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Collagen markers deoxypyridinoline and hydroxylysine glycosides: pediatric reference data and use for growth prediction in growth hormone-deficient children.

Skeletal growth is a complex process that includes at least three different tissue mechanisms (1): (a) growth in length, (b) growth in width, and (c) bone maintenance. Growth in length occurs mostly by endochondral bone en·do·chon·dral bone
n.
See cartilage bone.


endochondral bone,
n See bone, endochondral.
 formation at the level of growth plates and metaphyses. Bone growth in width is accomplished by what Frost (2) has termed "bone modeling". Bone modeling refers to the sculpting of a bone's inner and outer shape and involves osteoclast osteoclast /os·teo·clast/ (os´te-o-klast?)
1. a large multinuclear cell associated with absorption and removal of bone.

2. an instrument used for osteoclasis.
 and osteoblast osteoblast /os·teo·blast/ (os´te-o-blast?) a cell arising from a fibroblast, which, as it matures, is associated with bone production.

os·te·o·blast
n.
 action on opposite sides of a given piece of bone. Bone maintenance is achieved by remodeling, which is performed by the same effector effector /ef·fec·tor/ (e-fek´ter)
1. an agent that mediates a specific effect.

2. an organ that produces an effect in response to nerve stimulation.
 cells as modeling (3). However, in remodeling, osteoclasts Osteoclasts
Bone cells that break down and remove bone tissue.

Mentioned in: Bone Grafting, Osteoporosis
 and osteoblasts Osteoblasts
Cells in the body that build new bone tissue.

Mentioned in: Bone Grafting, Osteoporosis
 sequentially resorb resorb /re·sorb/ (re-sorb´) to take up or absorb again.

re·sorb
v.
1. To absorb again.

2. To dissolve and assimilate such things as bone tissue.
 and produce bone on the same bone surface with little effect on the amount or shape of the bone.

All three mechanisms characterizing skeletal growth involve the formation and degradation of collagen matrix. It is therefore not surprising that various biochemical markers derived from collagen reflect longitudinal growth for children (4, 5). We have shown previously (6-8) that this is also true for the urinary excretion of two collagen breakdown products, galactosyl hydroxylysine (Gal-Hyl) [4] and deoxypyridinoline (DPD DPD Department of Planning and Development
DPD Dihydropyrimidine Dehydrogenase
DPD Dead Peer Detection (Cisco)
DPD Division of Parasitic Diseases (US CDC)
DPD Dominant Wave Period
DPD Drug Product Database
). Both of these markers are derived from Hyl residues of collagen chains. DPD arises extracellularly from the covalent co·va·lent
adj.
Of or relating to a chemical bond characterized by one or more pairs of shared electrons.
 linkage of three Hyl residues (9), whereas Gal-Hyl is a product of the posttranslational post·trans·la·tion·al  
adj.
Of or relating to a substance or process, such as the addition of sugar groups to form a glycoprotein, that occurs or is formed after translation of protein: a posttranslational modification. 
 glycosylation of collagen at certain Hyl sites (10). Large proportions of the amounts of Gal-Hyl and DPD found in urine are derived from bone collagen and, therefore, are considered markers of bone turnover (10). A proportion of Gal-Hyl residues are further glycosylated to glucosyl(Glc)-Gal-Hyl. Concentrations of Glc-Gal-Hyl are higher in skin than in bone collagen (11). For this reason, Glc-Gal-Hyl is thought to reflect skin collagen metabolism rather than bone metabolism It is a common misconception that bones are static in nature and hardly change once an individual becomes an adult. On the contrary, bones are continuously undergoing a dynamic process of resorption and deposition known as bone metabolism. . Unglycosylated Hyl, Gal-Hyl, Glc-Gal-Hyl, and DPD are released during collagen degradation and are not reused for new collagen formation (10, 11).

Our earlier results (6-8) with Gal-Hyl and DPD prompted us to prospectively test the growth prediction potential of Gal-Hyl and DPD. Furthermore, we established a new reference database for these markers by studying a large group of healthy children. By slightly modifying our initial chromatographic chro·mat·o·graph  
n.
An instrument that produces a chromatogram.

tr.v. chro·mat·o·graphed, chro·mat·o·graph·ing, chro·mat·o·graphs
To separate and analyze by chromatography.
 method to measure Gal-Hyl (7), we were also able to investigate the urinary excretion of Glc-Gal-Hyl and Hyl.

