Prevention of Growth Failure in Turner Syndrome: Long-Term Results of Early Growth Hormone Treatment in the "Toddler Turner" Cohort.

INTRODUCTION: In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. METHODS: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. RESULTS: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>-2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = -0.30; p = 0.016]). No new safety concerns arose. CONCLUSION: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.

Health-related quality of life, depression, and metabolic parameters in overweight insulin-resistant adolescents.

INTRODUCTION: The purpose of this study was to examine the incidence and severity of depression and health-related quality of life (HRQoL) in youth with insulin resistance (IR) who are overweight/obese and to examine the impact on making lifestyle changes. METHOD: New patients presenting for treatment in an IR clinic were screened for depression and HRQoL and reassessed twice during a 1-year treatment period. Metabolic and growth parameters were obtained for each participant. RESULTS: Elevated symptoms of depression were reported in 51% of the sample, and these symptoms were stable over time. Approximately 10% of these youth reported moderate or severe symptoms of depression. HRQoL scores indicated a good quality of life overall with slight improvement in some areas over time. Depression scores were not associated with demographic variables or metabolic parameters. DISCUSSION: More than 50% of adolescents with IR and obesity reported elevated symptoms of depression. These results provide sufficient evidence for the need to conduct routine screening of depression for all youth with IR so that appropriate mental health referrals can be made.

Bilateral metabolic cataracts in 10-yr-old boy with newly diagnosed type 1 diabetes mellitus.

Classic symptoms of diabetes mellitus in childhood prompting parents to seek medical attention include polydipsia, polyuria, polyphagia, weight loss and kussmal breathing. Cataracts with juvenile diabetes usually occur in patients with long-standing, poorly controlled diabetes (1, 2). We describe a child in whom the acute loss of vision secondary to lenticular opacities was the initial sign of insulin-dependent diabetes mellitus.

Prevention of diabetes: effect of mycophenolate mofetil and anti-CD25 on onset of diabetes in the DRBB rat.

BACKGROUND: Anti-CD25 and mycophenolate mofetil (MMF) treatment of patients with new-onset diabetes is currently being tested as one of the trials in TrialNet. We tested the effectiveness of MMF and anti-CD25 in preventing autoimmune diabetes in the diabetes-resistant biobreeding (DRBB) rat. METHODS: Autoimmune diabetes in the DRBB rat was induced with a Treg cell depletion regimen starting at 24-26 d of age. Treatment was started on the first day of the depletion regimen in the following groups: (i) control (vehicle); (ii) MMF 25 mg/kg/d intramuscularly daily for 8 wk; (iii) anti-CD25 0.8 mg/kg/d intraperitoneally 5 d/wk for 3 wk; and (iv) combination of MMF and anti-CD25. In a second set of experiments, treatments were started on day 5 of the depletion regimen (delayed treatment) with groups 1, 3, and 4. Rats that had diabetes-free survival for at least 30 d after the treatment was stopped underwent a second Treg depletion (redepletion). RESULTS: In each of the three treatment groups (n = 10/group), onset of diabetes was delayed or prevented in 20, 40 and 80% in groups 2, 3, and 4, respectively. After redepletion, diabetes-free survival was unchanged in group 2 and decreased to 10 and 30% in groups 3 and 4, respectively. With delayed treatment, groups 3 and 4 had 33 and 50% diabetes-free survival that decreased to 0 and 33% after redepletion. SUMMARY: MMF and anti-CD25 alone or in combination are effective in delaying and preventing diabetes in the DRBB rat especially if treatment is started before stimulation and expansion of the autoreactive T cells.

Repulsive separation of the cytoplasmic ends of transmembrane helices 3 and 6 is linked to receptor activation in a novel thyrotropin receptor mutant (M626I).

