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【Key words】 somatomedins; diagnosis; growth hormone insensitive syndrome


insulin-like growth factor (insulin -like growth factor, IGF) generation test is commonly used in clinical endocrine dynamic testing, assessment of short stature are often regarded as a GH-IGF1 axis in the growth of one of the technologies, such as GH insensitivity syndrome (GH insensitive syndrome, GHIS) or Laron syndrome. In recent years,[link widoczny dla zalogowanych], with the study of hypothalamus - pituitary axis of pathological defects in the growth mechanism and recombinant human growth hormone (rhGH) Clinical application of the continuous deepening of awareness of IGF generation test a new understanding, but its clinical value still has some doubts. In this paper, 27 cases of short stature in children with IGF generation test to make a retrospective analysis,[link widoczny dla zalogowanych], to observe: (1) IGF generation test is able to predict the growth promoting effect of rhGH; (2) IGF generation test in primary growth hormone deficiency ( GHD), idiopathic short stature (ISS) and GHIS identify whether the patient has clinical value. 1 Materials and Methods 1.1 General Information 27 cases of short stature who are growth and development of children in our hospital out-patient treatment centers in children, 18 males and 9 females; average age of 10.2 years (5.8 to 15.0 years), are in early puberty (Tanner Ⅰ period). According to the following inclusion criteria were divided into GHD, ISS, and GHIS three groups, of which 15 cases GHD, ISS group of 11 patients and GHIS 1 case in Table 1. GHD and ISS patients were receiving rhGH treatment at the test dose of 0.1u / (kg · d), subcutaneous injection before going to sleep, and were followed up after 1 year of treatment growth rate (GV). GHD diagnosis based on: (1) height below the normal average level-2SD; (2) significantly reduced growth rate; (3) bone age (BA) behind the actual age of 2 years of age; (4) GH serum of drug provocation test GH peak 10μg / L; (5 ) no other endocrine disorders and chronic organic diseases, genetic metabolic and psychological abnormalities. GHIS clinical diagnosis based on: (1) height below the normal average level-2SD; (2) the peak serum GH was significantly higher (more> 20μg / L); (3) BA significantly delayed; (4) serum IGF1, insulin-like growth factor binding protein 3 (IGFBP3) and growth hormone binding protein (GHBP) was significantly lower; (5) rhGH treatment ineffective. 1.2 Methods 1.2.1 GH stimulation test all newly diagnosed children are receiving in the two GH provocative test drugs (clonidine, arginine). GH in serum were detected by quantitative radioimmunoassay kit (DPC products), PCS sensitivity 0.9ng/ml, group and group CV was> 5% and> 7%. 1.2.2 IGF1 generation test method by subcutaneous injection of rhGH dose of 0.1u / (kg · d), before going to sleep for 4 or 7 injections before the test and test the following morning after the blood serum were IGF1 and GHBP. IGF1 with RIA technology, Immunotech kit for the French company's products, the sensitivity was 3ng/ml, group and group CV was 7.4% and 15.5%; GHBP by enzyme-linked immunosorbent assay technique (ELISA), kit for the U.S. DSL products, the sensitivity was 1.69pmol / L, group and group CV was 3.17% and 6.2%. 1.2.3 IGF generation test in diagnosis of GH treatment parameters calculated on the basis of the GV after 1 year was calculated △ IGF1 serum diagnostic sensitivity and specificity of the calculations and draw the receiver operating characteristic curve (receiver operating characteristic curve, ROC curve .) Sensitivity (prediction true positive effect of good proportion of the group) = true positive effect of good group, the number of cases / (number of true positive cases of the number of false negative cases), specificity (true negative effect of the proportion of poor group) = effect of poor group true negative cases / (number of true negative cases of false positive cases), according to ROC determine the clinical efficacy of ISS children with GH to determine with high sensitivity and specificity of the cut point. 