In children with Prader-Willi syndrome (PWS), the benefits of growth hormone treatment are well established. Several one-year studies have shown that growth hormone is also beneficial for adults with ...PWS, improving body composition. However, little is known about the longer-term effects. Open-label, prospective study in 43 young adults with PWS with a median (IQR) age of 19.0 (17.5 to 20.7) years. Fat mass percentage SDS and lean body mass SDS were measured annually by DXA. Estimated mean (95% CI) fat mass percentage SDS decreased during the three-year study from 2.1 (1.9 to 2.3) SDS at start to 1.9 (1.8 to 2.1) SDS, p = 0.012, while lean body mass SDS remained stable at - 2.1 (- 2.4 to - 1.8) SDS at start to - 1.9 (- 2.3 to - 1.6) after 3 years, p = 0.15. Fasting glucose and insulin remained similar during the three-year study, glucose being 4.6 (4.4 to 4.8) mmol/l at start and 4.6 (4.5 to 4.7) mmol/l after 3 years of growth hormone, p = 0.93 and insulin being 59.5 (42.2 to 81.5) pmol/l and 55.0 (42.4 to 69.2) pmol/l, resp., p = 0.54. There were no growth hormone-related adverse events during the study. Three years of growth hormone treatment in young adults with PWS maintains the positive effects on body composition attained during childhood. Thus, adults with PWS benefit from longer-term growth hormone treatment.
In this paper, a 90-nm 128-Mcell non-volatile memory based on phase-change Ge 2 -Sb 2 -TeB alloy is presented. Memory cells are bipolar selected, and are based on a /xtrench architecture. ...Experimental investigation on multi-level cell (MLC) storage is addressed exploiting the chip MLC capability. To this end, a programming algorithm suitable for 2 bit/cell storage achieving tightly placed inner states (in terms of cell current or resistance) is proposed. Measurements showed the possibility of placing the required distinct cell current distributions, thus demonstrating the feasibility of the MLC phase-change memory (PCM) storage concept. Endurance tests were also carried out. Cumulative distribu tions after 2-bit/cell programming before cycling and after 100 k program cycles followed by 1 h/150 degC bake are presented. Experimental results on MLC endurance are also provided from a 180-nm 8-Mb PCM demonstrator with the same mutrench cell structure.
Objective
Some features of subjects with Prader‐Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has ...substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin‐like growth factor (IGF‐I) axis and the prevalence of GHD in previously GH‐treated young adults with PWS.
Design
Cross‐sectional study in 60 young adults with PWS.
Measurements
Serum IGF‐I and IGFBP‐3 levels, GH peak during combined growth hormone‐releasing hormone (GHRH)‐arginine stimulation test.
Results
Serum IGF‐I was <−2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP‐3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 μg/L (12.2; 29.7) ~53.4 mU/L and below 9 μg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 μg/L and IGF‐I < −2 SDS), also when BMI‐dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD).
Conclusions
In a large group of previously GH‐treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 μg/L during a GHRH‐arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.
Context:
Patients with Prader-Willi syndrome (PWS) are severely at risk to develop morbid obesity, diabetes mellitus type 2, and cardiovascular disease, leading to high mortality. They have an ...increased fat mass (FM) and decreased lean body mass (LBM). During childhood, GH treatment counteracts the natural course of increasing obesity. Discontinuation of GH treatment at attainment of adult height (AH) might deteriorate their improved clinical condition, whereas continuation might benefit them.
Objective:
To investigate the effects of GH versus placebo on body composition in young adults with PWS who were GH treated for many years during childhood and had attained AH.
Design:
Two-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and body mass index in 27 young adults with PWS.
Setting:
PWS Reference Center in The Netherlands.
Intervention:
Crossover intervention with GH (0.67 mg/m2 · d) and placebo, both during 1 year.
Main outcome measures:
Body composition, measured by dual-energy x-ray absorptiometry.
Results:
During placebo, FM increased (relative change +21.5%; P < .001). Compared with placebo, GH treatment resulted in lower FM (−2.9 kg; P = .004) and higher LBM (+1.5 kg; P = .005), representing relative changes of −17.3% FM and +3.5% LBM. Both limb and trunk FM percentage were lower during GH versus placebo (relative change +17.3% and +15.6%; P < .001 and P = .007, respectively). No GH-related adverse events occurred.
