Biomedical subjects

P D Lee

Publications and source records attributed to P D Lee.

At least 19 recordsLinked to original sources

PubMed2006

Modeling the investment casting of a titanium crown.

OBJECTIVE: The objective of this study was to apply computational modeling tools to assist in the design of titanium dental castings. The tools developed should incorporate state-of-the-art micromodels to predict the depth to which the mechanical properties of the crown are affected by contamination from the mold. The model should also be validated by comparison of macro- and micro-defects found in a typical investment cast titanium tooth crown. METHODS: Crowns were hand-waxed and investment cast in commercial purity grade 1 (CP-1) titanium by a commercial dental laboratory. The castings were analyzed using X-ray microtomography (XMT). Following sectioning, analysis continued with optical and scanning electron microscopy, and microhardness testing. An in-house cellular-automata solidification and finite-difference diffusion program was coupled with a commercial casting program to model the investment casting process. A three-dimensional (3D) digital image generated by X-ray tomography was used to generate an accurate geometric representation of a molar crown casting. Previously reported work was significantly expanded upon by including transport of dissolved oxygen and impurity sources upon the arbitrarily shaped surface of the crown, and improved coupling of micro- and macro-scale simulations. RESULTS: Macroscale modeling was found to be sufficient to accurately predict the location of the large internal porosity. These are shrinkage pores located in the thick sections of the cusp. The model was used to determine the influence of sprue design on the size and location of these pores. Combining microscale with macroscale modeling allowed the microstructure and depth of contamination to be predicted qualitatively. This combined model predicted a surprising result--the dissolution of silicon from the mold into the molten titanium is sufficient to depress the freezing point of the liquid metal such that the crown solidifies the subsurface. Solidification then progresses inwards and back out to the surface through the silicon-enriched near-surface layer. The microstructure and compositional analysis of the near-surface region are consistent with this prediction. SIGNIFICANCE: A multiscale model was developed and validated, which can be used to design CP-Ti dental castings to minimize both macro- and micro-defects, including shrinkage porosity, grain size and the extent of surface contamination due to reaction with the mold material. The model predicted the surprising result that the extent of Si contamination from the mold was sufficient to suppress the liquidus temperature to the extent that the surface (to a depth of approximately 100 microm) of the casting solidifies after the bulk. This significantly increases the oxygen pickup, thereby increasing the depth of formation of alpha casing. The trend towards mold materials with reduced Si in order to produce easier-to-finish titanium castings is a correct approach.

Chemical Phenomena↗

PubMed2005

Modeling the surface contamination of dental titanium investment castings.

OBJECTIVE: The objective of this study was to develop a computational tool for assisting the design of titanium dental castings with minimal defects and to compare computational simulations with casting experiments. METHODS: Modeling. An in-house cellular-automata solidification and finite-difference diffusion program was coupled with a commercial casting program and applied to (a) simple geometric wedge models and (b) a 3D-laser scan of a molar crown casting. Experimental. Wedges and molar crowns were hand-waxed and investment cast in commercial purity grade 1 (CP-1) titanium by a commercial dental laboratory. The castings were sectioned and analyzed using light and scanning electron microscopy, X-ray microanalysis, and microhardness testing. RESULTS: In the wedge sample, contamination with impurities (Al, Si), including intermetallic precipitates, was found to extend to a depth ranging from 30 to 120 microm depending on the section thickness and hence the local cooling rate. Microstructural and mechanical (hardness) effects were found to a depth ranging from 80 to 250 microm. The coupled micro/macro model predictions showed reasonable agreement for the pattern of contamination. SIGNIFICANCE: Dental and medical applications demand close dimensional tolerance and freedom from surface impurities and structural flaws in castings having unique shapes. The ability to predict the structural, mechanical, and chemical changes resulting from the casting process will help to design the casting and post-casting processes to minimize these problems.

Aluminum↗

PubMed2001

Microarray analysis of gene expression mirrors the biology of an ovarian cancer model.