Patients and Methods

HEALTHY CHILDREN

The healthy study group comprised 240 children and adolescents (124 girls, 116 boys; 6-19 years). The children were participants in the Dortmund Nutritional and Anthropometric an·thro·pom·e·try  
n.
The study of human body measurement for use in anthropological classification and comparison.



an
 Longitudinally Designed (DONALD) Study (12), an ongoing observational study investigating the interrelations of nutrition, growth, and metabolism in healthy children. This study is performed at the Research Institute for Child Nutrition in Dortmund, Germany. The cohort was initially recruited for an anthropometric study in a representative sample of school children of Dortmund and later through personal recommendations of parents whose children were already participating. Overall, the study population mostly comprises children of middle class families, and all participants are of Caucasian origin. On an annual basis, all participants undergo a full medical history and examination, which begin at infancy.

Height was determined to the next succeeding 1 mm with a wall-mounted Harpenden stadiometer. The mean of three measurements was noted. We measured weight to the nearest 0.1 kg, using digital electronic scales with the children clothed in underwear. The stage of sexual development was determined with the grading system defined by Tanner (13). Assessment of pubertal stage was refused by five boys and seven girls. Urine samples (24-h) were obtained once from all study participants. No efforts were made to control the diet of the participants before urine collection. All individuals showed normal physical development and were free of any signs of serious health impairment.

Informed consent was obtained from the children's parents or from the volunteers who were [greater than or equal to]18 years of age. In addition, written consent was also obtained from participants who were 14-17 years of age.

PATIENTS WITH GROWTH HORMONE DEFICIENCY growth hormone deficiency Hypopituitarism Endocrinology A condition which affects 1:4000 children; ♂:♀, 3-4:1 Etiology 70% of GHD is idiopathic and attributed to a prenatal insult, possibly due to hypothalamic dysfunction, given that GHD children  

Fifty-one prepubertal prepubertal /pre·pu·ber·tal/ (-pu´ber-tal) before puberty; pertaining to the period of accelerated growth preceding gonadal maturity.  children with growth hormone growth hormone or somatotropin (sōmăt'ətrō`pən), glycoprotein hormone released by the anterior pituitary gland that is necessary for normal skeletal growth in humans (see protein).  (GH) deficiency (14 girls, 37 boys; 3-14 years; mean [+ or -] SD, 8.0 [+ or -] 2.3 years) from 27 German centers for pediatric endocrinology Pediatric endocrinology (British: Paediatric) is a medical subspecialty dealing with variations of physical growth and sexual development in childhood, as well as diabetes and other disorders of the endocrine glands.  participated in this prospective longitudinal trial, which has been described in detail elsewhere (14). The diagnosis of GH deficiency was based on a height velocity (HV) below the 25th percentile for age and a maximal GH response of <10 [micro]g/L in at least two provocative tests. To avoid interference with growth attributable to pubertal development, only patients whose bone age was <10 years for boys and <9 years for girls and who had no clinical signs of puberty (pubic hair pubic hair,
n hair in the pubic region; secondary sexual characteristic that develops during puberty.
, breast development) were included in the study. Patients with a disorder of GH secretion secondary to chronic illness and malignancy were also excluded from the study.

GH replacement therapy was carried out with recombinant human GH at a standard dose of 0.07 IU * [kg.sup.-1] * [day.sup.-1] (0.023 mg * [kg.sup.-1] * [day.sup.-1]; Humatrope[R]; Lilly Deutschland GmbH). No other hormones were administered during the study period. Urine samples (24 h) were obtained before therapy and after 2, 4, 12, and 26 weeks of treatment. Urine was collected at home just before the visit, and samples were handed to the attending physician. Height was measured at baseline and after 3 and 12 months of therapy. HV after 3 months (HV 3) and after 12 months (HV+12) of therapy were calculated from these measurements. The study on GH-deficient patients was approved by all local ethical review boards of the participating centers, and written informed consent was obtained from the parents of the patients.

[FIGURE 1 OMITTED]

ANALYTICAL METHODS

Urine samples were stored at -20 [degrees]C until analysis. We measured Glc-Gal-Hyl, Gal-Hyl, and unglycosylated Hyl, using HPLC HPLC high-performance liquid chromatography.

