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PubMed1990

ICI 141,292 (epanolol)--pharmacokinetics after single and repeated oral administration in the elderly with moderate renal impairment.

The pharmacokinetics of ICI 141,292 (epanolol) were studies over 3 days after a single oral 200 mg dose and then over 24 h after 12 consecutive daily oral 200 mg doses in 16 elderly subjects (aged 65 to 94 years) with moderate renal impairment (mean creatinine clearance 33.2 ml.min-1). There was wide inter-individual variability in peak plasma ICI 141,292 concentrations (Cmax) but no significant difference was found between mean Cmax after a single dose (44.3 ng.ml-1) and after 12 doses (37.4 ng.ml-1). The mean observed time to peak plasma ICI 141,292 concentration (tmax) after a single dose (1.61 h) did not differ significantly from that after 12 doses (1.75 h). On several occasions an analytically significant second peak in ICI 141,292 plasma concentration was observed. Following the peak(s), the plasma concentrations declined biphasically and a mean terminal phase plasma half-life (t1/2) of 28.3 (range 10.2-84.8) h was calculated after a single dose. The inter-individual variability in the area under the plasma concentration-time curve to 24 h AUC (0-24) was 54 fold but there was no significant difference between AUC (0-24) after a single dose (mean 226.0 ng.h.ml-1) and AUC (0-24) after 12 consecutive doses of ICI 141,292 (mean 232.4 ng.h.ml-1). The results show that consecutive daily administration of 12 oral doses of ICI 141,292 (200 mg) does not result in significant accumulation of drug in elderly subjects with moderate renal impairment.

Administration, Oral↗
PubMed2005

Complex slow potential generators in a simplified attention paradigm.

We have recently obtained evidence for complex multifocal, individually variable generators of slow cortical potentials, elicited during performance of visual tasks involving expecting attention, comparison and memory [Basile, L.F.H., Ballester, G., Castro, C.C., and Gattaz, W.F., 2002. Multifocal slow potential generators revealed by high-resolution EEG and current density reconstruction. Int. J. Psychophysiol., 45 (3), 227-240; Basile, L.F.H, Baldo, M.V., Castro, C.C., and Gattaz, W.F. 2003. The generators of slow potentials obtained during verbal, pictorial and spatial tasks. Int. J. Psychophysiol., 48, 55-65]. The cue-target aspect of traditional paradigms for attention studies is equivalent to 'warning S1'-'imperative S2' in slow potential designs. We simplified Posner's spatial cueing task [Posner, M.I. 1980. Orienting of attention.Q. J. Exp. Psychol. Feb;32 (1), 3-25; Posner, M.I., Snyder, C.R., Davidson, B.J. 1980. Attention and the detection of signals. J Exp Psychol. Jun; 109 (2), 160-174] to temporal cuing only, by using visual cues to indicate the mere presence, on a known central position, of the eventual target (17 ms duration, +/-0.3 degrees grey circle). We recorded slow potentials on 12 healthy subjects, by 124-channel EEG system (Neuroscan Inc.), and modeled their generators using current density reconstruction (CDR) by L(p) 1.2 norm minimization ("Curry V4.6", Neurosoft Inc.) applied to the target onset time. MRIs were obtained for each subject for constraining source models to individual brain anatomy. Average slow potentials were computed from above 60 artifact-free EEG-epochs (ISI=1.6 s, average ITI=2.5 s). We tabulated individual cortical current distributions by cytoarchitectonic area of Brodmann, after scaling into negligible, low, moderate and strong local density, based on percentile bands with respect to absolute maximum current. Despite the task's simplicity, the main result was individual variability and complexity in both scalp voltage and cortical current distributions. As observed in our previous studies, there was strong intersubject variability in the exact distribution of task-related cortical activity. Only parietal area 7 bilaterally was non-negligibly active in all subjects (currents above 10% maximum). As opposed to drawing conclusions based on group averaged data, we propose that activity by cytoarchitectonic area be ranked and statistically analysed only after being scaled on each individual. Based on the present results, the concept of a universal attention-related set of cortical areas if restricted to common areas across subjects is challenged, since even area 7 may no longer be common when the sample size becomes larger. We discuss the fact that group averaging may de-emphasize weakly but consistently active areas, and emphasize strongly but inconsistently active ones.

