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OBJECTIVE: The aim of this work was to assess the specific food type (high carbohydrate, high fat, high protein) preference profiles of individuals with Prader-Willi syndrome (PWS), obese controls and normal weight individuals. DESIGN: Subjects tasted a food predominantly high in carbohydrate, a food predominantly high in protein and a food predominantly high in fat over repeated trials and indicated their most preferred, second preferred and least preferred foods. Specific items tested on a given trial were counterbalanced in a block randomized fashion. SUBJECTS: These were 12 individuals with Prader-Willi syndrome, 12 matched obese controls (obese, but otherwise normal) and 14 normal weight subjects. MEASUREMENTS: The basic data were expressed as a proportion of each food type selected as most preferred over the total 27 trials. RESULTS: PWS subjects preferred high carbohydrate foods over high protein foods and high protein foods over high fat foods. These subjects demonstrated a statistically reliable difference in preference for high carbohydrate foods over high fat foods. However, normal weight and obese control subjects demonstrated no difference in food preferences. The only significant between-group comparisons were between PWS subjects and obese controls, with the PWS group showing a significantly greater preference for high carbohydrate foods than obese controls. CONCLUSIONS: The obesity of PWS was shown to have a significant and distinctly different food preference profile from normal weight and obese controls. The differences in food preference between the obese PWS and non-PWS subjects is in accord with the growing recognition of functional subgroups within the obese population, that may have not only differing underlying etiologies, but also distinct behavioral profiles of ingestion. [ABSTRACT FROM AUTHOR]

Background: SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders., Results: By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells., Conclusions: Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To assess the efficacy of upper airway surgical intervention in patients with Prader-Willi syndrome (PWS). Due to reports of sudden death in children undergoing treatment with growth hormone for PWS, detection of sleep-disordered breathing by polysomnography (PSG) has been recommended., Design: Retrospective study., Setting: Multidisciplinary PWS Center at a tertiary care children's hospital., Patients: Thirteen pediatric patients with PWS who underwent adenotonsillectomy (T&A) with pre-PSG and post-PSG., Main Outcome Measures: Comparison of PSG results before and after T&A., Results: Six of our patients were girls (46%); 8 had genetic characteristics consistent with deletion (61%), and the remaining 5 had genetic characteristics consistent with uniparental disomy (39%). The median age at T&A was 3 years (age range, 6 months to 11 years), and the median age at start of growth hormone treatment was 8.5 months (range, 2 months to 6 years). Nine of the 13 patients had mild to moderate obstructive sleep apnea (OSA) or obstructive hypoventilation (69%); in 8 of these 9, breathing normalized after T&A. Four children had severe OSA prior to surgery (31%). Breathing normalized in 2 of these after surgery, but 2 had PSG findings of residual combined obstructive and central apneas postoperatively., Conclusions: Adenotonsillectomy, while effective in most children with PWS who demonstrate mild to moderate OSA, may not be curative in children with severe OSA. An increase in central apneas can occur in some children with PWS postoperatively, and it is important to repeat PSG after surgery. Further studies are necessary to determine optimal treatment for some children with PWS and sleep-disordered breathing.

The activities of two crucial enzymes of reverse cholesterol transport, cholesterol ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), and their relationships with lipid profile and fasting plasma glucose were examined in 35 type 1 diabetic children. The CETP and LCAT activities were significantly lower (p<0.05) in the 4 subjects with normal fasting plasma glucose levels (<6.39 mmol/l) than in the 28 with high plasma glucose levels (CEPT activity, 10.63+/-3.81 vs. 32.18+/-13.94 nmol/ml h; LCAT activity, 25.52+/-4.53 vs. 39.52+/-12.52 nmol/ml h; both p<0.05). The subjects with high plasma glucose levels also had higher total and LDL-cholesterol than those with normal glucose levels. CETP activity was positively correlated with fasting plasma glucose, CETP concentration, LCAT activity, total cholesterol, free cholesterol, LDL-C, and LDL-cholesteryl ester, while negatively correlated with cholesteryl ester to free cholesterol ratio, LDL triglyceride to protein ratio, and LDL triglyceride to cholesteryl ester ratio. LCAT activity was found to positively correlate with CETP activity, total cholesterol, free cholesterol, LDL-C, CETP concentration, and LDL-cholesteryl ester, while it negatively correlated with cholesteryl ester to free cholesterol ratio. The results observed in type 1 diabetic subjects suggest that (1) accelerated LCAT and CETP activities may result in the accumulation of LDL-cholesteryl ester; and (2) fasting plasma glucose may be a major determinant of CETP activity.

