Intracerebral hemorrhage (ICH) causes morbidity and mortality and commonly follows the reperfusion after an ischemic event. Tissue plasminogen activator (tPA), a fibrinolytic serine protease, is routinely given for the treatment of stroke. However, tPA also can promote neuronal death, suggesting that caution should be exercised when using it. Furthermore, tPA upon brain injury mediates microglial activation and modulates neuronal survival. To investigate the role of tPA and microglia during brain hemorrhage, we induced experimentally ICH by intracerebral injection of collagenase. Seven days after the introduction of ICH, it persisted in tPA-deficient (tPA(-/-)) mice but is drastically reduced in size in wild-type mice. Three weeks after ICH, there are still red blood cells in tPA(-/-) but not in wild-type animals. Activated microglia persist around the injury site. When microglial activation is inhibited by tuftsin fragment 1-3 macrophage/microglial inhibitory factor (MIF), the stroke injury volume is significantly reduced, and the neurobehavioral deficits exhibited by the mice are improved. Our results suggest that endogenous tPA assists in the clearance of intracerebral hemorrhage, presumably by affecting microglial activation, and MIF could be a valuable neuroprotective agent for the treatment of ICH.

Pediatric DCM patients continue to have multiple outcomes, with recovery of left ventricular systolic function occurring most frequently. Utilization of heart transplantation has led to improved survival after the diagnosis of pediatric DCM.

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Uteroplacental insufficiency and subsequent intrauterine growth retardation (IUGR) affects postnatal metabolism. In juvenile rats, IUGR alters skeletal muscle mitochondrial gene expression and reduces mitochondrial NAD ϩ /NADH ratios, both of which affect ␤-oxidation flux. We therefore hypothesized that gene expression and function of mitochondrial ␤-oxidation enzymes would be altered in juvenile IUGR skeletal muscle. To test this hypothesis, mRNA levels of five key mitochondrial enzymes (carnitine palmitoyltransferase I, trifunctional protein of ␤-oxidation, uncoupling protein-3, isocitrate dehydrogenase, and mitochondrial malate dehydrogenase) and intramuscular triglycerides were quantified in 21-d-old (preweaning) IUGR and control rat skeletal muscle. In isolated skeletal muscle mitochondria, enzyme function of the trifunctional protein of ␤-oxidation and isocitrate dehydrogenase were measured because both enzymes compete for mitochondrial NAD ϩ . Carnitine palmitoyltransferase I, the trifunctional protein of ␤-oxidation, and uncoupling protein 3 mRNA levels were significantly increased in IUGR skeletal muscle, whereas mRNA levels of isocitrate dehydrogenase and mitochondrial malate dehydrogenase were unchanged. Similarly, trifunctional protein of ␤-oxidation activity was increased in IUGR skeletal muscle mitochondria, and isocitrate dehydrogenase activity was unchanged. Interestingly, skeletal muscle triglycerides were significantly increased in IUGR skeletal muscle. We conclude that uteroplacental insufficiency alters IUGR skeletal muscle mitochondrial lipid metabolism, and we speculate that the changes observed in this study play a role in the long-term morbidity associated with IUGR. (Pediatr Res 50: 83-90, 2001) Abbreviations CPTI, carnitine palmitoyltransferase I IUGR, intrauterine growth retardation AGA, appropriate for gestational age ICD, isocitrate dehydrogenase MMD, mitochondrial malate dehydrogenase ND-4L, NADH-ubiquinone oxidoreductase subunit 4L HADH, trifunctional protein of ␤-oxidation HADHA, trifunctional protein of ␤-oxidation ␣ subunit UCP3, uncoupling protein 3 UCP3l, uncoupling protein 3-long isoform UCP3s, uncoupling protein 3-short isoform Uteroplacental insufficiency causes IUGR and is causally related to the development of multiple adult morbidities including insulin resistance, hypertension, coronary heart disease, and dyslipidemia (1). Although the effects of these pathophysiologies are most critically felt during adulthood, evidence exists that metabolism may already be altered in IUGR infants.Several investigators have demonstrated that IUGR infants expend more energy and consume more oxygen than AGA infants (2-6); moreover, Bohler et al.