Adult↗
PubMed2001

Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors.

BACKGROUND: Vinorelbine is a vinca alkaloid obtained by hemisynthesis, which makes the molecule more lipophilic than the other vincas. An injectable formulation is already marketed for the treatment of non small cell lung cancer (NSCLC) and advanced breast cancer (ABC). A new oral form has been developed and its file registration is being submitted. As part of its development, a clinical study was conducted to determine the absolute bioavailability and pharmacokinetics of oral vinorelbine administered as softgel capsules, and to evaluate its safety profile compared with intravenous administration. PATIENTS AND METHODS: Thirty-two patients with solid tumours were included in the study. Patients fasted and were randomised to receive vinorelbine on day 1, either as a 20 minute intravenous (i.v.) infusion of 25 mg/m2 or as softgel capsules at a dose of 80 mg/m2. Patients were treated with the alternate route after a one week wash-out period. Blood and urine samples for pharmacokinetic analysis were collected during each vinorelbine administration. Safety was assessed after each administration using the CALGB/expanded CTC classification. RESULTS: Twenty-four patients were eligible for pharmacokinetic evaluation. Oral vinorelbine was rapidly absorbed at 80 mg/m2 (Tmax 1.4 +/- 0.7 h) and showed a bioavailability of 43 +/- 14, and close to 40% based on AUC(last) and AUC(inf), respectively. A bioequivalence analysis was conducted on dosage-normalised blood exposures. Equivalence was demonstrated between 80 mg/m2 oral and 30 mg/m2 i.v., and between 60 mg/m2 oral and 25 mg/m2 i.v. The inter-individual variability was equivalent for both routes (CV: 38% and 39% for oral and i.v., respectively). A correlation was found in both methods between AUClast and % nadir variation in white blood cells (WBC) and polymorphonuclears (PMN). More cases of neutropenia (all grades pooled), leucopenia (grades 3-4 only) and nausea (grades 2-3) were induced by 80 mg/m2 oral vinorelbine than by 25 mg/m2 i.v. The greatest intensity of these effects, following oral administration, probably reflects the higher, observed drug exposure. CONCLUSION: At therapeutic dosage levels, pharmacokinetic behaviour and safety profiles were similar for both routes. The absolute bioavailability of the oral vinorelbine (new, soft gelatine capsule) was close to 40%. Inter-individual variability in drug exposure was equivalent in both routes. The pharmacokinetic/pharmacodynamic (PK/PD) relationship in haematological toxicity was independent of the routes of administration. Reliable, corresponding doses between oral and i.v. vinorelbine were established, which will result in bioequivalent AUC.

Administration, Oral↗
PubMed2005

Individual variation in the erythropoietic response to altitude training in elite junior swimmers.

OBJECTIVES: Inter-individual variations in sea level performance after altitude training have been attributed, at least in part, to an inter-individual variability in hypoxia induced erythropoiesis. The aim of the present study was to examine whether the variability in the increase in total haemoglobin mass after training at moderate altitude could be predicted by the erythropoietin response after 4 h exposure to normobaric hypoxia at an ambient Po(2) corresponding to the training altitude. METHODS: Erythropoietin levels were measured in 16 elite junior swimmers before and after 4 h exposure to normobaric hypoxia (Fio(2) 0.15, approximately 2500 m) as well as repeatedly during 3 week altitude training (2100-2300 m). Before and after the altitude training, total haemoglobin mass (CO rebreathing) and performance in a stepwise increasing swimming test were determined. RESULTS: The erythropoietin increase (10-185%) after 4 h exposure to normobaric hypoxia showed considerable inter-individual variation and was significantly (p<0.001) correlated with the acute erythropoietin increase during altitude training but not with the change in total haemoglobin mass (significant increase of approximately 6% on average). The change in sea level performance after altitude training was not related to the change in total haemoglobin mass. CONCLUSIONS: The results of the present prospective study confirmed the wide inter-individual variability in erythropoietic response to altitude training in elite athletes. However, their erythropoietin response to acute altitude exposure might not identify those athletes who respond to altitude training with an increase in total haemoglobin mass.

Adolescent↗
PubMed2002

Determinants of erythropoietin release in response to short-term hypobaric hypoxia.