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Diabetes mellitus is becoming a more frequently recognized complication of Prader-Willi syndrome. It has been reported that as many as 7-20% of individuals with Prader-Willi syndrome may develop this complication. Diabetes mellitus adds to the complexity of an already complex treatment program, causes many serious complications that greatly affect the quality of life of these individuals, and can lead to serious morbidity and mortality. Recent studies suggest that growth hormone (GH) might offer significant advantages to individuals with Prader-Willi syndrome. However, as a known diabetogenic agent, GH might also increase the propensity to develop diabetes mellitus. For this reason, the characteristics of the diabetes mellitus that develops in individuals with Prader-Willi syndrome must be studied and fully understood. The initial assumption has been that the diabetes mellitus associated with this syndrome is identical to that seen in obese individuals without Prader-Willi syndrome, in whom genetic factors and obesity lead to insulin resistance. Severe insulin resistance in turn leads to pancreatic failure and hence the symptom complex of type 2 diabetes mellitus. To determine if this same pattern is present in patients with Prader-Willi syndrome, we evaluated both obese children and adults with the syndrome. These patients were compared with obese individuals without Prader-Willi syndrome matched for age, gender and weight and who had not yet developed diabetes but had equally longstanding obesity. We compared the glucose and insulin responses of these two groups, using both oral and intravenous glucose challenges. The results demonstrated that individuals with Prader-Willi syndrome do not show the predicted insulin resistance that is seen in obese children without the syndrome. In fact, the individuals with Prader-Willi syndrome showed normal or increased insulin sensitivity. These data do not support the hypothesis that the high incidence of diabetes mellitus in patients with Prader-Willi syndrome is simply the result of obesity and therefore suggest a different aetiology.

Interpretation of tracer studies of amino acid kinetics in the fed state is dependent on knowledge of splanchnic uptake of diet-derived amino acids. We studied five healthy control children and five children with cystic fibrosis (CF). After an overnight fast, the children ingested, hourly, a formula diet for 11 h. 5,5,5-[2H3]Leucine was added to the feedings during the last 6 h, and an i.v. infusion of 1-[13C]leucine was administered during the last 2 h of the formula feeding. The mean rate of splanchnic uptake of leucine was similar in the CF and control group, 23.8 +/- 24.0 and 21.5 +/- 21.2 mumol.kg-1.h-1, respectively. Fractional splanchnic uptake of leucine was not significantly different in the patients with CF (0.16 +/- 0.112 mean +/- SD) compared with the control children (0.244 +/- 0.256(-1)). The rate of whole body protein breakdown was not significantly different between the groups (CF versus control) with (159 +/- 18 versus 135 +/- 28 mumol.kg-1.h-1) or without (135 +/- 14 versus 114 +/- 20 mumol.kg-1.h-1) correction for splanchnic leucine uptake. However, for the 10 cases combined, protein breakdown corrected for splanchnic leucine uptake (147 +/- 26 mumol.kg-1.h-1) was 18% greater than uncorrected protein breakdown (124 +/- 20 mumol.kg-1.h-1) (p = 0.009). The data suggest that companion studies of splanchnic uptake might enhance the interpretation of leucine kinetics in the fed state.