We have previously described an ovarian cancer model based on four independent spontaneously immortalized epithelial ovarian cancer cell lines (TOV-21G, TOV-81D, TOV-112D and OV-90) from patients who were never exposed to chemotherapy or radiation therapy. These cell lines are particularly interesting since they retain characteristics of the original epithelial ovarian cancers (EOC) from which they were derived. Here we report the characterization of this model system using high-density DNA microarrays in order to assess gene expression. Expression profiles were generated from total RNAs extracted from the four EOC cell lines. For comparison, expression profiling is also provided for a primary culture of normal ovarian surface epithelium (NOV-31) and a fresh EOC sample (TOV-578G). Comparison of expression profiles revealed patterns of expression that distinguish NOV-31 from that of all tumor derived samples. The expression pattern of TOV-81D, an EOC cell line that was derived from a patient with indolent disease, most closely resembles NOV-31 while profiles of samples derived from patients with more aggressive disease (TOV-21G, OV-90, TOV-112D and TOV-578G) showed more divergent patterns of expression. The microarray analysis (http://genome.mcgill.ca) results confirm the usefulness of an ovarian cancer model based on the characterization of these EOC cell lines.

Blotting, Northern↗

PubMed2001

Characterization of glycated hemoglobin in diabetic patients: usefulness of electrospray mass spectrometry in monitoring the extent and distribution of glycation.

A combination of chromatographic and mass spectrometric techniques was used to evaluate the extent and distribution of glycation within the glycated hemoglobin (GHb) molecule. Studies on quantification of hemoglobin (Hb) glycation by electrospray ionization mass spectrometry (ES-MS) of intact globins employed specimens from 10 diabetic individuals and five normal controls. Detailed structural analysis of the phenylboronate affinity chromatography/ion-exchange (IE) HPLC-separated sub-populations of GHb was performed on a specimen carrying 13.7% GHb. An efficient protocol for mapping glycation sites within alpha and beta globins was developed, e.g., Glu-C/Asp-N proteolytic digestion followed by LC-ES-MS. Relative site occupancy within discrete components of GHb was evaluated. A correlation between the degree of glycation measured at Hb level (by affinity chromatography) and at globin level (measured by ES-MS) was carried out. The above studies led us to conclude that during the process of phenylboronate chromatography GHb dimers, rather than tetramers, are bound to the affinity resin so a fraction of glycated dimers rather than tetramers is measured. This finding implies that a process of glycation affects a much higher number of native Hb tetramers than was previously contemplated. No glycation sites appear to be missed by phenylboronate affinity chromatography. We have found no evidence of the presence of multiple glycations within a single globin chain. While glycation of both globins within a dimer cannot be excluded, it is unlikely to be a significant phenomenon. According to ES-MS data, an equivalent of about one globin per alphabeta dimer of the affinity chromatography-isolated GHb carried glycation.

Amino Acid Sequence↗

PubMed2001

Monoclonal anti-acid-labile subunit oligopeptide antibodies and their use in a two-site immunoassay for ALS measurement in humans.