We measured blood erythropoietin (EPO) concentration, arterial O(2) saturation (Sa(O(2))), and urine PO(2) in 48 subjects (32 men and 16 women) at sea level and after 6 and 24 h at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m. Renal blood flow (Doppler) and Hb were determined at sea level and after 6 h at each altitude (n = 24) to calculate renal O(2) delivery. EPO increased significantly after 6 h at all altitudes and continued to increase after 24 h at 2,454 and 2,800 m, although not at 1,780 or 2,085 m. The increase in EPO varied markedly among individuals, ranging from -41 to 400% after 24 h at 2,800 m. Similar to EPO, urine PO(2) decreased after 6 h at all altitudes and returned to baseline by 24 h at the two lowest altitudes but remained decreased at the two highest altitudes. Urine PO(2) was closely related to EPO via a curvilinear relationship (r(2) = 0.99), although also with prominent individual variability. Renal blood flow remained unchanged at all altitudes. Sa(O(2)) decreased slightly after 6 h at the lowest altitudes but decreased more prominently at the highest altitudes. There were only modest, albeit statistically significant, relationships between EPO and Sa(O(2)) (r = 0.41, P < 0.05) and no significant relationship with renal O(2) delivery. These data suggest that 1) the altitude-induced increase in EPO is "dose" dependent: altitudes > or =2,100-2,500 m appear to be a threshold for stimulating sustained EPO release in most subjects; 2) short-term acclimatization may restore renal tissue oxygenation and restrain the rise in EPO at the lowest altitudes; and 3) there is marked individual variability in the erythropoietic response to altitude that is only partially explained by "upstream" physiological factors such as those reflecting O(2) delivery to EPO-producing tissues.

Acute Disease↗
PubMed2002

Spontaneous and induced genetic damage in T lymphocyte subsets evaluated by the Comet assay.

High inter- and intra-individual variability was reported in the level of DNA damage, both spontaneous and induced, when peripheral blood mononuclear leukocytes were used to perform the Comet assay. In order to find out the underlying causes for such variability, different subsets of T lymphocytes were isolated by immunomagnetic cell sorting. The level of DNA damage was evaluated with the alkaline version of the Comet assay by using three different parameters: tail moment, tail length and amount of DNA in the tail (%). Helper T cells (CD4+), cytotoxic T cells (CD8+), their negative fraction and the mixed cell population were evaluated both in untreated cells and after 10 and 20 microM H(2)O(2) treatments. Differences between cell subsets were only observed after H(2)O(2) treatment. The results indicate that, although CD4+ is the fraction with the highest induced level of genetic damage, this value is not high enough to explain the large inter- and intra-individual variability found.

Adult↗
PubMed2005

Hormone replacement therapy and cognition in an Australian representative sample aged 60-64 years.

OBJECTIVE: To investigate the relationship between hormone replacement therapy (HRT) and level of cognitive performance intra-individual variability, and interactions with statin use, progesterone therapy and type of menopause. METHODS: A representative sample of 60-64 year olds was recruited from the Canberra and Queanbeyan regions in Australia. They were administered tests of verbal memory, working memory, speed of information processing, simple and complex reaction time, verbal intelligence and the Mini-Mental State Exam. Intra-individual variation (consistency) on performance on simple and complex reaction time tasks was calculated. Women provided information on HRT use and demographic, health and lifestyle variables. RESULTS: Four hundred and four (35.0%) current postmenopausal HRT users, 316 (27.4%) previous HRT users and 434 (37.6%) women who had never used HRT, were included in this study. There were significant overall differences between HRT current and previous users on age, prevalence of diabetes, alcohol use, body mass index, level of anxiety and lung function. After controlling for potentially confounding health and demographic variables, there were no significant main effects detected between HRT groups on any cognitive measure. Significant interactions were detected between HRT group and statin use on intra-individual variability on simple reaction time, and between HRT group and menopause type on intra-individual variability on choice reaction time. All other interactions were non-significant. CONCLUSIONS: HRT use had no effect on level of cognitive performance. Two interactions were detected between HRT use and statin use, and type of menopause on intra-individual variability. Given the large number of comparisons, little weight can be placed on these significant results.

Analysis of Variance↗
PubMed2000

The use of safety or uncertainty factors in the setting of acute reference doses.

