Metabolic syndrome and associated factors in a population-based sample of schoolchildren in Colombia: The FUPRECOL Study

In contrast to the definition of metabolic syndrome (MetS) in adults, there is no standard definition of MetS in pediatric populations. We aimed to assess the differences in the prevalence of MetS in children and adolescents aged 9–17 years in the city of Bogota (Colombia) using four different operational definitions for these age groups and to examine the associated variables. A total of 673 children and 1,247 adolescents attending public schools in Bogota (54.4% girls; age range 9–17.9 years) were included. The prevalence of MetS was determined by the definitions provided by the International Diabetes Federation (IDF) and three published studies by Cook et al., de Ferranti et al., and Ford et al. The prevalence of MetS was 0.3%, 6.3%, 7.8%, and 11.0% according to the IDF, Cook et al., Ford et al., and de Ferranti et al. definitions, respectively. The most prevalent components were low high-density lipoprotein cholesterol and high triglyceride levels, whereas the least prevalent components were abdominal obesity and hyperglycemia. Overall, the prevalence of MetS was higher in obese than in non-obese schoolchildren. In conclusion, MetS diagnoses in schoolchildren strongly depend on the definition chosen. These findings may be relevant to health promotion efforts for Colombian youth to develop prospective studies and to define which cut-offs are the best indicators of future morbidity.

Children’s food and activity patterns following a six-month child weight management program

Objective To describe the impact of a parent-led, family focused child weight management program on the food intake and activity patterns of pre-pubertal children. Methods n assessor-blinded, randomized controlled trial involving 111 (64% female) overweight, pre-pubertal children 6 to 9 years of age randomly assigned to parenting-skills training plus intensive lifestyle education, parenting-skills training alone, or a 12-month wait-listed control. Study outcomes were assessed at baseline, 6 months, and 12 months. This paper presents data on food intake assessed via a validated 54-item parent completed dietary questionnaire and activity behaviours assessed via a parent-report 20-item activity questionnaire. Results Intake of energy-dense nutrient poor foods was lower in both intervention groups at 6 months (mean difference, P+DA -1.5 serves [CI -2.0;-1.0]; P -1.0 serves [-2.0;-0.5]) and 12 months (mean difference P+DA -1.0 serves [CI -2.0;-0.5]; P -1.0 serves [-1.5; 0.0]) compared to baseline. Intake of vegetables, fruit, breads and cereals, meat and alternatives and dairy foods remained unchanged. Regardless of study group there were significant reductions over time in the reported time spent engaged in small screen activities and an increase in the time reported spent in active play. Conclusion Child weight management intervention that promotes food intake in line with national dietary guidelines achieves a reduction in children’s intake of energy dense, nutrient poor foods. This was achieved without compromising intake of nutrient-rich food and changes in were maintained even once the intervention ceased.

A mega-analysis of genome-wide association studies for major depressive disorder

Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 x 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 x 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.

Mulibrey nanism : Clinical characteristics and pathophysiologic features of growth restriction, insulin resistance and tumour development

Background: Mulibrey nanism (MUL; Muscle-liver-brain-eye nanism; OMIM 253250) is an autosomal recessive growth disorder more prevalent in Finland than elsewhere in the world. Clinical characteristics include severe prenatal onset growth restriction, cardiopathy, multiple organ manifestations but no major neurological handicap. MUL is caused by mutations in the TRIM37 gene on chromosome 17q22-23, encoding a peroxisomal protein TRIM37 with ubiquitin E3-ligase activity. Nineteen different mutations have been detected, four of them present in the Finnish patients. Objective: This study aimed to characterize clinical and histopathological features of MUL in the national cohort of Finnish patients. Patients and methods: A total of 92 Finnish patients (age 0.7 to 77 years) participated in the clinical follow-up study. Patients hospital records and growth charts were reviewed. Physical, radiographic and laboratory examinations were performed according to a clinical protocol. Thirty patients (18 females) were treated with recombinant human GH for a median period of 5.7 years. Biopsies and autopsy samples were used for the histopathological and immunohistochemical analyses. Results: MUL patients were born small for gestational age (SGA) with immature craniofacial features after prenatal-onset growth restriction. They experienced a continuous deceleration in both height SDS and weight-for-height (WFH) postnatally. In infancy feeding difficulties and frequent pneumonias were common problems. At the time of diagnosis (median age 2.1 years) characteristic craniofacial, radiological and ocular features were the most constant findings. MUL patients showed a dramatic change in glucose metabolism with increasing age. While the children had low fasting glucose and insulin levels, 90% of the adults were insulin resistant, half had type 2 diabetes and an additional 42% showed impaired glucose tolerance (IGT). Seventy percent fulfilled the National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria for metabolic syndrome as adults. GH therapy improved pre-pubertal growth but had only minor impact on adult height (+5 cm). Interestingly, treated subjects were slimmer and had less frequent metabolic concerns as young adults. MUL patients displayed histologically a disturbed architecture with ectopic tissues and a high frequency of both benign and malignant tumours present in several internal organs. A total of 232 tumorous lesions were detected in our patient cohort. The majority of the tumours showed strong expression of endothelial cell marker CD34 as well as α-smooth muscle actin (α-SMA). Fifteen of the tumours were malignant and seven of them (five Wilms tumours) occurred in the kidney. Conclusions: MUL patients present a distinct postnatal growth pattern. Short-term response of GH treatment is substantial but the long-term impact remains modest. Although MUL patients form a distinct clinical and diagnostic entity, their clinical findings vary considerably from infancy to adulthood. While failure to thrive dominates early life, MUL adults develop metabolic syndrome and have a tendency for malignancies and vascular lesions in several organs. This speaks for a central role of TRIM37 in regulation of key cellular functions, such as proliferation, migration, angiogenesis and insulin signalling.

Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Genetic variation in the LDL receptor-related protein 5 (LRP5) gene : Association with bone health and metabolic parameters

Bone mass accrual and maintenance are regulated by a complex interplay between genetic and environmental factors. Recent studies have revealed an important role for the low-density lipoprotein receptor-related protein 5 (LRP5) in this process. The aim of this thesis study was to identify novel variants in the LRP5 gene and to further elucidate the association of LRP5 and its variants with various bone health related clinical characteristics. The results of our studies show that loss-of-function mutations in LRP5 cause severe osteoporosis not only in homozygous subjects but also in the carriers of these mutations, who have significantly reduced bone mineral density (BMD) and increased susceptibility to fractures. In addition, we demonstrated for the first time that a common polymorphic LRP5 variant (p.A1330V) was associated with reduced peak bone mass, an important determinant of BMD and osteoporosis in later life. The results from these two studies are concordant with results seen in other studies on LRP5 mutations and in association studies linking genetic variation in LRP5 with BMD and osteoporosis. Several rare LRP5 variants were identified in children with recurrent fractures. Sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses revealed no disease-causing mutations or whole-exon deletions. Our findings from clinical assessments and family-based genotype-phenotype studies suggested that the rare LRP5 variants identified are not the definite cause of fractures in these children. Clinical assessments of our study subjects with LPR5 mutations revealed an unexpectedly high prevalence of impaired glucose tolerance and dyslipidaemia. Moreover, in subsequent studies we discovered that common polymorphic LRP5 variants are associated with unfavorable metabolic characteristics. Changes in lipid profile were already apparent in pre-pubertal children. These results, together with the findings from other studies, suggest an important role for LRP5 also in glucose and lipid metabolism. Our results underscore the important role of LRP5 not only in bone mass accrual and maintenance of skeletal health but also in glucose and lipid metabolism. The role of LRP5 in bone metabolism has long been studied, but further studies with larger study cohorts are still needed to evaluate the specific role of LRP5 variants as metabolic risk factors.

Efeitos da exposição combinada de cafeína e etanol durante o desenvolvimento na atividade locomotora de camundongos adolescentes

