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Biomedical subjects

S E Tollefsen

Publications and source records attributed to S E Tollefsen.

At least 19 recordsLinked to original sources
PubMed1997

Biophysical and biological properties of naturally occurring high molecular weight insulin-like growth factor II variants.

A soluble form of the insulin-like growth factor II/mannose 6-phosphate receptor (sIGF-II/MPR) is present in fetal bovine serum and carries mature 7.5-kDa insulin-like growth factor II (IGF-II) and at least 12 different high molecular weight (Mr) IGF-II isoforms (Valenzano, K. J., Remmler, J., and Lobel, P. (1995) J. Biol. Chem. 270, 16441-16448). In this study, we used gel filtration and anion exchange chromatographies to resolve the isoforms into eight fractions that were characterized with respect to their biochemical, biophysical, and biological properties. Each fraction contained one to three major protein species with apparent sizes ranging from 11 to 17 kDa by SDS-polyacrylamide gel electrophoresis. The 11-kDa species contains no post-translational modifications and consists of an extended IGF-II backbone terminating at Gly-87. The remaining high Mr IGF-II isoforms are also composed of an 87-amino acid IGF-II peptide backbone but contain increasing amounts of sialated, O-linked sugars. Plasmon resonance spectroscopy experiments revealed that all the high Mr isoforms and mature 7.5-kDa IGF-II bound to immobilized recombinant soluble human IGF-I receptor, recombinant human IGF-binding protein 1, and sIGF-II/MPR with similar kinetics. In addition, radiolabeled tracer experiments demonstrated that both mature and high Mr IGF-II isoforms have similar binding profiles in fetal bovine serum and have similar affinities for IGF-II-binding proteins secreted from human fibroblasts. Finally, the biological activity of high Mr IGF-II was shown to be similar to or slightly better than mature IGF-II in stimulating amino acid uptake in fibroblasts and in inducing myoblast differentiation.

Animals↗
PubMed1996

Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis.

OBJECTIVE: Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium-sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis. PATIENTS AND METHODS: Three FHH kindreds (18 affected, 14 unaffected members) in which the proband had presented with recurrent pancreatitis were identified. The entire 3234bp coding region of the CaR gene was examined by direct DNA sequencing using fluorochrome labelled dideoxy-terminators. Mutations were confirmed and demonstrated to co-segregate with FHH by restriction enzyme analysis. RESULTS: Three novel heterozygous missense mutations (Asn178Asp, Arg220Gln and Pro221Ser) in the extracellular domain of the CaR were identified in each of the probands. These mutations, which co-segregated with the hypercalcaemia, were not detected as common polymorphisms in 55 unrelated normocalcaemic controls. CONCLUSIONS: Familial hypocalciuric hypercalcaemia with recurrent pancreatitis is associated with calcium-sensing receptor mutations, and thus this variant has the same genetic aetiology as typical familial hypocalciuric hypercalcaemia.

Adult↗
PubMed1992

Low prevalence of autoantibodies to the insulin-like growth factor I receptor in children with short stature.

Inhibition of IGF-I action by circulating IGF-I receptor autoantibodies is a potential mechanism of IGF-I resistance in growing children. To define the prevalence of IGF-I receptor antibodies in short-statured children, we have examined serum and plasma samples from a well-characterized group of 34 short, prepubertal, growth hormone-sufficient children and three growth hormone-deficient children. IGF-I receptor purified from human placental membranes was radioiodinated by the solid phase radioiodination method. Serum from a patient with severe insulin resistance immunoprecipitated 28.9-44.7% of the 125I-labeled IGF-I receptor. The ranges (mean +/- 3 SD) of 125I-labeled IGF-I receptor immunoprecipitated by 1:10 diluted and by undiluted nonimmune human serum were 1.99 +/- 0.63% and 4.42 +/- 1.32%, respectively. Immunoprecipitation of the 125I-labeled IGF-I receptor by eight samples from six children was greater than 3 SD above the mean when assayed at a 1:10 dilution. Nevertheless, when assayed undiluted, only one of these samples immunoprecipitated slightly more 125I-labeled IGF-I receptor than nonimmune serum. We conclude from these data that immunoprecipitating autoantibodies to the IGF-I receptor are not commonly present in short-statured children.

