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M B Ranke

Publications and source records attributed to M B Ranke.

At least 37 records · Page 2Linked to original sources
PubMed2001

In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade.

Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P: = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P: < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines. The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.

Adult↗
PubMed2001

Decreased expression of IGF-II and its binding protein, IGF-binding protein-2, in genital skin fibroblasts of patients with complete androgen insensitivity syndrome compared with normally virilized males.

The action of androgen by way of the AR is required for the development of male gonads and external genitalia. The interplay between androgens and the somatotropic axis, in particular the IGFs in sexual development, is currently under thorough investigation. The IGF system is thought to mediate the androgen action in androgen-responsive cells. To investigate the interaction of androgens with the IGF system, we compared the expression of IGFs and IGF-binding proteins in cultured genital skin fibroblasts from nine patients with the syndrome of complete androgen insensitivity with that in genital skin fibroblasts from 10 normally virilized males. Mutations in the AR gene and/or abnormalities of the AR protein in the immunoblot were detected in all complete androgen insensitivity genital skin fibroblast strains. They caused a complete failure of DHT binding. RIA and RT-PCR demonstrated that the genital skin fibroblast strains expressed IGF-II, IGF-binding protein-2, and IGF-binding protein-3, but no IGF-I. Most strikingly, complete androgen insensitivity genital skin fibroblast strains produced significantly lower IGF-II (P < 0.001; 42.2 +/- 9.7 vs. 106.9 +/- 11.8 ng/mg protein) and IGF-II mRNA (P < 0.01, by RT-PCR) than control genital skin fibroblast strains. The production of IGF-binding protein-2 was also decreased (P < 0.03) in complete androgen insensitivity genital skin fibroblasts, whereas that of IGF-binding protein-3 did not differ. Furthermore, high levels of IGF-binding protein-5 mRNA were detected in all genital skin fibroblast strains, whereby the 28-kDa band in the ligand blot, probably representing IGF-binding protein-5, was more abundant in complete androgen insensitivity genital skin fibroblasts. Exposure of the genital skin fibroblasts to T (5 x 10(-8) M) had only weak effects on the expression of IGFs and IGF-binding proteins. In conclusion, although the mechanism underlying these differences requires further study, it is conceivable that in addition to the endocrine actions of IGF-I, IGF-II and IGF-binding protein-2, as local growth factors, are involved in the mediation of androgen action and growth of genital tissues.

Androgen-Insensitivity Syndrome↗
PubMed2001

Recommendations for the diagnosis and management of Turner syndrome.

Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.

Adolescent↗
PubMed2001

Isolated GH deficiency with dominant inheritance: new mutations, new insights.

Autosomal dominantly inherited isolated GH deficiency is caused by mutations of GH-1 that alter the normal structure of GH. We studied 16 familial cases and 1 sporadic case with isolated GH deficiency type II from 1 Dutch and 4 German families by direct sequencing of PCR-amplified genomic DNA and ectopic transcript analysis of lymphocyte mRNA. In addition, the clinical data of the affected individuals were analyzed. Two previously reported mutations and 1 novel splice site mutation in intron III of GH-1 (+1G to C and +1G to A; new, +2T to C) were detected that cause exon 3 skipping. We also discovered a novel G6191 to T missense mutation in exon 4 of GH-1 that changes valine 110, which is highly conserved in mammalian and several nonmammalian GH, to phenylalanine. Splicing of the primary RNA transcript was not affected by this mutation, which is very likely to alter the normal GH structure at the protein level. The onset of growth failure was earlier, and the degree was more severe in affected children with GH-1 splice site mutations compared with those in children with the GH-1 missense mutation. In addition, the severity of the phenotype was variable, even within the same family. The age at diagnosis was between 0.8-9.6 yr (median, 5.1 yr); height at diagnosis was between -2.5 and -8.1 SD score (median, -4.0). Most of the children were lean at diagnosis, with a body mass index ranging from -1.7 to +3.3 SD score (median, -0.5). The 5 affected adults had final heights between -1.8 and -4.5 SD score (median, -3.6), centripetal obesity, and muscular hypotrophy. Before therapy, IGF-I and IGF-binding protein-3 serum levels of all affected children were severely diminished (<<5th percentiles for age). The maximum GH peak in a total of 25 stimulation tests was between 0.1-5.0 microg/liter (median, 0.9), indicating severe GH deficiency. The height of the adenohypophysis studied by magnetic resonance imaging was normal in 2 affected children and mildly decreased in 2 others. Substitution with GH resulted in good catch-up growth in all treated children. Children with severe GH and IGF-I deficiencies, but normal size of the adenohypophysis should be examined for GH-1 splice site and missense mutations. The observed discrepancy between the very homogeneous hormone data proving severe GH and IGF-I deficiencies and the high variability of growth failure even within the same family suggests that the onset and predominance of GH-dependent growth during infancy are individually different and modified by as yet unknown factors.