O Transtorno do Déficit de Atenção e Hiperatividade (TDAH) é uma desordem neurocomportamental caracterizada por graus variados de desatenção, atividade motora excessiva e impulsividade. Sua etiologia não é completamente conhecida, porém, um grande número de evidências sugere que, além de fatores de risco genéticos, a exposição gestacional ao etanol e a altas doses de cafeína contribuem para a manifestação deste transtorno. O etanol, presente na composição de bebidas alcoólicas, e a cafeína, presente na composição de diversas bebidas (refrigerantes, chás, café, e energéticos), alimentos derivados do cacau e medicamentos estão entre as substâncias neuroativas mais consumidas no mundo. Apesar das evidências epidemiológicas do uso combinado de cafeína e etanol por gestantes, as interações entre estas substâncias têm recebido pouca atenção em estudos experimentais. Este fato é particularmente importante visto que alguns estudos apontam que cafeína é capaz de ampliar alguns aspectos importantes da ação de outras substâncias com potencial neurotóxico. Nesse estudo avaliamos os efeitos da co-exposição à cafeína e ao etanol durante o desenvolvimento na atividade locomotora em camundongos adolescentes. Para tanto, camundongos Suíços foram expostos do primeiro dia gestacional até o vigésimo primeiro dia pós-natal (PN21), a solução de cafeína 0,1g/L (Grupo CAF1, 10 ninhadas), a solução de cafeína 0,3g/L (Grupo CAF3, 10 ninhadas) ou tiveram acesso à água potável (Grupo CAF0, 10 ninhadas). Em dias alternados de PN2 a PN8, os animais de cada ninhada receberam uma injeção intraperitoneal de 0,25 l/g de etanol (grupo ETOH25), 0,5 l/g de etanol (grupo ETOH50) ou de solução salina (grupo ETOH0). Em PN30, a atividade locomotora foi avaliada por 15 minutos no teste de Campo Aberto. A análise dos níveis de etanol sérico, realizada em uma amostra independente de animais em PN8, indicou que, para as duas doses de etanol, a alcoolemia dos animais do grupo CAF3 foi significativamente maior do que as dos grupos CAF0 e CAF1, que não diferiram entre si. No teste de campo aberto, apenas os animais expostos ao etanol apresentaram aumento da atividade locomotora. Tanto o grupo ETOH25 quanto o grupo ETOH50 tiveram a atividade maior que o grupo ETOH0. A exposição à cafeína, por si só, não afetou a atividade locomotora dos animais nem potencializou os efeitos do etanol. No grupo CAF3, a atividade locomotora não foi afetada pela exposição ao etanol. Nossos dados confirmam o papel da exposição precoce ao etanol na manifestação da hiperatividade locomotora. Além disso, a exposição à cafeína durante o desenvolvimento pode exercer um papel protetor para a manifestação da hiperatividade locomotora induzida pela exposição precoce ao etanol.

Developmental differences in locomotor responsiveness to amphetamine in rats

The developmental remodelling of motivational systems that underlie drug dependence and addiction may account for the greater frequency and severity of drug abuse in adolescence compared to adulthood. Recent advances in animal models have begun to identify the morphological and the molecular factors that are being remodelled, but little is known about the culmination of these factors in altered sensitivity to psycho stimulant drugs, like amphetamine, in adolescence. Amphetamine induces potent locomotor activating effects in rodents through increased dopamine release in the mesocorticolimbic dopamine system, which makes locomotor activity a useful behavioural marker of age differences in amphetamine sensitivity. The aim of the thesis was to investigate the neural basis for age differences in amphetamine sensitivity with a focus on the nucleus accumbens and the medial prefrontal cortex, which initiate and regulate amphetamine-induced locomotor activity, respectively. In study 1, I found pre- and post- pubertal adolescent rats to be less active (i.e., hypoactive) than adults to a first injection of 0.5, but not of 1.5, mg/kg of intraperitonealy (i.p.) administered amphetamine. Although initially hypoactive, only adolescent rats exhibited an increase in activity to a second injection of amphetamine given 24 h later, indicating that adolescents may be more sensitive to the rapid changes in amphetamineinduced plasticity than adults. Given that the locomotor activating effects of amphetamine are initiated in the nucleus accumbens, age differences in response to direct injections of amphetamine into this brain region were investigated in study 2. In contrast to i.p. injections, adolescents were more active than adults when amphetamine was given directly into the nucleus accumbens, indicating that hypo activity may be attributed to the development of regulatory regions outside of the accumbens. The medial prefrontal cortex (mPFC) is a key regulator of the locomotor activating effects of amphetamine that undergoes extensive remodelling in adolescence. In study 3, I found that an i.p. injection of 1.5, and not of 0.5, mg/kg of amphetamine resulted in a high expression of c-fos, a marker of neural activation, in the pre limbic mPFC only in pre-pubertal adolescent rats. This finding suggests that the ability of adolescent rats to overcome hypo activity at the 1.5 mg/kg dose may involve greater activation of the prelimbic mPFC compared to adulthood. In support of this hypothesis, I found that pharmacological inhibition of prelimbic D 1 dopamine receptors disrupted the locomotor activating effects of the 1.5 mg/kg dose of amphetamine to a greater extent in adolescent than in adult rats. In addition, the stimulation of prelimbic D 1 dopamine receptors potentiated locomotor activity at the 0.5 mg/kg dose of amphetamine only in adolescent rats, indicating that the prelimbic D1 dopamine receptors are involved in overcoming locomotor hypoactivity during adolescence. Given my finding that the locomotor activating effects of amphetamine rely on slightly different mechanisms in adolescence than in adulthood, study 4 was designed to determine whether the lasting consequences of drug use would also differ with age. A short period of pre-treatment with 0.5 mg/kg of amphetamine in adolescence, but not in adulthood, resulted in heightened sensitivity to an injection of amphetamine given 30 days after the start of the procedure, when adolescent rats had reached adulthood. The finding of an age-specific increase in amphetamine sensitivity is consistent with evidence for increased risk for addiction when drug use is initiated in adolescence compared to adulthood in people (Merline et aI., 2002), and with the hypothesis that adolescence is a sensitive period of development.