Conclusions:
GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment. FM increases during placebo, whereas GH versus placebo results in lower FM and higher LBM. Thus, GH treatment maintains the improved body composition without safety concerns.
In young adults with PWS who were treated with GH during childhood, stop of GH treatment at adult height leads to deteriorated body composition, while GH maintains the improved fat mass and lean mass.
Non-invasive prenatal testing (NIPT) allows the detection of placental chromosome aberrations. To verify whether the fetus also has the chromosome aberration, diagnostic follow-up testing is ...required. The aim of this retrospective study was to assess the added value of analyzing amniotic fluid (AF) cell cultures in addition to uncultured AF cells for the detection of fetal mosaicism.
NIPT was performed as part of the Dutch TRIDENT study. Cytogenetic studies in uncultured AF were performed using single nucleotide polymorphism (SNP)-array. Cultured AF cell colonies (in situ method) were investigated with fluorescent in situ hybridization and/or karyotyping. Clinical outcome data were collected in cases with discordant results.
Between April 2014 and December 2021, 368 amniocenteses were performed after a chromosomal aberration was detected with NIPT. Excluding 134 cases of common aneuploidies (confirmed by quantitative fluorescence polymerase chain reaction), 29 cases with investigation of uncultured cells only and 1 case without informed consent, 204 cases were eligible for this study. In 196 (96%) cases, the results in uncultured and cultured cells were concordant normal, abnormal or mosaic. Five cases (2%) showed mosaicism in cultured AF cells, whereas uncultured AF cells were normal. Two (1%) of these, one mosaic trisomy 13 and one mosaic trisomy 16, were considered true fetal mosaics.
The added value of investigating AF cell cultures in addition to uncultured cells is limited to two of 204 (1%) cases in which true fetal mosaicsm would otherwise be missed. The clinical relevance of one (trisomy 13) remained unknown and the other case also showed ultrasound anomalies, which determined pregnancy management. This seems to justify limiting prenatal cytogenetic confirmatory testing to SNP arrays on uncultured AF cells, considerably shortening the reporting time.
Abstract
Objective
Adults with Prader–Willi syndrome (PWS) are at increased risk of developing age-associated diseases early in life and, like in premature aging syndromes, aging might be ...accelerated. We investigated leukocyte telomere length (LTL), a marker of biological age, in young adults with PWS and compared LTL to healthy young adults of similar age. As all young adults with PWS were treated with growth hormone (GH), we also compared LTL in PWS subjects to GH-treated young adults born short for gestational age (SGA).
Design
Cross-sectional study in age-matched young adults; 47 with PWS, 135 healthy, and 75 born SGA.
Measurements
LTL measured by quantitative polymerase chain reaction, expressed as telomere/single copy gene ratio.
Results
Median (interquartile range) LTL was 2.6 (2.4–2.8) at a median (interquartile range) age of 19.2 (17.7–21.3) years in PWS, 3.1 (2.9–3.5) in healthy young adults and 3.1 (2.8–3.4) in the SGA group. Median LTL in PWS was significantly lower compared to both control groups (P < .01). In PWS, a lower LTL tended to be associated with a lower total IQ (r = 0.35, P = .08). There was no association between LTL and duration of GH treatment, cumulative GH dose, or several risk factors for type 2 diabetes mellitus or cardiovascular disease.
Conclusions
Young adults with PWS have significantly shorter median LTL compared to age-matched healthy young adults and GH-treated young adults born SGA. The shorter telomeres might play a role in the premature aging in PWS, independent of GH. Longitudinal research is needed to determine the influence of LTL on aging in PWS.
In children with Prader-Willi syndrome (PWS), growth hormone (GH) treatment has positive effects on bone mineral density (BMD). Two 1-year studies did not show a difference between GH or placebo on ...BMD in young adults with PWS. However, there are no studies investigating BMD during longer-term GH treatment in young adults with PWS.
Open-label, a prospective study in 43 young adults with PWS.
BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA.
In the total group, estimated mean (95% CI) of BMDTB remained similar during 3 years of GH, being -0.76 (-1.11 to -0.41) SDS at start and -0.90 (-1.27 to -0.54) SDS after 3 years (P = 0.11), as did BMADLS, being -0.36 (-0.72 to 0.01) SDS and -0.46 (-0.77 to -0.16) SDS, respectively (P = 0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMADLSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT).