Age Determination by Skeleton↗
PubMed2001

Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH).

Disorders in thyroid function can impair normal development in children. Therefore it was our aim to establish reference intervals for serum triiodothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), thyroxine binding globulin (TBG) and thyrotropin (TSH) which are applicable from birth to adulthood by using the non-isotopic automated chemiluminescence immunoassay system, Immulite (DPC Los Angeles, USA). Serum samples from 762 euthyroid newborns, children and adolescents (369 female, 393 male; age 1 day to 19 years) were examined; of these, 381 were classified as pubertal. Due to non-normal distribution, the 2.5th, 50th and 97.5th percentiles (the central 95% interval) were calculated for each group. The median concentrations of T4, fT4 and TSH were up to 3.2-fold higher during the first 2 weeks, while T4 increased during the first month of life. The concentrations in all age groups showed no sex differences. From 1 year onwards, the concentration of all parameters tended to decrease until adult age, with the exception of TBG which increased by >60% (p<0.02) and reached a maximum at approximately 5 years of age. The findings underscore the fact that thyroid hormones are not associated with sexual development, except for TBG, which decreased slightly (p<0.04) between Tanner stages 1 and 5. However, the reference intervals established here demonstrate that marked changes occur in concentrations of thyroid hormones after the neonatal period. Our findings complement these of earlier studies. The developed reference intervals can be used to assess the thyroid status of patients, particularly if the measurements are done on the Immulite/Immulite 2000 system.

Adolescent↗
PubMed2000

Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment.

BACKGROUND: Growth hormone (GH) contributes to insulin resistance, but whether children treated with GH are at increased risk of diabetes has not been established. We undertook a retrospective analysis of data from an international pharmacoepidemiological survey of children treated with GH to find out the incidence of impaired glucose tolerance and types 1 and 2 diabetes mellitus. METHODS: Reports to the survey of abnormal glucose metabolism were investigated and classified. The incidence and age-distribution of type 1 diabetes were compared with values from a model of reference data. The incidence of type 2 diabetes was compared with data from two reports of children not treated with GH. FINDINGS: 85 (0.36%) of 23333 children were reported with abnormal glucose metabolism. After investigation, 43 had confirmed glucose disorders (11 with type 1 diabetes, 18 with type 2 diabetes, and 14 with impaired glucose tolerance). The incidence and age at diagnosis of type 1 diabetes in children treated with GH did not differ from expected values. The incidence of type 2 diabetes was 34.4 cases per 100000 years of GH treatment which was six-fold higher than reported in children not treated with GH. Type 2 diabetes did not resolve after GH therapy was stopped. INTERPRETATION: GH treatment did not affect the incidence of type 1 diabetes mellitus in any age group. We postulate that the higher than expected incidence of type 2 diabetes mellitus with GH treatment may be an acceleration of the disorder in predisposed individuals.

Adolescent↗
PubMed2000

Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy is characterized by elevated arterial vascular resistance and impaired nitric oxide (NO)-dependent vasodilation. Insulin-like growth factor-I (IGF-I) has been shown to stimulate endothelial NO-synthase resulting in endothelium-dependent vasodilation. Growth hormone (GH) substitution therapy leads in GH-deficient patients to significant increases of IGF-I which may alter systemic vascular resistance by stimulating NO production. This study was designed to evaluate the effects of treatment with recombinant human growth hormone (GH) on NO production and NO-dependent vascular effects in patients with dilated cardiomyopathy. METHODS: 50 patients with dilated cardiomyopathy were randomly assigned to double-blind treatment with 2 I.U. of GH or placebo for 3 months. Central hemodynamics were determined by Swan-Ganz catheter and cardiac output was obtained by the thermodilution method. Serum GH and IGF-I levels were measured and systemic NO production was determined from urinary nitrate and cyclic GMP excretion rates in 42 patients. RESULTS: GH treatment caused in comparison to the placebo group a significant increase of IGF-I by 91 ng/ml (P = 0.0001). Urinary excretion rates of nitrate and cyclic GMP increased also significantly by 38 mumol/mmol creatinine (P = 0.027) and 65 nmol/mmol creatinine (P = 0.003), respectively. The parallel increase of both marker molecules indicates increased systemic NO production during GH treatment. CONCLUSION: GH treatment induces a significant, but moderate increase of systemic NO production in patients with dilated cardiomyopathy. This effect may be mediated by IGF-I stimulating endothelial NO synthase.