A 100-fold safety or uncertainty factor has been used for about 40 years to derive safe daily intakes for humans based on animal studies; the 100-fold factor comprises separate 10-fold factors to allow for species differences and inter-individual variability. Each factor has to allow for toxicokinetic and toxicodynamic differences. Sub-dividing the 10-fold factors into kinetic and dynamic defaults, which when multiplied give a product of 10, offers a number of advantages. The main rationale for this sub-division is so that chemical-specific data can be introduced to replace one or more of the default sub-factors, hence contributing to a chemical-related overall factor. However, sub-division of the 10-fold factors has allowed analysis of the appropriateness of the overall 10-fold defaults, and analysis of special situations, such as infants and children. The establishment of an acute reference dose based on animal studies has to allow for both species differences and inter-individual variability; comparison with the factors used for chronic effects suggests that modification of the usual defaults may be appropriate under certain specific circumstances, but that the usual default of 100 remains appropriate for most cases.

Animals↗
PubMed2004

In vitro conversion of irinotecan to SN-38 in human plasma.

Irinotecan is an active cytotoxic agent for various cancers, and is converted to SN-38, its most active metabolite, by carboxylesterase converting enzyme (CCE) in vivo. Although the primary metabolic site is in the liver, ex vivo studies have proven that irinotecan is also converted to SN-38 in intestines, plasma and tumor tissues. The present study attempted to elucidate the in vitro conversion efficiency in human plasma, and to examine possible inter-individual variability and its clinical significance. Plasma samples were taken from 57 patients with lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers. After addition of 157 mM irinotecan to plasma, time courses of SN-38 concentration, measured by high-performance liquid chromatography (HPLC), were investigated. All subjects showed linear increase in SN-38 concentration during the first 60-min period, followed by a plateau. Mean and standard deviation of the conversion rate in the first 60 min were 515.9 +/- 50.1 pmol/ml/h (n = 69), with a coefficient of variation of 0.097. Although most of the subjects showed comparable conversion rates, 3 subjects had significantly higher conversion rates. In conclusion, the results of this study suggest that the enzyme activity of CCE in human plasma may show inter-individual variability.

Adult↗
PubMed2002

No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients.

OBJECTIVE: This aim of this study was to compare the pharmacokinetics of topotecan in the presence and absence of preceding amifostine to reduce the risk of side effects in patients with advanced ovarian cancer. METHODS: Ten patients with advanced ovarian cancer received topotecan, 1.5 mg/m(2) for 5 days, as second-line therapy in an open phase-II study after previous platinum-containing first-line therapy. Patients were randomised to receive intravenous (IV) amifostine at a daily dose of 300 mg/m(2) prior to topotecan in the first cycle and topotecan alone in the second cycle or vice versa. Thereafter all patients were given amifostine and topotecan for additional four cycles. Topotecan was given as a 30-min IV infusion. On day 1 of the first and second treatment cycles, venous blood samples were collected up to 24 h after the start of topotecan infusion. Plasma concentrations of total topotecan and its active lactone form were determined using high-performance liquid chromatography. RESULTS: There was a rapid decline in total topotecan plasma concentrations after the end of the infusion followed by a slower decay. The initial decline was even faster for the lactone form. The inter-individual variability was pronounced and the area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) of the total topotecan plasma concentration ranged from 182 nmol/l h to 725 nmol/l h for topotecan alone and from 188 nmol/l h to 574 nmol/l h for topotecan and amifostine. The geometric mean of AUC(0-infinity) values were 326 nmol/l h and 297 nmol/l h, respectively ( P=0.41). In the cycles when the patients received topotecan alone, the plasma AUC of the lactone averaged 40% of the AUC of the total concentration compared with 39% in the cycles when topotecan was given after amifostine. The peak plasma concentration (C(max)) of the lactone averaged 72% of the C(max) of the total topotecan concentration in the topotecan-only group. The corresponding figure after topotecan and amifostine was 80% ( P=0.11). A large intra-individual pharmacokinetic of topotecan between cycles 1 and 2 was also observed. CONCLUSION: Amifostine, 300 mg/m(2), does not significantly affect the pharmacokinetics of topotecan and there are pronounced intra- and inter-individual variabilities in the topotecan pharmacokinetics.

Adult↗
PubMed2001

Identification and functional characterization of eight CYP3A4 protein variants.

