Variability and reproducibility of flow-mediated dilatation in a multicentre clinical trial.

AIMS: The aim of this study was to assess the reproducibility of flow-mediated dilatation (FMD) in a multicentre setting. METHODS AND RESULTS: This study was performed as part of the dal-VESSEL trial in which FMD was measured in 19 vascular imaging centres in six European countries. A subgroup of patients who were allocated in the placebo group and scanned twice at each trial time point (substudy) was analysed. Intra-sonographer variability was calculated from FMD measurements 48 h apart. Centre variability and short-, medium-, and long-term reproducibility of FMD were calculated at 48 h and at 3 and 9 months intervals, respectively. Intra- and inter-reader variability was assessed by re-analysing the FMD images by three certified readers at two time intervals, 7 days apart. Sixty-seven patients were included. Variability between centres was comparable at 48 h and 3 months interval but almost doubled at 9 months. The mean absolute difference in %FMD was 1.04, 0.99, and 1.45% at the three time intervals, respectively. Curves were generated to indicate the number of patients required for adequate power in crossover and parallel study designs. CONCLUSION: This study demonstrates for the first time that in a multicentre setting reproducible FMD measurements can be achieved for short- and medium-term evaluation, which are comparable with those reported from specialized laboratories. These findings justify the use of FMD as an outcome measure for short- and medium-term assessment of pharmacological interventions.

A comparison of pubertal maturity and growth.

BACKGROUND: Growth and pubertal development have each been studied in detail, but rarely in conjunction. AIM: The study aim was to determine what somatic and pubertal development have in common and how they differ and to quantify the association between milestones for growth and for pubertal development (in terms of pubic hair and genitalia/breast, Age of Peak Testes Velocity, APTV and menarche) in relation both to chronological (CA) and bone age (RUS). SUBJECTS AND METHODS: The data analysed are from the 1st Zurich Longitudinal Growth Study, with 120 boys and 112 girls with almost complete data from birth to adulthood. RESULTS: Variability of pubertal milestones was somewhat reduced in terms of RUS, in particular in later phases. Pubic hair phase PH2 appeared ∼1 year after the onset of the pubertal spurt. Around the age of maximal deceleration (T9) an adult-like appearance of pubic hair, genitalia and breasts was reached in most cases. APTV occurred close to T8. Correlations were large between milestones for growth and PH stages and also with menarche or APTV. CONCLUSIONS: A successful modelling of testis growth led to a new pubertal milestone, APTV. The high correlations between the phenomenologically different domains "linear growth" and "pubertal development", and the high correlations between RUS and linear growth previously established allow the conclusion that these different domains develop along similar biological mechanisms, which are steered mainly by genetic factors.

A comparison of skeletal maturity and growth.

BACKGROUND: Somatic and bone development have each been studied in detail, but rarely in conjunction. AIM: The aim of this study was to determine what somatic and bone development have in common and how they differ. A second aim was to check for a pubertal spurt in bone age (BA) and to quantify it in a similar way as has been done for height. The Preece-Baines model is used to fit longitudinal data for BA. SUBJECTS AND METHODS: The data analysed are from the 1st Zurich Longitudinal Growth Study comprising 120 boys and 112 girls with almost complete data from birth to adulthood. RESULTS: Variability of somatic milestones was reduced in terms of BA and there was an aftergrowth after reaching adult RUS score 1000. A strong increase in the RUS score was seen at a late stage of the pubertal spurt (PS). Somatic milestones correlated with the RUS score attained at these ages and more so at an early stage of the PS. A PS for BA was clearly identified with a location at 14.2 years for boys and 12.2 years for girls. Age of peak bone development correlated highly with age of peak velocity of somatic variables. CONCLUSIONS: BA can be successfully modelled as a semi-quantitative entity. Bone development shows marked associations with somatic development, despite the fact that the latter reflects changes in size, while the former is essentially a maturity index and reflects changes in biochemical composition of tissues.

CRP and CD14 polymorphisms correlate with coronary plaque volume in patients with coronary artery disease--IVUS substudy of the ENCORE trials.