Quantification of the acid-labile subunit (ALS) has to date been restricted to immunoassays utilizing polyclonal antibodies. By immunization with N-terminal and C-terminal specific ALS oligopeptides, we generated monoclonal antibodies (mAbs) that target ALS-specific sequences outside the nonspecific leucine-rich repeats in the ALS molecule. For mAb selection, a special screening method was developed. Monoclonal antibody 5C9, which targets the N-terminus of ALS, is immobilized and the anti-ALS mAb 7H3, directed against the C-terminus, is biotinylated and used as tracer Ab. Due to the extreme pH-lability of ALS, changes in immunorecognition of ALS were investigated after acidification for protein unfolding in different pH ranges and in a time-dependent manner. It was determined that acidification of the serum samples to pH 2.7 for 30 min, followed by neutralization and dilution to 1:100 was the optimal acid-neutralization method. For standardization purposes, a serum pool derived from healthy volunteers was assigned the value 1 U/ml ALS. The sandwich assay has a working range with a linear dose-response curve in a log/log system between 0.005 and 10 U/ml. ALS levels in seven acromegalic patients ranged from 2.0 to 4.2 U/ml, and in 12 untreated growth hormone deficient patients from 0.036 to 0.986 U/ml (mean=0.45 U/ml). After 12 months of growth hormone therapy, ALS levels increased significantly to 1.18+/-0.45 U/ml (mean+/-SD; p<0.0006). The increase ranged from 0.48 to 1.4 U/ml. The change in ALS with growth hormone (GH) therapy correlated closer with the change in IGF-I (r=0.798, p=0.0057; Spearman rank correlation) than with the change in insulin-like growth factor binding protein (IGFBP3; r=0.549, p=0.057). This specific sandwich assay for the measurement of ALS provides a potentially valuable indicator of growth hormone secretory status. With this mAb-based immunofluorometric assay, the nonspecific detection of other proteins containing leucine-rich repeat sequences can be excluded.

Acromegaly↗

PubMed2000

Effects of growth hormone treatment in children with Prader-Willi syndrome.

Short stature, decreased muscle mass (hypotonia), increased body fat, decreased bone mineral density and other somatic abnormalities are major causes of morbidity and social limitation in individuals with Prader-Willi syndrome. Detailed studies indicate that two major endocrine pathologies may account for many of these somatic abnormalities. A true deficiency of the growth hormone (GH)-insulin-like growth factor axis is a principal cause of the short stature and is probably a major contributor to the decreased muscle mass and osteopenia. Hypogonadotropic hypogonadism is the probable primary cause of osteopenia and osteoporosis. No other endocrine abnormalities have been specifically identified in Prader-Willi syndrome, although there may be increased risks of premature adrenarche and type 2 diabetes mellitus, both secondary to obesity. GH replacement therapy is effective in normalizing linear growth and also has positive effects on muscle mass and function, and on bone mineralization. Judicious gonadal steroid replacement may be effective in treating the osteopenia and preventing osteoporosis. GH and gonadal steroid replacement therapy should be considered for all patients with Prader-Willi syndrome.

Body Height↗

PubMed2000

Osmotic stress-induced changes of sucrose metabolism in cultured sweet potato cells.

The intra- and extracellular sugar contents, the activities of sucrose-metabolizing enzymes, and the metabolism of [U-(14)C] glucose in a pulse-chase experiment were compared between the normal and osmotically stressed (by 0.6 M sorbitol) sweet potato (Ipomoea batatas) suspension cells. The stress enhanced the levels of sucrose and sucrose phosphate synthase (SPS) activity. Northern blot analysis also showed that prolonged osmotic stress enhanced the SPS gene expression at the transcriptional level. Stressed cells also had higher activities of sucrose cleaving enzymes, such as alkaline invertase and sucrose synthase. The (14)C-sucrose isolated from normal and stressed cells had (14)C-fructose and (14)C-glucose ratios of 0.68 and 1, respectively. These data suggest the continual cycling of degradation and synthesis of sucrose in both types of cells. Among the enzymes used in constructing such futile cycling, besides invertase and SPS, sucrose synthase (SS) should be involved in normal cells, but not in stressed ones. It is apparent that the osmotic stress caused a significant change in the pattern of sucrose metabolism.

Cells, Cultured↗

PubMed2000

MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Increased expression of the multidrug resistance gene (MDR1) has been implicated in osteosarcoma prognosis. This study represents the first prospective assessment of the prognostic value of MDR1 mRNA expression in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: A series of patients with high-grade, nonmetastatic extremity osteosarcoma were enrolled from six tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 30 months). All patients were treated with (neo)adjuvant chemotherapy and surgery. Tumors from 123 patients were analyzed for MDR1 mRNA expression. The association of the level of MDR1 expression with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Using the highest MDR1 value for each patient, a dose-response relationship was not identified between the level of MDR1 expression and systemic relapse (relative risk, 1.15; P =.44). Analyses based on biopsy or resection values alone gave similar results (P =.11 and.41, respectively, log rank test). In multivariate analysis, large tumor size (> 9 cm) was the only significant independent predictor of systemic outcome (relative risk, 2.8; P =.002). CONCLUSION: We did not identify any correlation between MDR1 mRNA expression and disease progression in patients with osteosarcoma. It is likely that alterations in other genes are involved in resistance to chemotherapy in osteosarcoma and that they play a more critical role than MDR1 in this disease.

