Characterization of gsp-Mediated Growth Hormone Excess in the Context of McCune-Albright Syndrome

McCune-Albright syndrome (MAS) is a disorder characterized by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia of bone, and hyperfunctioning endocrinopathies, including GH excess. The molecular etiology of the disease is postzygotic activating mutations of the GNAS1 gene product, Gsα. The term gsp oncogene has been assigned to these mutations due to their association with certain neoplasms. The aim of this study was to estimate the prevalence of GH excess in MAS, characterize the clinical and endocrine manifestations, and describe the response to treatment. Fifty-eight patients with MAS were screened, and 22 with stigmata of acromegaly and/or elevated GH or IGF-I underwent oral glucose tolerance testing. Twelve patients (21%) had GH excess, based on failure to suppress serum GH on oral glucose tolerance test, and underwent a TRH test, serial GH sampling from 2000-0800 h, and magnetic resonance imaging of the sella. We found that vision and hearing deficits were more common in patients with GH excess (4 of 12, 33%) than those without (2 of 56, 4%). Of interest, patients with a history of precocious puberty and GH excess who had reached skeletal maturity achieved normal adult height despite a history of early epiphyseal fusion. All 9 patients tested had an increase in serum GH after TRH, 11 of 12 (92%) had hyperprolactinemia, and all 8 tested had detectable or elevated nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%) patients. All patients with elevated IGF-I levels were treated with cabergoline (7 patients), long-acting octreotide (LAO; 8 patients), or a combination of cabergoline and LAO (4 patients). In six of the seven patients (86%) treated with cabergoline, serum IGF-I decreased, but not to the normal range. In the eight patients treated with LAO alone, IGF-I decreased, and, in four, returned to the normal range. The remaining 4 patients were treated with a combination of cabergoline and LAO. For them, symptoms of GH excess diminished, and IGF-I decreased further, but did not enter the normal range. GH excess is common in MAS and results in a distinct clinical phenotype characterized by inappropriately normal stature, TRH responsiveness, prolactin cosecretion, small or absent pituitary tumors, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to LAO

An Instrument to Measure Skeletal Burden and Predict Functional Outcome in Fibrous Dysplasia of Bone

Abstract An instrument to measure skeletal burden in fibrous dysplasia was developed. Biological and clinical relevance was shown by correlating skeletal burden scores with bone markers, quality of life, and ambulatory status. Childhood scores predict adult ambulatory status, and scores were unaffected when bone markers decreased with bisphosphonate treatment or aging. Introduction: Fibrous dysplasia (FD) is a skeletal disease with a broad clinical expression. There is no objective method to assess the extent of skeletal involvement or predict outcome. We developed an instrument to measure skeletal burden that correlates with physical function, health-related quality of life (HRQL), and ambulatory status. Materials and Methods: Seventy-nine patients with FD underwent bone scintigraphy. The skeletal burden score was derived from a weighted score based on the regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. Six readers scored 20 scans twice to determine the inter- and intrareader agreement. To assess biological significance, scores were correlated with bone markers. To assess functional outcome, scores on the SF-36 (adults) or CHQ-PF50 (children) were correlated with skeletal burden scores. In a group of patients who had bone scans as children and adults (n = 6), the ability to predict ambulatory status was tested. Skeletal burden scores were assessed in patients before and after treatment with pamidronate (n = 5). Results: The inter- and intrareader agreement of burden scores were r = 0.96, and 0.98, respectively (p < 0.001 for both). The scores correlated with markers of bone metabolism and HRQL (Spearman rho, 0.54-0.67 p < 0.001 and −0.43, p = 0.001, respectively). The mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (p < 0.001 unassisted versus crutch and/or wheelchair). In unassisted ambulators, younger patients had higher scores, suggesting high childhood scores may predict adulthood impairment. In six patients with childhood and adulthood scans, childhood scores >30 predicted assisted ambulation in adulthood. There was a negative correlation between bone markers and age (Spearman rho, −0.42 to −0.70; p < 0.001), but not age and skeletal burden score. Pamidronate treatment decreased serum alkaline phosphatase but had no effect on the skeletal burden score. Conclusions: This is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome

Experimental validation of a nonparametric probabilistic model of nonhomogeneous uncertainties for dynamical systems