Adolescent↗
PubMed1991

Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation.

We have recently found that association of the two alpha beta dimers of the insulin-like growth factor I (IGF I) receptor is required for formation of a high-affinity binding site for IGF I [Tollefsen, S. E., & Thompson, K. (1988) J. Biol. Chem. 263, 16267-16273]. To determine the structural requirements for IGF I activated kinase activity, we have examined the effect of dissociation of the two alpha beta dimers of the IGF I receptor on beta subunit autophosphorylation. The alpha beta dimers formed after treatment with 2 mM dithiothreitol (DTT) at pH 8.75 for 5 min were separated from IGF I receptor remaining as tetramers after DTT treatment by fast protein liquid chromatography on a Superose 6 gel filtration column. Purification of the alpha beta dimers was confirmed by Western blot analysis using 125I-labeled alpha IR-3, a monoclonal antibody to the IGF I receptor. Autophosphorylation of the IGF I receptor (alpha beta)2 tetramer, treated without DTT or remaining after DTT treatment, is stimulated 1.6-2.9-fold by IGF I. In contrast, autophosphorylation of the alpha beta dimers incubated in the presence or absence of IGF I (100 ng/mL) does not occur. Both IGF I receptor dimers and tetramers exhibit similar kinase activities using the synthetic substrate Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly, indicating that the failure to detect autophosphorylation of the IGF I receptor dimers does not result from inactivation of the kinase by DTT treatment. We conclude that autophosphorylation of the IGF I receptor depends upon the interaction of the two alpha beta dimers.

Adenosine Triphosphate↗
PubMed1991

Endogenous insulin-like growth factor (IGF) binding proteins cause IGF-1 resistance in cultured fibroblasts from a patient with short stature.

The ED50 of insulin-like growth factor (IGF)-I-stimulated alpha-aminoisobutyric acid (AIB) uptake (mean +/- SD) in cultured fibroblasts from a child with short stature that we have reported (1.40 +/- 0.24 nM), is significantly higher than the ED50 of IGF-I-stimulated AIB uptake in fibroblasts from 11 normal subjects (0.42 +/- 0.12 nM) and from 127 short children (0.35 +/- 0.11 nM). Similarly, the ED50 of IGF-I-stimulated thymidine incorporation in fibroblasts from this child is 2.8 times higher than that in fibroblasts from four normal subjects. To minimize potential modulation of IGF-I action by endogenous IGF binding proteins in these assays, fibroblast responsiveness to [Q3,A4,Y15,L16]IGF-I, an IGF-I variant that has a 600-fold reduced affinity for serum IGF binding proteins, has been examined. The biological activity of this variant is comparable in the patient's and normal fibroblasts, suggesting that the resistance to IGF-I action cannot be attributed to a defective IGF-I receptor. To investigate directly the possibility that IGF-I sensitivity in the patient's fibroblasts is reduced by endogenous IGF binding proteins (IGFBP), binding proteins that are secreted into AIB assay buffer during a 3-h collection and that are cell-associated at the end of the collection have been analyzed. Ligand blot analysis of conditioned AIB assay buffer demonstrates that fibroblasts from the patient secrete 1.3-2.2 times more of Mr 46,400/42,900, 32,000, and 26,800 binding proteins than normal fibroblasts. The major difference between fibroblasts from the patient and from normal subjects is a striking 10-fold increase in the amount of a cell surface Mr 32,000 binding protein in the patient's fibroblasts. The Mr 32,000 binding protein is similar in size to IGFB-1 and different from IGFBP-2 and IGFBP-3, but it does not cross-react with an antibody against IGFBP-1. We conclude that the resistance to IGF-I action in the patient's fibroblasts is caused by an abnormal production and/or cell association of IGF binding proteins.

Aminoisobutyric Acids↗
PubMed1990

Whole body nitrogen kinetics and their relationship to growth in short children treated with recombinant human growth hormone.

