Inherited growth-hormone insensitivity (GHI) is a heterogeneous disorder that is often caused by mutations in the coding exons or flanking intronic sequences of the growth-hormone receptor gene (GHR). Here we describe a novel point mutation, in four children with GHI, that leads to activation of an intronic pseudoexon resulting in inclusion of an additional 108 nt between exons 6 and 7 in the majority of GHR transcripts. This mutation lies within the pseudoexon (A(-1)-->G(-1) at the 5' pseudoexon splice site) and, under in vitro splicing conditions, results in inclusion of the mutant pseudoexon, whereas the wild-type pseudoexon is skipped. The presence of the pseudoexon results in inclusion of an additional 36-amino acid sequence in a region of the receptor known to be involved in homo-dimerization, which is essential for signal transduction.

Activation of the pseudoexon in the GHR gene can lead to a variety of GHI phenotypes. Therefore, screening for the presence of this mutation should be performed in all GHI patients without mutations in the coding exons.

These data demonstrated that the rhIGF-I/rhIGFBP-3 complex was effective in increasing levels of circulating total and free IGF-I into the normal range for a 24-h period after a single sc administration in patients with GHIS, and that administration of rhIGF-I/rhIGFBP-3 was safe and well tolerated.

In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ mutations. rhIGF1 treatment improved height outcomes.

These gene dosage effects demonstrate that one functional IGFALS allele is insufficient to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination compared with severe PIGFD, ALS-deficient patients cannot mount a similar response. Alternative ways of rhIGF-I administration should be sought.

Background/Aims: Mutations in the acid-labile subunit (ALS) gene (IGFALS) have been associated with circulating insulin-like growth factor I (IGF-I) deficiency and short stature. Whether severe pubertal delay is also part of the phenotype remains controversial due to the small number of cases reported. We report 2 children with a history of growth failure due to novel IGFALS mutations. Methods: The growth hormone receptor gene (GHR) and IGFALS were analyzed by direct sequencing. Ternary complex formation was studied by size exclusion chromatography. Results: Two boys of 13.3 and 10.6 years, with pubertal stages 2 and 1, had mild short stature (–3.2 and –2.8 SDS, respectively) and a biochemical profile suggestive of growth hormone resistance. No defects were identified in the GHR. Patient 1 was homozygous for the IGFALS missense mutation P73L. Patient 2 was a compound heterozygote for the missense mutation L134Q and a novel GGC to AG substitution at position 546–548 (546–548delGGCinsAG). The latter causes a frameshift and the appearance of a premature stop codon. Size exclusion chromatography showed no peaks corresponding to ternary and binary complexes in either patient. Conclusion: Screening of the IGFALS is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.

Clinical and experimental data indicate that long-term corticosteroid use leads to atrophy of the type 2 muscle fibers. The purpose of this study was to characterize and quantify the nature of muscle function in rheumatic disease patients who have been on long-term corticosteroid therapy. Quadriceps function (i.e., peak torque and power) in 19 patients (11 with rheumatoid arthritis, five with systemic lupus erythematosis, and 3 other) and 11 age- and activity-matched normal controls was measured with an isokinetic dynamometer (Cybex II), during four constant velocity movements. Power was significantly lower for the patients at all speeds. At the higher speeds the patients' deficit in power production increased as indicated by a difference in the slopes of power-velocity regression lines. Measures of peak torque could not be consistently used to differentiate the groups. Patients with rheumatic diseases receiving corticosteroids have a decreased ability to generate muscle power. The method described allows for quantification of these deficits in a clinical setting.

In this paper we demonstrate that because of stagnating wages and rising job insecurity, there has been a change in the labor supply regime in the U.S. macroeconomy since the 1970s. There is now greater labor supply at any given officially measured unemployment rate. This induced growth in the quantity of labor effort is coming from experienced, incumbent workers and therefore does not show up in the official unemployment rate. While this may diminish family and community life, the increased aggregate labor supply means rising aggregate demand is being absorbed even at unemployment rates of less than 5 percent without sparking inflationary pressures. Because of this upward structural trend in weekly hours, monetary policy authorities must now recognize that standard jobless measures have become a misleading gauge of available labor.labor supply, working time, monetary policy, job insecurity, job instability,