HPLC

high performance liquid chromatography.

HPLC High-performance liquid chromatography Lab instrumentation A highly sensitive analytic method in which analytes are placed
 basically as we described previously (7). Samples were derivatized with dansyl and separated on a C18 column with a solvent gradient system between two buffers containing 125 mL/L and 500 mL/L acetonitrile acetonitrile /ac·e·to·ni·trile/ (as?e-to-ni´tril) a colorless liquid with an etherlike odor used as an extractant, solvent, and intermediate; ingestion or inhalation yields cyanide as a metabolic product. . Our only modification was to use a slightly different buffer gradient in this study from the buffer gradient in our previous report (7), allowing the additional separation of the peaks corresponding to Glc-Gal-Hyl and unglycosylated Hyl. Control urine samples (n = 8) with known concentrations of unglycosylated Hyl, Gal-Hyl, and Glc-Gal-Hyl were added to each analytical run of 40 samples for quality control. Mean intraassay variability for unglycosylated Hyl (at a concentration of 42.2 [micro]mol/ L), Gal-Hyl (at 65.0 [micro]mol/L), and Glc-Gal-Hyl (at 53.7 [micro]mol/L) was 2.6%, 2.4%, and 3.3%, respectively. Interassay variability was 5.5%, 2.5%, and 6.5%, respectively. Total Hyl was calculated as the sum of Glc-Gal-Hyl, Gal-Hyl, and unglycosylated Hyl.

Urinary DPD was determined with a commercially available chemiluminescence chemiluminescence /chemi·lu·mi·nes·cence/ (kem?i-loo?mi-nes´ens) luminescence produced by direct transformation of chemical energy into light energy.  assay, according to according to
prep.
1. As stated or indicated by; on the authority of: according to historians.

2. In keeping with: according to instructions.

3.
 the manufacturer's instructions (IMMULITE[R] Pyrilinks[R]-D; Diagnostic Products Corporation). Urinary creatinine creatinine /cre·at·i·nine/ (kre-at´i-nin) an anhydride of creatine, the end product of phosphocreatine metabolism; measurements of its rate of urinary excretion are used as diagnostic indicators of kidney function and muscle mass.  (Cr) was quantified by the Jaffe method. Insulin-like growth factor 1 (IGF-1) was measured with an IGF-binding, protein-blocked RIA in the presence of a large excess of IGF-2 (Mediagnost), as described previously (15).

STATISTICAL ANALYSES

The significance of differences between sexes, age groups, and pubertal stages were tested by ANOVA anova

see analysis of variance.

ANOVA Analysis of variance, see there
. For post hoc post hoc  
adv. & adj.
In or of the form of an argument in which one event is asserted to be the cause of a later event simply by virtue of having happened earlier:
 testing for significance among individual groups, Bonferroni's adjustment was used. Associations were given as Pearson's correlation coefficients. Stepwise stepwise

incremental; additional information is added at each step.


stepwise multiple regression
used when a large number of possible explanatory variables are available and there is difficulty interpreting the partial regression
 multiple regression analyses were performed in the forward mode. We transformed results in children with GH deficiency into SD scores using the formula: SD score = [(result in patient) - (age--and sex-specific mean value in the healthy population)]/(age--and sex-specific SD in the healthy population).

All tests were two-tailed, and P <0.05 was considered significant. These calculations were performed with SPSS A statistical package from SPSS, Inc., Chicago (www.spss.com) that runs on PCs, most mainframes and minis and is used extensively in marketing research. It provides over 50 statistical processes, including regression analysis, correlation and analysis of variance.  software (Ver. 6.0 for Windows; SPSS Inc.).

Results

RESULTS IN HEALTHY CHILDREN AND ADOLESCENTS

Anthropometric characteristics of the healthy study population are shown in Table 1. The variation with age in the urinary excretion of Hyl glycosides, unglycosylated Hyl, and DPD is shown in Table 2. The pattern of these changes with age was similar for all indices, with the highest values in the youngest children and lowest results in the oldest age group. Two-way ANOVA showed that the effect of age was highly significant for each index, whereas no significant effect of sex was found. However, the interaction term between age and sex reached significance for the ratios of Gal-Hyl/Cr and DPD/Cr, showing that the variation with age was different between girls and boys. This was attributable to higher values for Gal-Hyl/Cr in 6- to 7-year-old girls and lower values for Gal-Hyl/Cr and DPD/Cr in girls at 14-15 years of age.