The genetic component of the inter-individual variability in CYP3A4 activity has been estimated to be between 60% and 90%, but the underlying genetic factors remain largely unknown. A study of 213 Middle and Western European DNA samples resulted in the identification of 18 new CYP3A4 variants, including eight protein variants. A total of 7.5% of the population studied was found to be heterozygous for one of these variants. In a bacterial heterologous expression system, two mutants, R130Q and P416L, did not result in detectable P450 holoprotein. One mutant, T363M, expressed at significantly lower levels than wild-type CYP3A4. G56D, V170I, D174H and M445T were not significantly different when compared with wild-type CYP3A4 in expression or steroid hydroxylase activity. L373F displayed a significantly altered testosterone metabolite profile and a four-fold increase in the Km value for 1'-OH midazolam formation. The results suggest a limited contribution of CYP3A4 protein variants to the inter-individual variability of CYP3A4 activity in Caucasians. Some variants may, however, play a role in the atypical response to drugs or altered sensitivity to carcinogens.

Base Sequence↗
PubMed2001

Relationship between response of gamma-glutamyl transpeptidase to alcohol drinking and risk factors for coronary heart disease.

Alcohol drinking has been reported to influence the risk factors for coronary heart disease (CHD), such as the serum levels of triglycerides, HDL-cholesterol and uric acid, and the level of blood pressure. To examine whether there was individual variability in the response of these parameters to alcohol drinking, a cross-sectional study was conducted in 3130 men with a body-mass index (BMI) below 24. The subjects were divided into two groups; a normal gamma-glutamyl transpeptidase (rGTP) (<40 IU/l) group and a high rGTP (> or =40 IU/l) group, and the values were compared after adjusted for age, BMI, exercise and smoking. The level of triglycerides increased according to the amount of drinking in the high rGTP group, whereas no association was observed in the normal rGTP group. The level of HDL-cholesterol increased with drinking in the normal and high rGTP groups, and no difference was observed in the levels of HDL-cholesterol between the two groups. The levels of uric acid and blood pressure also increased with drinking in both groups, but the increase was bigger in the high rGTP group than in the normal rGTP group. The results indicated that there was large individual variability in the responses of the risk factors for coronary heart disease to drinking. Subjects whose rGTP responds less to drinking may have less disadvantageous effects of drinking.

Adult↗
PubMed2003

Relations between brain network activation and analgesic effect induced by low vs. high frequency electrical acupoint stimulation in different subjects: a functional magnetic resonance imaging study.

Two- or 100-Hz electrical acupoint stimulation (EAS) can induce analgesia via distinct central mechanisms. It has long been known that the extent of EAS analgesia showed tremendous difference among subjects. Functional MRI (fMRI) studies were performed to allocate the possible mechanisms underlying the frequency specificity as well as individual variability of EAS analgesia. In either frequencies, the averaged fMRI activation levels of bilateral secondary somatosensory area and insula, contralateral anterior cingulate cortex and thalamus were positively correlated with the EAS-induced analgesic effect across the subjects. In 2-Hz EAS group, positive correlations were observed in contralateral primary motor area, supplementary motor area, and ipsilateral superior temporal gyrus, while negative correlations were found in bilateral hippocampus. In 100-Hz EAS group, positive correlations were observed in contralateral inferior parietal lobule, ipsilateral anterior cingulate cortex, nucleus accumbens, and pons, while negative correlation was detected in contralateral amygdala. These results suggest that functional activities of certain brain areas might be correlated with the effect of EAS-induced analgesia, in a frequency-dependent dynamic. EAS-induced analgesia with low and high frequencies seems to be mediated by different, though overlapped, brain networks. The differential activations/de-activations in brain networks across subjects may provide a neurobiological explanation for the mechanisms of the induction and the individual variability of analgesic effect induced by EAS, or that of manual acupuncture as well.

Acupuncture Analgesia↗
PubMed2005

Shortening velocity of human triceps surae muscle measured with the slack test in vivo.

