Regulation of growth-hormone-receptor gene expression by growth hormone and pegvisomant in human mesangial cells

Regulation of growth-hormone-receptor gene expression by growth hormone and pegvisomant in human mesangial cells.BackgroundMice transgenic for growth hormone develop mesangial proliferation, glomerular hypertrophy, and progressive glomerular sclerosis suggesting that the growth hormone–insulin-like growth factor I (IGF-I) pathway plays an important role. Therefore, we studied the impact of variable concentrations of 22 kD, 20 kD growth hormone, as well as of the growth hormone receptor antagonist pegvisomant (B2036-PEG), on both the growth hormone receptor (GHR/GHBP) gene expression and growth hormone binding protein (GHBP) formation in a human glomerular mesangial cell line. Further, the impact on collagen, IGF-I and IGF binding protein-1 (IGFBP-1) formation was studied.MethodsIn order to assess transcription, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used.ResultsPhysiologic doses of 22 kD or 20 kD growth hormone caused a dose-dependent and significant (P < 0.01) up-regulation of GHR/GHBP gene transcription, whereas supraphysiologic doses (50 and 500ng/mL) resulted in down-regulation (P < 0.001). Whenever pegvisomant was used, there was no increase in GHR/GHBP expression. These data were confirmed using run-on experiments. Further, the assessment of GHBP presented a constant, dose-dependent increase, which was completely abolished in the experiments where pegvisomant was used.ConclusionWe present data showing that growth hormone has a direct impact on GHR/GHPB gene transcription and that pegvisomant is a potent growth hormone receptor antagonist in human mesangial cells. In addition, although the GHR/GHBP gene transcription is down-regulated by supraphysiologic growth hormone concentrations, this effect was not found when GHBP levels were measured. This finding may reflect a self-inhibitory effect of growth hormone on the level of GHR/GHBP gene transcription, which does not involve the regulation of the shedding of GHBP and may, therefore, be of physiologic interest

Cardiac involvement in patients with Becker muscular dystrophy: new diagnostic and pathophysiological insights by a CMR approach

<p>Abstract</p> <p>Background </p> <p>Becker-Kiener muscular dystrophy (BMD) represents an X-linked genetic disease associated with myocardial involvement potentially resulting in dilated cardiomyopathy (DCM). Early diagnosis of cardiac involvement may permit earlier institution of heart failure treatment and extend life span in these patients. Both echocardiography and nuclear imaging methods are capable of detecting later stages of cardiac involvement characterised by wall motion abnormalities. Cardiovascular magnetic resonance (CMR) has the potential to detect cardiac involvement by depicting early scar formation that may appear before onset of wall motion abnormalities.</p> <p>Methods </p> <p>In a prospective two-center-study, 15 male patients with BMD (median age 37 years; range 11 years to 56 years) underwent comprehensive neurological and cardiac evaluations including physical examination, echocardiography and CMR. A 16-segment model was applied for evaluation of regional wall motion abnormalities (rWMA). The CMR study included late gadolinium enhancement (LGE) imaging with quantification of myocardial damage.</p> <p>Results </p> <p>Abnormal echocardiographic results were found in eight of 15 (53.3%) patients with all of them demonstrating reduced left ventricular ejection fraction (LVEF) and rWMA. CMR revealed abnormal findings in 12 of 15 (80.0%) patients (p = 0.04) with 10 (66.6%) having reduced LVEF (p = 0.16) and 9 (64.3%) demonstrating rWMA (p = 0.38). Myocardial damage as assessed by LGE-imaging was detected in 11 of 15 (73.3%) patients with a median myocardial damage extent of 13.0% (range 0 to 38.0%), an age-related increase and a typical subepicardial distribution pattern in the inferolateral wall. Ten patients (66.7%) were in need of medical heart failure therapy based on CMR results. However, only 4 patients (26.7%) were already taking medication based on clinical criteria (p = 0.009).</p> <p>Conclusion </p> <p>Cardiac involvement in patients with BMD is underdiagnosed by echocardiographic methods resulting in undertreatment of heart failure. The degree and severity of cardiac involvement in this population is best characterised when state-of-the-art CMR methods are applied. Further studies need to demonstrate whether earlier diagnosis and institution of heart failure therapy will extend the life span of these patients.</p

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Contextual Interactions in Grating Plaid Configurations Are Explained by Natural Image Statistics and Neural Modeling

Processing natural scenes requires the visual system to integrate local features into global object descriptions. To achieve coherent representations, the human brain uses statistical dependencies to guide weighting of local feature conjunctions. Pairwise interactions among feature detectors in early visual areas may form the early substrate of these local feature bindings. To investigate local interaction structures in visual cortex, we combined psychophysical experiments with computational modeling and natural scene analysis. We first measured contrast thresholds for 2x2 grating patch arrangements (plaids), which differed in spatial frequency composition (low, high or mixed), number of grating patch co-alignments (0, 1 or 2), and inter-patch distances (1° and 2° of visual angle). Contrast thresholds for the different configurations were compared to the prediction of probability summation (PS) among detector families tuned to the four retinal positions. For 1° distance the thresholds for all configurations were larger than predicted by PS, indicating inhibitory interactions. For 2° distance, thresholds were significantly lower compared to PS when the plaids were homogeneous in spatial frequency and orientation, but not when spatial frequencies were mixed or there was at least one misalignment. Next, we constructed a neural population model with horizontal laminar structure, which reproduced the detection thresholds after adaptation of connection weights. Consistent with prior work, contextual interactions were medium-range inhibition and long-range, orientation-specific excitation. However, inclusion of orientation-specific, inhibitory interactions between populations with different spatial frequency preferences were crucial for explaining detection thresholds. Finally, for all plaid configurations we computed their likelihood of occurrence in natural images. The likelihoods turned out to be inversely related to the detection thresholds obtained at larger inter-patch distances. However, likelihoods were almost independent of inter-patch distance, implying that natural image statistics could not explain the crowding-like results at short distances. This failure of natural image statistics to resolve the patch distance modulation of plaid visibility remains a challenge to the approach