[FIGURE 2 OMITTED]

The variation of these indices with pubertal stage is shown in Table 3. Two-way ANOVA showed no effect of sex, whereas pubertal stage had a highly significant influence on all indices. The interaction term between sex and pubertal stage was of borderline significance only for DPD/Cr, attributable to higher results in prepubertal girls (Table 3).

For consistency with the literature on this topic (5), we are presenting urinary markers of collagen metabolism relative to urinary Cr concentrations. Because timed urine samples were obtained, it was also possible to separate the developmental changes in collagen markers and Cr from one another. The variation with age and pubertal stage in the daily urinary excretion of Gal-Hyl, DPD, and Cr is shown in Fig. 1. Cr excretion increased steadily with age and pubertal stage. In contrast, Gal-Hyl and DPD increased to a peak at 12-13 years of age in girls and 12-15 years in boys and decreased thereafter.

Multiple regression analyses were performed to test which of the anthropometric characteristics (age, pubertal stage, weight, height, HV) were independently associated with collagen markers. As shown in Table 4, only age and HV had an independent influence on these biochemical markers. The relative importance of the significant contributors is indicated by the [beta] values. HV had a higher influence on Gal-Hyl/Cr than age, whereas age was more important for the other biochemical indices.

STUDIES IN CHILDREN WITH GH DEFICIENCY

The course of the collagen markers in children with GH deficiency before and during GH treatment is shown in Fig. 2. Compared with baseline results, concentrations of DPD/Cr, Gal-Hyl/Cr, and unglycosylated Hyl/Cr already had increased after 2 weeks of treatment (P <0.01), whereas the increase in Glc-Gal-Hyl/Cr was significant only after 4 weeks (P <0.001). Thereafter, all markers remained significantly above baseline values throughout the first 6 months of therapy (P <0.01).

[FIGURE 3 OMITTED]

Next, we evaluated the relationship between the short-term response of these collagen markers and growth in the first year of treatment. The correlation coefficients for the relationship between these indices and HV+12 were highest after 4 weeks of therapy, with correlation coefficients ranging from 0.42 to 0.79. This relationship for Gal-Hyl/Cr and DPD/Cr is shown in Fig. 3.

A multivariate linear regression Linear regression

A statistical technique for fitting a straight line to a set of data points.
 model using Gal-Hyl/Cr at 4 weeks, HV+3, and baseline concentrations of IGF-1 as predictive variables accounted for 80% of the variability in HV+12 {r = 0.91; P <0.0001; regression equation Regression equation

An equation that describes the average relationship between a dependent variable and a set of explanatory variables.
: HV+12 (in cm/year) = 4.08 + (0.00505 x [micro]mol Gal-Hyl/mmol Cr) + [0.313 x HV+3 (in cm/year)] - [0.010 x [micro]g/L IGF-1]}. When DPD/Cr was used instead of Gal-Hyl/Cr, the model explained 83% of the variability in HV+12 {r = 0.92; P <0.0001; regression equation: HV+12 (in cm/year) = 4.63 + (0.00518 x nmol DPD/ mmol Cr) + [0.371 x HV+3 (in cm/year)] - (0.0134 x [micro]g/L IGF-1)}. The SD of the prediction error (SD of the regression residuals) was 1.08 cm/year for the model using Gal-Hyl/Cr and 1.07 cm/year for the model using DPD/Cr, respectively.

Discussion

In this study, we examined the relationship between growth and the urinary excretion of DPD, Hyl, and Hyl glycosides. Several authors have studied the urinary DPD/Cr ratio in healthy children and have reported broadly similar changes with age as in the present study (6, 8, 16-21). We examined previously urinary GalHyl/Cr ratios in a smaller group of healthy individuals from 4 to 18 years of age with results very similar to those in the present study (7). The urinary excretion of Glc-Gal-Hyl and unglycosylated Hyl has been investigated in only small groups of children and adolescents (11, 22, 23). In accordance with Segrest et al. (11) and Krane et al. (22), we found higher urinary Gal-Hyl than Glc-Gal-Hyl during growth, whereas the amounts of both glycosides were about equal in the oldest study group with slow or no growth. This is consistent with the finding that Gal-Hyl is the predominant Hyl glycoside in bone collagen, whereas Glc-Gal-Hyl prevails in collagen from other sources, such as skin (11).