We studied the effects of growth hormone on retention of 15N-labeled amino acids in 34 short, prepubertal, growth hormone-sufficient children and three growth hormone-deficient subjects. All 34 non-growth hormone-deficient children had apparently normal circulating growth hormone molecules and no mutations were detected in the growth hormone or IGF-I genes of any subjects. Fibroblasts from 34 children responded normally when challenged with recombinant human IGF-I. During the last 72 h of a 4-d challenge with recombinant human growth hormone (16 micrograms/kg body wt), retention of a mixed 15N-amino acid dose varied between 5.7 and 50.5%. Whole body protein synthesis, breakdown, and net anabolism calculated from the 15N kinetics were all increased by the acute growth hormone challenge. However, no routine clinical feature or laboratory determination correlated with the nitrogen retention response. After subsequent treatment (75 micrograms/kg three times a week) with recombinant human growth hormone for 1 y, there was a significant increase in height velocity, but this increase was not related significantly to pretreatment variables other than inversely to pretreatment height velocity. There was a significant (p = 0.03) correlation between the change in height velocity Z score and the degree of nitrogen retention to acute challenge with growth hormone, but this correlation was too weak (r = 0.37) to be of practical value in predicting the treatment growth response in an individual child.

Adolescent↗
PubMed1989

Insulin-like growth factors (IGF) in muscle development. Expression of IGF-I, the IGF-I receptor, and an IGF binding protein during myoblast differentiation.

The insulin-like growth factors (IGFs) I and II exert pleiotropic effects on diverse cell types through interaction with specific high affinity cell surface receptors and with locally produced binding proteins. In skeletal muscle and in myoblast cell lines, the functions of IGF-I and -II are complex. Both growth factors appear capable of stimulating cellular proliferation and differentiation, as well as exerting insulin-like effects on intermediary metabolism. We have demonstrated recently that the expression of IGF-II and its receptor is induced during the terminal differentiation of the myoblast cell line, C2, and have suggested that IGF-II may be an autocrine growth factor in these cells (Tollefsen, S.E., Sadow, J.L., and Rotwein, P. (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 1543-1547). We now have examined this cell line for expression of other components involved in IGF signaling. The synthesis of IGF-I is low during myoblast proliferation; IGF-I mRNA can be detected only through use of a sensitive solution hybridization assay. Typical IGF-I receptors can be measured in myoblasts, whereas IGF binding proteins cannot be detected in proliferating cells or in conditioned culture medium. During myogenic differentiation, IGF-I mRNA levels increase transiently by 6-10-fold within 48-72 h. The expression of IGF-I mRNA is accompanied by a 2.5-fold accumulation of IGF-I in the culture medium. IGF-I receptors also increase transiently, doubling by 48 h after the onset of differentiation. By contrast, secretion of a Mr 29,000 IGF binding protein is induced 30-fold to 100 ng/ml within 16 h and continues to increase throughout differentiation. These studies demonstrate that several components critical to IGF action are produced in a fusing skeletal muscle cell line in a differentiation-dependent manner and suggest that both IGF-I and IGF-II may be autocrine factors for muscle.

Amino Acid Sequence↗
PubMed1989

Coordinate expression of insulin-like growth factor II and its receptor during muscle differentiation.

The role of polypeptide growth factors in promoting muscle differentiation is uncharacterized. We have used a fusing skeletal muscle cell line, C2, to examine the endogenous expression of one peptide, insulin-like growth factor II (IGF-II), and its receptor during differentiation. The synthesis of IGF-II is low during proliferation of myoblasts; IGF-II mRNA can be detected only through use of a highly sensitive solution-hybridization assay. Competition binding studies reveal that the IGF-II receptor is similarly nonabundant in myoblasts. During differentiation IGF-II mRNA rises rapidly. A nearly 4-fold increase is seen within 16 hr of onset of the differentiation process, and levels are 25 times higher than those in myoblasts by 96 hr, when myotubes have formed and muscle-specific alpha-actin mRNAs are synthesized. IGF-II accumulates in conditioned culture medium with similar kinetics. The expression of IGF-II receptors on the cell surface increases almost 6-fold 24 hr after the onset of differentiation and remains high. These studies suggest that IGF-II and its receptor are coordinately regulated during myogenic differentiation in C2 cells and that IGF-II may be an autocrine factor for skeletal muscle.

Amino Acid Sequence↗
PubMed1988

The structural basis for insulin-like growth factor I receptor high affinity binding.