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

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

Association between foot growth and musculoskeletal loading in children with Prader-Willi syndrome before and during growth hormone treatment

OBJECTIVE: To explore how foot growth relates to musculoskeletal loading in children with Prader-Willi syndrome (PWS). STUDY DESIGN: In 37 children with PWS, foot length (FL) before and after 6 years of growth hormone therapy (GHT) was retrospectively evaluated with parental and sibling's FL, height, and factors reflecting musculoskeletal loading, such as weight for height (WfH), lean body mass (LBM; dual energy X-ray absorptiometry, deuterium labeled water), physical activity (accellerometry), and walk age. Because of the typically biphasic evolution of body mass and the late walk age in PWS, 2 age groups were separated (group 1, &gt;2.5 years; group 2, &lt; or =2.5 years). RESULTS: Children with PWS normalized height, but not FL after 6 years of GHT. Parental FL correlation with PWS's FL was lower than with sibling's FL. In group 1, FL positively correlated with WfH, LBM, and physical activity. In group 2, FL negatively correlated with age at onset of independent ambulation. Foot catch-up growth with GHT was slower in group 2 compared with group 1. CONCLUSION: In PWS, FL is positively associated with musculoskeletal loading. Small feet in children with PWS before and during long-term GHT may be more than just another dysmorphic feature, but may possibly reflect decreased musculoskeletal loading influencing foot growth and genetic and endocrine factors

A critical evaluation of bioimpedance spectroscopy analysis in estimating body composition during GH treatment : comparison with bromide dilution and dual X-ray absorptiometry

Objective: To compare estimates by Bioimpedance Spectroscopy Analysis (BIS) of extracellular water (ECW), fat mass (FM), and fat free mass (FFM) against standard techniques of bromide dilution and DXA during intervention that causes significant changes in water compartments and body composition. Methods: Body composition analysis using BIS, bromide dilution, and DXA was performed in 71 healthy recreational athletes (43 men, 28 women; aged 18-40 years; BMI 24±0.4 kg/m2) who participated in a double-blinded, randomized, placebo-controlled study of growth hormone (GH) and testosterone treatment. The comparison of BIS with bromide dilution and DXA was analyzed using linear regression and the Bland-Altman method. Results: At baseline, there was a significant correlation between BIS and bromide dilution derived estimates for ECW, and DXA for FM and FFM (p<0.001). ECW by BIS was 3.5±8.1 % lower compared to bromide dilution, while FM was 22.4±26.8 % lower and FFM 13.7±7.5 % higher compared to DXA (p<0.01). During treatment, the change in ECW was similar between BIS and bromide dilution, whereas BIS gave a significantly greater reduction in FM (19.4±44.8 %) and a greater increase in FFM (5.6±3.0 %) compared to DXA (p<0.01). Significant differences in body composition estimates between the BIS and DXA were observed only in men, particularly during the treatment that caused greatest change in water compartments and body composition. Conclusion: In healthy adults, bioimpedance spectroscopy is an acceptable tool for measuring ECW, however BIS overestimates FFM and substantially underestimates FM compared to DXA

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

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

Leydig-cell tumour in children: variable clinical presentation, diagnostic features, follow-up and genetic analysis of four cases

BACKGROUND: Testicular tumours are relatively uncommon in infants and children, accounting for only 1-2% of all paediatric solid tumours. Of these approximately 1.5% are Leydig-cell tumours. Further, activating mutations of the luteinizing hormone receptor gene (LHR), as well as of the G protein genes, such as Gsalpha (gsp) and Gialpha (gip2) subunits, and cyclin-dependent kinase gene 4(CDK4) have been associated with the development of several endocrine neoplasms. AIMS/METHODS: In this report, the clinical variability of Leydig-cell tumours in four children is described. The LHR-, gsp-, gip2- and CDK4 genes were investigated to establish the possible molecular pathogenesis of the variable phenotype of the Leydig-cell tumours. RESULTS: No activating mutations in these genes were found in the four Leydig-cell tumours studied. Therefore, the absence of activating mutations in LHR, as well as in both the 'hot spot' regions for activating mutations within the G-alpha subunits and in the regulatory 'hot spot' on the CDK4 genes in these tumours indicates molecular heterogeneity among Leydig-cell tumours. CONCLUSION: Four children with a variable phenotype caused by Leydig-cell tumours are described. A molecular analysis of all the 'activating' genes and mutational regions known so far was performed, but no abnormalities were found. The lessons learnt from these clinically variable cases are: perform ultrasound early and most importantly, consider discrepancies between testicular swelling, tumour size and androgen production