It may be surprising that, in accordance with earlier studies (6, 7, 18), no clear pubertal peak was discernible for any of the markers of the present study. On the other hand, there is little doubt that bone turnover does increase during puberty, because all three mechanisms contributing to bone turnover in growing individuals (longitudinal growth, modeling and remodeling) accelerate at this time of life (24-26). As shown in this study, there is some evidence of a pubertal peak in the daily excretion of collagen breakdown products, but this pubertal increase is obfuscated by the concomitant increase in Cr excretion. Nevertheless, the Cr-related values correlate well with individual HV. It would therefore be advantageous to analyze these results as a function of the temporal relationship with the age at peak HV rather than as a function of age or Tanner stage Tanner stage
n.
A stage of puberty in the Tanner growth chart, based on the growth of pubic hair in both sexes, the development of the genitalia in boys, and the development of the breasts in girls.
, as was done in the present study. However, for the younger participants of this study, age at peak HV will be known several years from now, and therefore this analysis cannot be done at present.

The relationship between HV and collagen markers has consequences for the application of these indices in clinical practice. When Gal-Hyl/Cr and DPD/Cr are used as diagnostic markers in metabolic bone disease, it is important to know whether the disease process affects bone metabolism apart from its effect on HV. This question can be addressed with the results presented in Table 4. These multiple regression data allow for calculation of age- and HV-dependent SD scores with the general equation: SD score = (measured result - predicted result)/SD of the prediction. For example, assume that a boy (13.4 years) has a Gal-Hyl/Cr result of 3.5 [micro]mol/mmol. If his HV is 12 cm/year, the regression predicts a result of 5.05 - (0.15 x 13.4) + (0.27 x 12) = 6.3 [micro]mol/mmol. The SD of the prediction is 1.19 [micro]mol/mmol (Table 4), and therefore the SD score is (3.5 - 6.3)/1.19 = -2.3. This would be interpreted as a low value. However, if the HV of this boy is only 3 cm/year, analogous calculations yield a SD score of -0.29, which would be regarded as a normal result. Thus, if the HV of a patient is known, individualized reference intervals can be calculated from the multiple regression data.

Since Jasin et al. (27) first reported on the relationship between collagen metabolism and HV four decades ago, dozens of reports have concluded that bone and collagen markers are "potentially useful" indicators of growth. Until now, however, very few attempts have been made to actually put this potential to use. Predicting the response to GH treatment could be one of the clinically most relevant situations for the use of growth indicators. The individual therapeutic effect on growth varies greatly among individuals, and indeed it would be helpful to have a way to evaluate responsiveness after a short period of therapy. At present, therapeutic success is typically assessed only after 1 year of therapy, and the dosage is increased when growth is not satisfactory. A sufficiently precise prognosis of whether the growth response will match the expectations would allow a faster dose adjustment.

Several authors (17, 28-32) have examined the relationship between the short-term response of bone and collagen markers and growth in the first year of therapy. The observed correlations between these biochemical markers and HV+12 were lower than or, at best, similar to those we found for Gal-Hyl, Glc-Gal-Hyl, and DPD. Although these associations are highly statistically significant, it is clear that the accuracy of a growth prediction on the basis of these markers is insufficient for practical purposes. We therefore have developed a multivariate regression model comprising variables that reflect different aspects of growth regulation (14). In the original model, DPD/Cr was used as a marker of bone metabolism, but as shown in the present report, similar results can be obtained when Gal-Hyl/Cr is used instead. The accuracy of the prediction that can be achieved in this manner might be adequate for clinical use. However, this model obviously still requires validation in a larger group of individuals before any firm conclusions can be reached.