We have recently identified high and low affinity insulin-like growth factor I (IGF I) binding sites in solubilized human placental membranes and purified the high affinity IGF I receptor by IGF I affinity chromatography (Tollefsen, S. E., Thompson, K., and Petersen, D. J. (1987) J. Biol. Chem. 262, 16461-16469). To define the structural basis for high affinity IGF I binding, we have examined the effect of disulfide bond reduction on the binding parameters of the high affinity IGF I receptor. We find that the disulfide bonds linking the two alpha beta dimers of the IGF I receptor heterotetramer are reduced by incubation at pH 8.75 with 2 mM dithiothreitol (DTT) for 5 min at room temperature. Gel filtration chromatography on a Superose 12 fast protein liquid chromatography column indicates that the alpha beta dimers do not remain associated by noncovalent interactions after reduction. Scatchard plots of IGF I binding to the IGF I receptor incubated at pH 8.75 with or without DTT indicate that the IGF I receptor alpha beta dimers have a 6.1 +/- 1.6 (mean +/- S.D.) times lower affinity than the heterotetramer for IGF I. The total binding capacity of the IGF I receptor treated with DTT is 1.6 +/- 0.3 (mean +/- S.D.) times higher than that of an equal amount of receptor treated without DTT. These results are consistent with a model in which the heterotetramer binds a single IGF I molecule with high affinity, whereas each of the two alpha beta dimers binds an IGF I molecule with lower affinity after dissociation. We conclude that association of two alpha beta dimers is required for formation of an IGF I receptor with high affinity for its ligand.

Binding, Competitive↗
PubMed1988

The cation-independent mannose 6-phosphate receptor binds insulin-like growth factor II.

The bovine cation-independent mannose 6-phosphate receptor (CI-MPR) and the human insulin-like growth factor II (IGF-II) receptor have recently been shown to be 80% identical in their amino acid sequences as deduced from cDNA clones (Morgan, D. O., Edman, J. C., Standring, D. N., Fried, V. A., Smith, M. C., Roth, R. A., and Rutter, W. J. (1987) Nature 329, 301-307). We have studied the binding of IGF-II to affinity-purified CI-MPR in order to obtain direct evidence that the same protein binds mannose 6-phosphate-containing ligands and IGF-II. In equilibrium binding studies, the CI-MPR bound 0.95 mol of IGF-II/mol of receptor with a Kd of 0.2 nM. The pH optimum of binding was 7.4. The addition of mannose 6-phosphate did not affect binding, indicating that the two ligands interact with different binding sites on the receptor. IGF-I bound to the receptor with a much lower affinity (Kd of 0.4 microM), and insulin binding could not be detected. IGF-II did not bind to the cation-dependent mannose 6-phosphate receptor. We conclude that the cation-independent mannose 6-phosphate receptor and the IGF-II receptor are the same protein.

Animals↗
PubMed1988

Role of terminal fucose residues in clearance of human glycosylated alpha-amylase.

Human glycosylated alpha-amylase contains a single biantennary N-linked oligosaccharide that terminates with the structure Fuc alpha 1,3(Gal beta 1,4)GlcNAc. To examine the role of terminal fucose in the clearance of alpha-amylase, we used lectin affinity chromatography to isolate an alpha-amylase fraction that contains two terminal fucoses (one in each branch of the oligosaccharide) and a fraction from which both terminal fucoses have been enzymatically removed. In the rat, the rate of clearance of the radioiodinated fraction with terminal fucoses is rapid (t1/2 = 12 min) and is slowed by mannosylated but not galactosylated bovine serum albumin. The rate of clearance of the radioiodinated alpha-amylase fraction with no terminal fucoses is also rapid (t1/2 = 9.5 min), but the clearance is now slowed by galactosylated bovine serum albumin. These findings indicate that the fucosylated and defucosylated alpha-amylase fractions are recognized by different carbohydrate-specific receptors. We conclude therefore that terminal fucose is the recognition marker that effects the physiological clearance of this glycoprotein.

Carbohydrate Conformation↗
PubMed1987

Separation of the high affinity insulin-like growth factor I receptor from low affinity binding sites by affinity chromatography.