Benzodiazepine receptor (BZR) agonists, used extensively for their anxiolytic effects, have been shown to increase food intake in many mammalian species. Little information, however, is available on the effects of BZR agonists on feeding behaviors of humans. Food intake was evaluated in a 60-minute free-feeding standardized test after the acute administration of the BZR agonist chlordiazepoxide (CDP, Librium; 5 mg or 20 mg) or placebo. Subjects were 12 individuals with the Prader-Willi syndrome (PWS), a disorder characterized by extreme hyperphagia and morbid obesity, and 11 controls with obesity. PWS subjects showed the characteristic hyperphagia associated with the appetite disorder, consuming more than six times as many sandwiches as controls with obesity. Results revealed no significant effect of either dose of CDP on the food intake of either group. Serum assays revealed that dose-dependent, clinically effective levels of CDP and active metabolites were achieved. These results suggest that acute administration of the BZR agonist CDP, at the therapeutic levels used, may not increase food intake in populations with obesity. However, the chronic effects of CDP on appetite in human populations still need to be explored.

To determine whether a 13C-bicarbonate, isotope dilution technique could be used to estimate relative changes in energy expenditure of leisure activities of short duration, we studied eight adolescents who performed the following activities: watching television (120 min); playing a stringed instrument (60 min plus 60 min of sitting); and walking plus rest during two approximately isocaloric sessions (slow walk at 40% of peak VO2 for 43 min plus 77 min of sitting; fast walk at 73% of peak VO2 for 22 min plus 98 min of sitting). The rate of appearance of CO2 (RaCO2) was determined from the ratio of the oral dose of 13C-bicarbonate and the isotopic enrichment of breath CO2. The net rates of excretion of CO2 (VCO2) and oxygen consumption were measured. VCO2 and RaCO2, were correlated (r = 0.93; P < 0.05). To adjust for the systematic difference in CO2 production between methods, determinations were expressed as a fraction of that during television viewing. For RaCO2, the ratios for instrument playing, walking at 40% peak VCO2, and walking at 73% peak VO2 were respectively 133 +/- 20%, 186 +/- 38%, and 206 +/- 34%; for VCO2, the respective ratios were 129 +/- 19, 210 +/- 50, and 232 +/- 39 (P > 0.05 for methods and interaction, two-way ANOVA). RaCO2 may be a useful method for detecting relative differences in energy expenditure associated with leisure activities of brief duration.

We report on our findings of 4 patients with mosaicism for a deletion of chromosome 15, most commonly associated with Prader-Willi syndrome (PWS). We examined a series of typical and atypical PWS patients in order to identify cytogenetically undetected deletions, using fluorescence in situ hybridization. In 4 of the patients analyzed we detected a deletion in 14-60% of peripheral blood leukocytes, using four commercially available probes. Our results indicate that mosaicism may play a role in the etiology of some PWS cases. These findings may be especially useful in patients who display discrepancies between clinical phenotype and established diagnostic criteria. Methylation and microsatellite polymorphism analyses of 2 patients with low-level mosaicism failed to identify the deletion. We propose that fluorescence in situ hybridization is the most effective method for detecting somatic mosaicism, since a large number of cells can be individually examined for the presence or absence of a specific deletion.