In conclusion, in this study we present reference data for urinary markers of bone and collagen metabolism and examine their relation to growth. These markers give some early indication of therapeutic success of GH therapy in children with GH deficiency, but the prediction of an individual marker is too imprecise to serve as a basis for clinical decisions. Markers of bone and collagen metabolism might be more useful as components of multivariate growth prediction models This article outlines the various propagation models currently used by the wireless industry for signal transmission at both 900 MHz and 1800 MHz. We start with the foundation of free-space transmission, followed by Picquenard’s multiple knife edge diffraction model. .

Received July 27, 2001; accepted November 19, 2001.

References

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e·las·tin
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The osteoclasts are multi-nucleated cells that contain numerous mitochondria and lysosomes.
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pl.n.
A set of laboratory test values used to characterize apparently healthy individuals, now replaced by reference values.
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[4] Nonstandard non·stan·dard  
adj.
1. Varying from or not adhering to the standard: nonstandard lengths of board.

2.
 abbreviations: Gal-Hyl, galactosyl-hydroxylysine; DPD, deoxypyridinoline; Glc, glucosyl; GH, growth hormone; HV, height velocity; HV+3, height after 3 months of therapy; HV+12, height after 12 months of therapy; Cr, creatinine; and IGF (Internet Governance Forum) An international organization of governments and U.N. agencies that was founded to discuss Internet issues such as security and spam. It was created at the United Nations Summit in 2005 after the U.S. , insulin-like growth factor.

FRANK RAUCH, [1] * MAREILE GEORG, [1] ANGELIKA STABREY, [1] CHRISTINA NEU NEU Neutral
NEU Northeastern University (Boston, MA, USA)
NEU Near East University (North Cyprus, Turkey)
NEU Northeast University (China) 
, [1,2] WERNER F. BLUM, [3] THOMAS REMER, [2] FRIEDRICH MANZ, [2] AND ECKHARD SCHOENAU [1]

[1] Children's Hospital, University of Cologne The University of Cologne (German Universität zu Köln) is one of the oldest universities in Europe and, with over 44,000 students, the largest university in Germany. , Josef-Stelzmann Strasse 9, 50924 Cologne, Germany

[2] Research Institute for Child Nutrition, Heinstuck 11, 44225 Dortmund, Germany

[3] Children's Hospital, University of Giessen The University of Gießen (German: Universität Gießen) is officially called Justus Liebig-Universität Gießen after its most famous member, Justus von Liebig, the founder of modern agricultural chemistry and inventor of artificial fertiliser. , Germany and Lilly Deutschland GmbH, Saalburgstrasse 153, 61350 Bad Homburg, Germany

* Address correspondence to this author at: Genetics Unit, Shriners Hospital for Children, 1529 Cedar Ave., Montreal, Qc H3G 1A6 Canada. Fax 1-514-8425581; e-mail frauch@shriners.mcgill.ca.
Table 1. Anthropometric characteristics of the healthy study
population. (a)

          Age, years   n    Weight, kg             Height, cm

Girls     6-7          20   23.6 [+ or -] 3.4      122.1 [+ or -] 5.0
          8-9          21   30.2 [+ or -] 6.6      133.5 [+ or -] 6.7
          10-11        28   43.5 [+ or -] 10.5     151.4 [+ or -] 8.1
          12-13        23   51.5 [+ or -] 13.5     158.2 [+ or -] 8.1
          14-15        8    61.2 [+ or -] 17.5     170.9 [+ or -] 7.3
          16-19        24   61.8 [+ or -] 11.1     168.9 [+ or -] 8.1
Boys      6-7          20   24.1 [+ or -] 4.8      122.4 [+ or -] 5.6
          8-9          15   29.8 [+ or -] 4.6      134.7 [+ or -] 6.9
          10-11        33   40.9 [+ or -] 8.7      149.2 [+ or -] 9.2
          12-13        19   51.1 [+ or -] 9.8      159.8 [+ or -] 8.8
          14-15        14   60.3 [+ or -] 7.0      174.0 [+ or -] 6.2
          16-19        15   69.0 [+ or -] 9.7      178.6 [+ or -] 8.9

          HV, cm/year

Girls     6.2 [+ or -] 0.9
          6.0 [+ or -] 1.6
          6.5 [+ or -] 1.8
          5.4 [+ or -] 2.3
          2.0 [+ or -] 2.6
          0.4 [+ or -] 0.6
Boys      6.5 [+ or -] 1.0
          6.4 [+ or -] 0.8
          5.6 [+ or -] 1.5
          7.0 [+ or -] 2.7
          7.2 [+ or -] 3.0
          1.5 [+ or -] 2.0

(a) Values are mean [+ or -] SD.