1.3 Statistical analysis Data are mean ± standard deviation (± s) that the relevant indicators between groups using t test and analysis of variance (ANOVA, pairwise comparison method with the smallest range that LSD test), P < ; 0.05 was considered significant. All statistical analysis of all the SPSS 11.0 software. Children with short stature groups Table 1 General Information (slightly) Note: △ IGF1, △ IGFBP3 IGF1 after excitation, respectively, before stimulation and IGFBP3 compared with the difference, △% IGF1, △% IGFBP3 were IGF1 and IGFBP3 after excitation said before stimulation compared with the percentage difference, GV for the growth rate, △ GV GV is the added value of rhGH treatment,[link widoczny dla zalogowanych], △ HtSDS rhGH treatment height SD for the added value of integration 2 results 2.1 IGF generation test based on the value basis of GHD group, the average value of serum IGF1SDS -1.5 ± 0.8, ISS group was -0.90 ± 0.3, the two groups was significant difference (t = 2.17, P = 0.003). According to ROC curve analysis shows that GHD and ISS of the IGF1 discriminant cutoff value 221.6ng/ml (see Figure 1, Figure 2), the sensitivity was 54.5%, specificity of 84.6%. GHD group, the average base value of serum IGFBP3 (4352.85 ± 369.77) μg / L,[link widoczny dla zalogowanych], GHBP was (115.0 ± 11.9) pmol / L; ISS group IGFBP3 is (6186.444 ± 433.79) μg / L, GHBP was (148.0 ± 22.0) pmol / L, no significant difference between the two groups (IGFBP3 t = 1.54, P = 0.14 and GHBP t = 1.45, P = 0.16), Table 1. Figure 1 corresponds to the peak stimulated GH IGF1 in patients with baseline map (omitted) Figure 2 peak in patients with GH, IGF and IGF baseline baseline (omitted) 2.2 IGF generation test response value in patients with GHD and ISS Percentage difference in serum IGF1 evoked response (△% IGF1) was significant difference [(51.9 ± 10)% and (38.7 ± 7)%, t = 2.23, P = 0.03)]; GHD and ISS patients IGFBP3SDS response value difference also significant (1.17 ± 1.0 and 4.14 ± .72; t = 3.17, P = 0.005) (Table 1). Response value of serum GHBP was no significant difference [(151.0 ± 12.7) and (168.5 ± 22.5) pmol / L; t = 1.57, P = 0.13)]. IGF generation test prompted GHBP observed no significant response to the value parameter. 2.3 Correlation analysis based IGF1SDS 2.3.1 GHD group and △% IGF1 and △ GV negative correlation (r =- 0.79, P = 0.001 and r =- 0.59, P = 0.028); GH peak and △% IGF1, △ GV negative correlation (r =- 0.78, P = 0.001 and r =- 0.64, P = 0.01); IGF1 response value of 1 year after treatment with rhGH was positively correlated with serum IGF1 (r = 0.89, P = 0.07 ); △% IGF1 and △ GV was positively correlated (r = 0.63, P = 0.015); △% IGF1 and △% IGFBP3 was positively correlated (r = 0.727, P = 0.011). GHD patients can see the value of IGF1 and IGF generation test based on the degree of response and rhGH replacement therapy exists between the association. 2.3.2 ISS group of patients with HtSDS △% IGF1 and IGF1 was negatively correlated with baseline values ​​(r =- 0.61, P = 0.047; r =- 0.64, P = 0.036). △ IGF1 GV corresponding changes before and after rhGH treatment shown in Figure 2. Effect of rhGH 2.4 Prediction of serum △ IGF1 this prediction as to determine efficacy of GH (GV) cut points, good group effects were calculated true positive and false negative cases and the number of true negative effect of poor groups and the number of false-positive cases and cut points were calculated to determine the efficacy of the sensitivity and specificity. △ IGF1 on ISS can be seen in children with GH to determine with high sensitivity and specificity of the effect of the cut point is about 165.9μg / L (Table 2, Figure 3). Table 2 IGF generation test GV Changes in the ROC point analysis to determine △ IGF1 (abbreviated) Figure 3 ISS △ IGF1 in patients with IGF generation test corresponds to rhGH treatment before treatment and 1 year after the GV changes (slightly) 3 discussed the design of clinical application of IGF1 test has generated more than 20 years, the test principle is stimulated by exogenous GH secretion in peripheral target cells, IGF, to evaluate the effects of GH stimulation. Therefore, the purpose of the inspection should include two aspects: (1) detection of GH receptor (GHR) to its ligand sensitivity of the reaction: when the normal activity of GHR function, exogenous GH was significantly increased after stimulation of serum IGF1; Conversely, GHR function defects were no significant changes in response to IGF1, which can be diagnosed GHR insensitive (GHI) and the predicted growth-promoting effect of exogenous GH. (2) test the functional activity of endogenous GH: When the number of endogenous GH secretion in normal and functional defects, the use of exogenous GH stimulation can produce good responses, IGF significantly improved compared with baseline. Based on this view, IGF generation test has been designed as a function of GH-IGF axis dynamic tests are used to identify the complete GH insensitivity (GHI, the Laron syndrome). 