Dynamic Upper Leg Strength and Neuromuscular Function in Children, Adolescents and Adults

This study examined muscle strength, muscle performance, and neuromuscular function during contractions at different velocities across maturation stages and between sexes. Participants included pre-pubertal, late-pubertal and adult males and females. All completed 8 isometric and 8 isokinetic leg extensions at two different velocities. Peak torque (PT), rate of torque development (PrTD), electromechanical-day (EMD), rate of muscle activation (Q30), muscle activation efficiency and coactivation were determined. Sex, maturity, and velocity main effects were found in PT and PrTD, reflecting greater values in men, adults, and isometric contractions respectively. When values were normalized to quadriceps cross-sectional area (qCSA), there was still an increase with maturity. EMD decreased with maturity. Adults had greater activation efficiency than children. Overall, differences in muscle size and neuromuscular function failed to explain group differences in PT or PrTD. More research is needed to investigate why adults may be affected to a greater extent by increasing movement velocity.

The relationship between muscle size and bone geometry during growth and in response to exercise

As muscles become larger and stronger during growth and in response to increased loading, bones should adapt by adding mass, size, and strength. In this unilateral model, we tested the hypothesis that (1) the relationship between muscle size and bone mass and geometry (nonplaying arm) would not change during different stages of puberty and (2) exercise would not alter the relationship between muscle and bone, that is, additional loading would result in a similar unit increment in both muscle and bone mass, bone size, and bending strength during growth. We studied 47 competitive female tennis players aged 8–17 years. Total, cortical, and medullary cross-sectional areas, muscle area, and the polar second moment of area (Ip) were calculated in the playing and nonplaying arms using magnetic resonance imaging (MRI); BMC was assessed by DXA. Growth effects: In the nonplaying arm in pre-, peri- and post-pubertal players, muscle area was linearly associated BMC, total and cortical area, and Ip (r = 0.56–0.81, P < 0.09 to < 0.001), independent of age. No detectable differences were found between pubertal groups for the slope of the relationship between muscle and bone traits. Post-pubertal players, however, had a higher BMC and cortical area relative to muscle area (i.e., higher intercept) than pre- and peri-pubertal players (P < 0.05 to < 0.01), independent of age; pre- and peri-pubertal players had a greater medullary area relative to muscle area than post-pubertal players (P < 0.05 to < 0.01). Exercise effects: Comparison of the side-to-side differences revealed that muscle and bone traits were 6–13% greater in the playing arm in pre-pubertal players, and did not increase with advancing maturation. In all players, the percent (and absolute) side-to-side differences in muscle area were positively correlated with the percent (and absolute) differences in BMC, total and cortical area, and Ip (r = 0.36–0.40, P < 0.05 to < 0.001). However, the side-to-side differences in muscle area only accounted for 11.8–15.9% of the variance of the differences in bone mass, bone size, and bending strength. This suggests that other factors associated with loading distinct from muscle size itself contributed to the bones adaptive response during growth. Therefore, the unifying hypothesis that larger muscles induced by exercise led to a proportional increase in bone mass, bone size, and bending strength appears to be simplistic and denies the influence of other factors in the development of bone mass and bone shape.

Is growth inhibited in non-elite competitive female gymnasts?

PURPOSE
We asked: 1) is statural growth inhibited in non-elite competitive female gymnasts?; and 2) if growth is reduced, is the effect similar for legs and spine?

METHODS
Height(Ht), sitting height(StHt) and leg length(LL) were measured in gymnasts and controls at baseline and every 12 mths for 2 yrs. Pubertal status was assessed by Tanner stage. Gymnasts were from USGF levels 4–10 and trained 7.5 to 22.5 hrs/wk. Age-adjusted Z-scores were determined for gymnasts on the anthropometric measures and based on linear regression analyses of data for 45 controls.

