Thymic hormone activity and spontaneous autoimmunity in dwarf mice and their littermates.
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Serum thymic hormone activity (TA) was determined in hereditary hypopituitary dwarf mice (dw/dw) and their littermates (+/dw or +/+). It was found to be very low in the dwarf animals in comparison to their littermates. At 14 weeks of age, the dwarf littermates exhibited significant glomerular lesions characterized by deposits of IgG, IgG1, IgG2, IgA, IgM and C3, which were augmented by thymectomy of adult females. In contrast, hypopituitary dwarf mice had minimal glomerular deposits of immunoglobulins. Unlike these animals, their littermates showed antinuclear antibodies (ANA) and anti-deoxyribonucleic acid (DNA) antibodies in their serum. The present findings are discussed in relation to recent hypotheses on: (1) the role of the hypophysis in thymus-dependent immunological functions; and (2) the significance of T-cell deficiency in the development of autoimmunity. (+info)
Growth hormone resistance: clinical states and animal models.
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GH exerts pleiotropic effects on growth and metabolism through the GH receptor. A deficiency in the GH receptor gene is thus associated with GH resistance and dwarfism. Complete GH resistance in humans, or Laron syndrome, has been associated with numerous inherited defects in the GH receptor, including point mutations, complete or partial gene deletions, and splice site alterations. Analysis of the GH receptor genes of these patients has provided considerable insight into structure-function relationships of the GH receptor. However, the relative rarity of this disease and the obvious difficulties involved in human research have prompted a search for an animal model of GH resistance. Numerous models have been proposed, including the sex-linked dwarf chicken, the guinea pig, and the Laron mouse. In this review, the characteristics and etiology of Laron syndrome and these animal models will be discussed. The insight provided by these disorders into the roles and mechanism of action of GH will also be reviewed. (+info)
Disruption of differentiated functions during viral infection in vivo. V. Mapping of a locus involved in susceptibility of mice to growth hormone deficiency due to persistent lymphocytic choriomeningitis virus infection.
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Lymphocytic choriomeningitis virus (LCMV) Armstrong strain selectively and persistently infects the majority of growth hormone (GH) producing cells in the anterior lobe of pituitary glands of C3H/St mice but negligibly infects GH producing cells of BALB/WEHI mice (Oldstone et al., Virology 142, 175--182, 1985; Oldstone et al., Science 218, 1125--1127, 1982). Although infected GH cells remain free of structural damage, disrupted initiation of GH transcription (Klavinskis and Oldstone, J. Gen. Virol. 68, 1867--1873, 1989; Valsamakis et al., Virology 156, 214--220, 1987) occurs with a resultant decrease in the synthesis of GH, leading to a failure of growth and development (Oldstone et al., Science 218, 1125--1127, 1982). Microsatellite mapping of DNA obtained from 101 individual C3H/St x BALB/WEHI F1 x F1 mice shows that the growth failure correlates with host genes linked (P value 0.0008) on chromosome 17 just outside of the H-2D MHC site between D17 Mit24 and D17 Mit51, a distance of 2.5 cM. The genetic mapping done here excludes alpha-dystroglycan (alpha-DG), a known receptor for LCMV (Cao et al., Science 282, 2079--2081, 1998) in pathogenesis of GH disease, as alpha-DG is encoded in the mouse by a gene residing on chromosome 9 (Yotsumoto et al., Hum. Mol. Genet. 5, 1259--1267, 1996). (+info)
Diagnostic interest of acid-labile subunit measurement in relationship to other components of the IGF system in pediatric patients with growth or eating disorders.
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OBJECTIVE: To analyze the possible utility of measuring acid-labile subunit (ALS) in some types of pathologies in which the IGF system is altered and to compare it with the clinical implications of measurements of other components of this axis. DESIGN AND METHODS: We studied serum ALS concentrations in 20 children with normal variants of short stature (NVSS) at diagnosis and 24 with growth hormone deficiency (GHD), 18 obese patients and 18 girls with anorexia nervosa at diagnosis and during a follow-up period. RESULTS: In patients with GHD and anorexia nervosa, mean ALS concentrations were significantly reduced, but there was a high percentage of overlap with control values. At diagnosis, ALS concentrations were normal in obese patients and children with NVSS. During follow-up, these values normalized in children with GHD who were treated with GH, tended to normalize in those with anorexia nervosa who showed weight gain, and did not change in obese children upon weight loss. However, ALS measurement was less accurate than that of IGF-I or IGF binding protein (IGFBP)-3 in diagnosis of GHD. The correlations found between ALS and some IGF system components at diagnosis either decreased or were non-significant during follow-up of these clinical conditions. CONCLUSION: ALS adds little information to that obtained with IGF-I and IGFBP-3 determinations. (+info)
Deficiency of growth hormone-releasing hormone signaling is associated with sleep alterations in the dwarf rat.