BACKGROUND: Several proinflammatory single-nucleotide polymorphisms (SNPs) have been linked to the progression of atherosclerosis and coronary artery disease (CAD). Plaque size and its destabilization by inflammatory processes are major determinants of ischemia and acute coronary syndromes. Intravascular ultrasound (IVUS) allows for quantification of plaque size in vivo. We therefore investigated the relation of plaque size with mutations of proinflammatory genes in patients with CAD. METHODS: In 196 patients with stable CAD enrolled in the ENCORE trials coronary plaque and vessel volume was assessed by IVUS. 173 patients were successfully genotyped for polymorphisms of proinflammatory genes CD14 C(-260)T and CRP C(+1444)T using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach. RESULTS: Baseline characteristics were comparable for all genotype groups. Higher ratios of plaque volume/vessel volume were observed in patients with the CRP 1444TT (n=11) and CD14 260TT (n=33) genotypes (p=0.016 and p=0.026, respectively). CONCLUSION: In patients with stable coronary artery disease the CRP 1444TT and CD14 260TT variants are associated with larger coronary plaque volume independently of concomitant cardiovascular risk factors.

Development of motor speed and associated movements from 5 to 18 years.

AIM: To study the development of motor speed and associated movements in participants aged 5 to 18 years for age, sex, and laterality. METHOD: Ten motor tasks of the Zurich Neuromotor Assessment (repetitive and alternating movements of hands and feet, repetitive and sequential finger movements, the pegboard, static and dynamic balance, diadochokinesis) were administered to 593 right-handed participants (286 males, 307 females). RESULTS: A strong improvement with age was observed in motor speed from age 5 to 10, followed by a levelling-off between 12 and 18 years. Simple tasks and the pegboard matured early and complex tasks later. Simple tasks showed no associated movements beyond early childhood; in complex tasks associated movements persisted until early adulthood. The two sexes differed only marginally in speed, but markedly in associated movements. A significant laterality (p<0.001) in speed was found for all tasks except for static balance; the pegboard was most lateralized, and sequential finger movements least. Associated movements were lateralized only for a few complex tasks. We also noted a substantial interindividual variability. INTERPRETATION: Motor speed and associated movements improve strongly in childhood, weakly in adolescence, and are both of developmental relevance. Because they correlate weakly, they provide complementary information.

High-intensity training increases spontaneous physical activity in children: a randomized controlled study.

OBJECTIVE: To test the hypothesis that resistance training may increase spontaneous physical activity in children. STUDY DESIGN: Two junior ice hockey teams were randomly assigned to unchanged training schedules (team ZSC, 21 boys; mean age, 13.2 years) or to participate twice weekly in guided resistance training for 4 months (team GCK, 25 boys; mean age, 13.4 years). Spontaneous physical activity energy expenditure (SpAEE; 3-axial accelerometry for 7 days), muscle strength, and body composition (dual energy x-ray absorptiometry) were measured at 0, 4, and 12 months. RESULTS: Baseline measures did not differ in the groups, except for higher leg and trunk strength in team ZSC. In the intervention group compared with the control group, SpAEE significantly (P < or = .02) increased at 4 months (+25.5% versus 0%) and 12 months (+13.5% versus -9.5%). Leg and arm strength increased because of training intervention; all other variables were unchanged. None of these variables correlated with changes in SpAEE. CONCLUSION: In boys who play ice hockey, spontaneous physical activity is inducible with resistance training; this effect seems to be independent of changes in body composition and strength. If this was confirmed in unselected children, resistance training might be a new strategy for childhood obesity prevention programs.

Neuromotor performance of normally developing left-handed children and adolescents.

Neuromotor functioning - i.e., timed performance and quality of movements - was examined in 66 left-handed children and adolescents between 5 and 18.5 years by means of the Zurich Neuromotor Assessment. Quality of movements was assessed by the degree and the frequency of associated movements. Results were compared to normative data from 593 right-handers. The overall scores for timed motor performance were similar for left-handers and right-handers, while left-handers had more associated movements than right-handers with both sides. In agreement with previous studies in adults, we found that left-handed children were less lateralized than right-handers. They performed faster with their non-dominant side and slower with their dominant side. This finding was roughly independent of age, which may indicate that handedness does not reflect long-term effects of previous motor experience, but may be primarily attributed to genetic factors.

Alzheimer disease versus mixed dementias: an EEG perspective.