Table 2. Urinary excretion of Hyl compounds and DPD. (a)

         Age, years   n         Glc-Gal-Hyl/Cr,      Gal-Hyl/Cr,
                                [micro]mol/mmol      [micro]mol/mmol

Girls    6-7          20        5.0 [+ or -] 1.1     6.0 [+ or -] 1.1
         8-9          21        4.6 [+ or -] 0.6     5.5 [+ or -] 0.8
         10-11        28        4.3 [+ or -] 1.3     5.4 [+ or -] 1.4
         12-13        23        4.0 [+ or -] 1.1     4.9 [+ or -] 1.4
         14-15        8         3.1 [+ or -] 0.7     3.3 [+ or -] 1.1
         16-19        24        2.5 [+ or -] 0.6     2.5 [+ or -] 0.7
Boys     6-7          20        4.4 [+ or -] 1.1     5.2 [+ or -] 1.2
         8-9          15        4.5 [+ or -] 0.8     5.4 [+ or -] 0.9
         10-11        33        4.4 [+ or -] 1.4     5.3 [+ or -] 1.8
         12-13        19        4.2 [+ or -] 0.8     5.1 [+ or -] 1.1
         14-15        14        3.7 [+ or -] 0.8     4.5 [+ or -] 1.2
         16-19        15        2.8 [+ or -] 0.8     2.9 [+ or -] 1.2

P
  Sex (c)             NS        NS                   NS
  Age group (d)       <0.0005   <0.0005              <0.0005
  Interaction (e)     NS        0.02                 NS

         Unglyc. (b) Hyl/Cr,    Total Hyl/Cr,        DPD/Cr,
         [micro]mol/mmol        [micro]mol/mmol      nmol/mmol

Girls    2.4 [+ or -] 0.8       13.4 [+ or -] 2.3    23.3 [+ or -] 9.2
         2.1 [+ or -] 0.7       12.2 [+ or -] 1.8    18.5 [+ or -] 4.9
         1.9 [+ or -] 0.7       11.7 [+ or -] 3.2    15.6 [+ or -] 5.5
         2.0 [+ or -] 0.8       10.8 [+ or -] 2.9    14.2 [+ or -] 6.0
         2.0 [+ or -] 1.4       8.4 [+ or -] 2.9     7.8 [+ or -] 2.8
         1.0 [+ or -] 0.3       6.0 [+ or -] 1.3     7.6 [+ or -] 3.5
Boys     2.6 [+ or -] 0.9       12.2 [+ or -] 2.6    17.4 [+ or -] 4.2
         2.2 [+ or -] 1.2       12.1 [+ or -] 2.3    16.7 [+ or -] 5.2
         2.3 [+ or -] 1.0       11.9 [+ or -] 3.7    14.5 [+ or -] 5.1
         1.8 [+ or -] 0.6       11.1 [+ or -] 2.2    17.1 [+ or -] 6.6
         1.5 [+ or -] 0.7       9.7 [+ or -] 2.3     12.7 [+ or -] 7.0
         1.2 [+ or -] 0.5       6.8 [+ or -] 2.2     8.5 [+ or -] 4.8

P
  Sex (c)          NS           NS
  Age group (d)    <0.0005      <0.0005
  Interaction (e)  NS           0.005

(a) Variation with age in healthy children and adolescents. Values are
mean [+ or -] SD.

(b) Unglyc., unglycosylated; NS, not significant.

(c) Significance of the effect of sex.

(d) Significance of the effect of age group.

(e) Significance of the two-way interaction term between sex
and pubertal stage (by two-way ANOVA).