We have identified high and low affinity insulin-like growth factor I (IGF I)-binding sites with mean dissociation constants of 0.37 and 6.25 nM, respectively, in solubilized placental membranes. We have separated these sites and purified the high affinity IGF I receptor 1,300-fold, with an overall yield of 9.9%, using wheat germ agglutinin-Sepharose chromatography, insulin affinity chromatography, and IGF I affinity chromatography. The Scatchard plot of IGF I binding to the high affinity receptor is linear, suggesting the purification of a single homogeneous class of binding sites. Insulin is two orders of magnitude less effective than IGF I in competitively inhibiting IGF I binding to this receptor. The high affinity IGF I receptor is composed of alpha and beta subunits with apparent molecular weights of 135,500 and 96,200, respectively. IGF I at concentrations of greater than or equal to 50 ng/ml stimulates autophosphorylation of the beta subunit of the purified high affinity receptor 4.6-fold. Low affinity IGF I-binding sites run through the IGF I affinity column or are eluted from the insulin affinity column. The separation of IGF I receptors with different binding affinities by sequential affinity chromatography will make it possible to examine directly the determinants of receptor affinity.

Binding Sites↗
PubMed1984

The B4 lectin from Vicia villosa seeds interacts with N-acetylgalactosamine residues on erythrocytes with blood group Cad specificity.

We have previously shown that the B4 lectin from Vicia villosa seeds interacts with N-acetylgalactosamine alpha-linked to serine or threonine in cell surface glycoproteins. In the present study, we show that the lectin also binds to Cad erythrocytes (0.44-2.78 X 10(6) sites/cell) with an association constant of 0.61-0.84 X 10(7)M-1. Variability in the number of B4 lectin binding sites in Cad erythrocytes from different individuals parallels reactivity of these erythrocytes with other N-acetylgalactosamine-binding lectins. Agglutination of Cad erythrocytes with B4 lectin is inhibited by urinary Tamm-Horsfall Sda-active glycoprotein. Since the Cad and Sda determinants share the terminal GalNAc beta 1.4----Gal sequence, our results indicate that Vicia villosa B4 lectin can also interact with terminal beta-linked N-acetylgalactosamine in closely-spaced oligosaccharide units of cell surface glycoproteins.

Acetylgalactosamine↗
PubMed1983

The B4 lectin from Vicia villosa seeds interacts with N-acetylgalactosamine residues alpha-linked to serine or threonine residues in cell surface glycoproteins.

We have examined the carbohydrate binding specificity of the B4 lectin from Vicia villosa seeds. The B4 lectin agglutinates Tn-exposed erythrocytes specifically and binds to these erythrocytes (1.4 X 10(6) sites/cell) with an association constant of 4.2 X 10(7) M-1. The concentrations of saccharides and glycopeptides of defined structure which cause 50% inhibition of B4 lectin binding to Tn-exposed erythrocytes were determined. N-Acetylgalactosamine is the best monosaccharide inhibitor, causing 50% inhibition of binding at a concentration of 0.04 mM. Other monosaccharides inhibit lectin binding in the following order of decreasing potency: N-acetylgalactosamine greater than methyl-alpha-galactopyranoside greater than p-nitrophenyl-alpha- or beta-galactopyranoside greater than methyl-beta-galactopyranoside, galactose greater than galactosamine greater than mannose, N-acetylglucosamine. The disaccharide Gal beta 1,3GalNAc causes 50% inhibition of binding at a concentration of 2.8 mM, a concentration similar to that of the p-nitrophenyl-alpha- or beta-galactopyranosides. Glycopeptides containing O-glycosidically linked oligosaccharide units are significantly more potent inhibitors of lectin binding than the oligosaccharide units alone. The most potent glycopeptide inhibitor is a fetuin glycopeptide containing two alpha-linked N-acetylgalactosamine units. This glycopeptide causes 50% inhibition of lectin binding at a concentration of 0.00034 mM and probably closely resembles the B4 lectin binding site on Tn-exposed erythrocytes.

Acetylgalactosamine↗
PubMed1983

Isolation and characterization of lectins from Vicia villosa. Two distinct carbohydrate binding activities are present in seed extracts.