Unloaded shortening velocity (V(0)) of human triceps surae muscle was measured in vivo by applying the 'slack test', originally developed for determining V(0) of single muscle fibres, to voluntary contractions at varied activation levels (ALs). V(0) was measured from 10 subjects at five different ALs defined as a fraction (5, 10, 20, 40 and 60%) of the maximum voluntary contraction (MVC) torque. Although individual variability was apparent, V(0) tended to increase with AL (R(2) = 0.089; P = 0.035) up to 60%MVC (8.6 +/- 2.6 rad s(-1)). This value of V(0) at 60%MVC was comparable to the maximum shortening velocity of plantar flexors reported in the previous studies. Electromyographic analysis showed that the activities of soleus, medial gastrocnemius and lateral gastrocnemius muscles increased with AL during isometric contraction and after the application of quick release in a similar manner. Also, it showed that the activity of an antagonist, tibialis anterior muscle, was negligible, even though a slight increase took place after the quick release of agonist. Correlation analysis showed that there were no significant correlations between V(0) and MVC torque normalized with respect to body mass, although the correlation coefficient was relatively high at low ALs. The results suggest that in human muscle, V(0) represents the unloaded velocity of the fastest muscle fibres recruited, and increases with AL possibly because of progressive recruitment of faster fibres. Individual variability may be explained, at least partially, by the difference in fibre-type composition.

Adult↗
PubMed2005

Trough levels of mycophenolic acid and its glucuronidated metabolite in renal transplant recipients.

OBJECTIVE: The prophylactic use of the immunosuppressant prodrug, mycophenolate mofetil (MMF) to prevent graft rejection in renal transplant patients is continuing to increase. We measured trough levels of the active metabolite, mycophenolic acid (MPA) and its inactive glucuronide (MPAG) in renal recipients with the aim of characterizing individual variability and of ascertaining factors influencing trough levels, in particular the effect of differences in renal function and the effect of drugs given concurrently. METHODS: Laboratory and clinical data obtained in 35 renal recipients treated with triple therapy (MMF, cyclosporin A (CsA), steroids) were included in this retrospective study. Trough levels of MPA and MPAG were obtained after transplantation and up to 16 months post transplantation where the mean observation period was 5.7 months. Plasma levels were measured using a validated HPLC assay. RESULTS: A total of 212 plasma concentrations of MPA and 209 of MPAG were measured. There was considerable intra- and interindividual variability in MPA and MPAG trough levels especially in the early post-transplantation phase. At a fixed dose of 2 g/d MMF, the mean MPA level during the first 30 days averaged 1.46 +/- 1.31 microg/ml vs. 1.87 +/- 0.89 microg/ml after 30 days and later (p = 0.130) and the mean MPAG concentration averaged 188.1 = 142.8 [microg/ml vs. 98.09 +/- 52.4 microlg/ml (p 0.003). The MPAG levels were positively correlated with the serum creatinine concentrations (r = 0.815, p < 0.001), and in the case of MPA there was a correlation with the serum protein concentrations (r = 0.258, p = 0.001). Concomitant drug treatment using CsA, steroids and furosemide were without effect of the measured plasma concentrations, but in the case of xipamide (+) and diltiazem (-) an effect on MPA and MPAG levels and a co-effect depending on the serum creatinine could not be excluded. Neither CsA trough levels nor hemoglobin levels were related to MPA and MPAG trough levels. CONCLUSIONS: The data of this study demonstrate that there is substantial individual variability in the trough levels of MPA and MPAG after renal transplantation which may be associated with the functional status of the graft and the serum protein level. Whether comedication with xipamide and diltiazem affects the plasma levels of MPA and MPAG remains to be clarified in further investigations.

Adolescent↗
PubMed2002

Daily energy expenditure, activity patterns, and energy costs of the various activities in French 12-16-y-old adolescents in free living conditions.

BACKGROUND: Changes in lifestyle and increases in sedentary activities during recent decades have been shown to contribute to the prevalence of overweight in adolescents. OBJECTIVES: To determine the inter-individual variability and the day-to-day variations in daily energy expenditure (DEE) and activity pattern, and the energy costs and EE of the various activities of adolescents in free-living conditions. DESIGN: Sixty adolescents (four groups of 14-16 boys or girls aged 12-16 y) participated in this cross-sectional study during spring or autumn. Activity patterns and EE were determined during five consecutive days, using both a diary and the heart rate recording method validated by whole-body calorimetry and laboratory tests. RESULTS: Mean DEE increased significantly with age in boys, but not in girls. However, the physical activity level did not vary significantly with sex and age. Mean DEE was significantly higher in spring than in autumn in the 12.6-y-old subjects. It was also 21% higher during the free days than during the schooldays in the active subjects, but 7% lower in the sedentary subjects. The energy cost of 22 activities was determined. Time and energy devoted to moderate and sport activities exhibited great inter-individual variability. They were lower in girls than in boys and decreased with age. The increase in EE resulting from moderate and sport activities instead of sedentary activities ranged from 0.2 to 2.7 MJ/day over the week. CONCLUSION: The great variability in DEE of adolescents resulted mainly from differences in the nature, duration and intensity of physical activities during the free days.