OBJECTIVE: To examine differences between patients with AD (n=54) and mixed (vascular Alzheimer) dementia (n=24), and controls (n=66), with respect to clinic, neuropsychology, neuroradiology and quantitative EEG (QEEG). METHODS: We used CAMDEX, CT and QEEG. RESULTS: Patients with mixed dementia had more subcortical lesions. Increased slow frequency EEG power was observed in mixed dementia compared to AD, whereas the level of high frequency power was nearly normal in mixed dementia, but decreased in pure AD. Topography of slow band power was unaltered in both groups, but was changed for fast bands. The Hachinski score and neuropsychological tests showed small differences between mixed dementia and pure AD. CONCLUSION: Neuroimaging and QEEG made a greater differential diagnostic contribution than clinical symptoms and neuropsychology. An alteration of slow frequency power with nearly normal high frequency power in mixed dementia may reflect subcortical pathology, whereas cortical pathology in pure AD may relate to decreased fast frequency power. With vascular pathology, less AD pathology is needed for a similar severity of dementia. SIGNIFICANCE: In dementia of the Alzheimer type a vascular component is often found - especially at an older age. The quantitative EEG can contribute to a better understanding of the interaction of the two components.

Association between short sleeping hours and physical activity in boys playing ice hockey.

OBJECTIVES: To determine physical activity in healthy boys and how physical activity relates to training and daily awake hours. STUDY DESIGN: In 66 boys (5 to 15 years) affiliated with an ice-hockey club, we measured total daily energy expenditure (TDEE, doubly-labeled water) and basal metabolic rate (ventilated-hood method). Physical activity energy expenditure for the whole day (DAEE), during training, and during spontaneous physical activity was measured by accelerometry and activity protocols. Univariate (UA) and multivariate (MA) correlation analysis was applied. RESULTS: Physical activity level, DAEE, and TDEE for prepubertal (2.0 and 2.2 Mcal/d) and pubertal (bone age >or=13 years; 1.8 and 2.8 Mcal/d) boys were matched to literature data from normal boys of equal age. In prepubertal boys DAEE correlated positively with awake hours (r(UA) = 0.55, r(MA) = 0.39, P < .01). In pubertal boys this correlation was not significant, the slopes between the 2 groups being significantly different (P = .025). In prepubertal boys spontaneous physical activity expenditure correlated significantly positively with training activity expenditure (r(UA) = 0.72, r(MA) = 0.52, P < .001). CONCLUSION: Contrary to findings in adults, where short sleepers had lower physical activity and intensive training was negatively compensated reducing spontaneous physical activity, in physically active prepubertal boys, total daily and spontaneous physical activity relate positively to awake hours and training; suggesting child-specific control of physical activity.

Reliability of the Zurich Neuromotor Assessment.

Reliability of measurements of timed performance and ratings of associated movements (AMs) for tasks of the Zurich Neuromotor Assessment is investigated and methods to improve it are proposed. Better results were found for timed performance than for AMs. On average, intra-rater, inter-rater, and test-retest reliability (measured via intraclass correlation) were around 0.95, 0.9, and 0.65 for timed performance, and around 0.8, 0.7, and 0.45 for AMs. Reliability can be dramatically improved by considering neuromotor components (i.e., summary measures of individual measurements obtained at different tasks) instead of single tasks, which is significant for clinical work and research.

Quantitative reference curves for associated movements in children and adolescents.

Intensity of contralateral associated movements (AMs) is a measure of movement quality assessed using frequency and degree of AMs. A sample of 593 right-handed participants without disability (286 males, 307 females; aged 5y-18y 6mo) was studied with the Zurich Neuromotor Assessment (ZNA). The ZNA is a standardized testing procedure which assesses performance on standardized motor tasks according to timed performance and frequency and degree of AMs. In contrast to frequency and degree, intensity of AMs allowed the calculation of centiles which were quasi-continuous. Centile curves of contralateral AMs for the ZNA and data on inter- and intraobserver reliability are presented. The significance of age, sex, and side differences are discussed. Intensity of AMs offers clinical and scientific advantages for measurement of movement quality. There is a decrease of AMs with age depending on the complexity of tasks. Females showed consistently fewer AMs than males, whereas only minor side differences were shown.

Cross-sectional study of weight gain and increase in BMI throughout pregnancy.

OBJECTIVE: To generate reliable new reference ranges for weight gain and increase in body mass index (BMI) during pregnancy from a large population. STUDY DESIGN: In a prospective cross-sectional study at the Obstetric outpatient clinic, Zurich University Hospital, weight gain and BMI, before gestation and at the booking visit, were determined in 4034 pregnant women with accurately dateable singleton pregnancies (Caucasian: N = 3242, Asian (predominantly from Sri Lanka, Thailand and the Philippines): N = 578 and Black: N = 214). Women with known insulin-dependent diabetes mellitus before pregnancy were excluded. Fifth, 50th and 95th centiles were presented for Caucasians and corresponding centile curves for Asians and Blacks. Simple and multiple regression analyses were performed for various risk factors. A significance level of P < 0.05 was used in all tests. RESULTS: Mean weight gain was 15.5+/-5.9 kg (34.2+/-13.0 lb) at term with values >25.4 kg (56.0 lb) and <5.7 kg (12.6 lb) for the 95th and the 5th centile, respectively. Mean BMI increased slightly and steadily to 28 kgm(-2) at term. Parity and pre-pregnancy BMI were significant determinants in Caucasians. Weight gain and BMI was slightly lower in Asians and Blacks. CONCLUSIONS: BMI centile curves have the advantage in that they consider height during the whole course of pregnancy. It may be an additional helpful tool in controlling weight gain in pregnancy. Further studies are required to determine the prognostic implications of values > or = 95th centile and < or = 5th centile.

Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia.

A large number of children treated from the time of diagnosis with modern transfusion and chelation therapy are now entering early adolescence or early adulthood, and only now can we evaluate how many complications, secondary to iron overload, can be prevented by daily s.c. desferrioxamine (DFX) therapy. In 1989, we planned a multi-centre study on growth and endocrine complications in patients who started chelation therapy with DFX early in life. Height, weight, endocrine complications, haematological variables and compliance with DFX were evaluated in a study group of 238 patients aged 2-17 years with beta-thalassaemia major regularly followed in 13 paediatric and haematological Italian centres. The LMS method by Cole and Green and the Mann-Whitney test were applied for statistical analysis. Twenty-six patients with thalassaemia (12.4%) had growth hormone insufficiency, five patients (2.1%) had primary hypothyroidism and four patients (1.7%) had hypoparathyroidism. Delayed puberty was present in 18.4% of boys and 17.7% of girls. At the beginning of chelation, standing height was in the normal range when compared to Swiss standards, while in the following years a progressive decline of growth was observed in both sexes. In conclusion, our study noted a positive effect of DFX therapy on sexual maturation and endocrine complications. Nevertheless, short stature has persisted despite major advances in treatment.

Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart- Willi syndrome.

CONTEXT: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS), central or peripheral, remains unexplained. OBJECTIVES: The objectives of this study were to investigate the cause of hypogonadism in PWS and determine whether human chorionic gonadotropin (hCG) treatment can restore pubertal development. DESIGN: This was a clinical follow-up study, divided into two samples, over a duration of 1.5 and 4.5 yr. PATIENTS: Eight male infants and six peripubertal boys (age at start of observation, 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied. INTERVENTION: hCG (500-1500 U twice weekly) was given from age 13.5 yr to the present. MAIN OUTCOME MEASURES: Serum FSH, LH, inhibin B, and testosterone levels and pubertal development were the main outcome measures. RESULTS: Infants with PWS presented normal LH (2.3 +/- 0.7 U/liter) and testosterone (2.5 +/- 0.9 nmol/liter) levels (mean +/- sem at 5 months) compared with the reference range. However, two thirds of the boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr, 72 +/- 17 pg/ml), whereas FSH secretion increased (9.9 +/- 2.6 U/liter). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 +/- 2 nmol/liter) and reduced FSH (at 16 yr, 1.1 +/- 0.9 U/liter) levels. Testicular volume (5.6 +/- 1 ml) and inhibin B (26.5 +/- 11.9 pg/ml) remained low. CONCLUSION: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B and high FSH) hypogonadism, suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization.

Correction of muscle artefacts in the EEG power spectrum.

OBJECTIVE: To provide a method for correcting muscle artefacts in fast band power at EEG derivations. METHODS: We define an indicator of surface EMG as power in the band 51.0-69.0 Hz ('muscle power'). This indicator is used to approximately eliminate the contribution of muscle activity on fast band power via a regression model. RESULTS: (1) Patients show a larger proportion of muscle activity in fast band power. (2) There is a clear topographic pattern, frontal-temporal derivations being most susceptible to EMG artefacts. (3) The contribution of surface EMG can be drastically reduced by the proposed correction method. (4) Without correction, results for fast bands can be biased when e.g. comparing control and patient groups and the proposed correction method by and large eliminates this bias. CONCLUSIONS: It is advisable to correct the quantitative EEG reflecting fast activity for the extent of EMG artefacts. SIGNIFICANCE: To render the quantitative EEG more valid as an indicator of cerebral activity.

Modelling neuromotor ratings with floor-effects.