Ligand-dependent activation of G protein-coupled receptors (GPCRs) involves repositioning of the juxtacytoplasmic ends of transmembrane helices TM3 and TM6. This concept, inferred from site-directed spin labeling studies, is supported by chemical cross-linking of the cytoplasmic ends of TM3 and TM6 blocking GPCR activation. Here we report a novel constitutive active mutation (M626I) in TM6 of the TSH receptor (TSHR), identified in affected members of a family with nonautoimmune hyperthyroidism. The specific constitutive activity of M626I, measured by its basal cAMP generation corrected for cell surface expression, was 13-fold higher than that of wild-type TSHR. Homology modeling of the TSHR serpentine domain based on the rhodopsin crystal structure suggests that M626 faces the side chain of I515 of TM3 near the membrane-cytoplasmic junction. Steric hindrance of the introduced isoleucine by I515 is consistent with the fact that shorter or more flexible side chains at position 626 did not increase constitutivity. Furthermore, a reciprocal mutation at position 515 (I515M), when introduced into the M626I background, acts as revertant mutation by allowing accommodation of the isoleucine sidechain at position 626 and fully restoring the constitutive activity to the level of wild-type TSHR. Thus, repulsive separation of the juxtacytoplasmic TM6 and TM3 in the M626I model conclusively demonstrates a direct link between the opening of this cytoplasmic face of the receptor structure and G protein coupling.

Increasing dietary palmitic acid decreases fat oxidation and daily energy expenditure.

BACKGROUND: Oleic acid (OA) is oxidized more rapidly than is palmitic acid (PA). OBJECTIVE: We hypothesized that changing the dietary intakes of PA and OA would affect fatty acid oxidation and energy expenditure. DESIGN: A double-masked trial was conducted in 43 healthy young adults, who, after a 28-d, baseline, solid-food diet (41% of energy as fat, 8.4% as PA, and 13.1% as OA), were randomly assigned to one of two 28-d formula diets: high PA (40% of energy as fat, 16.8% as PA, and 16.4% as OA; n = 21) or high OA (40% of energy as fat, 1.7% as PA, and 31.4% as OA; n = 22). Differences in the change from baseline were evaluated by analysis of covariance. RESULTS: In the fed state, the respiratory quotient was lower (P = 0.01) with the high OA (0.86 +/- 0.01) than with the high-PA (0.89 +/- 0.01) diet, and the rate of fat oxidation was higher (P = 0.03) with the high-OA (0.0008 +/- 0.0001) than with the high-PA (0.0005 +/- 0.0001 mg . kg fat-free mass(-1) . min(-1)) diet. Resting energy expenditure in the fed and fasting states was not significantly different between groups. Change in daily energy expenditure in the high-OA group (9 +/- 60 kcal/d) was significantly different from that in the high-PA group (-214 +/- 69 kcal/d; P = 0.02 or 0.04 when expressed per fat-free mass). CONCLUSIONS: Increases in dietary PA decrease fat oxidation and daily energy expenditure, whereas decreases in PA and increases in OA had the opposite effect. Increases in dietary PA may increase the risk of obesity and insulin resistance.

Prediction of daily energy expenditure during a feeding trial using measurements of resting energy expenditure, fat-free mass, or Harris-Benedict equations.

BACKGROUND: During feeding trials, it is useful to predict daily energy expenditure (DEE) to estimate energy requirements and to assess subject compliance. OBJECTIVE: We examined predictors of DEE during a feeding trial conducted in a clinical research center. DESIGN: During a 28-d period, all food consumed by 26 healthy, nonobese, young adults was provided by the investigators. Energy intake was adjusted to maintain constant body weight. Before and after this period, fat-free mass (FFM) and fat mass were assessed by using dual-energy X-ray absorptiometry, and DEE was estimated from the change (after - before) in body energy (DeltaBE) and in observed energy intake (EI): DEE = EI - DeltaBE. We examined the relation of DEE to pretrial resting energy expenditure (REE), FFM, REE derived from the average of REE and calculated from FFM [REE = (21.2 x FFM) + 415], and an estimate of DEE based on the Harris-Benedict equation (HB estimate) (DEE = 1.6 REE). RESULTS: DEE correlated (P < 0.001) with FFM (r = 0.78), REE (r = 0.73), average REE (r = 0.82), and the HB estimate (r = 0.81). In a multiple regression model containing all these variables, R(2) was 0.70. The mean (+/-SEM) ratios of DEE to REE, to average REE, and to the HB estimate were 1.86 +/- 0.06, 1.79 +/- 0.04, and 1.02 +/- 0.02, respectively. CONCLUSIONS: Although a slightly improved prediction of DEE is possible with multiple measurements, each of these measurements suggests that DEE equals 1.60-1.86 x REE. The findings are similar to those of previous studies that describe the relation of REE to DEE measured directly.