Adolescent↗
PubMed2006

Urinary calcium excretion in healthy children and children with primary monosymptomatic nocturnal enuresis.

PURPOSE: We investigated the role of urinary Ca excretion in monosymptomatic nocturnal enuresis, and defined normality and intra-individual variability in Ca excretion in healthy children. MATERIALS AND METHODS: We included 46 Danish children with desmopressin resistant nocturnal enuresis and 96 healthy controls. We performed fractional urine collections at home during 2 days in controls or during hospitalization in children with enuresis. Urine volume, osmolality, and Ca and creatinine measurements were performed and Ca-to-creatinine ratios were calculated and compared between groups. Based on nocturnal urine output children with enuresis were characterized as having polyuria (nocturnal urine volume greater than 130% of expected bladder capacity) or not having polyuria. RESULTS: We did not find any differences in controls compared with children with enuresis who did not and did have nocturnal polyuria in daytime Ca excretion (mean +/- SE 0.121 +/- 0.012, 0.078 +/- 0.014 and 0.095 +/- 0.020 mg/mg creatinine), nighttime Ca excretion (0.115 +/- 0.011, 0.092 +/- 0.019 and 0.139 +/- 0.029 mg/mg creatinine) or 24-hour Ca excretion (0.118 +/- 0.011, 0.083 +/- 0.014 and 0.106 +/- 0.020 mg/mg creatinine, respectively). Urinary Ca excretion was not influenced by patient age, sex or body weight and, furthermore, we did not find evidence of diurnal variation. However, we observed considerable intra-individual variability in diurnal, nocturnal and total 24-hour urinary Ca-to-creatinine ratios. CONCLUSIONS: These observations contradict several previous reports and speculations on a role of Ca in the pathogenesis of nocturnal enuresis.

Adolescent↗
PubMed2005

Identification and functional analysis of genetic variants of the human beta-glucuronidase in a German population sample.

The deleterious consequences of total beta-glucuronidase deficiency, leading to symptomatic mucopolysaccharidosis type VII (MPS VII), have been firmly established. However, the question of whether sequence variations in beta-glucuronidase of non-MPS VII patients affect expression of the enzyme, thereby explaining the wide inter-individual expression, has not been addressed in a systematic manner. In the present study, a population of 965 subjects were screened for enzyme activity and relevant fractions of the beta-glucuronidase gene were sequenced in those individuals belonging to the highest or lowest decile of activity. The study showed a substantial inter-individual variability of beta-glucuronidase in plasma (range 0.5-150.2 micromol/min) and confirmed the association of beta-glucuronidase activity with gender (P < 0.001), age (r = 0.218; P < 0.001) and body mass index (r = 0.311; P < 0.001). We were able to identify six beta-glucuronidase single base substitutions (-1026A > G, -72G > T, -12G > A, +7728C > T, +14 209C > T and +14 604A > G) in 193 non-MPS VII patients at a rate of one single nucleotide polymorphism (SNP) per 520 bp sequenced. The GG genotype of +14 604A > G and the CT genotype of +14 209C > T were associated with higher beta-glucuronidase activity (P < 0.05). Subsequently, reporter gene assays were carried out to elucidate the effects of the SNPs -1026A > G, -72G > T and -12G > A, and the combined genotype -1026A > G and -12G > A observed in one of the subjects. Variant -12G > A reduced the promoter activity (75%; 95% confidence interval 70-84%, P < 0.05). The present study demonstrates that three of the described SNPs influence the activity and/or expression of beta-glucuronidase. Taken together, the data indicate a rather limited influence of genetic factors on inter-individual variability in beta-glucuronidase activity.

Cross-Sectional Studies↗