Background/Aims: Treatment of children with growth disorders with recombinant human growth hormone is necessary for improved outcomes, including final height. Methods: Adherence data from the Observational Study Saizen®-online, recorded with the easypod™ device collected between October 2009 and May 2011, were analyzed in pediatric patients receiving recombinant human growth hormone treatment for a variety of growth disorders. Results: Data from 75 children (46 boys, 29 girls) with different growth disorders were analyzed over a period of 343 ± 201 (SD) days. Boys and girls showed similar mean ± SD adherence rates of 90.5 ± 3.1% and 92.2 ± 10.7%, respectively. Pubertal children (n = 41) had a significantly lower adherence rate (89.1 ± 13.7%) than prepubertal children (n = 29) (96.5 ± 3.9%; p < 0.005). There were nonsignificant differences in adherence rates according to diagnosis: growth hormone deficiency (n = 48) 91.4 ± 11.0%, small for gestational age (n = 18) 91.1 ± 15.3%, Turner syndrome (n = 6) 86.0 ± 14.5%, and chronic renal failure (n = 3) 99.3 ± 1.0%, although the latter two groups were small. Conclusion: Our data indicate that only a small number of pediatric patients using the easypod device had poor adherence to treatment. Further reliable adherence data are required to identify factors affecting long-term adherence in this population.

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Overexpression or clustering of the transmembrane form of the extracellular matrix heparan sulfate proteoglycan agrin (TM-agrin) induces the formation of highly dynamic filopodialike processes on axons and dendrites from central and peripheral nervous system-derived neurons. Here we show that the formation of these processes is paralleled by a partitioning of TM-agrin into lipid rafts, that lipid rafts and transmembraneagrin colocalize on the processes, that extraction of lipid rafts with methyl-␤-cyclodextrin leads to a dose-dependent reduction of process formation, that inhibition of lipid raft synthesis prevents process formation, and that the continuous presence of lipid rafts is required for the maintenance of the processes. Association of TM-agrin with lipid rafts results in the phosphorylation and activation of the Src family kinase Fyn and subsequently in the phosphorylation and activation of MAPK. Inhibition of Fyn or MAPK activation inhibits process formation. These results demonstrate that the formation of filopodia-like processes by TM-agrin is the result of the activation of a complex intracellular signaling cascade, supporting the hypothesis that TM-agrin is a receptor or coreceptor on neurons.Agrin is a proteoglycan with a molecular mass of more than 500 kDa that is expressed in many tissues (for a review, see Ref. 1). Despite its widespread expression, the function of agrin is best characterized in skeletal muscle, where it is a key organizer during formation, maintenance, and regeneration of the neuromuscular junction (2, 3). Accordingly, mice with an inactivation of the agrn gene die at birth due to nonfunctional neuromuscular junctions and subsequent respiratory failure (4).Little is known about the role of agrin in other tissues, in particular in the central nervous system (for a review, see Ref. 5). Although neurons from mice with a targeted deletion of the agrn gene form synaptic specializations in vitro and in vivo (6, 7), the acute suppression of agrin expression or function by antisense probes or antibodies influences the formation and function of interneuronal synapses (8, 9). Likewise, brains of agrin-deficient mice, whose perinatal death was prevented by the reexpression of agrin specifically in motor neurons, have a severely reduced number of pre-and postsynaptic specializations at excitatory synapses (10). In addition, agrin isoforms are highly expressed by central nervous system neurons before synapse formation, suggesting additional functions for agrin during axonal and dendritic elongation (11-16). Although these data are consistent with a role of agrin during CNS 4 synaptogenesis, the precise role of agrin during CNS development remains to be clarified.Alternative first exon usage generates either a secreted soluble agrin molecule (NtA-agrin) or a transmembrane form of agrin (TM-agrin) (17, 18). The secreted form of agrin specifically interacts with the laminin ␥1-chain via its NtA-domain, resulting in a stable association with basal laminae (19,20). In contrast, in TM-agrin, t...

Clustering or overexpression of the transmembrane form of the extracellular matrix proteoglycan agrin in neurons results in the formation of numerous highly motile filopodia-like processes extending from axons and dendrites. Here we show that similar processes can be induced by overexpression of transmembrane-agrin in several non-neuronal cell lines. Mapping of the process-inducing activity in neurons and non-neuronal cells demonstrates that the cytoplasmic part of transmembrane agrin is dispensable and that the extracellular region is necessary for process formation. Site-directed mutagenesis reveals an essential role for the loop between ␤-sheets 3 and 4 within the Kazal subdomain of the seventh follistatin-like domain of TM-agrin. An aspartic acid residue within this loop is critical for process formation. The seventh follistatin-like domain could be functionally replaced by the first and sixth but not by the eighth follistatin-like domain, demonstrating a functional redundancy among some follistatin-like domains of agrin. Moreover, a critical distance of the seventh follistatin-like domain to the plasma membrane appears to be required for process formation. These results demonstrate that different regions within the agrin protein are responsible for synapse formation at the neuromuscular junction and for process formation in central nervous system neurons and suggest a role for agrin's follistatin-like domains in the developing central nervous system.Agrin is a proteoglycan with a molecular mass of Ͼ500 kDa that is expressed in many tissues (1, 2). The function of agrin is best characterized in skeletal muscle where it is a key organizer during formation, maintenance, and regeneration of the neuromuscular junction (2-4). Accordingly, mice with an inactivation of the agrn gene die at birth due to non-functional neuromuscular junctions and consequent respiratory failure (5).Little is known about the role of agrin in tissues other than skeletal muscle, in particular in the central nervous system (for review see Refs. 1, 2, 6). Although neurons from mice with a targeted deletion of the agrn gene form synaptic specializations in vitro and in vivo (7,8), the acute suppression of agrin expression or function by antisense oligonucleotides or antibodies influences the formation and function of interneuronal synapses (9, 10). Likewise, brains of agrin-deficient mice, whose perinatal death was prevented by the re-expression of agrin in motor neurons, have a severely reduced number of pre-and postsynaptic specializations as well as functional deficits at excitatory synapses in the CNS 3 (11). Although these data are consistent with a role of agrin during CNS synaptogenesis, the precise function of agrin during CNS development remains unclear.Agrin has been cloned from several species, and the sequences are highly homologous. The agrin cDNAs predict a number of domains with similarity to other extracellular matrix proteins, including four EGF-like repeats and three domains with similarity to globular domain of the lamini...