1994, Blum et al [1] diagnostic criteria for the trial of the experiment (points system), that is, the standard injection of exogenous GH for 4 days, serum IGF1 response increased from baseline values ​​<15μg / L, IGFBP3 <0.4 mg / L. This experimental observation of the object did not meet the diagnostic criteria mentioned above, combined with the normal and the clinical value of serum GHBP good growth-promoting effect of rhGH, thus excluding complete GHI. 1 patient in our hospital were children suspected GHI, the IGF generation test based on serum IGF1 is 19.1μg / L, reaction value 10.0μg / L; IGFBP3 baseline 663.1μg / L, reaction value 352.1μg / L; GHBP 15pmol / L and without rhGH treatment, consistent with complete GHI (reported in another paper). Identification of IGF generation test shows complete GHI has some clinical value. On IGF generation test of growth hormone deficiency (GHD), non-GHD of idiopathic short stature (ISS) and some of the differential diagnosis of GHI has been a lot of observation reports, but results to differ materially, the main problem may also lies defect detection results of different pathological excessive overlap. Has yet to identify clinical trials to establish a consistent standard. GH has been reported to stimulate the individual peak identification based on GHI no practical value. Attie and put forward in 1995 [2]: 20% ISS patients presented with low serum GHBP and IGF1, suggesting possible role of GH resistance, but the IGF generation test does not meet the complete diagnostic criteria for GHI experiments, that is part of the ISS could be a GHI species of the cause. Goddard, etc. Also the same year the first report [3] in patients with ISS GH receptor gene mutations exist, is part of the molecular pathogenesis of GHI. Therefore suggesting that the stimulation test can identify a certain extent, some of the GHI, indicates that rhGH adverse effect, or prompt treatment should increase the dose of GH. Clinical observations of this group, GHD and ISS patients with baseline serum IGF1 significant difference; in the ISS group, only the tips △ IGF1 was 165μg / L when the clinical effect of GH may be better, but may be limited to observation of ISS limited sample, not shown Identification of the statistical value of the diagnosis of partial GHI truncation standards. The IGF generation test in children with clinical value of ISS is still somewhat controversial [4], the reason may be lack of uniform testing procedures and criteria concerning the test results, such as the GH dose and time, blood collection time, IGF and other measurement methods, and the lack of different age and gender were evaluated exogenous GH normal reference standards. At present, some scholars have been proposed [5 ~ 8], doses of exogenous GH stimulation test results is critical, large doses of no significant advantage on the test sensitivity, low-dose stimulation should be adopted to increase the sensitivity of test reactions, especially the recognition of partial GHI; In addition, stimulation of an appropriate extension of time may help in the clinical differential diagnosis of overlap to improve the test results, while serum IGF1 response could be detected IGFBP3, a combination of both can get more information. Conclusion, IGF generation test the clinical value is constantly being understanding and demonstration. This observation indicates that: (1) IGF generation test is complete and reliable laboratory diagnosis of GHI basis; (2) IGF generation test has a certain growth promoting effect of rhGH forecast; (3) patients in the ISS to provide some of the clinical differential GHI diagnostic information is also observed to be expanding the number of samples in order to enrich and reliable information.
Generation of insulin-like growth factor, and clinical application value of clinical papers



Abstract Objective insulin-like growth factor (insulin-like growth factor, IGF) generation test is commonly used in clinical endocrine dynamic testing, evaluation is often regarded as GH insensitivity syndrome (GH insensitive syndrome , GHIS) little growth in patients with GH-IGF1 axis technologies. This paper aimed to investigate: (1) IGF generation tests in the IGF1 response value (△ IGF1) are growth-promoting effects of rhGH reflect; (2) IGF generation test for GHD, ISS whether patients with GHIS three clinical differential value. Methods 27 cases of short stature in children with IGF generation test to make a retrospective analysis, the average age of 10.2 years (5.8 to 15.0 years), are in early puberty (Tanner Ⅰ period), in which primary growth hormone deficiency (GHD n = 15), idiopathic short stature (ISS) 11 cases and GH insensitivity syndrome (GHIS) that Laron syndrome in 1 case. Detection of IGF generation test parameters include: peak serum GH, IGF1 and growth hormone binding protein (GHBP). Based on growth rate (GV) to explore △ IGF1 