Adolescent↗

PubMed1999

Agonist-induced changes in substituted cysteine accessibility reveal dynamic extracellular structure of M3-M4 loop of glutamate receptor GluR6.

Recent evidence suggests that the transmembrane topology of ionotropic glutamate receptors differs from other members of the ligand-gated ion channel superfamily. However, the structure of the segment linking membrane domains M3 and M4 (the M3-M4 loop) remains controversial. Although various data indicate that this loop is extracellular, other results suggest that serine residues in this segment are sites of phosphorylation and channel modulation by intracellular protein kinases. To reconcile these data, we hypothesized that the M3-M4 loop structure is dynamic and, more specifically, that the portion containing putative phosphorylation sites may be translocated across the membrane to the cytoplasmic side during agonist binding. To test this hypothesis, we mutated Ser 684, a putative cAMP-dependent protein kinase site in the kainate-type glutamate receptor GluR6, to Cys. Results of biochemical and electrophysiological experiments are consistent with Cys 684 being accessible, in the unliganded state, from the extracellular side to modification by a Cys-specific biotinylating reagent followed by streptavidin (SA). Interestingly, our data suggest that this residue becomes inaccessible to the extracellular biotinylating reagent during agonist binding. However, we find it unlikely that Cys 684 undergoes membrane translocation, because the addition of SA to Cys-biotinylated GluR6(S684C) has no effect on peak glutamate-evoked current and only a small effect on macroscopic desensitization. We conclude that residue 684 in GluR6 is extracellular in the receptor-channel's closed, unliganded state and does not cross the membrane after agonist binding. However, an agonist-induced conformational change in the receptor substantially alters accessibility of position 684 to the extracellular environment.

Biotinylation↗

PubMed1999

Differentially and developmentally regulated expression of three rice sucrose synthase genes.

The spatial and temporal distribution of sucrose synthase (RSuS) in rice (Oryza sativa L.) was studied by Western and immunohistochemical analyses using the monospecific antibodies for three RSuS isoforms. In leaf tissues, RSuS1 was localized in the mesophyll while RSuS2 was in the phloem in addition to the mesophyll. In the roots, only RSuS1 was found in the phloem. No RSuS3 could be detected in any parts of etiolated seedlings. The expression of each RSus gene is closely linked to the seed development. RSuS1 was present in the aleurone layers of developing seeds, and at a low level in endosperm cells. RSuS2 was evenly distributed in seed tissues other than the endosperm. RSuS3 was localized predominantly in the endosperm cells. The tissue specific localizations of the three gene products suggest that RSuS1 plays a role in sugar transport into endosperm cells where the reaction catalyzed by RSuS3 provides the precursor of starch synthesis. RSus2, which is ubiquitously expressed, may play a housekeeping role.

Amino Acid Sequence↗

PubMed1999

Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia.

BACKGROUND: Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia. METHODS: Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis. RESULTS: After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure. CONCLUSIONS: The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.

