Mitoxantrone repression of astrocyte activation: relevance to multiple sclerosis.

Mitoxantrone has been approved by the FDA for the treatment of multiple sclerosis (MS). However, the mechanisms by which mitoxantrone modulates MS are largely unknown. Activated astrocytes produce nitric oxide (NO), TNF-α, and IL-1ß, molecules which can be toxic to central nervous system (CNS) cells including oligodendrocytes, thus potentially contributing to the pathology associated with MS. MCP-1 is a chemokine believed to modulate the migration of monocytes to inflammatory lesions present in the CNS of MS patients. IL-12 and IL-23 have been demonstrated to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, by contributing to the development of CD4(+) T cell lineages termed Th1 and Th17, respectively. The current study demonstrates that mitoxantrone inhibits lipopolysachharide (LPS) induction of NO, TNF-α, IL-1ß, and MCP-1 production by primary astrocytes. Mitoxantrone also inhibited IL-12 and IL-23 production by these cells. Furthermore, mitoxantrone suppressed the expression of C-reactive protein (CRP). Finally, we demonstrate that mitoxantrone suppressed LPS induction of NF-κB DNA-binding activity, suggesting a novel mechanism by which mitoxantrone suppresses the expression of proinflammatory molecules. Collectively, these studies demonstrate that mitoxantrone represses astrocyte production of potentially cytotoxic molecules, as well as molecules capable of altering T-cell phenotype. These in vitro studies suggest mechanisms by which mitoxantrone may modulate inflammatory diseases including MS.

Stenting for superior vena cava obstruction in pediatric heart transplant recipients.

BACKGROUND: Superior vena cava (SVC) obstruction can be a complication in heart transplant recipients. We reviewed our experience with relief of SVC obstruction using endovascular stents in pediatric heart transplant recipients. METHODS: Study cohort included pediatric heart transplant recipients, followed at our institution, who required endovascular stent placement for SVC obstruction. Data retrieved retrospectively included cardiac diagnosis, age, and weight at transplant, surgical technique of transplant (bicaval vs. biatrial anastomosis), previous cardiovascular surgeries, presenting symptoms, date of SVC stent placement, and need for reintervention. RESULTS: From March 1990 to June 2006, 5.1% (7/138) pediatric heart transplant recipients who were followed at our institution had SVC obstruction requiring stent placement. Median age and weight at transplant was 9 months and 8.7 kg, respectively. Four patients previously had a cavopulmonary anastomosis. Transplant surgery involved bicaval anastomosis in 6 and biatrial in 1. Of the 7 patients included in the study, 2 were asymptomatic, 2 were symptomatic (1 with chylothorax, 1 with headache), and 3 were identified at the time of transplant surgery. Median time from transplant surgery to SVC stent placement was 2 months (0-14 months). Three patients required reintervention as redilation of SVC stent (n = 1) or additional SVC stent (n = 2). In one patient the stent migrated to the pulmonary artery but was retrieved. CONCLUSION: SVC obstruction can be an important complication following heart transplantation, especially in infants with previous cavopulmonary anastomosis, undergoing heart transplant using bicaval technique. SVC obstruction can be safely and effectively treated using endovascular stents.