diagnostic sensitivity and specificity of the cut point. Results GHD and ISS patients IGF1SDS baseline and △% IGF1 significant difference (t = 2.17, P = 0.003; t = 2.23, P = 0.03). GHD group of patients based IGF1SDS and △% IGF1 and △ GV negative correlation (r =- 0.79, P = 0.001 and r =- 0.59, P = 0.028); GH peak and △ IGF1, △ GV negative correlation (r = -0.78, P = 0.001 and r =- 0.64, P = 0.01); △% IGF1 and △ GV was positively correlated (r = 0.63, P = 0.015). ISS group of patients with HtSDS △ IGF1 and IGF1 baseline was a negative correlation (r =- 0.61, P = 0.047; r =- 0.64, P = 0.036); ROC curve can be seen from the ISS △ IGF1 on GH to determine efficacy in children with high sensitivity and specificity of the cut point was about 165.9μg / L. Conclusion (1) IGF generation test is complete and reliable laboratory diagnosis of GHI; (2) IGF generation test has a certain growth-promoting effects of rhGH predicted effect; (3) the failure on the part of the GHI to provide clinical diagnostic information. Key words somatomedins class; generation test; of Insulin-like growth factor generation test and its clinical value
【Abstract】 Objective The insulin- like growth factor (IGF) generation test has been used to assess growth hormone (GH) responsiveness in children with short stature in clinic.The aim of this study was to seek a cutting value (1) in effect of prediction for growth promoting with recombinant human GH (rhGH) therapy in children with idiopathic short stature (ISS) and (2) in differential diagnosis between GH deficiency (GHD) ISS and GH insensitive syndrome (GHIS). Methods Twenty-seven pre-pubertal children with short stature (including 15 GHD, 11 ISS and 1 GHIS), mean age 10.2 years (5.8 ~ 15.0), were retrospectively studied.All the patients received rhGH treatment over one year except the GHIS patient.Serum GH peak value, IGF1 and GH binding protein (GHBP ) levels were measured.The diagnostic cut-off line of IGF1 responding levels (△ IGF1) during standard IGF generation test was sought on the basis of growth velocity (GV). Results Among the GHD and ISS groups, distinct differences were shown in serum basal IGF1SDS levels (t = 2.17, P = 0.003) and △% IGF1 levels (t = 2.23, P = 0.03). In GHD group we found negative relationships between the basal IGF1SDS and △% IGF1 (r =- 0.79, P = 0.001), between the basal IGF1SDS and △ GV (r =- 0.59, P = 0.028), between GH peak level and the △ IGF1 level (r =- 0.78, P = 0.001) and between GH peak level and △ GV (r =- 0.64, P = 0.01). Positive relationship was shown between △% IGF1 and △ GV (r = 0.63, P = 0.015) in GHD patients.In ISS group, negative relationships were shown between △ IGF1 and HtSDS (r =- 0.61, P = 0.047) and between △ IGF1 and basal IGF1 value (r =- 0.64, P = 0.036). The ROC plot showed that the best cut-off line of △ IGF1 for prediction of rhGH therapeutic effect was likely 165.9μg / L. Conclusion (1) The IGF generation test is a reliable clinical laboratory diagnostic parameter for complete GHI; (2) IGF generation test was suspected valuable in prediction of growth promoting effect in short stature with rhGH treatment; (3) The diagnostic value of IGF generaton test for partial GH insensitivity need to be clarified.


【Reference】 1 Rosenfeld RG, Albertsson-Wikland K, Cassorla F, et al.Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revised.J Clin Endocrinol Metab ,1995,[link widoczny dla zalogowanych],80:1532-1540. 2 Blair JC, Camacho-Hubner C. Standard and low-dose IGF1 generation tests and spontaneous growth hormone secretion in children with idiopathic short stature.Clinical Endocrinol, 2004,60 ( 2) :163-168. 3 Attie KM, Carlsson LM, Rundle AC, et al.Evidence for partial growth hormone insensitivity among patients with idiopathic short stature.The national Cooperative Growth Study.J Pediatr, 1995,127:244 -250. 4 Cotteril AM, Camacho-Hubner C, Woods, et al.The insulin-like growth factor 1 generation test in the investigation of short stature.Acta Paediatr.1994 ,399:128-130. 5 Goddard AD, Dowd P, Chernausek S, et al.Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic stature.J Paediatr ,1997,131:51-55. 6 Buckway CK, Guevara -Aguirre J, Pratt KL, et al.The IGF-1 generation test revisted: a marker of GH sensitivity.J Clin Endocrinol Metab ,2001,86:5176-5183. 7 Buckway CK, Selva KA, Pratt KL, et al.Insulin like growth factor binding protein-3 generation as a measure of GH sensitivity.J Clin Endocrinol Metab ,2002,87:4754-4765. 8 Darendelilre F, Ocal C, Bas F, et al.Evaluation of insulin like growth factor (IGF) -1 and IGF binding protein-3 generation test in short stature.J Clin Endocrinol Metab ,2005,18:443-452.
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