Cardiomyopathy, Dilated↗
PubMed2000

The somatotrophic system in patients with dilated cardiomyopathy: relation of insulin-like growth factor-1 and its alterations during growth hormone therapy to cardiac function.

OBJECTIVE: Treatment with human recombinant growth hormone has yielded conflicting results in patients with congestive heart failure. In addition, growth hormone resistance has been reported in severe heart failure. Therefore, the purpose of this study was to evaluate the somatotrophic axis and effects of growth hormone on haemodynamics in patients with heart failure due to dilated cardiomyopathy. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Fifty clinically-stable patients with moderate heart failure (mean left ventricular ejection fraction = 26 +/- 2%) due to dilated cardiomyopthy were examined. MEASUREMENTS: Patients were randomly assigned to treatment with placebo or 2 IU/d sc human recombinant growth hormone for a mean of 14 weeks. Cardiac size and function were evaluated by magnetic resonance imaging. Central haemodynamics were obtained by right heart catheterization. Measurements of plasma noradrenaline, serum insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were performed by standard assays at baseline and at the end of the treatment period. RESULTS: The severity of heart failure as determined by stroke volume, left ventricular end diastolic diameter and plasma noradrenaline concentrations correlated significantly to baseline serum insulin-like growth factor-1 levels (each P < 0.05). The growth hormone-induced increase of insulin-like growth factor-1 predicted the changes in ejection fraction (P < 0.05). A significant increase in ejection fraction of 7% was observed in patients whose insulin-like growth factor-1 increased by more than the median increase in comparison to the patients with an increase below the median (+ 4.0 +/- 2.3% vs. - 3.0 +/- 1.8%; P = 0.03). CONCLUSIONS: Serum levels of insulin-like growth factor-1, reflecting growth hormone secretion, are diminished in relation to the severity of heart failure in patients with dilated cardiomyopathy. Growth hormone induced increases of insulin-like growth factor-1 of more than 77 ng/l caused significant improvement of ejection fraction.

Adult↗
PubMed2000

X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients.

Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenital adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disorder are scarce. Here we present a detailed documentation of longitudinal data relating to three cases. We retrospectively collected clinical data on three boys (6, 14 and 14.5 years old) who we examined over a period ranging between 5 and 14 years. Mutational analysis of the DAX-1 gene was performed by means of direct sequencing of PCR products. The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially erroneously diagnosed with isolated aldosterone deficiency. Glucocorticoid deficiency was established by means of ACTH stimulation tests at 4 months, 3 and 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during infancy, as penis size was normal, the testes were descended, and serum samples contained normal testosterone levels. One boy exhibited transient hypergonadotrophism at age 9 but showed no clinical signs of puberty or an increase in serum testosterone. Onset of puberty and LHRH tests proved to be normal in his case as well as in another patient studied. In two patients, genetic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame shift and premature stops at codons 263 and 398. One boy was affected by a new nonsense mutation of codon 39 (W39X) inherited from his mother. Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitory functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first indicators of defects in the gonadal axis, although normal initiation of puberty is not rare. The definitive diagnosis was established by means of molecular analysis of the DAX-1 gene. There was no correlation between types of mutations and phenotypes. The diagnostic procedure in male children and adolescents presenting with adrenal crisis should include ACTH stimulation tests and mutational analysis of DAX-1 in the absence of another proven aetiology.

Adolescent↗
PubMed2000

Energy expenditure, energy intake and prevalence of obesity after therapy for acute lymphoblastic leukemia during childhood.