Associated movements (AMs) are a classical diagnostic tool to assess differences between normal children and children with some motor dysfunction. This paper presents a methodology to produce age- and gender-dependent reference-curves for AMs of normal children, for various tasks of a test battery. Data available consist of separate ratings of duration and extent of AMs, which are ordinal quantities with few levels. Other problems are severe age- and gender-dependent floor-effects (as well as some ceiling-effects), leaving little information for analysis at older ages. To get a better scale, we combined the two ordinal ratings into one meaningful and quasi-continuous quantity referred to as intensity of AMs. In order to solve problems due to floor-effects, ceiling-effects and discreteness, we assumed left- , right- and interval-censored values, respectively. We considered a censored regression problem and postulated a truncated normal distribution for the non-censored values (after an appropriate transformation of the data). Using Wei and Tanner's poor man's data augmentation algorithm, together with the technique of linear mixed effects modelling, useful reference-curves could be produced. In contrast to the cumulative probabilities approach for ordinal data, our methodology allows the calculation of individual age- and gender-standardized values, which puts us in a position to investigate numerous scientific questions.

Growth hormone and body composition in children younger than 2 years with Prader-Willi syndrome.

OBJECTIVES: To assess body composition of infants with Prader-Willi syndrome (PWS) by using deuterium dilution and investigating the efficacy of early institution of growth hormone (GH) therapy in increasing lean mass (LM) and preventing massive obesity. STUDY DESIGN: One group of 11 children with PWS <2 years before and during 30-month GH therapy (GH group) was compared with 6 infants administered only coenzyme Q(10) for 1 year (Q10 group). LM adjusted for height (LM(Ht)) and relative fat mass (%FM(Age)) standard deviation scores (SDS) were calculated from data of 95 healthy children. RESULTS: Initially, LM(Ht) of all patients was below the normal average. LM(Ht) decreased by -0.46 +/- 0.3 SD (P=.03) per year in the Q10 group but rose by 0.25 +/- 0.3 SD (P=.02) per year during GH therapy, normalizing after 30 months (-0.70 +/- 1.0 SD). Despite low to normal weight for height (WfH), %FM(Age) was above the normal average (GH group, 31.0% +/- 4.5%, Q10 group, 32.4% +/- 9.5%). In the Q10 infants, %FM(Age) increased by 0.71 +/- 0.7 SD per year, whereas in the GH group, %FM(Age) remained more stable up to 30 months. CONCLUSIONS: Diminished LM(Ht) found in infants with PWS further declines during the early years. Early institution of GH therapy lifts LM(Ht) into the normal range and delays fat tissue accumulation.

EEG power and coherence in children with educational problems.

SUMMARY: SUMMARY This study deals with the quantitative EEG (QEEG) of children attending schools for the mentally retarded and learning disabled. Questions are in which way do the EEGs of these children differ from normal development and whether deviations are restricted to a subgroup of children. The topographic distribution of EEG power is of particular interest. Based on a sample of n = 158 normal children, age-standardized values of absolute power (delta, theta, alpha 1, alpha 2, beta 1, beta 2 at F4, F3, C4, C3, CZ, PZ, O2, O1) and of coherence are computed for all children. The topographic distribution is assessed by analysis of variance (ANOVA) and by a principal component approach. The EEG of children with educational problems differs substantially from normal development in the slow bands and differs less in the fast bands. Deviations affect a subgroup of children, mainly children attending a school for the mentally retarded. Topographic distribution is an important factor in all bands. Coherence analysis leads to rather weak results that lack a clear interpretation. The QEEG is useful for understanding neurophysiological development in children with educational problems as a group more than individually. Parameters of topographic distribution provide strong additional information to power itself.

Increased adrenal androgen levels in patients with Prader-Willi syndrome are associated with insulin, IGF-I, and leptin, but not with measures of obesity.

BACKGROUND/AIM: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. METHODS: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. RESULTS: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. CONCLUSIONS: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.

Assessing intrarater, interrater and test-retest reliability of continuous measurements.

In this paper we review the problem of defining and estimating intrarater, interrater and test-retest reliability of continuous measurements. We argue that the usual notion of product-moment correlation is well adapted in a test-retest situation, whereas the concept of intraclass correlation should be used for intrarater and interrater reliability. The key difference between these two approaches is the treatment of systematic error, which is often due to a learning effect for test-retest data. We also consider the reliability of a sum and a difference of variables and illustrate the effects on components. Further, we compare these approaches of reliability with the concept of limits of agreement proposed by Bland and Altman (for evaluating the agreement between two methods of clinical measurements) and show how product-moment correlation is related to it. We then propose new kinds of limits of agreement which are related to intraclass correlation. A test battery to study the development of neuro-motor functions in children and adolescents illustrates our purpose throughout the paper.