During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMDTBSDS, probably due to insufficient SSRT. We recommended to continue GH treatment in young adults with PWS and to start SSRT during adolescence unless puberty progresses normally.
Summary
Context
The prevalence of osteoporosis is increased in adults with Prader‐Willi syndrome (PWS). In children with PWS, growth hormone (GH) treatment has beneficial effects on bone mineral ...density (BMD). BMD might deteriorate after cessation of GH at adult height (AH), while continuing GH might maintain BMD.
Objective
To investigate the effects of GH vs placebo, and furthermore the effects of sex steroid replacement therapy (SSRT), on BMD in GH‐treated young adults with PWS who had attained AH.
Design
Two‐year, randomized, double‐blind, placebo‐controlled, crossover GH study.
Patients
Twenty‐seven young adults with PWS were stratified for gender and BMI and then randomly and blindly assigned to receive GH (0.67 mg/m2/day) or placebo for 1 year, after which they crossed over to the alternative treatment for another year.
Measurements
Bone mineral density of the total body (BMDTB) and lumbar spine (BMDLS) SDS were measured by dual‐energy x‐ray absorptiometry.
Results
At AH, BMDTBSDS was significantly lower compared to healthy peers (P < .01), while BMADLSSDS was similar. Both BMDTBSDS and BMADLSSDS were similar during 1 year of GH vs 1 year of placebo. In hypogonadal young adults without SSRT, BMDTBSDS and BMADLSSDS decreased during the 2‐year study (P = .11 and P = .01), regardless of GH or placebo, while BMDTBSDS increased in those with SSRT (P < .01).
Conclusions
Compared to GH treatment, 1 year of placebo after attainment of AH does not deteriorate BMD SDS in young adults with PWS. In addition, our data suggest that GH is not able to prevent the decline in BMD SDS in hypogonadal young adults with PWS, unless it is combined with SSRT.
Context
Growth hormone (GH) has been approved for children with Prader‐Willi syndrome (PWS) and significantly improves body composition in adults with PWS. Adults with PWS are predisposed to develop ...impaired glucose tolerance (IGT) and diabetes mellitus type 2 (DMT2). Continuation of GH maintains body composition, but GH is known to induce insulin resistance, which might affect glucose homeostasis. Studies on long‐term effects of GH treatment in adults are very limited.
Objective
To investigate effects of 3 years of GH treatment on glucose homeostasis and prevalence of metabolic syndrome (MS) in adults with PWS.
Design
Open‐label, prospective study.
Patients
43 young adults with PWS.
Setting
Dutch PWS Reference Center.
Main outcome measures
Glucose and insulin during oral glucose tolerance test.
Results
Estimated mean (95% CI) fasting glucose and insulin levels remained stable during 3 years of GH treatment. Glucose being 4.6 (4.4‐4.8) mmol/l at start and 4.7 (4.6‐4.9) mmol/l after 3 years (P = .07); insulin being 59.5 (45.2‐75.8) pmol/l and 56.7 (45.2‐69.6) pmol/l resp. (P = .72). Sex, ethnicity and fat mass percentage were significantly associated with fasting glucose levels, while IGF‐I or GH‐dose were not. Blood pressure, lipids and prevalence of MS remained stable during 3 years of GH. IGT prevalence was variable over time, six patients had IGT at start and eleven after 3 years of GH. One patient developed DMT2. However, prevalence of IGT or DMT2 was not significantly higher after 3 years than at study start.
Conclusions
Three years of GH treatment in adults with PWS does not impair glucose homeostasis and does not lead to an increased prevalence of DMT2.
The potential of the Levenberg–Marquardt method combined with an explicit Runge–Kutta method for non-stiff systems, and, an implicit Rosenbrock method for stiff systems to investigate burning ...velocities using explosion bombs was explored. The implementation of this combination of methods was verified on three benchmark test problems, and, by the application of two integral balance models to laminar hydrogen-air and methane-air explosions. The methodology described here was subsequently applied to quantify the coefficients of a turbulent burning velocity correlation for a methane-air explosion in the decaying flow field of the standard 20-litre explosion sphere. The outcome of this research indicates that the usefulness of the 20-litre sphere can be extended beyond the measurement of practical explosion parameters. When combined with the methodology in this paper, turbulent burning velocity correlations can be assessed in different parts of the Borghi-diagram.
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