Carlie White

Juvenile Graves disease: Usefulness and limitations of thyrotropin receptor antibody determinations

Thyrotropin receptor antibodies (TRAb) were measured in serum from 49 patients with active and inactive juvenile Graves disease, and the results were compared with values from control subjects and patients with Hashimoto disease. With a thyrotropin binding inhibition immunoglobulin (TBII) assay, TRAb were found in serum from 25 (93%) of 27 patients with untreated, active Graves disease. The TRAb values remained positive in 20 (72%) of 29 patients during the first 6 months of antithyroid therapy and in 13 (54%) of 24 patients during the second 6 months. After discontinuation of antithyroid therapy, 15 patients experienced 18 episodes of relapse of thyrotoxicosis; during relapse TRAb values were positive in all but one patient. Among 19 patients who remained clinically and biochemically euthyroid after cessation of antithyroid therapy, TRAb were not detected in 28 (78%) of 36 serum specimens. Of the eight positive values from six patients, no antiidiotypic antibodies were found, and thyroid stimulating immunoglobulins (TSI) were not detected in four specimens. The TRAb determination correctly predicted the subsequent clinical course in 26 (72%) of 36 patients. Furthermore, TRAb values and results of triiodothyronine suppression tests were in agreement in 27 of 36 patients, or 75% of the time. TSI were present in serum from only 19 (73%) of 26 patients with active disease; however, TSI were negative in all patients with inactive Graves disease. During the management of Graves disease, TRAb measurements by TBII determinations are valuable in the diagnosis of active disease, assist in the decision to discontinue antithyroid drug therapy, and are useful as the T3 suppression test to predict the clinical course of the disease. The TSI measurement is most useful to determine the activity of the disease when TRAb values are positive in a euthyroid patient.

Increased frequency of the G972R variant of the insulin receptor substrate-1 (irs-1) gene among girls with a history of precocious pubarche

To test the hypothesis that lower sex hormone-binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism.Association study. Academic research environment. Adolescent girls with a history of PP and healthy adolescent female control subjects. Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes.Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.

IgE synthesis in man. II. Comparison of tetanus and diphtheria IgE antibody in allergic and nonallergic children.

Abstract Specific IgE and IgG antibodies were quantitated in 91 allergic and 80 nonallergic age- and sex-matched children between 4 and 17 yr of age. Statistically significant increased antidiphtheria and antitetanus IgE antibodies (p 500 U/ml, 19 of 52 (37%) and 25 of 52 (48%) had elevations (>2 SD above nonallergic control mean) of serum antitetanus or antidiphtheria IgE antibody, respectively, whereas only 2 of 35 allergic children with serum IgE 2 SD) of these antibodies. Antitetanus and antidiphtheria IgG antibodies were measured by passive sheep red blood cell (SRBC) hemagglutination. Geometric mean antitetanus IgG antibodies were higher in allergic (4.9 AU/ml) as compared to nonallergic (1.7 AU/ml) children (p

Inconsistent effects of the proline12 → alanine variant of the peroxisome proliferator-activated receptor-γ2 gene on body mass index in children and adolescent girls

OBJECTIVE To ascertain whether variation in peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear ligand-dependent transcription factor affecting both adipocyte differentiation and insulin sensitivity, influences body mass index (BMI). DESIGN Association study. SETTING Academic research environment. PATIENT(S) Children with premature pubic hair and adolescent girls with hyperandrogenism. INTERVENTION(S) Assay for P12A and P115Q variants and measure BMI. MAIN OUTCOME MEASURE(S) BMI and PPAR-gamma genotypes. RESULT(S) Fourteen subjects were heterozygous for P12A; two were homozygous. None carried the P115Q allele. No significant differences in BMI or basal androstenedione concentrations between P12 carriers and noncarriers were found. Thirty-nine subjects had BMI values at two time points; mean BMI was significantly greater in the P12A carriers at time point 2. Those P12A carriers obese at time point 1 became more obese; lean mutation carriers tended to remain lean. Annual rate of increase in BMI was significantly greater in the P12A carriers than the noncarriers. CONCLUSION(S) Our findings suggest that P12A may be a genetic marker indicating risk for obesity persisting into adolescence. Future studies are needed to determine whether the divergent effects of P12A persist into adulthood, to elucidate the mechanism of this effect, and to replicate our findings in other populations.

Evaluating Protocols for Embryonic Stem Cell Differentiation into Insulin-Secreting β-Cells Using Insulin II-GFP as a Specific and Noninvasive Reporter

Stable and full differentiation of pluripotent stem cells into functional beta-cells offers the potential to treat type I diabetes with a theoretically inexhaustible source of replacement cells. In addition to the difficulties in directed differentiation, progress toward an optimized and reliable protocol has been hampered by the complication that cultured cells will concentrate insulin from the media, thus making it difficult to tell which, if any, cells are producing insulin. To address this, we utilized a novel murine embryonic stem cell (mESC) research model, in which the green fluorescent protein (GFP) has been inserted within the C-peptide of the mouse insulinII gene (InsulinII-GFP). Using this method, cells producing insulin are easily identified. We then compared four published protocols for differentiating mESCs into beta-cells to evaluate their relative efficiency by assaying intrinsic insulin production. Cells differentiated using each protocol were easily distinguished based on culture conditions and morphology. This comparison is strengthened because all testing is performed within the same laboratory by the same researchers, thereby removing interlaboratory variability in culture, cells, or analysis. Differentiated cells were analyzed and sorted based on GFP fluorescence as compared to wild type cells. Each differentiation protocol increased GFP fluorescence but only modestly. None of these protocols yielded more than 3% of cells capable of insulin biosynthesis indicating the relative inefficiency of all analyzed protocols. Therefore, improved beta-cells differentiation protocols are needed, and these insulin II GFP cells may prove to be an important tool to accelerate this process.

Reagin synthesis in inbred rats: II. Genetic control of reaginic antibody synthesis☆

Specific reaginic (IgE) and hemagglutinating (IgG) antibodies were quantified after immunization with ovalbumin aluminum hydroxide gel in BN and ACI inbred rats, as well as their F1, F1 X BN backcross, F2, and F3, and F3 progeny. The dissimilarity of these immune responses indicated that reaginic (IgE) antibody synthesis was influenced by polygenic factors, but not sex, and was controlled by loci different from that governing hemagglutinating (IgG) antibody synthesis. In addition, tissue typing of the BN, ACI, F1, and F3 hybrids suggested that reaginic antibody synthesis was not linked to the major rat histocompatibility locus.

Association of the −243 A→G polymorphism of the glutamate decarboxylase 2 gene with obesity in girls with premature pubarche

OBJECTIVE To test the a priori hypothesis that the frequency of a single-nucleotide polymorphism (SNP) located in the promoter region of the glutamate decarboxylase 2 (GAD2) gene (-243A-->G) would be overrepresented among children with higher body mass index (BMI) values. DESIGN Genotype-phenotype correlation study. SETTING University-based pediatric endocrinology practice. PATIENT(S) Eighty-seven girls with PP and 70 adolescent girls with hyperandrogenism. INTERVENTION(S) Blood was obtained for genotype analysis, glucose measurement, and hormone (Delta(4)-A, insulin, 17-hydroxyprogesterone, and T) determinations. MAIN OUTCOME MEASURE(S) Frequency of this SNP in the GAD2 gene and correlation of this SNP with BMI and hormone concentrations. RESULT(S) Among the girls followed longitudinally, the presence of one or more G alleles was associated with increased BMI at both initial and recent visits and with greater BMI z score at the initial visit. No associations were found between androgen concentrations and the G-allele variant. CONCLUSION(S) Similar to the findings among French children, this SNP in the GAD2 gene was associated with increased BMI in late childhood and adolescence in this population of girls from western Pennsylvania. Additional prospective studies that replicate our findings are crucial. Verification of our findings will encourage the use of lifestyle interventions for young girls who carry the G allele.

8 THYROTROPIN RECEPTOR ANTIBODIES (TRAb) IN PATIENTS WITH JUVENILE GRAVES DISEASE (JGD)

To determine if serum TRAb measurements are useful in diagnosis and management of JGD, we studied 48 pts with JGD & 113 controls: 41 adults; 41 children & 31 with Hashimotos Disease (HD), 9 with ↑ TSH levels. We tested 3 groups of JGD pts, I: active and untreated disease; II: recurrent disease; III: in remission on no therapy. TRAb was measured by displacement of labeled bTSH from porcine thyroid membranes (C1. Endocr. 20:539,1984), and values expressed as % inhibition of tracer TSH binding.No antiidiotypic antibodies were detected. There was no correlation between TRAb and TSH in HD with ↑ elevated TSH. False negative TRAb results occurred in 2 JGD-I (7%) pts and 1 JGD-II (6%) pt; false positive TRAb results occurred in 6 JGD-III (17%) pts, and were not associated with relapse of the disease.In conclusion: Abnormal TRAb values will confirm the diagnosis of JGD in > 90% of pts with hyperthyroidism, and are found in > 90% of JGD pts in relapse. TRAb values are greater at initial diagnosis than during relapse, probably reflecting a shorter duration and less severity of disease during relapse. Abnormal TRAb values during remission may result from TRAb without thyroid stimulation, or the development of co-existing HD.