Adolescent↗

PubMed1999

Elevated serum levels of free insulin-like growth factor I in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulation in women. Previous studies suggest that the pathogenesis of PCOS may involve interrelated abnormalities of the insulin-like growth factor (IGF) and ovarian steroidogenesis systems. We investigated this hypothesis in fasting serum samples from 140 women with PCOS (age, 27.4 +/- 0.4 yr; body mass index, 26.3 +/- 0.5 kg/m2; mean +/- SEM). IGF-related parameters were also studied in a group of normoovulatory women (n = 26; age, 26 +/- 4 yr; body mass index, 23.6 +/- 4.3 kg/m2). For the PCOS group, the mean testosterone (T) level was 2.5 +/- 0.1 nmol/L, and it was significantly correlated with LH (r = 0.41; P < 10(-6)), estrone (r = 0.33; P = 0.016), estradiol (r = 0.18; P = 0.04), and androstenedione (AD; P < 10(-6)), but not with dehydroepiandrosterone sulfate (P = 0.71), a marker of adrenal steroidogenesis. T and AD were also related to total ovarian follicle number and ovarian size, as previously found with normoovulatory women (1). There were no differences between the PCOS subjects and the normoovulatory group for total IGF-I, IGF-II, or IGF-binding protein-3 (IGFBP-3). However, IGFBP-1 levels were significantly decreased in the PCOS group (1.0 +/- 0.2 vs. 7.3 +/- 1.1 ng/mL; P < 0.001) and were inversely correlated with serum insulin levels (r = -0.50; P < 10(-8)). Serum levels of free IGF-I (fIGF-I) were elevated (5.9 +/- 0.3 vs. 2.7 +/- 0.3 ng/mL; P < 0.001) in inverse relation with IGFBP-1 (r = -0.31; P = 0.046). Serum fIGF-I levels were related to total follicle number (r = - 0.35; P < 10(-4)) and to the ratio of sex hormone-binding globulin to T (r = -0.23; P = 0.009). However, these relationships were not independent of other variables. Despite the more than 2-fold elevation in fIGF-I levels, significant relationships between fIGF-I and markers of ovarian steroidogenesis (T, AD, estradiol, and estrone) could not be demonstrated. In conclusion, although we confirmed correlations between LH and hyperandrogenemia and have found abnormalities in the IGF system in a large cohort of PCOS subjects, a direct relationship between hyperandrogenism and the IGF system could not be shown. Previous studies suggest that elevated LH and hyperinsulinemia lead to excess ovarian androgen synthesis in PCOS and that the intraovarian IGF system is important for normal follicle development and may be important in the arrested state of follicle development in PCOS. However, the data presented in this cross-sectional study suggest that insulin-related changes in circulating IGFBP-1 and subsequent elevation of fIGF-I reflect insulin resistance and have little enhancing effects on ovarian steroidogenesis in this disorder.

Adult↗

PubMed1999

Insulin-like growth factor-binding protein-3 is partially responsible for high-serum-induced apoptosis in PC-3 prostate cancer cells.

Cells are known to undergo apoptosis when cultured in high serum concentrations. However, the serum factors responsible for this induction of apoptosis have not been identified. The IGF-binding protein-3 (IGFBP-3), a negative growth regulator, is found at concentrations of 5 microgram/ml in serum. We have recently demonstrated that IGFBP-3 induces apoptosis in PC-3 cells, a prostate cancer cell line, at a concentration of 500 ng/ml. In this communication, we demonstrate the role of IGFBP-3 as one of the apoptosis-inducing agents in high serum concentrations. Treatment of PC-3 cells with increasing concentrations (40% to 90%) of intact human serum (HS) resulted in a dose-dependent decrease in cell growth. Valinomycin, an ionophore, was used as a positive control to measure the induction of apoptosis by serum treatment in PC-3 cells. Treatment with 90% serum showed significant suppression of growth (P<0.001) compared with the effect of 10% serum. Treatment with increasing concentrations of HS (40% to 90%) resulted in a dose-dependent increase in apoptosis. Treatment with 90% HS showed a 10-fold increase in apoptotic index compared with cells treated with 10% HS. Treatment of PC-3 cells with IGFs and IGFBP-3-depleted 90% human sera (depleted serum=DS) demonstrated significantly lower levels of apoptosis (50% reduction in the effect of 90% HS) suggesting a role of IGFBP-3 in inducing apoptosis in high serum concentration. Furthermore, treatment with DS supplemented with recombinant IGFBP-3 (500 ng/ml) brought the apoptotic index down close to the level of apoptosis induced by 90% intact serum treatment (P<0.001). However, DS supplemented with physiological concentrations of IGFs (500 ng/ml) showed only partial recovery of cell survival demonstrated by 90% DS. This data indicates that IGFBP-3 is one of the factors in serum that is responsible for high-serum-induced apoptosis.

