Long-term effects of physiologic concentrations of dexamethasone on human bone-derived cells

Bone cells derived from human trabecular explants display osteoblastic features. We examined the modulation of alkaline phosphatase activity and cAMP production as the result of exposing trabecular explants to physiologic concentrations of dexamethasone for 4 weeks during cellular outgrowth and subculture. Cells treated with dexamethasone were observed to grow generally more slowly than control cells. Cells appeared larger and more polygonal, and staining for alkaline phosphatase was more intense in the dexamethasone-exposed cultures. There was a progressive increase in cellular PTH responsiveness with increasing duration of exposure of cells to dexamethasone. Cells grown for 6 weeks in 3 x 10(-8) M dexamethasone had a 10-fold increase in PTH-stimulated cyclic AMP accumulation. Dexamethasone-treated cells also had a significantly increased alkaline phosphatase activity. 1,25-(OH)2D3-stimulated alkaline phosphatase activity was increased approximately 20-fold. cAMP responses were significantly increased to PTH (21.7-fold), PGE1 (2.67-fold), and forskolin (4.81-fold), but not to cholera toxin. Dexamethasone-treated cells also had a mean decrease in 1,25-(OH)2D3-stimulated osteocalcin production to 26.2% of control values (p less than 0.001). Hydrocortisone treatment gave rise to similar effects but of smaller magnitude than those of dexamethasone. Testosterone did not have a significant effect on alkaline phosphatase activity or cAMP production. Skin fibroblasts showed a significant enhancement of alkaline phosphatase activity in response to dexamethasone, but of a much smaller magnitude than in bone cells. The phenotypic changes induced by long-term culture in dexamethasone are consistent with the promotion of a more differentiated osteoblastic phenotype.     

Total anomalous pulmonary venous drainage. Seventeen-year surgical experience

Between 1968 and 1985, 80 children underwent correction of total anomalous pulmonary venous drainage. There were 47 boys and 33 girls whose ages ranged from 3 days to 16 years (median 2 months, interquartile range 5 years). Seventy (87.5%) were less than 1 year of age at operation. Fifty-eight (72.5%) weighed less than 5 kg, the range being 1.6 to 42 kg (median 3.7 kg, interquartile range 2.4 kg). Forty-five (56%) patients had supracardiac, 14 (17.5%) cardiac, 15 (19%) infracardiac, and 6 (7.5%) had mixed total anomalous pulmonary venous drainage. Follow-up was complete in 78 (97.5%) and ranged from 6 to 189 months (median 58 months, interquartile range 59 months). There were 14 (17.5%) early and six (7.5%) late deaths. Analysis by various factors revealed year of operation as the only factor to affect survival at the 5% level of significance. Early mortality was 29% between 1968-1977 and 11% between 1978-1985 (p = 0.04). Postoperative pulmonary venous obstruction occurred in five (6%) patients between 6 weeks and 3 months after operation. All 5 died, three after reoperation. Five (6%) other children had reoperations, four for residual shunts and one for superior vena caval obstruction.     

A question of rhythm: recent advances in growth hormone research.

Research by Dr. Gloria Shaffer Tannenbaum at the McGill University-Montreal Children's Hospital Research Institute has led to the development of a new test to differentiate children who are deficient in growth hormone from those who are short but growing normally. This clinical application is the fruit of Tannenbaum's discovery that growth hormone secretion occurs in a rhythmic pattern regulated by intricate interactions between two neurohormones: growth hormone-releasing hormone (GHRH) and somatotropin release-inhibiting factor (SRIF). In the test an analogue of SRIF is used to allow stores of growth hormone to build up. A subsequent challenge with GHRH is then used to identify children with a genuine deficiency. Tannenbaum's research also indicates that there are sexual differences in the pattern of growth hormone release and that growth hormone regulates its own secretion by means of a negative feedback system.     

Superiority of the University of Wisconsin solution over simple crystalloid for extended heart preservation. A study of left ventricular pressure-volume relationship.

To compare the effects of the University of Wisconsin solution with those of an extracellular crystalloid solution, Krebs-Ringer bicarbonate, as cardiac preservation media, we studied 35 adult dogs in an isolated heart preparation. Four groups of seven hearts were preserved in University of Wisconsin solution for 6 or 12 hours or in Krebs-Ringer bicarbonate solution for 6 or 12 hours. An additional group of seven hearts with no ischemia was used for a control group. In the four preservation groups, hearts were arrested by electrolyte solution (Normosol with potassium chloride, 20 mEq/L, added, 4 degrees C), flushed with 200 ml of the preservation solution, and then stored in the same solution at 1 degree to 2 degrees C. The hearts were mounted on an isolated heart preparation equipped with a computer-controlled servo-pump system that used a mock arterial system to modulate the aortic input impedance presented to the left ventricle. Left ventricular pressure-volume loops were measured on-line for 2 hours of reperfusion with autologous warm oxygenated blood. Elastance was derived from the end-systolic pressure-volume relationship, and diastolic compliance was derived from the end-diastolic pressure-volume relationship. The total left ventricular performance was assessed by the preload recruitable stroke work area, the slope, and its x-intercept, all of which derived from the stroke work (pressure-volume area)-end-diastolic volume relationship. Extended global ischemia had more deleterious effects on the end-diastolic than the end-systolic pressure-volume relationship. In confirmation with other studies, elastance did not accurately reflect the level of ventricular contractile dysfunction because of the significant amount of diastolic dysfunction. The preservation of myocardial systolic and diastolic functions, as demonstrated by the preload recruitable stroke work area and diastolic compliance, was better in the University of Wisconsin solution groups than in the Krebs-Ringer bicarbonate solution groups after 6 and 12 hours of preservation. In addition, 6 hours of preservation with University of Wisconsin solution maintained normal systolic and diastolic functions as compared with those of the control group. Preservation with University of Wisconsin solution prevented any myocardial edema formation; by contrast, this was significantly increased after 12 hours in Krebs-Ringer bicarbonate solution. Groups preserved with University of Wisconsin solution had less reperfusion injury as evidenced by the release of coronary sinus creatine kinase during reperfusion; they also had improved oxygen use during reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)