OBJECTIVES: To investigate the prevalence and potential risk factors of obesity after therapy for childhood acute lymphoblastic leukemia (ALL). STUDY DESIGN: 39 ALL patients (age 10.7-20.5 years) who were in first remission for 3.4-14.6 years after standardized treatment with chemotherapy plus cranial irradiation (n = 25) or with chemotherapy alone (n = 14) were examined. After fasting overnight, the following parameters were investigated: body mass index (BMI) of patients and their parents; patients' BMI before ALL therapy; serum free thyroxin, growth hormone-dependent factors, estradiol, testosterone, cortisol, leptin and c-peptide; fat-free mass (bioelectrical impedance); resting metabolic rate (RMR, indirect calorimetry); caloric intake (24-hour recall); and physical activity (questionnaire). RMR data were applied to the fat-free mass and compared with 83 controls. RESULTS: The prevalence of obesity (criterion: BMI > 2 SDS) was significantly (p < 0.05) higher after ALL therapy (38%; irradiated patients 48%, non-irradiated patients 21%) than before therapy (3%). Compared to non-irradiated patients, irradiated patients had significantly lower RMRs (-1.07 +/- 0.24 vs. -0.32 +/- 0.21 SDS; p < 0.05), reduced physical activity levels (1.41 +/- 0.03 vs. 1.52 +/- 0.03; p < 0.05), and lower concentrations of insulin-like growth factor-binding protein-3 (-0.65 +/- 0.17 vs. 0.25 +/- 0.33 SDS; p < 0.05) and of free thyroxin (1.17 +/- 0.06 vs. 1.38 +/- 0.08 ng/dl; p < 0.05). Caloric intake was adequate. CONCLUSIONS: After ALL during childhood, patients face a higher risk of obesity. In the cranially irradiated patients, the likely causes are low physical activity, RMRs and hormonal insufficiency.

Adolescent↗
PubMed2000

Experience with growth hormone therapy in Turner syndrome in a single centre: low total height gain, no further gains after puberty onset and unchanged body proportions.

The experience gained since 1987, through observation of 85 girls with Turner syndrome under growth hormone (GH) treatment, has enabled the analysis of one of the largest cohorts. Our results show that age, karyotype and height reflect the heterogeneity of the patients examined at our growth centre. In 47 girls, followed over 4 years on GH (median dose 0.72 IU/kg/week), the median age was 9.4 years and mean height SDS was -3.55 (Prader) and -0.14 (Turner-specific), while height and other anthropometrical parameters [weight, body mass index, sitting height (SH), leg length (LL) SH/LL, head circumference, arm span] were documented and compared to normative data as well as to Turner-specific references established on the basis of a larger (n = 165) untreated cohort from Tübingen. The latter data are also documented in this article. Although there was a trend towards normalization of these parameters during the observation period, no inherent alterations in the Turner-specific anthropometric pattern occurred. In 42 girls who started GH treatment at a median age of 11.8 years, final height (bone age >15 years) was achieved at 16.7 years. The overall gain in height SDS (Turner) from start to end of GH therapy was 0.7 (+/- 0.8) SD, but 0.9 (+/- 0.6) SD from GH start to onset of puberty (spontaneous 12.2 years, induced 13.9 years) and -0.2 (+/- 0.8) from onset of puberty to end of growth. Height gain did not occur in 12 patients (29%) and a gain of > 5 cm was only observed in 16 patients (38%). Height gain correlated positively with age at puberty onset, duration, and dose of GH, and negatively with height and bone age at the time GH treatment started. Final height correlated positively with height SDS at GH start and negatively with the ratio of SH/LL (SDS). We conclude that, in the future, GH should be given at higher doses, but oestrogen substitution should be done cautiously, owing to its potentially harmful effect on growth. LL appears to determine height variation in Turner syndrome and the potential to treat short stature successfully with GH.

Adolescent↗
PubMed2000

Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children.

The role of IGF-I and IGFBP-3 measurements in the diagnostic work-up of short children is established but remains controversial. Little information exists on the value of IGFBP-2 measurements. Based on reference data established in 388 children we have reinvestigated the issue, using data from 392 short children who underwent the same diagnostic procedures between 1987 and 1998 (GHD, n = 187; non-GHD, n = 205, including patients with ISS, n = 76; IUGR, n = 46; and TS, n = 83). In comparing IGF-I, IGFBP-3 and IGFBP-2 serum levels of GHD and ISS children with reference data, we calculated the sensitivity, specificity, efficiency and positive predictive value for the diagnosis of GHD. The overall sensitivity of the parameters was high, the rank order being as follows: IGF-I >IGFBP-3 >IGFBP-2 (75, 67 and 62%, respectively). In contrast, the specificity was relatively low: IGFBP-3 >IGFBP-2 >IGF-I (50, 50 and 32%, respectively). The efficiency and positive predictive value of parameters was in the order of 40, 60 and 70--80%, respectively. In repeated measurements, the recorded basal levels of IGF-I and IGFBP-3 showed an overall narrow range of variation. We conclude that the determination of basal IGF parameters is, together with anthropometry and imaging techniques, an indispensable tool for differentiating between GHD and ISS; and that IGFBP-2 plays an additional role in this process.

Adolescent↗