Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH defi- ciency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS The study included 31 patients, grouped as (1) GHD (n=20) and (2) non-GHD (Turner syndrome n=7; Noonan syndrome n=4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4 ± 2.5 vs. -1.8 ± 1.0; P < 0.001). IGF-I (-1.8 SDS ± 2.2) and IGFBP-3 (-1.1 SDS ± 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS ± 1.4) while IGFBP-3 (1.1 SDS ± 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0.77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 g/l; median after 12 months treatment 2.4 g/l; P = 0.02) but not the non-GHD (median before treatment 3.0 g/l; median after 12 months treatment 2.6 g/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during longterm GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD

GH safety workshop position paper: A critical appraisal of recombinant human GH therapy in children and adults

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-Term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-Term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement

Growth Hormone Research Society perspective on biomarkers of GH action in children and adults

Objective The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. Participants GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Evidence Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Consensus process Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. Conclusions The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly

Automating the Moire Interferometry technique

SIGLEAvailable from British Library Document Supply Centre- DSC:DX185794 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

3-M syndrome: a growth disorder associated with IGF2 silencing

3-M syndrome is an autosomal recessive disorder characterised by pre- and postnatal growth restriction, facial dysmorphism, normal intelligence and radiological features (slender long bones and tall vertebral bodies). It is known to be caused by mutations in the genes encoding Cullin 7, Obscurin like-1 and Coiled-Coil Domain Containing 8. The mechanisms through which mutations in these genes impair growth are unclear. The aim of this study was to identify novel pathways involved in the growth impairment in 3-M syndrome. RNA was extracted from fibroblast cell lines derived from four 3-M syndrome patients and 3 control subjects, hybridised to Affymetrix HU 133 plus 2.0 arrays with quantitative real time PCR used to confirm changes found on microarray. IGF-II protein levels in serum and conditioned cell culture medium were measured by ELISA. Of the top 10 downregulated probesets 3 represented IGF2 while H19 was identified as the 23rd most upregulated probeset. QRT-PCR confirmed upregulation of H19(p&lt;0.001) and downregulation of IGF2 (p&lt;0.001). Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than for 3-M fibroblasts (10.2 ± 2.9ng/ml v 0.6 ± 0.9ng/ml, p&lt;0.01). 3-M syndrome is associated with a gene expression profile of reduced IGF2 expression and increased H19 expression similar to that found in Silver Russell syndrome. Loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M syndrome

Pattern of growth and adiposity from infancy to adulthood in atopic dematitis

Background Impaired linear growth has been reported in children with atopic dermatitis (AD) but the pattern of growth in height and weight through childhood and adolescence has not been described. Objectives To define the pattern of linear growth and adiposity in AD from early childhood through to adult life. Patients and methods Growth measurements of 70 male and 40 female patients with AD followed through childhood and adolescence were studied retrospectively and compared with the 1990 U.K. normal values. Height, weight and body mass index (BMI) were converted to standard deviation scores (SDS). Regression analysis examined whether the mean trend was different from zero. Results While dermatitis was the predominant atopic problem in all 110 patients, 92 had a history of asthma which was mild in 85 of 92. Regression analyses showed that the trends in height, weight and BMI SDS for AD patients were significantly different from zero and also different between males and females. Both sexes were short and relatively overweight from early childhood, a trend that was more pronounced in males than females. At 5 years (school entry), the 50th centile BMI of male (but not female) patients was 0·44 kg m-2 higher than the reference population but height and weight were lower. The age at adiposity rebound in AD males and females was 0·8 year and 0·7 year later than the U.K. population (6·2 years vs. 5·4 years and 6·2 years vs. 5·3 years, respectively). AD patients attained peak height velocity later than the 1990 U.K. population (males 16·0 years vs. 13·5 years, P = 0·0002; females 13·4 years vs. 11·0 years, P = 0·008). In addition, males had greater mean gain in height during late adolescence (12·2 vs. 8·8 cm, P = 0·03) and were shorter as young adults (170·9 vs. 177·6 cm, P = 0·0005). Conclusions Our patients with AD were relatively overweight very early but had a later adiposity rebound, were short in childhood and had a delayed adolescent growth spurt. Serial growth measurements should be done on all children with troublesome AD and can be helpful in counselling about the growth prognosis

Multimodal perception of interpersonal synchrony: Evidence from global and continuous ratings of improvised musical duo performances

Investigating cues that underpin perceptual judgments of interpersonal coordination has important implications for understanding sociocognitive evaluations of the quality of human interactions. With a focus on musical interpersonal coordination, we conducted 2 experiments investigating the impact of music style, modality of stimulus presentation, rater expertise, and audio/visual stimulus features on ratings of perceived synchrony in improvised duo performances. In the first experiment, participants made synchrony ratings following 10-s excerpts of musical performances, whereas in the second experiment, participants rated longer (up to 1 min) excerpts continuously as the music unfolded. Several consistent results emerged across the 2 experiments, including that participants perceived standard jazz improvisations featuring a regular beat as significantly more synchronous than free improvisations that aimed to eschew the induction of such a beat. However, ratings of perceived synchrony were more similar across these 2 styles when only the visual information from the performance was available, suggesting that performers’ bodily cues functioned similarly to communicate and coordinate musical intentions. Computational analysis of the audio and visual aspects of the performances indicated that synchrony ratings increased with increases in audio event density and when coperformers engaged in periodic movements at similar frequencies, whereas the salience of visual information increased when synchrony ratings were made continuously over longer timescales. These studies reveal new insights about the correspondence between objective and subjective measures of synchrony and contribute methodological advances indicating both parallels and divergences between the results obtained in paradigms utilizing global versus continuous ratings of musical synchron