Apoptosis↗

PubMed1998

Relationship between non-enzymatic glycosylation and changes in serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in patients with type 2 diabetes mellitus.

The possible occurrence of increased non-enzymatic glycosylation of serum insulin-like growth factor binding protein-3 (IGFBP-3) in vivo and the changes that would simultaneously occur in serum levels of IGFBP-3 and insulin-like growth factor-1 (IGF-I) were investigated. We measured levels of IGF-I and IGFBP-3 and the degree of glycation of total serum protein and IGFBP-3, in serum samples obtained from patients with poorly controlled non-insulin-dependent diabetes (type 2) and from age-matched non-diabetic controls. Type 2 diabetic patients had significantly higher glycated serum protein (GlyP) levels. GlyP significantly correlated with age in the control (r = 0.315, P<0.05) but not in the type 2 diabetes group. Control and diabetic subjects had comparable serum IGF-I levels and in both groups IGF-I levels tended to decrease with age (r = -0.567, P<0.001 and r = -0.465, P<0.05 for control and type 2 diabetic subjects, respectively). In the type 2 diabetes group, IGF-I levels showed a negative correlation with serum GlyP values (r = -0.476, P<0.05). Type 2 diabetic and control patients had comparable serum IGFBP-3 levels, which were significantly higher in diabetic patients in the older age subgroups. A negative correlation was found between IGFBP-3 levels and age in the control (r = -0.705, P<0.001) and in the type 2 diabetes groups (r = -0.463, P<0.05). A significant negative correlation was found between IGFBP-3 levels and GlyP in control (r = -0.449, P<0.002) but not in type 2 diabetic subjects. The mean glycated IGFBP-3 (GlyIGFBP-3) levels were higher in the oldest type 2 diabetic patients. In these patients, GlyIGFBP-3 was negatively associated with IGF-I levels (r = -0.447, P<0.05). The IGF-I/IGFBP-3 molar ratio was significantly reduced in the 46-60-year-old type 2 diabetic group, whereas the IGF-I/IGFBP-3 ratio was positively and significantly correlated with GlyP levels only in the control group (r = 0.489, P<0.01). Our results show that: a) increased non-enzymatic glycosylation of IGFBP-3 occurs in vivo; and b) this effect is accompanied by an increase in IGFBP-3 levels. These results suggest that the IGF-I/IGFBP-3 system is another target for the metabolic derangements of type 2 diabetes. Its alterations might play a role in diabetic complications.

Adult↗

PubMed1998

The insulin-like growth factor axis and plasma lipid levels in the elderly.

The activity of the hypothalamic-GH-insulin-like growth factor (IGF) network declines with age. It has recently been shown that increased cardiovascular mortality occurs in adults with GH deficiency. As hypercholesterolemia is common in GH-deficient adults, and because there is experimental evidence that GH may play a role in regulating plasma cholesterol, we decided to investigate the activity of the GH-IGF axis in an elderly population by measuring serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and to study their relationship with blood lipid levels. One hundred and thirty-two elderly subjects, 52 men and 80 women, were studied (age range, 60-91 yr). Men had significantly lower levels of IGFBP-3, high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) compared to the women, whereas IGF-I and IGF-II were only slightly lower. Using linear regression analysis, we observed an inverse relationship of age with IGF-I (r = -0.35; P < 0.001), IGF-II (r = 0.40; P < 0.001), IGFBP-3 (r = 0.52; P < 0.001), body mass index, and lipid levels. Univariate regression analysis showed a strong and positive correlation of both IGF-I and IGFBP-3 with HDL-C and ApoA1. Partial correlation analysis, after adjustment for age and body mass index, showed that IGFBP-3 and IGF-II were still significantly and positively related to HDL-C and ApoA1. Furthermore, a strong association was documented among IGF-I, IGF-II, and IGFBP-3. These data demonstrate that even in an elderly population, further aging is accompanied by a progressive decline in circulating IGF-I, IGF-II, and IGFBP-3, suggesting a continuing diminution of the GH-IGF axis throughout aging. Moreover, the strong correlation between HDL-C and an index of GH secretion, such as IGFBP-3, suggests that GH might play an important role in lipid metabolism in healthy elderly subjects.

