Ethics takes time, but not that long

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Fetal, developmental, and parental influences on childhood systolic blood pressure in 600 sib pairs: the Uppsala Family study.

BACKGROUND: Little is known about the contribution of maternal and paternal factors to the inverse association between birth weight and later blood pressure in human offspring. A study of within- and between-family associations of birth weight with blood pressure, which collected data on both parents, would address this gap in our knowledge. METHODS AND RESULTS: The study examined families composed of mother, father, and 2 full sibs delivered between 38 and 41 weeks' gestation within 36 months of each other. A total of 1967 families meeting our inclusion criteria were contacted and 602 were examined (children 5 to 14 years old, 1998 to 2000). Birth weight and gestational age were available from obstetric records. Systolic blood pressure in childhood was inversely associated with birth weight within families (-2.3 mm Hg/kg, 95% CI -4.4 to -0.3) after adjustment for gestational age, sex, height, and weight at examination. The between-family effect (-1.5 mm Hg/kg, -3.1 to 0.0) was strengthened on adjustment for maternal and paternal height and weight, whereas adjustment for paternal and maternal systolic blood pressure at examination independently attenuated the effect. CONCLUSIONS: The existence of an inverse association of birth weight with systolic blood pressure within families (adjusted for height and weight at examination) demonstrates that factors that vary between pregnancies in the same woman (including fetal genotype) can influence the later blood pressure of offspring. We conclude that this apparent fetal programming effect on blood pressure will not be eliminated solely by interventions aimed at modifying growth and cumulative nutritional status from conception through childhood or other fixed characteristics of future mothers

Fetal, developmental, and parental influences on cystatin C in childhood: the Uppsala Family Study.

BACKGROUND: The aim was to identify determinants (biomedical and social characteristics of children and their parents) of cystatin C levels in healthy children drawn from a population sample. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 425 pairs of consecutive full siblings born 1987-1995 in Uppsala were identified using the Swedish Medical Birth Registry and invited with their parents for examination in 2000-2001. OUTCOME: Serum cystatin C level was log-transformed and analyzed using random-effects models. MEASUREMENTS: The examination in parents and children consisted of a nonfasting blood sample, anthropometry, and questionnaires about lifestyle and socioeconomic position. Tanner stage was used for assessment of pubertal status. RESULTS: In age-, height-, and body mass index-adjusted analyses, cystatin C level increased by 2.6% (95% CI, 0.3%-4.8%) higher in Tanner stage 2 vs 1 girls, and 1.6% (95%CI, 0.2%-3.1%) lower in boys than girls. For every 10% increase in maternal cystatin C level, offspring cystatin C level increased by 3.0% (95% CI, 2.2%-3.8%); the equivalent effect for paternal cystatin C level was 2.1% (95% CI, 1.3%-2.9%). Lower maternal education was associated with a 2.4% (95% CI, 0.3%-4.6%) higher cystatin C level in their offspring. LIMITATIONS: Cross-sectional study design, missing cystatin C values for subset of parents, lack of urinary measurements, no gold-standard measurement of glomerular filtration rate. CONCLUSIONS: There are intergenerational associations of cystatin C level in families in line with previous reports of heritability of kidney disease. Lower maternal education is associated with higher cystatin C levels in their children. Further studies of healthy children are needed to explore the biological mechanisms for these findings. If cystatin C is measured, these studies will need to record pubertal stages

Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.

Context: Weight-based growth hormone (GH) dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). Objective: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. Setting: 153 short prepubertal children diagnosed with isolated GHD or ISS (n=43) and >/=1 SDS below mid-parental height standard deviation score(MPHSDS) were included in this 2-year multicenter study. Intervention: The children were randomized to either a standard (43 microg/kg/d) or an individualized GH dose (17-100 microg/kg/d). Main outcome measure: Deviation of HeightSDS from individual MPHSDS (diffMPHSDS). The primary endpoint was difference in the range of 'diffMPHSDS' between the two groups. Results: diffMPHSDS range was reduced by 32% in the individualized-dose group relative to the standard-dose group (p<0.003), whereas the mean 'diffMPHSDS' was equal: -0.42+/-0.46 and -0.48+/-0.67, respectively. Gain in HeightSDS 0-2 yrs was equal for the GH-deficient and the ISS groups; 1.31+/-0.47 and 1.36+/-0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24h profile. Conclusion: Individualized GH doses during catch-up growth significantly reduces the proportion of unexpectedly good and poor responders around a predefined individual growth target and results in equal growth responses in children with GHD and ISS

Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion

Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i. e. idiopathic isolated GH deficiency. Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH(33) mu g/kg/day for >= 1 year. They were randomized to receive 67 mu g/kg/day (GH(67)) given as one (GH(67x1); n = 35) or two daily injections (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/day dose (GH(33x1); n = 40). Growth was assessed as height SDS gain for prepubertal, pubertal and total periods, as well as AH SDS versus the population and the midparental height. Results: Pubertal height SDS gain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33x1), 0.41, p < 0.05). AH(SDS) was greater on GH(67) (GH(67x1), -0.84; GH(33x2), -0.83) than GH(33) (-1.25, p < 0.05), and height SDS gain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target height SDS. Conclusion: Pubertal height SDS gain and AH SDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once-and twice-daily GH(67) regimens. (C) 2014 S. Karger AG, Basel

Dose-Dependent Effect of Growth Hormone on Final Height in Children with Short Stature without Growth Hormone deficiency.

Context: Effect of GH therapy in short non GH deficient children, especially idiopathic short stature (ISS) has not been clearly established owing to lack of controlled trials until final height (FH). Objective: To investigate the effect of two GH doses compared with untreated controls on growth to FH in short children mainly with ISS. Design and Setting: A randomized, controlled, long-term multicenter trial in Sweden. Intervention: Two doses of GH (Genotropin): 33 or 67 microg/kg/d plus untreated controls. Subjects: 177 subjects with short stature were enrolled. Of these, 151 were included in the Intent to Treat (AllITT) Population and 108 in the Per Protocol (AllPP) Population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) Population and 68 subjects in the PP (ISSPP) Population. Main Outcome Measures: FH SDS, difference in SDS to midparenteral height (diff MPHSDS), and gain in HeightSDS. Results: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP Population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg/d: -1.7+/-0.70, 67 microg/kg/d: -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001), the diff MPHSDS -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001), and the gain in HeightSDS 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. Conclusion: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm), and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls