ABSTRACT
Runx2 is an essential factor for skeletogenesis and heterozygous loss causes cleidocranial dysplasia in humans and a corresponding phenotype in the mouse. Homozygous Runx2-deficient mice lack hypertrophic cartilage and bone. We compared the expression profiles of E14.5 wildtype and Runx2(-/-) murine embryonal humeri to identify new transcripts potentially involved in cartilage and bone development. Seventy-one differentially expressed genes were identified by two independent oligonucleotide-microarray hybridizations and quantitative RT-PCR experiments. Gene Ontology analysis demonstrated an enrichment of the differentially regulated genes in annotations to terms such as extracellular, skeletal development, and ossification. In situ hybridization on E15.5 limb sections was performed for all 71 differentially regulated genes. For 54 genes conclusive in situ hybridization results were obtained and all of them showed skeletal expression. Co-expression with Runx2 was demonstrated for 44 genes. While 41 of the 71 differentially expressed genes have a known role in bone and cartilage, we identified 21 known genes that have not yet been implicated in skeletal development and 9 entirely new transcripts. Expression in the developing skeleton was demonstrated for 21 of these genes.
Subject(s)
Bone Development/genetics , Core Binding Factor Alpha 1 Subunit/deficiency , Core Binding Factor Alpha 1 Subunit/genetics , Animals , Bone Development/physiology , Cleidocranial Dysplasia/genetics , Core Binding Factor Alpha 1 Subunit/physiology , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation, Developmental , Humans , In Situ Hybridization , Mice , Mice, Knockout , Oligonucleotide Array Sequence Analysis , Phenotype , Polymerase Chain ReactionABSTRACT
We describe three critically ill patients who displayed indirect evidence of transient corticotropin deficiency. All these patients were elderly, were poorly nourished, and had unexplained hypotension intraoperatively or immediately postoperatively. During the hypotensive episodes, they had inappropriately low plasma cortisol levels (10, 12, and 6 micrograms/dl) and responded dramatically to the administration of glucocorticoids. A normal response to infusion of synthetic corticotropin excluded primary adrenal insufficiency. Two patients tested had low thyroxine levels without increased thyrotropin concentrations and depressed levels of gonadotropins. In all three patients, the dose of glucocorticoids was successfully tapered and then discontinued. After recovery, serum thyroxine levels increased, gonadotropins reverted to normal concentrations, and the administration of metyrapone to two patients demonstrated normal hypothalamic-pituitary-adrenal function. Cortisol levels of less than 15 micrograms/dl in critically ill patients suggest the presence of adrenal insufficiency. The infusion of synthetic corticotropin may not exclude adrenal insufficiency attributable to corticotropin deficiency. If direct tests of corticotropin reserve are impractical, treatment with glucocorticoids is warranted.
Subject(s)
Adrenocorticotropic Hormone/deficiency , Critical Illness , Aged , Cosyntropin , Critical Illness/therapy , Dexamethasone/therapeutic use , Female , Humans , Hydrocortisone/blood , Hydrocortisone/therapeutic use , Hypotension/etiology , Male , Middle AgedABSTRACT
A 19-year-old woman with Graves' disease developed thyroid storm 8 days after radioactive iodine therapy. The clinical manifestations of thyroid storm promptly improved after treatment with large doses of propylthiouracil, potassium iodide, propranolol hydrochloride, and dexamethasone. Four days after discontinuing dexamethasone, the syndrome recurred and was corrected by reinstitution of the glucocorticoid. We conclude that dexamethasone was an important adjunct for treating thyroid storm and was effective mainly by reducing peripheral triiodothyronine production.