RESULTS
At baseline, pre-(N=40), peri-(N=16) and post-pubertal(N=11) gymnasts were shorter than controls(-0.9 to -1.3 SD, p < 0.01). In pre- and peri-pubertal gymnasts, this was due to a reduction in StHt (-0.8 to -1.3 SD) and LL (-0.8 to -1.1 SD)(p < 0.01). In post-pubertal gymnasts, StHt (-0.8 SD) was reduced (p < 0.05). No differences were observed in z-score deficits between pubertal groups, nor were there any differences in StHt and LL deficits. During 12 mths follow-up in 39 gymnasts, deficits in Ht z-scores were reduced further in pre-pubertal gymnasts (-0.2 SD, p < 0.001) due to a greater increase in the deficit in LL (-0.3 SD, p < 0.001). While the magnitude of z-score deficits for peri-pubertal gymnasts remained unchanged, Ht z-scores improved in post-pubertal gymnasts(+0.2SD, p < 0.05) due primarily to an increase in StHt (+0.4 SD, p < 0.01). Similar results were found in 16 gymnasts followed for 2 yrs.

CONCLUSION
Although small size may relate to self-selection for gymnastics, some non-elite female gymnasts may experience attenuated growth during early puberty due mainly to reduced leg growth. The increased growth observed in post-pubertal gymnasts is consistent with catch-up growth associated with delayed maturation.

Role of exercise in the development of bone strength during growth

Exercise during growth may increase peak bone mass; if the benefits are maintained it may reduce the risk of fracture later in life (1). It is hypothesised that exercise will preferentially enhance bone formation on the surface of cortical bone that is undergoing bone modeling at the time (2). Therefore, exercise may increase bone mass accrual on the outer periosteal surface during the pre- and peri-pubertal years, and on the inner endocortical surface during puberty (3). An increase in bone formation on the periosteal surface is, however, more effective for increasing bone strength than medullary contraction (4). While exercise may have a role in osteoporosis prevention, there is little evidential basis to support this notion. It is generally accepted that weight-bearing exercise is important, but it is not known how much, how often, what magnitude or how long children need to exercise before a clinically important increase in bone density is obtained. In this thesis, the effect of exercise on the growing skeleton is investigated in two projects. The first quantifies the magnitude and number of loads associated with and in a moderate and low impact exercise program and non-structured play. The second project examines how exercise affects bone size and shape during different stages of growth. Study One: The Assessment of the Magnitude of Exercise Loading and the Skeletal Response in Girls Questions: 1) Does moderate impact exercise lead to a greater increase in BMC than low impact exercise? 2) Does loading history influence the osteogenic response to moderate impact exercise? 3) What is the magnitude and number of loads that are associated with a moderate and low impact exercise program? Methods: Sixty-eight pre-and early-pubertal girls (aged 8.9±0.2 years) were randomised to either a moderate or low impact exercise regime for 8.5-months. In each exercise group the girls received either calcium fortified (-2000 mg/week) or non-fortified foods for the duration of the study. The magnitude and number of loads associated with the exercise programs and non-structured play were assessed using a Pedar in-sole mobile system and video footage, respectively. Findings: After adjusting for baseline BMC, change in length and calcium intake, the girls in the moderate exercise intervention showed greater increases in BMC at the tibia (2.7%) and total body (1.3%) (p ≤0.05). Girl's who participated in moderate impact sports outside of school, showed greater gains in BMC in response to the moderate impact exercise program compared to the low impact exercise program (2.5 to 4.5%, p ≤0.06 to 0.01). The moderate exercise program included -400 impacts per class, that were applied in a dynamic manner and the magnitude of impact was up to 4 times body weight. Conclusion: Moderate-impact exercise may be sufficient to enhance BMC accrual during the pre-pubertal years. However, loading history is likely to influence the osteogenic response to additional moderate impact exercise. These findings contribute towards the development of school-based exercise programs aimed at improving bone health of children. Study Two: Exercise Effect on Cortical Bone Morphology During Different Stages of Maturation in Tennis Players Questions: 1) How does exercise affect bone mass (BMC) bone geometry and bone strength during different stages of growth? 2) Is there an optimal stage during growth when exercise has the greatest affect on bone strength? Methods: MRI was used to measure average total bone, cortical and medullary areas at the mid- and distal-regions of the playing and non-playing humerii in 47 pre-, peri- and post-pubertal competitive female tennis players aged 8 to 17 years. To assess bone rigidity, each image was imported into Scion Image 4.0.2 and the maximum, minimum and polar second moments of area were calculated using a custom macro. DXA was used to measure BMC of the whole humerus. Longitudinal data was collected on 37 of the original cohort. Findings: Analysis of the entire cohort showed that exercise was associated with increased BMC and cortical area (8 to 14%), and bone rigidity (11 to 23%) (all p ≤0.05). The increase in cortical bone area was associated with periosteal expansion in the pre-pubertal years and endocortical contraction in the post-pubertal years (p ≤0.05). The exercise-related gains in bone mass that were accrued at the periosteum during the pre-pubertal years, did not increase with advanced maturation and/or additional training. Conclusion: Exercise increased cortical BMC by enhancing bone formation on the periosteal surface during the pre-pubertal years and on the endocortical surface in the post-pubertal years. However, bone strength only increased in response to bone acquisition on the periosteal surface. Therefore the pre-pubertal years appear to be the most opportune time for exercise to enhance BMC accrual and bone strength