Table 3. Urinary excretion of Hyl compounds and DPD. (a)

            Pubertal   n         Glc-Gal-Hyl/Cr,     Gal-Hyl/Cr,
            stage                [micro]mol/mmol     [micro]mol/mmol

Girls       1          47        4.6 [+ or -] 0.9    5.5 [+ or -] 0.9
            2          12        4.8 [+ or -] 1.8    5.9 [+ or -] 1.8
            3          11        4.4 [+ or -] 1.1    5.6 [+ or -] 1.4
            4          9         4.1 [+ or -] 1.1    4.9 [+ or -] 1.7
            5          38        2.8 [+ or -] 0.7    2.9 [+ or -] 0.9
Boys        1          58        4.4 [+ or -] 1.2    5.2 [+ or -] 1.4
            2          11        4.3 [+ or -] 1.4    5.3 [+ or -] 1.9
            3          8         4.3 [+ or -] 0.2    5.2 [+ or -] 0.9
            4          12        3.9 [+ or -] 0.7    5.0 [+ or -] 0.9
            5          22        3.1 [+ or -] 1.0    3.4 [+ or -] 1.5

P
 Sex (c)               NS        NS                  NS
 Pubertal stage (d)    <0.0005   <0.0005             <0.0005
 Interaction (e)       NS        NS                  NS

            Unglyc. (b) Hyl/Cr,  Total Hyl/Cr,       DPD/Cr,
            [micro]mol/mmol      [micro]mol/mmol     nmol/mmol

Girls       2.1 [+ or -] 0.7     12.1 [+ or -] 2.1   19.2 [+ or -] 7.2
            2.1 [+ or -] 0.8     12.8 [+ or -] 4.3   16.8 [+ or -] 6.6
            2.0 [+ or -] 0.9     11.9 [+ or -] 3.1   15.1 [+ or -] 5.4
            2.2 [+ or -] 1.0     11.3 [+ or -] 3.2   14.4 [+ or -] 6.7
            1.3 [+ or -] 0.7     7.0 [+ or -] 2.0    8.1 [+ or -] 3.4
Boys        2.4 [+ or -] 1.0     12.0 [+ or -] 3.0   15.7 [+ or -] 4.8
            1.9 [+ or -] 0.8     11.5 [+ or -] 3.8   16.0 [+ or -] 6.2
            1.9 [+ or -] 0.5     11.4 [+ or -] 1.2   17.6 [+ or -] 7.0
            1.9 [+ or -] 0.9     10.8 [+ or -] 2.3   14.3 [+ or -] 6.8
            1.3 [+ or -] 0.4     7.8 [+ or -] 2.7    10.4 [+ or -] 6.4

P
  Sex (c)            NS           NS
  Pubertal stage (d) <0.0005      <0.0005
  Interaction (e)    NS           0.03

(a) Variation with pubertal stage in healthy children and adolescents.
Values are mean [+ or -] SD.

(b) Unglyc., unglycosylated; NS, not significant.

(c) Significance of the effect of sex.

(d) Significance of the effect of pubertal stage.

(e) Significance of the two-way interaction term between sex
and pubertal stage (by two-way ANOVA).

Table 4. Multiple regression analysis in healthy children and
adolescents. (a)

Marker                 Regression      [beta]     [r.sup.2     SD
                       term (b)

Glc-Gal-Hyl/Cr,        5.02
[micro]mol/mmol
                       -0.14 (age)     -0.41      0.39         0.99
                       +0.13 (HV)      0.29
Gal-Hyl/Cr,            5.05
[micro]mol/mmol
                       -0.15 (age)     -0.32      0.48         1.19
                       +0.27 (HV)      0.45
Unglyc. (c) Hyl/Cr,    2.25
[micro]mol/mmol
                       -0.08 (age)     -0.34      0.23         0.75
                       +0.06 (HV)      0.19
Total Hyl/Cr,          12.76
[micro]mol/mmol
                       -0.39 (age)     -0.4       0.47         2.5
                       +0.46 (HV)      0.37
DPD/Cr, nmol/mmol      19.9
                       -0.74 (age)     -0.39      0.32         5.58
                       +0.59 (HV)      0.24

(a) Prediction of Hyl compounds and DPD from sex, age, pubertal stage,
weight, height, and HV. Only indices with a significant contribution
are included in the equations. All correlations are highly significant
(P <0.0001 each).

(b) Age, years; HV, cm/year.

(c) Unglyc., unglycosylated.
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Title Annotation:Endocrinology and Metabolism
Author:Rauch, Frank; Georg, Mareile; Stabrey, Angelika; Neu, Christina; Blum, Werner F.; Remer, Thomas; Man
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Feb 1, 2002
Words:5248
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