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The somatotropic axis, and particularly growth hormone-releasing hormone (GHRH), is implicated in the regulation of sleep-wake activity. To evaluate sleep in chronic somatotropic deficiency, sleep-wake activity was studied in dwarf (dw/dw) rats that are known to have a defective GHRH signaling mechanism in the pituitary and in normal Lewis rats, the parental strain of the dw/dw rats. In addition, expression of GHRH receptor (GHRH-R) mRNA in the hypothalamus/preoptic region and in the pituitary was also determined by means of reverse transcription-PCR, and GHRH content of the hypothalamus was measured. Hypothalamic/preoptic and pituitary GHRH-R mRNA levels were decreased in the dw/dw rats, indicating deficits in the central GHRHergic transmission. Hypothalamic GHRH content in dw/dw rats was also less than that found in Lewis rats. The dw/dw rats had less spontaneous nonrapid eye movement sleep (NREMS) (light and dark period) and rapid eye movement sleep (REMS) (light period) than did the control Lewis rats. After 4 hr of sleep deprivation, rebound increases in NREMS and REMS were normal in the dw/dw rat. As determined by fast Fourier analysis of the electroencephalogram (EEG), the sleep deprivation-induced enhancements in EEG slow-wave activity in the dw/dw rats were only one-half of the response in the Lewis rats. The results are compared with sleep findings previously obtained in GHRH-deficient transgenic mice. The alterations in NREMS are attributed to the defect in GHRH signaling, whereas the decreases in REMS might result from the growth hormone deficiency in the dw/dw rat. (+info)
Growth hormone deficiency in adults and clinical use of recombinant human growth hormone.
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OBJECTIVE: To review the modern recognition of growth hormone deficiency (GHD) in adults and the beneficial effects of growth hormone (GH) treatment in such cases. DATA SOURCES AND METHODS: Most published original articles about GH and GHD in recent domestic and world wide related literatures were available. STUDY SELECTION: More than 65 originally identified articles were reviewed and 29 were selected that especially addressed the stated purpose. RESULTS: Treatment of GHD in adult human beings became an option following the development of rhGH and the numerous reports on the effect of rhGH therapy in such patients. The syndrome of GH deficiency in adults principally comprises abnormalities in body composition, cardiovascular risk factor, and psychological well-being. In comparison with normal individuals, these patients have increased total-body fat mass (particularly visceral adiposity), reduced muscle mass, reduced muscle strength exercise performance, and reduced bone mass. The psychological dysfunction comprises self-reported reduction in energy, mood, and sleep, along with objective reductions in marital and socioeconomic performance. CONCLUSION: The evidence that rhGH administration may be beneficial for the prevention, as well as treatment, of various clinical situations. (+info)
Collagen markers deoxypyridinoline and hydroxylysine glycosides: pediatric reference data and use for growth prediction in growth hormone-deficient children.
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BACKGROUND: In children and adolescents, markers of bone and collagen metabolism reflect the dynamics of skeletal growth and development. The aim of this study was to assess the relationship of the urinary collagen markers deoxypyridinoline (DPD) and hydroxylysine (Hyl) and its glycosides [galactosyl-Hyl (Gal-Hyl) and glucosyl-Gal-Hyl] with growth. METHODS: Urine samples from 240 apparently healthy children and adolescents (6-19 years; 124 girls) and from 51 prepubertal children with growth hormone (GH) deficiency (3-14 years; 14 girls) were analyzed. Urinary Hyl and its glycosides were quantified by HPLC, and DPD was assessed by chemiluminescence assay. Urinary concentrations of all markers were related to urinary creatinine. RESULTS: Multiple regression analysis revealed that only age and height velocity were independently associated with these markers in healthy children. In GH-deficient patients, the urinary excretion of both analytes after 4 weeks of GH therapy correlated significantly with the height increase during the first treatment year (r = 0.79 for Gal-Hyl; r = 0.70 for DPD; P <0.001 each). In a multivariate linear regression model using Gal-Hyl concentrations at 4 weeks, baseline concentrations of insulin-like growth factor 1 and height velocity after 3 months accounted for 80% of the variability in height gain during the first treatment year. A model using DPD concentrations at 4 weeks, in place of Gal-Hyl concentrations, as well as baseline concentrations of insulin-like growth factor 1 and height velocity after 3 months accounted for 83% of the variability. CONCLUSIONS: These urinary bone and collagen markers give some early indication of growth response, 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. (+info)
Measurement of IGF-1, IGFBP-3 and free IGF-1 levels by ELISA in growth hormone (GH) deficient children before and after GH replacement.
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Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels reflect the growth hormone (GH) status. A few percent of IGF-1 circulate in a free form which is believed to represent the IGF biological activity. We retrospectively studied the changes of serum IGF-1, serum IGFBP-3, and plasma free IGF-1 levels in growth hormone deficient (GHD) children before and after treatment with recombinant human growth hormone (rhGH) for a period of 6 months and 1 year. Twenty-one GHD children (16 boys and 5 girls) who had the mean chronological and bone ages of 7.7 +/- 0.7 and 4.8 +/- 0.6 years, respectively, were treated with a mean rhGH dose of 11.66 +/- 0.42 U/m2 body surface area/week. Serum IGF-1 level increased from 162.5 +/- 42.9 ng/ml before treatment to 252.8 +/- 49.5 ng/ml (p = 0.007) and 282.7 +/- 86.9 ng/ml after treatment for 6 months and 1 year, respectively. Plasma free IGF-1 also increased from 0.38 +/- 0.30 ng/ml before treatment to 1.21 +/- 0.30 (p = 0.001) and 1.17 +/- 0.42 ng/ml after 6 months and 1 year of treatment. However, serum IGFBP-3 did not significantly increase after treatment. In addition, the free/total IGF-1 ratio decreased after treatment with rhGH. The height velocities at 6 months and 1 year after treatment were negatively correlated with plasma free IGF-1 before treatment. In conclusion, therefore, plasma free IGF-1 levels could serve as a good predictor of growth hormone responses. Furthermore, their circulating levels would be modified by serum IGF-1 status, and possibly, IGFBP-3 protease activity. (+info)