Obesity is a common component of non-insulin-dependent diabetes mellitus (NIDDM) and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi syndrome (PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. It has been assumed that the etiology for this increased rate of NIDDM is related to the morbid obesity and concomitant insulin resistance, but this remains controversial. To shed light on the glucoregulatory mechanisms in PWS, we studied both pediatric and adult PWS patients with normoglycemia. The objectives of our study were (1) to examine glucose, insulin, and C-peptide responses to oral (OGTT) and intravenous (IVGTT) glucose tolerance tests; (2) to characterize acute first- and second-phase insulin secretion during an IVGTT; (3) to assess hepatic insulin extraction (HIE) and insulin clearance (IC) in PWS subjects; and (4) to determine whether beta-cell function in PWS is age-dependent. These results in PWS were compared with values obtained in age-, sex-, and body mass index (BMI)-matched non-PWS obese controls. Three groups were studied. Group I consisted of nine PWS subjects under the age of 13 years and 22 age-, sex-, weight-, and puberty stage-matched obese subjects who underwent OGTT. Group II consisted of 14 adult PWS subjects and 10 age-, weight-, and BMI-matched obese adults who underwent OGTT. Group III consisted of nine adult PWS subjects and eight age-, sex-, and weight-matched obese adults who underwent frequently sampled IVGTT (FSIVGTT). During the OGTT in the pediatric group, fasting (86 +/- 3 v 89 +/- 2 mg/dL), peak (144 +/- 11 v 147 +/- 4 mg/dL), and total area under the curve (AUC) (6,984 +/- 1,320 v 6,963 +/- 615 mg/dL x min) glucose levels were not significantly different in PWS versus obese children, respectively. In contrast, fasting (20 +/- 6 v 37 +/- 4 microU/mL), peak (114 +/- 24 v 214 +/- 23 microU [correction of mU]/mL), and total AUC (12,673 +/- 2,176 v 26,734 +/- 2,608 microU/mL microU/mL min) insulin levels were significantly lower in pediatric PWS. During the OGTT in the adult groups, neither fasting insulin (16.7 +/- 2.8 v 13.5 +/- 2.5 microU/mL) nor total AUC for insulin (10,664 +/- 1,955 v 11,623 +/- 1,584 microU/mL x min) were significantly different in adult PWS and obese groups. During the IVGTT in adults, both first-phase (138 +/- 42 v 454 +/- 102 microU/mL x min) and second-phase (295 +/- 66 v 1,015 +/- 231 microU/mL x min) insulin release were significantly reduced in PWS subjects despite similar glucose levels. Similarly, first-phase (8.6 +/- 2.3 v 21 +/- 4.6 ng/dL x min) and second-phase (47 +/- 4.6 v 75 +/- 14 ng/dL x min) C-peptide responses were also significantly reduced in PWS subjects. In contrast, mean HIE and IC was 33% higher in PWS subjects versus obese controls (15.4 +/- 1.5 v 10.3 +/- 1.6). Similarly, poststimulation HIE and IC was significantly greater (5.2 +/- 0.8 v 2.4 +/- 0.4) in the PWS group compared with the obese group (P < .01). In summary, this study demonstrates that nondiabetic PWS subjects manifest (1) a reduced beta-cell response to glucose stimulation, (2) a significantly increased HIE compared with obese controls, and (3) a dissociation of obesity and insulin resistance, in contrast to normal obese subjects. We conclude that glucoregulatory mechanisms are different in obese PWS versus non-PWS subjects.

We hypothesized that there is less suppression of whole-body protein breakdown with feeding in patients with cystic fibrosis (CF) who exhibit decreased insulin secretion after a single meal. Using [1-13C]leucine, we measured rates of nonoxidative leucine disappearance (whole-body protein synthesis) and protein breakdown in nine CF patients (6-11 y of age) and five healthy control subjects (8-10 y of age) during feeding and fasting. In the CF patients, synthesis and breakdown (x +/- SD) were 172 +/- 61 and 157 +/- 67 mumol.kg-1.h-1 during feeding and 140 +/- 24 and 178 +/- 26 mumol.kg-1.h-1 during fasting. The respective control values were 129 +/- 27 and 114 +/- 20 mumol.kg-1.h-1 during feeding and 136 +/- 13 and 173 +/- 18 mumol.kg-1.h-1 during fasting. Leucine balance was nearly identical in the two groups. By analysis of variance, there was a significant effect of feeding on protein breakdown but no difference between the groups. However, when each group was analyzed separately, feeding resulted in a 34% decrease in breakdown in the control subjects (P = 0.001) and a 23% increase in synthesis in the CF group (P = 0.058). Plasma insulin concentrations did not differ in the two groups. Thus, feeding may affect protein turnover differently in children with CF than in control children independently of plasma insulin concentration.

