Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome.

PURPOSE: Children with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. METHODS: Children from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction. RESULTS: Extraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03). CONCLUSIONS: Extraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Comparison of intravenous and endotracheal epinephrine during cardiopulmonary resuscitation in newborn piglets.

OBJECTIVE: To compare the efficacy of intravenous and endotracheal epinephrine administration, and intravenous administration above and below the diaphragm, during cardiopulmonary resuscitation in newborn piglets. DESIGN: Prospective, randomized, experimental laboratory protocol. SETTING: Perinatal cardiovascular research laboratory at a university school of medicine. SUBJECTS: Forty newborn piglets (Sus domesticus). INTERVENTIONS: After cardiac arrest by ventricular fibrillation, cardiopulmonary resuscitation was begun. Radiolabeled epinephrine or placebo (0.9% sodium chloride) was administered into the right atrium, femoral vein, or endotracheal tube. Chest compressions and ventilation were continued for 10 mins. MEASUREMENTS AND MAIN RESULTS: After epinephrine or placebo administration, samples were obtained from the systemic arterial circulation for measurement of radioisotope activity and plasma epinephrine concentrations. Mean carotid arterial blood pressure, right atrial, and inferior vena caval pressures were measured continuously. Epinephrine administration via the right atrium and femoral vein resulted in significant increases in plasma epinephrine concentration, percent of radioisotope recovery, and mean carotid arterial blood pressure, whereas endotracheal epinephrine administration did not. Placebo administered into the femoral vein resulted in a significant increase in percent radioisotope recovery, but not in plasma epinephrine concentration or carotid arterial blood pressure. Endotracheal administration of placebo did not result in significant increases in plasma epinephrine concentration, percent radioisotope recovery, or carotid arterial blood pressure. There were no significant differences between right atrial or inferior vena caval pressures among the groups. CONCLUSIONS: During cardiopulmonary resuscitation in newborn piglets, intravenous administration of epinephrine is more efficacious than endotracheal administration. Furthermore, efficacy is similar between femoral venous and right atrial administration.