Aged↗

PubMed1998

The insulin-like growth factor axis and growth in children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.

Children with chronic renal failure (CRF) are often growth recarded despite normal serum levels of GH and insulin-like growth factors (IGFs). Recent studies suggest that excess IGF-binding proteins (IGFBPs) in the 35-kDa fractions of CRF serum contribute to CRF growth failure. This report characterizes the relationship between IGFBP-3 and IGF peptides in the serum of growth-retarded CRF children. Size-exclusion chromatography at pH 7.4 found IGFBP-3 and IGFs almost exclusively in the 150-kDa fractions of normal serum, where their molar stoichiometry was approximately 1:1. However, similar chromatography of CRF serum found a molar excess of IGFBP-3 over total IGFs in the 150-kDa fractions and large amounts of IGFs in the 35-kDa fractions. In the 150-kDa fractions of CRF serum, IGFBP-3 was present in normal amounts, but a greater than normal amount was in the form of a 29-kDa IGFBP-3 fragment. Treatment of these CRF children with recombinant human GH increased the molar excess of IGFBP-3 over total IGFs in the 150-kDa fractions, the amount of IGFBP-3 and total IGFs in the 150-kDa fractions, and the amount of IGFs, but not IGFBPs, in the 35-kDa fractions. These data suggest that in untreated CRF children, proteolysis of IGFBP-3 in the 150-kDa fractions releases IGFs to the excess IGFBPs in the 35-kDa fractions, but insufficient IGF is released to overcome the growth-inhibiting effects of these excess IGFBPs. Treatment with recombinant human GH increases levels of IGFs and IGFBP-3 in the 150-kDa fractions, and subsequent IGFBP-3 proteolysis releases sufficient IGF to overcome the growth inhibitory effects of excess IGFBPs in the 35-kDa fractions of CRF serum.

Child↗

PubMed1997

Developmental patterns of serum 3 alpha-androstanediol glucuronide.

3 alpha-androstanediol glucuronide (3 alpha diolG) is a marker of peripheral tissue androgen metabolism. There are no previous data regarding complete paediatric reference ranges for 3 alpha diolG. In order to obtain reference values for 3 alpha diolG we have measured serum levels of 3 alpha diolG in 283 healthy children and adolescents, 146 boys and 137 girls, age 1 month to 20 years and 28 adults. A non-extraction, solid phase radioimmunoassay employing a polyclonal antiserum that is specific for 3 alpha diolG was used to measure serum 3 alpha diolG levels (intra assay variation 5.1-10.1%, inter assay variation 2.7-9.0%). There was a strong sex and age dependence (r = 0.8; p < 0.0001) of 3 alpha diolG levels throughout childhood and adolescence with males showing significantly higher levels of the androgen than females (p < 0.05). 3 alpha diolG serum levels (nmol/l +/- SD) correlated significantly with pubertal stage (p < 0.01). Interestingly, in 35 children with CAH serum 3 alpha diolG levels correlated well with clinical and metabolic status, i.e. 17OHP serum levels. In summary, we have established percentile curves for 3 alpha diolG levels in healthy children and adolescents. We hypothesize that on the basis of our reference values the single measurement of serum 3 alpha diolG could serve as a means to determine androgen status in children with disorders of puberty and sexual development.

17-alpha-Hydroxyprogesterone↗

PubMed1997

Developmental patterns of serum 3 alpha-androstanediol glucuronide.

Adolescent↗