The association between mild routine exercise and glucose homeostasis, insulin dynamics, and risk factors for coronary artery disease was investigated in obese adolescent males. Subjects (n = 7; mean +/- SD age 13.3 +/- 1.4 yr) were tested before and after 15 wk of supervised mild intensity exercise. Serum glucose (GLU), insulin (IN), and C-peptide (CP) were measured in response to a mixed meal before and after the 15 wk period. Weight, body composition, peak oxygen uptake (peak VO2), resting blood pressure (BP), and blood lipid levels were also assessed pre- and post-training. After training, percent fat and body weight were not decreased compared to the initial values. Relative changes (p < or = 0.02) in mean values for GLU and peptides after training were: fasting GLU, -15%; total GLU response, -15%; peak IN response, -51%; total IN response, -46%; peak CP response, +55%; and total CP response, +53%. Following training, the subjects did not have an increased peak VO2, but showed consistent reductions in systolic BP and LDL-cholesterol (p < 0.05). Increases in hepatic insulin clearance (decreased insulin levels but increased CP levels) might be training adaptations unique to low intensity exercise or to obese youth. Decreased insulin levels with concurrent decreases in resting blood pressure and the LDL-cholesterol levels suggest that mild exercise training may reduce health risk factors without weight loss in the obese adolescent male.

We sought to determine how a stationary activity such as playing a stringed instrument may affect energy expenditure (EE) in adolescents. Using automated indirect calorimetry, we measured EE in eight adolescents (1 male, 7 females, 14.2 +/- 2.1 yr) while they each performed the following activities: watching television (TV) (60 min), playing a stringed instrument (60 min), and walking at 40% of peak oxygen uptake (43 min). Measurements were made during three, 6- to 7-min steady state periods of each activity. EE (mean +/- SD) was lower during TV (1.0 +/- 0.2 kcal.min-1) and instrument playing (1.4 +/- 0.2 kcal.min-1) than during walking (3.4 +/- 0.4 kcal.min-1) (P < 0.05). EE during instrument playing was 41% greater than during television viewing (P < 0.05). We conclude that relatively sedentary activities such as playing a stringed instrument can elevate EE. Conceivably, other stationary, leisure activities performed by adolescents may increase EE and have substantial, cumulative effects on long-term energy balance and fat accretion.

We hypothesized that elevated hepatic glucose output (HGO) may occur in children with cystic fibrosis (CF) as an early sign of declining insulin secretion and that tolbutamide therapy would correct the defect. We studied eight glucose-tolerant CF patients (mean +/- SD, 9.1 +/- 1.9 y) and five healthy controls (9.0 +/- 1.6 y). Fasting glucose, insulin, and insulin-connecting peptide concentrations were not different in the CF and control subjects; however, meal stimulation tests in the CF patients suggested that insulin secretion was defective in the fed state. HGO (mg.kg-1 body weight.min-1) was 26% higher in the CF patients (4.2 +/- 0.7 versus 3.1 +/- 0.6 in HC) (p = 0.016). When normalized for fat-free mass (mg.kg fat-free mass-1.min-1), HGO was 27% higher in CF (4.9 +/- 0.8 versus 3.8 +/- 0.5) (p = 0.015). However, when expressed as a function of resting energy expenditure (mg.kcal-1), HGO was not significantly different in CF (121 +/- 22) versus healthy controls (116 +/- 30). In seven of the CF group, HGO was re-assessed after a 2-h glucose infusion at a rate of 0.90 +/- 0.02 mg.kg-1.min-1. HGO was suppressed (p < 0.05) by an amount equal to 103 +/- 18% of the glucose infusion rate. Finally, in five CF patients, HGO was re-measured after 2 wk of oral therapy with tolbutamide (750 mg/d). Tolbutamide did not affect HGO (fasting or during the glucose infusion). In conclusion, fasting HGO was elevated in the CF patients in proportion to energy expenditure.

Seven children with cystic fibrosis (aged 7 to 12 years) were studied in the fasted and fed states. Using a primed, constant, intravenous infusion of NaH13CO3, the rate of appearance of CO2 (RaCO2) was estimated. Net CO2 excretion (VCO2) was also measured. Energy expenditure was calculated using the food quotient. RaCO2 (mean +/- SD) (mumol.kg-1.min-1) in the fasted and fed states (297 +/- 59 and 359 +/- 67) was 117% and 105% of VCO2 (259 +/- 48 and 352 +/- 72). Feeding induced a 23% and a 37% increase in RaCO2 and VCO2, respectively, and respective 19% and 33% increases in energy expenditure (p < .05). Measurement of CO2 production by isotopic dilution is a useful index of group changes in energy expenditure, including those induced by feeding.