Further nationwide surveys together with monitoring the progress of the national programme eliminating IDD are required in suburban areas surrounding the city and also in rural areas.
Usefulness of the free α‐subunit to diagnose hypogonadotropic hypogonadism
Authors: Mainieri Alberto Scofano , Elnecave Regina Helena
Published: August 2003

objective Differentiating constitutional delay of growth and puberty from hypogonadotropic hypogonadism is still a problem in clinical practice. Our previous study demonstrated that the peak/basal ratio of the free α‐subunit of the glycoprotein hormones is higher in normal prepubertal boys than in male adults with hypogonadotropic hypogonadism. The objective of this study was to assess the performance of this ratio in normal male patients at different ages and levels of pubertal development, and in patients with hypogonadotropic hypogonadism, both isolated and combined with other pituitary hormone deficiencies.

design Cohort study.

patients Twenty‐eight normal prepubertal males between 6 and 8 years; 20 normal prepubertal males between 9 and 13 years; 18 males with constitutional delay of growth and puberty; 26 normal pubertal males; 13 adult men with isolated hypogonadotropic hypogonadism; 21 adult men with complete hypogonadotropic hypogonadism combined with other hormone deficiencies; and 11 adult men with partial hypogonadotropic hypogonadism combined with other hormone deficiencies.

measurements Serum levels of free α‐subunit immediately before (basal), and 30 and 60 min after 100 µg intravenous GnRH were measured by immunofluorimetry. Median and P25–P75 range of the peak/basal ratio of the free α‐subunit was determined for each group. A receiver operating characteristics curve was calculated. Results were compared using the Kruskal–Wallis test.

results The peak/basal ratio of the free α‐subunit was higher in patients with constitutional delay of growth and puberty (7·46) than in those with isolated hypogonadotropic hypogonadism (2·73), complete combined hypogonadotropic hypogonadism (1·58), and partial combined hypogonadotropic hypogonadism (2·61; P < 0·001). A peak/basal ratio < 3·26 identified hypogonadotropic hypogonadism with 93·2% sensitivity and 94·4% specificity when compared to constitutional delay of growth and puberty. There was no statistical difference between the peak/basal ratio of prepubertal patients between 6 and 8 years (7·20), patients between 8 and 13 years (8·71), normal pubertal males (8·10) and those with constitutional delay of growth and puberty (7·46). In a group of boys with delayed puberty, a cut‐off point of 3·69 defined hypogonadotropic hypogonadism with 95·6% sensitivity and 94·4% specificity. A cut‐off point of 4·81 gave 100% sensitivity (88·9% specificity), and 3·09 gave 100% specificity (86·7% sensitivity).

conclusions The peak/basal ratio of the free α‐subunit can be used for the differential diagnosis of constitutional delay of growth and puberty and hypogonadotropic hypogonadism, irrespective of age. This distinction allows early investigation and treatment of patients with hypogonadotropic hypogonadism and reassurance for those with constitutional delay of growth and puberty.
Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin‐induced hypoglycaemia in humans
Authors: Giordano Roberta , Grottoli Silvia , Brossa PierClaudio , Pellegrino Micaela , Destefanis Silvia , Lanfranco Fabio , Gianotti Laura , Ghigo Ezio , Arvat Emanuela
Published: August 2003

objective Alprazolam (ALP), a benzodiazepine‐activating GABAergic receptor, possesses clear centrally mediated inhibitory effects on ACTH and cortisol secretion that could reflect an inhibitory influence on CRH‐ and/or AVP‐secreting neurones. An inhibitory effect of ALP on catecholamine release has also been shown while its effect on GH secretion is unclear. To further clarify the neuroendocrine actions of ALP, we studied the ALP effects on the neurohormonal responses to hypoglycaemia in a group of normal subjects.

design In eight normal subjects [four women and four men, 22–34 years old, body mass index (BMI) 20–25 kg/m2] the ACTH, cortisol, GH, adrenaline (A) and noradrenaline (NA) responses to insulin‐induced hypoglycaemia [ITT, 0·1 UI/kg regular insulin intravenously (i.v.) at 0 min] preceded by placebo or ALP (0·02 mg/kg orally at −90 min) were studied in two sessions at least 10 days apart.

measurements Blood samples were taken basely at −90 and 0 min and every 15 min up to +120 min. ACTH, cortisol, GH, A and NA level were assayed at each time point in both sessions.

results All subjects experienced hypoglycaemia (plasma glucose levels below 2·2 mmol/l). After placebo ITT induced clear‐cut increases in ACTH (peak vs. baseline, mean ± SEM: 27·9 ± 3·9 vs. 7·1 ± 1·5 pmol/l), cortisol (438·1 ± 32·0 vs. 237·7 ± 19·3 nmol/l) and GH (38·1 ± 9·7 vs. 5·7 ± 2·0 µg/l) levels (P < 0·05). Marked increase in A (6627·2 ± 116·7 vs. 263·7 ± 71·4 pmol/l) and NA (3·8 ± 1·5 vs. 1·6 ± 1·0 nmol/l) levels were also recorded (P < 0·05). Pretreatment with ALP significantly inhibited the ACTH peak response to ITT (17·8 ± 5·0 pmol/l, P < 0·05), while the cortisol response showed a non significant reduction (342·1 ± 38·7 nmol/l). ALP also significantly reduced the GH (21·7 ± 4·7 µg/l, P < 0·02) and A (3828·0 ± 1400·7 pmol/l, P < 0·02) responses to ITT. On the contrary, ALP lowered basal NA levels (P < 0·05) but did not significantly affect its response to ITT (2·2 ± 1·2 nmol/l). Glucose changes induced by ITT were not modified by ALP.

conclusions This study shows that GABAergic activation by alprazolam significantly inhibits the neuroendocrine and adrenomedullary responses to hypoglycaemia.