International audienceThe paper deals with an experimental validation of a nonparametric probabilistic model of nonhomogeneous uncertainties for dynamical systems. The theory used, recently introduced, allows model uncertainties and data uncertainties to be simultaneously taken into account. An experiment devoted to this validation was specifically developed. The experimental model is constituted of two simple dural rectangular plates connected together with a complex joint. In the mean mechanical model, the complex joint, which is constituted of two additional plates attached with 40 screw-bolts, is modeled by a homogeneous orthotropic continuous plate with constant thickness, as usual. Consequently, the mean model introduces a region (the joint) which has a high level of uncertainties. The objective of the paper is to present the experiment and the comparisons of the theoretical prediction with the experiments

Evaluacija svojstava vezanja sluzi sjemenki biljke Plantago psyllium

Mucilage extracted from Plantago psyllium seeds was evaluated for inertness and safety parameters. The suitability of psyllium mucilage for a pharmaceutical binder was assessed in paracetamol tablets. Properties of the granules prepared using different concentrations of psyllium mucilage was compared with PVP and tragacanth. Psyllium mucilage at 5 % (m⁄m) level was found to be comparable with 3 % (m⁄m) of PVP. Investigated paracetamol tablets indicated that psyllium mucilage can retard the drug release.U radu je ispitivana neškodljivost i sigurnost uporabe sluzi ekstrahirane iz sjemenki biljke Plantago psyllium. Primjenjivost te sluzi kao veziva u farmaceutskim pripravcima ispitana je na tabletama paracetamola. Granule pripravljene s različitim koncentracijama sluzi uspoređene su s granulama s PVP-om i tragakantom. Sluz s udjelom 5 % (m/m) usporediva je s otopinom PVP-a masenog udjela 3 %. Pripravljene tablete paracetamola ukazuju na to da ispitivana sluz može usporiti oslobađanje lijeka

A Novel Mouse c-fos Intronic Promoter That Responds to CREB and AP-1 Is Developmentally Regulated In Vivo

BACKGROUND: The c-fos proto-oncogene is an archetype for rapid and integrative transcriptional activation. Innumerable studies have focused on the canonical promoter, located upstream from the transcriptional start site. However, several regulatory sequences have been found in the first intron. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe an extremely conserved region in c-fos first intron that contains a putative TATA box, and functional TRE and CRE sites. This fragment drives reporter gene activation in fibroblasts, which is enhanced by increasing intracellular calcium and cAMP and by cotransfection of CREB or c-Fos/c-Jun expression vectors. We produced transgenic mice expressing a lacZ reporter controlled by the intronic promoter. Lac Z expression of this promoter is restricted to the developing central nervous system (CNS) and the mesenchyme of developing mammary buds in embryos 12.5 days post-conception, and to brain tissue in adults. RT-QPCR analysis of tissue mRNA, including the anlage of the mammary gland and the CNS, confirms the existence of a novel, nested mRNA initiated in the first intron. CONCLUSIONS/SIGNIFICANCE: Our results provide evidence for a novel, developmentally regulated promoter in the first intron of the c-fos gene

Efficient preparation of Arabidopsis pollen tubes for ultrastructural analysis using chemical and cryo-fixation

The pollen tube (PT) serves as a model system for investigating plant cell growth and morphogenesis. Ultrastructural studies are indispensable to complement data from physiological and genetic analyses, yet an effective method is lacking for PTs of the model plant Arabidopsis thaliana. Methods: Here, we present reliable approaches for ultrastructural studies of Arabidopsis PTs, as well as an efficient technique for immunogold detection of cell wall epitopes. Using different fixation and embedding strategies, we show the amount of PT ultrastructural details that can be obtained by the different methods. Results: Dozens of cross-sections can be obtained simultaneously by the approach, which facilitates and shortens the time for evaluation. In addition to in vitro-grown PTs, our study follows the route of PTs from germination, growth along the pistil, to the penetration of the dense stylar tissue, which requires considerable mechanical forces. To this end, PTs have different strategies from growing between cells but also between the protoplast and the cell wall and even within each other, where they share a partly common cell wall. The separation of PT cell walls in an outer and an inner layer reported for many plant species is less clear in Arabidopsis PTs, where these cell wall substructures are connected by a distinct transition zone. Conclusions: The major advancement of this method is the effective production of a large number of longitudinal and cross-sections that permits obtaining a detailed and representative picture of pollen tube structures in an unprecedented way. This is particularly important when comparing PTs of wild type and mutants to identify even subtle alterations in cytoarchitecture. Arabidopsis is an excellent plant for genetic manipulation, yet the PTs, several-times smaller compared to tobacco or lily, represent a technical challenge. This study reveals a method to overcome this problem and make Arabidopsis PTs more amenable to a combination of genetic and ultrastructural analyses