Muscle determinants of bone mass, geometry and strength in prepubertal girls

Purpose: The aim of this study was to compare the relative contribution of peak muscle force (isokinetic peak torque) with surrogate estimates of muscle force, including leg lean tissue mass (LTM) and vertical jump height (VJH), on bone mass, geometry and strength in healthy prepubertal girls (n = 103).

Methods: Total leg and FN BMC and leg LTM were measured by DXA; the hip strength analysis program was used to assess FN diameter, cross-sectional area (CSA) and section modulus (Z). Isokinetic peak torque of the knee extensors and flexors (60°·s-1) were used as direct measures of peak muscle force. VJH was measured as an estimate of neuromuscular function. Total leg length or femoral length was used as a surrogate measure of moment arm length.

Results: All estimates of muscle function, except VJH, were positively associated with leg BMC (r = 0.72 - 0.90) and FN BMC, geometry and strength (r = 0.35-0.65) (all, P < 0.001). Multiple linear regression analyses revealed that leg LTM and isokinetic peak torque were independently and equally predictive of leg BMC and FN BMC, bone geometry and strength, explaining 8 to 28% of the variance in each of the bone traits after accounting for moment arm length. When isokinetic peak torque was corrected for both leg LTM and moment arm length, it remained an independent predictor of BMC, CSA and Z, but only accounted for an additional 2 to 5% of the variance.

Conclusion: These data suggest that DXA-derived leg LTM can be used as a reasonable surrogate for isokinetic peak muscle forces when assessing bone strength in relation to muscular function in healthy pre-pubertal girls.

Tissue remodeling in Guinea pig lateral prostate at different ages after estradiol treatment

Estrogen seems to have an essential role in the fibromuscular growth characteristic of benign prostatic hyperplasia (BPH). This paper describes the effects of chronic estradiol treatment on Guinea pig prostatic stroma at different ages. Tissues from experimental animals were studied by histological and histochemical procedures, morphometric-stereological analysis and transmission electron microscopy (TEM). Marked fibromuscular hypertrophy was observed after estradiol treatment in animals of pre-pubertal and adult ages. Increases in the density and thickness of the collagen and elastic fibers were observed by histochemistry. TEM revealed wide distributions of collagen fibrils and large elastic fibers adjacent to the epithelial basal lamina and between the stromal cells, establishing contacts between them. These results indicate that the Guinea pig prostate simulates the stromal modifications observed in BPH in some aged animals after estrogen treatment at different ages, making it a good model for this disease. (c) 2005 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.

Participação da via alfa-2 adrenérgica no controle da secreção do hormônio do crescimento no período prépúbere em novilhas da raça Nelore

This study investigated GH secretion after clonidine (alpha-2 adrenergic agonist) treatment in pre-pubertal Nelore heifers. Clonidine (10 mg/kg, IV, 15 min samples for 4 h) was administrated in the same Nelore heifers at eight (n = 4), 12 (n = 5) and 15 (n = 4) months of age. The GH concentration was measured by radioimmunoassay (sensivity = 0.25 ng/mL, CV = 16%). At eight months, clonidine increased GH average concentration, total area of peaks, the total area of GH secretion and increased peak amplitude and reduced time to onset of peak (P < 0.05). At 15 months, the administration of clonidine increased the GH average concentration and at 12 months the increased occurred only in restricted intervals (P < 0.05). Clonidine injection stimulated GH secretion in prepubertal heifers and this effect was more evident in Nelore heifers at eight months compared to 12 and 15 months of age.