Fgfs direct embryogenesis of several organs, including the lung, limb, and anterior pituitary. Here we report male-to-female sex reversal in mice lacking Fibroblast growth factor 9 (Fgf9), demonstrating a novel role for FGF signaling in testicular embryogenesis. Fgf9(-/-) mice also exhibit lung hypoplasia and die at birth. Reproductive system phenotypes range from testicular hypoplasia to complete sex reversal, with most Fgf9(-/-) XY reproductive systems appearing grossly female at birth. Fgf9 appears to act downstream of Sry to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis. While Sry is found only in some mammals, Fgfs are highly conserved. Thus, Fgfs may function in sex determination and reproductive system development in many species.
Objective Systemic corticosteroids are known to induce osteoporosis and increase the risk of fractures in adults and children. Inhaled corticosteroids have been shown to increase the risk of osteoporosis and fractures in adults at risk. However, long-term prospective studies in children to assess risks of multiple short courses of oral corticosteroids and chronic inhaled corticosteroids have not been done. Thus, we assessed the effects of multiple short courses of oral corticosteroids and long-term inhaled corticosteroids on bone mineral accretion over a period of years. Patients and Methods This was a cohort followup study for a median of 7 years of children with mild to moderate asthma initially randomized into the Childhood Asthma Management Program (CAMP) trial. Serial dual-energy x-ray absorptiometry (DEXA) scans of the lumbar spine for bone mineral density (BMD) were performed in all patients. Annual bone mineral accretion was calculated in 531 boys and 346 girls with asthma aged 5–12 years at baseline (84% of the initial cohort). Results Oral corticosteroid bursts produced a dose-dependent reduction in bone mineral accretion (0.052, 0.049, and 0.046 gm/cm2/year, p=0.0002) and an increase in risk of osteopenia (10%, 14% and 21%, p=0.02) for 0, 1–4, and 5+ courses, respectively, in males but not females. Cumulative inhaled corticosteroid use was associated with a small decrease in bone mineral accretion in males (p=0.05) but not females, but no increased risk of osteopenia. Conclusion Multiple oral corticosteroid bursts over a period of years can produce a dose-dependent reduction in bone mineral accretion and increased risk of osteopenia in children with asthma. Inhaled corticosteroid use has the potential for reducing bone mineral accretion in male children progressing through puberty but this risk is likely to be outweighed by the ability to reduce the amount of oral corticosteroids used in these children.
The rat intestinal fatty acid binding protein (I-FABP) gene has been used as a model to study temporal and spatial differentiation of the gut epithelium while its protein product has been used as a model for examining the atomic details of noncovalent fatty acid-protein interactions. We have isolated the mouse I-FABP gene (Fabpi) and determined its nucleotide sequence. Comparisons of the orthologous mouse, rat, and human I-FABP genes revealed three conserved domains in their otherwise divergent 5' nontranscribed sequences. RNA blot hybridization and multilabel immunocytochemical methods were used to compare the developmental stage-specific patterns of activation of the rat and mouse genes. In addition, Fabpi expression in enterocytes was examined as a function of their differentiation along the crypto-to-villus and duodenal-to-colonic axes of the small intestine. Based on the similar temporal and geographic patterns of mouse and rat I-FABP expression described here and the results of our earlier studies of transgenic mice containing rat Fabpi/human growth hormone fusion genes, we propose that one of the conserved domains, spanning nucleotides -500 to -419 in mouse Fabpi, and/or a 14-bp element, are necessary for establishing and maintaining its region-specific expression along the duodenal-to-colonic axis of the perpetually renewing gut epithelium. Finally, predictions of the structure of mouse I-FABP using the refined 2.0 A model of rat I-FABP, suggest that a proline found at position 69 of the mouse, but not rat, protein may affect its ligand binding properties.
The region of Saccharomyces cerevisiae chromosome III centromere-distal to the PGK gene is the site of frequent chromosome polymorphisms. We have sequenced this region from fragments of chromosome III isolated from three different yeast strains, GRF88, CN31C and CF4-16B. The sequence analysis demonstrates that these polymorphisms are associated with the presence of Ty and delta elements and defines a region of the chromosome which is a hot-spot for transposition events (the RAHS). The three strains can be arranged into a logical evolutionary series in which successive transposition and recombination events insert Ty elements and fuse them with consequent deletions of chromosome and of transposon sequences. The influence of such events on yeast genome evolution is discussed.
An 8-week-old infant presented to the emergency department with lethargy, tachycardia, and a blood glucose concentration of 1.8 mmol/L. After admission, hypoglycemia recurred on 3 additional occasions. Initial urinalysis results were negative for ketones, and the results of additional laboratory tests did not support the diagnosis of cortisol or growth hormone deficiency, oral hypoglycemic ingestion, or an inborn error of metabolism. Difficulty restoring and maintaining glucose concentrations along with a transient response to glucagon during 1 hypoglycemic episode suggested hyperinsulinism. In 1 hypoglycemic episode, elevated insulin and low C-peptide concentrations suggested exogenous insulin administration, but 2 subsequent blood samples obtained during hypoglycemia contained appropriately decreased concentrations of insulin. The insulin immunoassay initially used in this case (Roche ElecSys/cobas [Roche Diagnostics, Indianapolis, IN]) was insensitive to insulin analogs. Two additional immunoassays, 1 with intermediate (Immulite [Siemens, Deerfield, IL]) and 1 with broad (radioimmunoassay [Millipore, Inc, Billerica, MA]) reactivity to insulin analogs were used to characterize insulin in each of the critical blood samples. Samples obtained during hypoglycemia displayed a graded reactivity similar to that observed in type 1 diabetic patients prescribed insulin analogs, whereas a sample obtained from the patient and a control subject during euglycemia showed equal reactivity among the 3 assays. These data suggested administration of insulin analog to the child, and further characterization of insulin by using tandem mass spectrometry confirmed the presence of Humalog. The child was subsequently placed in foster care with no further recurrence of hypoglycemia.
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