An uncharacterized lectin from Vicia villosa seeds has been reported to bind specifically to mouse cytotoxic T lymphocytes (Kimura, A., Wigzell, H., Holmquist, G., Ersson, B., and Carlsson, P., (1979) J. Exp. Med. 149, 473-484). We have found that V. villosa seeds contain at least three lectins which we have purified by affinity chromatography on a column of immobilized porcine blood group substances eluted with varying concentrations of N-acetylgalactosamine and by anion exchange chromatography. The three lectins are composed of two different subunits with Mr = 35,900 (subunit B) and 33,600 (subunit A), estimated from their mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Sedimentation equilibrium analysis suggests that the purified lectins are tetramers. They have been designated B4, A4, and A2B2 to indicate their apparent subunit compositions. The purified B4 and A4 lectins contain 6.7-9.8% carbohydrate by weight; in addition, both are rich in the acidic and hydroxylic amino acids and lack cysteine and methionine. The A4 lectin agglutinates A erythrocytes specifically and binds to A1 erythrocytes (273,000 sites/cell) with an association constant of 1.8 X 10(7) M-1. Although a blood group A agglutinating activity was recognized in the original preparation of V. villosa lectins, lectins with this activity were obtained in relatively small amounts from seed extracts. The predominant lectin in V. villosa seeds, B4, does not agglutinate A, B, or O erythrocytes.

Amino Acids↗
PubMed1982

Growth hormone receptors in isolated rat adipocytes.

Specific GH binding sites in isolated rat adipocytes have been partially characterized. Binding of [125I]iodohuman(h)GH was rapid, reversible, and was time and temperature dependent. Maximum specific binding occurred at 37 C in approximately 40 min at pH 7.4. Bound labeled hGH was rapidly dissociable, with the addition of excess unlabeled hormone. Specific binding is inhibited by as little as 1.0-1.5 ng/ml hGH, and 50% inhibition was obtained with 15-20 ng/ml. No inhibition was observed with insulin, glucagon, hPRL, or hTSH at concentrations up to 1 micrograms/ml. This receptor does not discriminate between monkey GH, rat GH, bovine GH, and porcine GH. Specific binding varied linearly with cell concentration. Scatchard analysis revealed linear plots with a Ka of approximately 10(9) M-1 and 15,000 sites per cell. There was less than 15% degradation of [125I]iodo-hGH over 90 min at 37 C. There was a striking increase in [125I]iodo-hGH binding to adipocytes at pH 4.85. Scatchard analysis of binding at pH 4.85 revealed a curvilinear plot with an apparent increase of sites per cell from 15,000 to 60,000, and a modest increase in the apparent affinity constant of the high affinity, low capacity sites using the two-compartment model for curvilinear plots. The GH receptors in rat fat cells displayed no ability to bind labeled hPRL or human placental lactogen, consistent with minimal recognition of lactogenic peptides by these receptors. Thus, the rat adipocyte contains specific binding sites for GH that fulfill the major criteria for receptor binding. The presence of such receptors in these cells may facilitate the study of GH receptors in relation to the biological effects of the hormone on adipose tissue in various metabolic settings.

Adipose Tissue↗
PubMed1981

Effect of growth hormone on metaphyseal uptake of 99mTc-methylene diphosphonate.

Eight children with short stature and GH deficiency were studied with 99mTc-methylene diphosphate before, during (occasionally), and after 4 months of GH therapy. Using digital images of the femoral shaft and distal metaphysis, the percent change in metaphysis-to-shaft, metaphysis-to-background (muscle), and metaphysis-to-injected dose ratios were calculated and compared to percent change in growth velocity over 4 months. The percent change in metaphysis-to-shaft and metaphysis-to-background ratios showed no significant correlation with percent change in growth velocity. The percent change in metaphysis-to-dose ratio demonstrated a significant correlation with change in growth velocity (r = 0.66; P less than 0.05). In addition, five of six patient studies before 4 months (after 1-68 days of GH therapy) demonstrated an increased metaphysis-to-dose ratio compared to baseline. In conclusion, GH therapy in GH-deficient children appears to increase the uptake of 9mmTc-methylene diphosphonate in the metaphysis, shaft, and muscle to a similar extent, and this increase appears to occur in most patients early after initiation of therapy.

Adolescent↗